Tulobuterol transdermal patch 0.5 mg / 1 mg/ 2 mg.

Each 2.5 cm² patch contains 0.5 mg of tulobuterol

Transdermal patch

0.5 mg /1 mg /2 mg

4.1 Therapeutic indications

For treatment of patients with asthma and COPD without co-morbidity.

4.2 Posology and method of administration

Posology

Usually, 2 mg for adults, 0.5 mg for children aged between 0.5 and 3 years, 1 mg for children aged between 3 to 9 years or 2 mg aged over 9 years as tulobuterol is applied once daily on the chest, back or upper arm area.

Application site:

1)Before applying tulobuterol, clean and dry the application site.

2)Choose a new site each time to avoid cutaneous irritation.

3)Place tulobuterol on an area that is out of reach of children who may peel it off.

4)Tulobuterol should not be used within the wound as animal studies (rat) showed an increase in the blood level when tulobuterol was applied on the compromised skin.

4.3 Contraindications

Tulobuterol is contraindicated in the following patients: Patients with a history of drug hypersensitivity to any of the ingredients of tulobuterol

4.4 Special warnings and precautions for use

1.Careful Administration (Tulobuterol should be applied with care in the following patients.)

1.Patients with hyperthyroidism [Symptoms may be aggravated.]

2.Patients with hypertension [Blood pressure may be increased.]

3.Patients with heart disorder [Palpitation or arrhythmia may occur.]

4.Patients with diabetes mellitus [Glucose metabolism and blood glucose may increase.]

5.Patients with atopic dermatitis [Pruritus or redness may appear on application site.]

6.Elderly patients

2.Important Precautions

a. Anti-inflammatory drugs such as inhaled steroids are essential for principles of long-term management of the treatment of bronchial asthma. Only if no improvement of symptoms is noted or concomitant treatment with inhaled steroids, etc. are considered appropriate according to the severity of patient's condition, tulobuterol should be applied concomitantly with inhaled steroids. Since tulobuterol is not an alternative anti-inflammatory drug such as inhaled steroids, careful instruction should be given to the patients, the patient's guardian or other appropriate designated person that the patients should not to reduce or discontinue the inhaled steroids, etc. without a physician advice and to use tulobuterol alone even if the patients feel improvement of symptoms with the use of tulobuterol.

b. Careful instruction should be given to the patients, the patient's guardian or other appropriate designated person that the patients should use other appropriate drugs such as short-acting beta-stimulator for acute attack occurred during application of tulobuterol in the long-term management for the treatment of bronchial asthma. Further, if the doses of those drugs are increased or they become ineffective, careful instruction should be given to the patients, the patient's guardian or other appropriate designated person that the patients should visit medical institutions to receive treatment as soon as possible since asthma may not be adequately controlled. As this condition may be life-threatening, intensification of anti-inflammatory therapy should be pursued.

c. If tulobuterol is ineffective even when properly used according to dosage and administration (approx. One to two weeks as a guide), application should be discontinued as tulobuterol is considered inappropriate. In addition, proper instruction and adequate follow-up should be provided for pediatric use.

d. As continue use of tulobuterol beyond the dose range may cause arrhythmia or occasionally cardiac arrest, caution should be given not to use beyond the dose limit.

4.5 Interaction with other medicinal products and other forms of interaction

Precaution for coadminstration (Tulobuterol should be applied with care when coadministered with the following drugs.)

4.6 Use in special populations

Pregnancy & Lactation

• Tulobuterol may be applied to pregnant women or women who may be pregnant only when medical benefits outweigh the risk. [The safety of Tulobuterol in pregnancy has not been established.]
• If Tulobuterol is applied to nursing mothers, breast feeding should be avoided.

Pediatric Use

• The safety of Tulobuterol has not been established in infants less than 6 months of age.
• The safety of long term use of Tulobuterol has not been established in children.

Elderly population

Since physiological function is generally weakened in elderly people, Tulobuterol should be carefully applied, e.g., by starting with lower dose.

4.7 Effects on ability to drive and use machines

No known drug-drug interaction

4.8 Undesirable effect

No investigation of tulobuterol such as drug use surveillance to clarify the incidence of adverse reactions is performed.

1) Clinically significant adverse reactions (incidence unknown) (1) Anaphylactoid symptoms: Since anaphylactoid symptoms may occur, the patient should be closely observed. If any symptoms such as dyspnea, generalized flushing, angioedema and urticaria are noted, application should be discontinued and appropriate measures should be taken.

(2) Serious decreased serum potassium level: Serious decreased serum potassium has been reported with β2 stimulant. Since the serum potassium-lowering effect of β2 stimulant may increase with concomitant use of xanthine derivatives, steroids and diuretics, special caution should be given in patients with severe asthma. Furthermore, hypoxemia may enhance the effect of decreased serum potassium level on cardiac rhythm. In such case, serum potassium level should be monitored.

2) Other adverse reactions

If any symptoms are observed, application of tulobuterol should be discontinued.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to:medico@zuventus.com

Website: https://www.zuventus.com/drug-safety-reporting 

By reporting side effects, you can help provide more information on the safety of this medicine.

5.1 Mechanism of action/Pharmacodynamic properties

TULOBUTEROL has a selective β receptor stimulating activity. ATP is converted to cAMP and the contraction of bronchial smooth muscle is suppressed by activating adenylate cyclase after binding to β2 receptor.

5.2 Pharmacokinetic properties

Bioequivalence testing

The concentration of tulobuterol in plasma was measured (crossover method) after single transdermal application (chest, 24 hours) of tulobuterol patch 0.5 mg, 1 mg and 2 mg and standardized preparation corresponding to each standard to healthy adult males, and the statistical analysis of pharmacokinetic parameters (AUC, Cmax) confirmed bioequivalence for both drugs.

(The usual dose in adults is 2 mg per dose as tulobuterol.)

Pharmacokinetic parameters during application of tulobuterol patch

Serum concentration and parameters such as AUC and Cmax may differ from test conditions such as the selection of subjects, number of fluid collected and time.

6.1 Animal Toxicology or Pharmacology

No known animal toxicology data

Tulobuterol is a β2-adrenergic agonist, is the first bronchodilator to be available as a transdermal patch. It is hydrochloride salt of 2-(tert-butylamino)-1-(2-chlorophenyl) ethan-1-ol. Its average molecular weight is 264.191 g/mol

• Tuloplast Transdermal Patch is prescribed for the treatment of asthma and COPD.
• Before using Tuloplast Transdermal Patch, clean and dry the application site.
• Apply Tuloplast Transdermal Patch once daily on chest, back, or upper arm as per the specified dosage regimen.
• Do not apply Tuloplast Transdermal Patch to damaged areas (irritated, injured, cut area of skin). Always use a new site for patch application to avoid skin irritation.
• Apply this medicine to a site where children cannot touch, since they might remove the tape.
• Inform your doctor if you are suffering from diabetes, high blood pressure, thyroid disorder, and heart disease. 
• Seek medical attention if you experience sudden difficulty in breathing, flushing, swelling of the lips and face, and skin rashes.
• Avoid smoking and minimise your exposure to pollution, dust, pollens and fumes. Along with that, a little exercise each day can help you stay strong.

14.10.2024

Rosuvastatin Tablet IP 10mg/20mg/40mg

Revostat 10mg

Each film-coated tablet contains:

Rosuvastatin Calcium IP equivalent to Rosuvastatin 10mg

Excipients q.s.

Revostat 20mg

Each film-coated tablet contains:

Rosuvastatin Calcium IP equivalent to Rosuvastatin 20mg

Excipients q.s.

Revostat 40mg

Each film-coated tablet contains:

Rosuvastatin Calcium IP equivalent to Rosuvastatin 40mg

Excipients q.s.

Tablet 10/20/40mg

4.1 Therapeutic indication

1) As an adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia.

2) As an adjunctive therapy to diet to slow the progression of atherosclerosis in adult patients as part of a treatment strategy to lower Total-C and LDL-C

3) Risk reduction of MI stroke and arterial evascularisation procedure in patients without clinically evident CHD but with multiple risk factor

4.2 Posology and method of administration

Before treatment initiation the patient should be placed on a standard cholesterol-lowering diet that should continue during treatment. The dose should be individualised according to the goal of therapy and patient response, using current consensus guidelines.

Revostat may be given at any time of day, with or without food.

Treatment of hypercholesterolaemia

The recommended start dose is 5 or 10 mg orally once daily in both statin naï ve or patients switched from another HMG CoA reductase inhibitor. The choice of start dose should take into account the individual patient's cholesterol level and future cardiovascular risk as well as the potential risk for adverse reactions (see below). A dose adjustment to the next dose level can be made after 4 weeks, if necessary.

Prevention of cardiovascular events

In the cardiovascular events risk reduction study, the dose used was 20 mg daily

Paediatric population

Paediatric use should only be carried out by specialists.

Children and adolescents 6 to 17 years of age (Tanner Stage< II-V)

Heterozygous familial hypercholesterolaemia

In children and adolescents with heterozygous familial hypercholesterolaemia the usual start dose is 5 mg daily.

• In children 6 to 9 years of age with heterozygous familial hypercholesterolaemia, the usual dose range is 5-10 mg orally once daily. Safety and efficacy of doses greater than 10 mg have not been studied in this population.
• In children 10 to 17 years of age with heterozygous familial hypercholesterolaemia, the usual dose range is 5-20 mg orally once daily. Safety and efficacy of doses greater than 20 mg have not been studied in this population.

Titration should be conducted according to the individual response and tolerability in paediatric patients, as recommended by the paediatric treatment recommendations (see section 4.4). Children and adolescents should be placed on standard cholesterol-lowering diet before rosuvastatin treatment initiation; this diet should be continued during rosuvastatin treatment.

Homozygous familial hypercholesterolaemia

In children 6 to 17 years of age with homozygous familial hypercholesterolaemia, the recommended maximum dose is 20 mg once daily.

A starting dose of 5 to 10 mg once daily depending on age, weight and prior statin use is advised. Titration to the maximum dose of 20 mg once daily should be conducted according to the individual response and tolerability in paediatric patients, as recommended by the paediatric treatment recommendations (see section 4.4). Children and adolescents should be placed on standard cholesterol-lowering diet before rosuvastatin treatment initiation; this diet should be continued during rosuvastatin treatment.

There is limited experience with doses other than 20 mg in this population.

The 40 mg tablet is not suitable for use in paediatric patients.

Children younger than 6 years

The safety and efficacy of use in children younger than 6 years has not been studied. Therefore, Revostat is not recommended for use in children younger than 6 years.

Use in the elderly

A start dose of 5 mg is recommended in patients>70 years. No other dose adjustment is necessary in relation to age.

Dosage in patients with renal insufficiency

No dose adjustment is necessary in patients with mild to moderate renal impairment. The recommended start dose is 5 mg in patients with moderate renal impairment (creatinine clearance <60 ml/min). The use of Revostat in patients with severe renal impairment is contraindicated for all doses.

Dosage in patients with hepatic impairment

There was no increase in systemic exposure to rosuvastatin in subjects with Child-Pugh scores of 7 or below. However, increased systemic exposure has been observed in subjects with Child-Pugh scores of 8 and 9 (see section 5.2). In these patients an assessment of renal function should be considered (see section 4.4). There is no experience in subjects with Child-Pugh scores above 9. Revostat is contraindicated in patients with active liver disease.

4.3 Contraindications

Contraindicated:

• Patients with hypersensitivity to rosuvastatin or to any of the excipients.
• Patients with active liver disease including unexplained, persistent elevations of serum transaminases and any serum transaminase elevation exceeding 3 times the upper limit of normal (ULN).
• Patients with severe renal impairment (creatinine clearance <30 ml/min).
• Patients with myopathy.
• Patients receiving concomitant combination of sofosbuvir/velpatasvir/voxilaprevir
• Patients receiving concomitant ciclosporin.
• Pregnancy and lactation and in women of childbearing potential not using appropriate contraceptive measures.

4.4 Special warnings and precautions for use

Renal Effects

Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients treated with higher doses of Revostat, in particular 40 mg, where it was transient or intermittent in most cases. Proteinuria has not been shown to be predictive of acute or progressive renal disease.The reporting rate for serious renal events in post-marketing use is higher at the 40 mg dose.

Skeletal Muscle Effects

Effects on skeletal muscle e.g. myalgia, myopathy and, rarely, rhabdomyolysis have been reported in Revostat-treated patients with all doses and in particular with doses > 20 mg. Very rare cases of rhabdomyolysis have been reported with the use of ezetimibe in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be excluded (see section 4.5) and caution should be exercised with their combined use. As with other HMG-CoA reductase inhibitors, the reporting rate for rhabdomyolysis associated with Revostat in post-marketing use is higher at the 40 mg dose.

Creatine Kinase Measurement

Creatine Kinase (CK) should not be measured following strenuous exercise or in the presence of a plausible alternative cause of CK increase which may confound interpretation of the result. If CK levels are significantly elevated at baseline (>5xULN) a confirmatory test should be carried out within 5 – 7 days. If the repeat test confirms a baseline CK >5xULN, treatment should not be started.

Before Treatment

Revostat, as with other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with pre-disposing factors for myopathy/rhabdomyolysis. Such factors include:

• renal impairment
• hypothyroidism
• personal or family history of hereditary muscular disorders
• previous history of muscular toxicity with another HMG-CoA reductase inhibitor or fibrate
• alcohol abuse
• age >70 years
• situations where an increase in plasma levels may occur
• concomitant use of fibrates.

In such patients the risk of treatment should be considered in relation to possible benefit and clinical monitoring is recommended. If CK levels are significantly elevated at baseline (>5xULN) treatment should not be started.

Whilst on Treatment

Patients should be asked to report inexplicable muscle pain, weakness or cramps immediately, particularly if associated with malaise or fever. CK levels should be measured in these patients. Therapy should be discontinued if CK levels are markedly elevated (>5xULN) or if muscular symptoms are severe and cause daily discomfort (even if CK levels are ≤ 5xULN). If symptoms resolve and CK levels return to normal, then consideration should be given to re-introducing Revostat or an alternative HMG-CoA reductase inhibitor at the lowest dose with close monitoring. Routine monitoring of CK levels in asymptomatic patients is not warranted. There have been very rare reports of an immune-mediated necrotising myopathy (IMNM) during or after treatment with statins, including rosuvastatin. IMNM is clinically characterised by proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment.

In few cases, statins have been reported to induce de novo or aggravate pre-existing myasthenia gravis or ocular myasthenia (see section 4.8). Revostat should be discontinued in case of aggravation of symptoms. Recurrences when the same or a different statin was (re-) administered have been reported.

In clinical trials, there was no evidence of increased skeletal muscle effects in the small number of patients dosed with Revostat and concomitant therapy. However, an increase in the incidence of myositis and myopathy has been seen in patients receiving other HMG-CoA reductase inhibitors together with fibric acid derivatives including gemfibrozil, ciclosporin, nicotinic acid, azole antifungals, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when given concomitantly with some HMG-CoA reductase inhibitors. Therefore, the combination of Revostat and gemfibrozil is not recommended. The benefit of further alterations in lipid levels by the combined use of Revostat with fibrates or niacin should be carefully weighed against the potential risks of such combinations.

Revostat must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination .Patients should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness. Statin therapy may be re-introduced seven days after the last dose of fusidic acid. In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g. for the treatment of severe infections, the need for co-administration of Revostat and fusidic acid should only be considered on a case by case basis and under close medical supervision.

Revostat should not be used in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g. sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders; or uncontrolled seizures).

Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which could be life-threatening or fatal, have been reported with rosuvastatin .At the time of prescription, patients should be advised of the signs and symptoms of severe skin reactions and be closely monitored. If signs and symptoms suggestive of this reaction appear, Revostat should be discontinued immediately and an alternative treatment should be considered.

If the patient has developed a serious reaction such as SJS or DRESS with the use of Revostat, treatment with Revostat must not be restarted in this patient at any time.

Liver Effects

As with other HMG-CoA reductase inhibitors, Revostat should be used with caution in patients who consume excessive quantities of alcohol and/or have a history of liver disease.

It is recommended that liver function tests be carried out prior to, and 3 months following, the initiation of treatment. Revostat should be discontinued or the dose reduced if the level of serum transaminases is greater than 3 times the upper limit of normal. The reporting rate for serious hepatic events (consisting mainly of increased hepatic transaminases) in post-marketing use is higher at the 40 mg dose.

In patients with secondary hypercholesterolaemia caused by hypothyroidism or nephrotic syndrome, the underlying disease should be treated prior to initiating therapy with Revostat.

Race

Pharmacokinetic studies show an increase in exposure in Asian subjects compared with Caucasians.

Protease Inhibitors

Increased systemic exposure to rosuvastatin has been observed in subjects receiving rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Consideration should be given both to the benefit of lipid lowering by use of Revostat in HIV patients receiving protease inhibitors and the potential for increased rosuvastatin plasma concentrations when initiating and up titrating Revostat doses in patients treated with protease inhibitors. The concomitant use with certain protease inhibitors is not recommended unless the dose of Revostat is adjusted.

Lactose Intolerance

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Interstitial Lung Disease

Exceptional cases of interstitial lung disease have been reported with some statins, especially with long-term therapy.Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

Diabetes Mellitus

Some evidence suggests that statins as a class raise blood glucose and in some patients, at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/l, BMI >30 kg/m2, raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.

In the JUPITER study, the reported overall frequency of diabetes mellitus was 2.8% in rosuvastatin and 2.3% in placebo, mostly in patients with fasting glucose 5.6 to 6.9 mmol/l.

Paediatric Population

The evaluation of linear growth (height), weight, BMI (body mass index), and secondary characteristics of sexual maturation by Tanner staging in paediatric patients 6 to 17 years of age taking rosuvastatin is limited to a two-year period. After two years of study treatment, no effect on growth, weight, BMI or sexual maturation was detected (see section 5.1).

In a clinical trial of children and adolescents receiving rosuvastatin for 52 weeks, CK elevations >10xULN and muscle symptoms following exercise or increased physical activity were observed more frequently compared to observations in clinical trials in adults.

4.5 Interaction with other medicinal products and other forms of interaction

Effect of co-administered medicinal products on rosuvastatin

Transporter protein inhibitors: Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake transporter OATP1B1 and efflux transporter BCRP. Concomitant administration of Revostat with medicinal products that are inhibitors of these transporter proteins may result in increased rosuvastatin plasma concentrations and an increased risk of myopathy

Ciclosporin: During concomitant treatment with Revostat and ciclosporin, rosuvastatin AUC values were on average 7 times higher than those observed in healthy volunteers (see Table 1). Revostat is contraindicated in patients receiving concomitant ciclosporin.Concomitant administration did not affect plasma concentrations of ciclosporin.

Protease inhibitors: Although the exact mechanism of interaction is unknown, concomitant protease inhibitor use may strongly increase rosuvastatin exposure. For instance, in a pharmacokinetic study, co-administration of 10 mg rosuvastatin and a combination product of two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers was associated with an approximately three-fold and seven-fold increase in rosuvastatin AUC and Cmax respectively. The concomitant use of Revostat and some protease inhibitor combinations may be considered after careful consideration of Revostat dose adjustments based on the expected increase in rosuvastatin exposure.

Gemfibrozil and other lipid-lowering products: Concomitant use of Revostat and gemfibrozil resulted in a 2-fold increase in rosuvastatin C_max and AUC.

Based on data from specific interaction studies no pharmacokinetic relevant interaction with fenofibrate is expected, however a pharmacodynamic interaction may occur. Gemfibrozil, fenofibrate, other fibrates and lipid lowering doses (> or equal to 1 g/day) of niacin (nicotinic acid) increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors, probably because they can produce myopathy when given alone. The 40 mg dose is contraindicated with concomitant use of a fibrate (see sections 4.3 and 4.4). These patients should also start with the 5 mg dose.

Ezetimibe: Concomitant use of 10 mg Revostat and 10 mg ezetimibe resulted in a 1.2-fold increase in AUC of rosuvastatin in hypercholesterolaemic subjects.A pharmacodynamic interaction, in terms of adverse effects, between Revostat and ezetimibe cannot be ruled out.

Antacid: The simultaneous dosing of Revostat with an antacid suspension containing aluminium and magnesium hydroxide resulted in a decrease in rosuvastatin plasma concentration of approximately 50%. This effect was mitigated when the antacid was dosed 2 hours after Revostat. The clinical relevance of this interaction has not been studied.

Erythromycin: Concomitant use of Revostat and erythromycin resulted in a 20% decrease in AUC and a 30% decrease in Cmax of rosuvastatin. This interaction may be caused by the increase in gut motility caused by erythromycin.

Ticagrelor: Ticagrelor might affect renal excretion of rosuvastatin, increasing the risk for rosuvastatin accumulation. Although the exact mechanism is not known, in some cases, concomitant use of ticagrelor and rosuvastatin led to renal function decrease, increased CPK level and rhabdomyolysis.

Cytochrome P450 enzymes: Results from in vitro and in vivo studies show that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a poor substrate for these isoenzymes. Therefore, drug interactions resulting from cytochrome P450-mediated metabolism are not expected. No clinically relevant interactions have been observed between rosuvastatin and either fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4).

Interactions requiring rosuvastatin dose adjustments (see also Table 1): When it is necessary to co-administer Revostat with other medicinal products known to increase exposure to rosuvastatin, doses of Revostat should be adjusted. Start with a 5 mg once daily dose of Revostat if the expected increase in exposure (AUC) is approximately 2-fold or higher. The maximum daily dose of Revostat should be adjusted so that the expected rosuvastatin exposure would not likely exceed that of a 40 mg daily dose of Revostat taken without interacting medicinal products, for example a 20 mg dose of Revostat with gemfibrozil (1.9-fold increase), and a 10 mg dose of Revostat with combination ritonavir/atazanavir (3.1-fold increase).

If medicinal product is observed to increase rosuvastatin AUC less than 2-fold, the starting dose need not be decreased but caution should be taken if increasing the Revostat dose above 20mg.

The following medical product/combinations did not have a clinically significant effect on the AUC ratio of rosuvastatin at coadministration:

Aleglitazar 0.3 mg 7 days dosing; Fenofibrate 67 mg 7 days TID dosing; Fluconazole 200mg 11 days OD dosing; Fosamprenavir 700 mg/ritonavir 100 mg 8 days BID dosing; Ketoconazole 200 mg 7 days BID dosing; Rifampin 450 mg 7 days OD dosing; Silymarin 140 mg 5 days TID dosing. Effect of rosuvastatin on co-administered medicinal products

Vitamin K antagonists: As with other HMG-CoA reductase inhibitors, the initiation of treatment or dosage up-titration of Revostat in patients treated concomitantly with vitamin K antagonists (e.g. warfarin or another coumarin anticoagulant) may result in an increase in International Normalised Ratio (INR). Discontinuation or down-titration of Revostat may result in a decrease in INR. In such situations, appropriate monitoring of INR is desirable.

Oral contraceptive/hormone replacement therapy (HRT): Concomitant use of Revostat and an oral contraceptive resulted in an increase in ethinyl estradiol and norgestrel AUC of 26% and 34%, respectively. These increased plasma levels should be considered when selecting oral contraceptive doses. There are no pharmacokinetic data available in subjects taking concomitant Revostat and HRT, therefore, a similar effect cannot be excluded. However, the combination has been extensively used in women in clinical trials and was well tolerated.

Other medicinal products:

Digoxin: Based on data from specific interaction studies no clinically relevant interaction with digoxin is expected.

Fusidic Acid: Interaction studies with rosuvastatin and fusidic acid have not been conducted. The risk of myopathy, including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. The mechanism of this interaction (whether it is pharmacodynamic or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination.

If treatment with systemic fusidic acid is necessary, Revostat treatment should be discontinued throughout the duration of the fusidic acid treatment. Also see section 4.4.

Paediatric population: Interaction studies have only been performed in adults. The extent of interactions in the paediatric population is not known.

4.6 Fertility, pregnancy and lactation

Revostat is contraindicated in pregnancy and lactation.

Women of child bearing potential should use appropriate contraceptive measures.

Since cholesterol and other products of cholesterol biosynthesis are essential for the development of the foetus, the potential risk from inhibition of HMG-CoA reductase outweighs the advantage of treatment during pregnancy. Animal studies provide limited evidence of reproductive toxicity . If a patient becomes pregnant during use of this product, treatment should be discontinued immediately.

Rosuvastatin is excreted in the milk of rats. There are no data with respect to excretion in milk in humans .

4.7 Effects on ability to drive and use machines

Studies to determine the effect of Revostat on the ability to drive and use machines have not been conducted. However, based on its pharmacodynamic properties, Revostat is unlikely to affect this ability. When driving vehicles or operating machines, it should be taken into account that dizziness may occur during treatment.

4.8 Undesirable effects

The adverse reactions seen with Revostat are generally mild and transient. In controlled clinical trials, less than 4% of Revostat-treated patients were withdrawn due to adverse reactions.

Tabulated list of adverse reactions Based on data from clinical studies and extensive post-marketing experience, the following table presents the adverse reaction profile for rosuvastatin. Adverse reactions listed below are classified according to frequency and system organ class (SOC).

The frequencies of adverse reactions are ranked according to the following convention: Common (≥ 1/100 to <1/10); Uncommon (≥ 1/1,000 to <1/100); Rare (≥ 1/10,000 to <1/1000); Very rare (<1/10,000); Not known (cannot be estimated from the available data).

Table 2. Adverse reactions based on data from clinical studies and post-marketing experience

As with other HMG-CoA reductase inhibitors, the incidence of adverse drug reactions tends to be dose dependent.

Renal effects: Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients treated with Revostat. Shifts in urine protein from none or trace to ++ or more were seen in <1% of patients at some time during treatment with 10 and 20 mg, and in approximately 3% of patients treated with 40 mg. A minor increase in shift from none or trace to + was observed with the 20 mg dose. In most cases, proteinuria decreases or disappears spontaneously on continued therapy. Review of data from clinical trials and post-marketing experience to date has not identified a causal association between proteinuria and acute or progressive renal disease.

Haematuria has been observed in patients treated with Revostat and clinical trial data show that the occurrence is low.

Skeletal muscle effects: Effects on skeletal muscle e.g. myalgia, myopathy (including myositis) and, rarely, rhabdomyolysis with and without acute renal failure have been reported in Revostat-treated patients with all doses and in particular with doses > 20 mg.

A dose-related increase in CK levels has been observed in patients taking rosuvastatin; the majority of cases were mild, asymptomatic and transient. If CK levels are elevated (>5xULN), treatment should be discontinued.

Liver effects: As with other HMG-CoA reductase inhibitors, a dose-related increase in transaminases has been observed in a small number of patients taking rosuvastatin; the majority of cases were mild, asymptomatic and transient.

The following adverse events have been reported with some statins:

Sexual dysfunction. Exceptional cases of interstitial lung disease, especially with long term therapy .

The reporting rates for rhabdomyolysis, serious renal events and serious hepatic events (consisting mainly of increased hepatic transaminases) is higher at the 40 mg dose.

Paediatric population: Creatine kinase elevations >10xULN and muscle symptoms following exercise or increased physical activity were observed more frequently in a 52-week clinical trial of children and adolescents compared to adults .In other respects, the safety profile of rosuvastatin was similar in children and adolescents compared to adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website: https://www.zuventus.com/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

There is no specific treatment in the event of overdose. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Liver function and CK levels should be monitored. Haemodialysis is unlikely to be of benefit.

5.1 Mechanism of action

Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor for cholesterol. The primary site of action of rosuvastatin is the liver, the target organ for cholesterol lowering.

Rosuvastatin increases the number of hepatic LDL receptors on the cell-surface, enhancing uptake and catabolism of LDL and it inhibits the hepatic synthesis of VLDL, thereby reducing the total number of VLDL and LDL particles.

5.2 Pharmacodynamic effects

Revostat reduces elevated LDL-cholesterol, total cholesterol and triglycerides and increases HDL-cholesterol. It also lowers ApoB, non-HDL-C, VLDL-C, VLDL-TG and increases ApoA-I (see Table 3). Revostat also lowers the LDL-C/HDL-C, total C/HDL-C and non-HDL-C/HDL-C and the ApoB/ApoA-I ratios.

Table 3 Dose response in patients with primary hypercholesterolaemia (type IIa and IIb) (adjusted mean percent change from baseline)

A therapeutic effect is obtained within 1 week following treatment initiation and 90% of maximum response is achieved in 2 weeks. The maximum response is usually achieved by 4 weeks and is maintained after that.

5.3 Pharmacokinetic properties

Absorption: Maximum rosuvastatin plasma concentrations are achieved approximately 5 hours after oral administration. The absolute bioavailability is approximately 20%.

Distribution: Rosuvastatin is taken up extensively by the liver which is the primary site of cholesterol synthesis and LDL-C clearance. The volume of distribution of rosuvastatin is approximately 134 L. Approximately 90% of rosuvastatin is bound to plasma proteins, mainly to albumin.

Metabolism: Rosuvastatin undergoes limited metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a poor substrate for cytochrome P450-based metabolism. CYP2C9 was the principal isoenzyme involved, with 2C19, 3A4 and 2D6 involved to a lesser extent. The main metabolites identified are the N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin whereas the lactone form is considered clinically inactive. Rosuvastatin accounts for greater than 90% of the circulating HMG-CoA reductase inhibitor activity.

Excretion: Approximately 90% of the rosuvastatin dose is excreted unchanged in the faeces (consisting of absorbed and non-absorbed active substance) and the remaining part is excreted in urine. Approximately 5% is excreted unchanged in urine. The plasma elimination half-life is approximately 19 hours. The elimination half-life does not increase at higher doses. The geometric mean plasma clearance is approximately 50 litres/hour (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, the hepatic uptake of rosuvastatin involves the membrane transporter OATP-C. This transporter is important in the hepatic elimination of rosuvastatin.

Linearity: Systemic exposure of rosuvastatin increases in proportion to dose. There are no changes in pharmacokinetic parameters following multiple daily doses.

6.1 Animal Toxicology or Pharmacology

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenicity potential. Specific tests for effects on hERG have not been evaluated. Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels were as follows: In repeated-dose toxicity studies histopathologic liver changes likely due to the pharmacologic action of rosuvastatin were observed in mouse, rat, and to a lesser extent with effects in the gall bladder in dogs, but not in monkeys. In addition, testicular toxicity was observed in monkeys and dogs at higher dosages. Reproductive toxicity was evident in rats, with reduced litter sizes, litter weight and pup survival observed at maternally toxic doses, where systemic exposures were several times above the therapeutic exposure level.

CRESTOR (rosuvastatin) is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA)-reductase inhibitor

Chemical Name: s bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino] pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]

Molecular Formula: (C22H27FN3O6S)2Ca a

Molecular Weight: 1,001.14.

Structure:

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

Refer on pack.

8.3 Packaging information

3 Blister strips of 10 tablets each

8.4 Storage and handing instructions

Store below 30°C. Protect from light & moisture.

Keep out of reach of children.

Patients should be instructed not to take 2 doses of rosuvastatin calcium within 12 hours of each other.

Skeletal Muscle Effects

Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing rosuvastatin calcium.

Concomitant Use of Antacids

When taking rosuvastatin calcium with an aluminum and magnesium hydroxide combination antacid, the antacid should be taken at least 2 hours after rosuvastatin calcium administration.

Embryo fetal Toxicity

Advise females of reproductive potential of the risk to a fetus, to use effective contraception during treatment, and to inform their healthcare provider of a known or suspected pregnancy.

Lactation

Advise women not to breastfeed during treatment with rosuvastatin

Liver Enzymes

It is recommended that liver enzyme tests be performed before the initiation of rosuvastatin calcium and if signs or symptoms of liver injury occur. All patients treated with rosuvastatin calcium should be advised to promptly report any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.

10th October 2024

Rosuvastatin Tablet IP 10mg/20mg/40mg

Revostat 10mg

Each film-coated tablet contains:

Rosuvastatin Calcium IP equivalent to Rosuvastatin 10mg

Excipients q.s.

Revostat 20mg

Each film-coated tablet contains:

Rosuvastatin Calcium IP equivalent to Rosuvastatin 20mg

Excipients q.s.

Revostat 40mg

Each film-coated tablet contains:

Rosuvastatin Calcium IP equivalent to Rosuvastatin 40mg

Excipients q.s.

Tablet 10/20/40mg

4.1 Therapeutic indication

1) As an adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia.

2) As an adjunctive therapy to diet to slow the progression of atherosclerosis in adult patients as part of a treatment strategy to lower Total-C and LDL-C

3) Risk reduction of MI stroke and arterial evascularisation procedure in patients without clinically evident CHD but with multiple risk factor

4.2 Posology and method of administration

Before treatment initiation the patient should be placed on a standard cholesterol-lowering diet that should continue during treatment. The dose should be individualised according to the goal of therapy and patient response, using current consensus guidelines.

Revostat may be given at any time of day, with or without food.

Treatment of hypercholesterolaemia

The recommended start dose is 5 or 10 mg orally once daily in both statin naï ve or patients switched from another HMG CoA reductase inhibitor. The choice of start dose should take into account the individual patient's cholesterol level and future cardiovascular risk as well as the potential risk for adverse reactions (see below). A dose adjustment to the next dose level can be made after 4 weeks, if necessary.

Prevention of cardiovascular events

In the cardiovascular events risk reduction study, the dose used was 20 mg daily

Paediatric population

Paediatric use should only be carried out by specialists.

Children and adolescents 6 to 17 years of age (Tanner Stage< II-V)

Heterozygous familial hypercholesterolaemia

In children and adolescents with heterozygous familial hypercholesterolaemia the usual start dose is 5 mg daily.

• In children 6 to 9 years of age with heterozygous familial hypercholesterolaemia, the usual dose range is 5-10 mg orally once daily. Safety and efficacy of doses greater than 10 mg have not been studied in this population.
• In children 10 to 17 years of age with heterozygous familial hypercholesterolaemia, the usual dose range is 5-20 mg orally once daily. Safety and efficacy of doses greater than 20 mg have not been studied in this population.

Titration should be conducted according to the individual response and tolerability in paediatric patients, as recommended by the paediatric treatment recommendations (see section 4.4). Children and adolescents should be placed on standard cholesterol-lowering diet before rosuvastatin treatment initiation; this diet should be continued during rosuvastatin treatment.

Homozygous familial hypercholesterolaemia

In children 6 to 17 years of age with homozygous familial hypercholesterolaemia, the recommended maximum dose is 20 mg once daily.

A starting dose of 5 to 10 mg once daily depending on age, weight and prior statin use is advised. Titration to the maximum dose of 20 mg once daily should be conducted according to the individual response and tolerability in paediatric patients, as recommended by the paediatric treatment recommendations (see section 4.4). Children and adolescents should be placed on standard cholesterol-lowering diet before rosuvastatin treatment initiation; this diet should be continued during rosuvastatin treatment.

There is limited experience with doses other than 20 mg in this population.

The 40 mg tablet is not suitable for use in paediatric patients.

Children younger than 6 years

The safety and efficacy of use in children younger than 6 years has not been studied. Therefore, Revostat is not recommended for use in children younger than 6 years.

Use in the elderly

A start dose of 5 mg is recommended in patients>70 years. No other dose adjustment is necessary in relation to age.

Dosage in patients with renal insufficiency

No dose adjustment is necessary in patients with mild to moderate renal impairment. The recommended start dose is 5 mg in patients with moderate renal impairment (creatinine clearance <60 ml/min). The use of Revostat in patients with severe renal impairment is contraindicated for all doses.

Dosage in patients with hepatic impairment

There was no increase in systemic exposure to rosuvastatin in subjects with Child-Pugh scores of 7 or below. However, increased systemic exposure has been observed in subjects with Child-Pugh scores of 8 and 9 (see section 5.2). In these patients an assessment of renal function should be considered (see section 4.4). There is no experience in subjects with Child-Pugh scores above 9. Revostat is contraindicated in patients with active liver disease.

4.3 Contraindications

Contraindicated:

• Patients with hypersensitivity to rosuvastatin or to any of the excipients.
• Patients with active liver disease including unexplained, persistent elevations of serum transaminases and any serum transaminase elevation exceeding 3 times the upper limit of normal (ULN).
• Patients with severe renal impairment (creatinine clearance <30 ml/min).
• Patients with myopathy.
• Patients receiving concomitant combination of sofosbuvir/velpatasvir/voxilaprevir
• Patients receiving concomitant ciclosporin.
• Pregnancy and lactation and in women of childbearing potential not using appropriate contraceptive measures.

4.4 Special warnings and precautions for use

Renal Effects

Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients treated with higher doses of Revostat, in particular 40 mg, where it was transient or intermittent in most cases. Proteinuria has not been shown to be predictive of acute or progressive renal disease.The reporting rate for serious renal events in post-marketing use is higher at the 40 mg dose.

Skeletal Muscle Effects

Effects on skeletal muscle e.g. myalgia, myopathy and, rarely, rhabdomyolysis have been reported in Revostat-treated patients with all doses and in particular with doses > 20 mg. Very rare cases of rhabdomyolysis have been reported with the use of ezetimibe in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be excluded (see section 4.5) and caution should be exercised with their combined use. As with other HMG-CoA reductase inhibitors, the reporting rate for rhabdomyolysis associated with Revostat in post-marketing use is higher at the 40 mg dose.

Creatine Kinase Measurement

Creatine Kinase (CK) should not be measured following strenuous exercise or in the presence of a plausible alternative cause of CK increase which may confound interpretation of the result. If CK levels are significantly elevated at baseline (>5xULN) a confirmatory test should be carried out within 5 – 7 days. If the repeat test confirms a baseline CK >5xULN, treatment should not be started.

Before Treatment

Revostat, as with other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with pre-disposing factors for myopathy/rhabdomyolysis. Such factors include:

• renal impairment
• hypothyroidism
• personal or family history of hereditary muscular disorders
• previous history of muscular toxicity with another HMG-CoA reductase inhibitor or fibrate
• alcohol abuse
• age >70 years
• situations where an increase in plasma levels may occur
• concomitant use of fibrates.

In such patients the risk of treatment should be considered in relation to possible benefit and clinical monitoring is recommended. If CK levels are significantly elevated at baseline (>5xULN) treatment should not be started.

Whilst on Treatment

Patients should be asked to report inexplicable muscle pain, weakness or cramps immediately, particularly if associated with malaise or fever. CK levels should be measured in these patients. Therapy should be discontinued if CK levels are markedly elevated (>5xULN) or if muscular symptoms are severe and cause daily discomfort (even if CK levels are ≤ 5xULN). If symptoms resolve and CK levels return to normal, then consideration should be given to re-introducing Revostat or an alternative HMG-CoA reductase inhibitor at the lowest dose with close monitoring. Routine monitoring of CK levels in asymptomatic patients is not warranted. There have been very rare reports of an immune-mediated necrotising myopathy (IMNM) during or after treatment with statins, including rosuvastatin. IMNM is clinically characterised by proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment.

In few cases, statins have been reported to induce de novo or aggravate pre-existing myasthenia gravis or ocular myasthenia (see section 4.8). Revostat should be discontinued in case of aggravation of symptoms. Recurrences when the same or a different statin was (re-) administered have been reported.

In clinical trials, there was no evidence of increased skeletal muscle effects in the small number of patients dosed with Revostat and concomitant therapy. However, an increase in the incidence of myositis and myopathy has been seen in patients receiving other HMG-CoA reductase inhibitors together with fibric acid derivatives including gemfibrozil, ciclosporin, nicotinic acid, azole antifungals, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when given concomitantly with some HMG-CoA reductase inhibitors. Therefore, the combination of Revostat and gemfibrozil is not recommended. The benefit of further alterations in lipid levels by the combined use of Revostat with fibrates or niacin should be carefully weighed against the potential risks of such combinations.

Revostat must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination .Patients should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness. Statin therapy may be re-introduced seven days after the last dose of fusidic acid. In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g. for the treatment of severe infections, the need for co-administration of Revostat and fusidic acid should only be considered on a case by case basis and under close medical supervision.

Revostat should not be used in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g. sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders; or uncontrolled seizures).

Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which could be life-threatening or fatal, have been reported with rosuvastatin .At the time of prescription, patients should be advised of the signs and symptoms of severe skin reactions and be closely monitored. If signs and symptoms suggestive of this reaction appear, Revostat should be discontinued immediately and an alternative treatment should be considered.

If the patient has developed a serious reaction such as SJS or DRESS with the use of Revostat, treatment with Revostat must not be restarted in this patient at any time.

Liver Effects

As with other HMG-CoA reductase inhibitors, Revostat should be used with caution in patients who consume excessive quantities of alcohol and/or have a history of liver disease.

It is recommended that liver function tests be carried out prior to, and 3 months following, the initiation of treatment. Revostat should be discontinued or the dose reduced if the level of serum transaminases is greater than 3 times the upper limit of normal. The reporting rate for serious hepatic events (consisting mainly of increased hepatic transaminases) in post-marketing use is higher at the 40 mg dose.

In patients with secondary hypercholesterolaemia caused by hypothyroidism or nephrotic syndrome, the underlying disease should be treated prior to initiating therapy with Revostat.

Race

Pharmacokinetic studies show an increase in exposure in Asian subjects compared with Caucasians.

Protease Inhibitors

Increased systemic exposure to rosuvastatin has been observed in subjects receiving rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Consideration should be given both to the benefit of lipid lowering by use of Revostat in HIV patients receiving protease inhibitors and the potential for increased rosuvastatin plasma concentrations when initiating and up titrating Revostat doses in patients treated with protease inhibitors. The concomitant use with certain protease inhibitors is not recommended unless the dose of Revostat is adjusted.

Lactose Intolerance

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Interstitial Lung Disease

Exceptional cases of interstitial lung disease have been reported with some statins, especially with long-term therapy.Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

Diabetes Mellitus

Some evidence suggests that statins as a class raise blood glucose and in some patients, at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/l, BMI >30 kg/m2, raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.

In the JUPITER study, the reported overall frequency of diabetes mellitus was 2.8% in rosuvastatin and 2.3% in placebo, mostly in patients with fasting glucose 5.6 to 6.9 mmol/l.

Paediatric Population

The evaluation of linear growth (height), weight, BMI (body mass index), and secondary characteristics of sexual maturation by Tanner staging in paediatric patients 6 to 17 years of age taking rosuvastatin is limited to a two-year period. After two years of study treatment, no effect on growth, weight, BMI or sexual maturation was detected (see section 5.1).

In a clinical trial of children and adolescents receiving rosuvastatin for 52 weeks, CK elevations >10xULN and muscle symptoms following exercise or increased physical activity were observed more frequently compared to observations in clinical trials in adults.

4.5 Interaction with other medicinal products and other forms of interaction

Effect of co-administered medicinal products on rosuvastatin

Transporter protein inhibitors: Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake transporter OATP1B1 and efflux transporter BCRP. Concomitant administration of Revostat with medicinal products that are inhibitors of these transporter proteins may result in increased rosuvastatin plasma concentrations and an increased risk of myopathy

Ciclosporin: During concomitant treatment with Revostat and ciclosporin, rosuvastatin AUC values were on average 7 times higher than those observed in healthy volunteers (see Table 1). Revostat is contraindicated in patients receiving concomitant ciclosporin.Concomitant administration did not affect plasma concentrations of ciclosporin.

Protease inhibitors: Although the exact mechanism of interaction is unknown, concomitant protease inhibitor use may strongly increase rosuvastatin exposure. For instance, in a pharmacokinetic study, co-administration of 10 mg rosuvastatin and a combination product of two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers was associated with an approximately three-fold and seven-fold increase in rosuvastatin AUC and Cmax respectively. The concomitant use of Revostat and some protease inhibitor combinations may be considered after careful consideration of Revostat dose adjustments based on the expected increase in rosuvastatin exposure.

Gemfibrozil and other lipid-lowering products: Concomitant use of Revostat and gemfibrozil resulted in a 2-fold increase in rosuvastatin C_max and AUC.

Based on data from specific interaction studies no pharmacokinetic relevant interaction with fenofibrate is expected, however a pharmacodynamic interaction may occur. Gemfibrozil, fenofibrate, other fibrates and lipid lowering doses (> or equal to 1 g/day) of niacin (nicotinic acid) increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors, probably because they can produce myopathy when given alone. The 40 mg dose is contraindicated with concomitant use of a fibrate (see sections 4.3 and 4.4). These patients should also start with the 5 mg dose.

Ezetimibe: Concomitant use of 10 mg Revostat and 10 mg ezetimibe resulted in a 1.2-fold increase in AUC of rosuvastatin in hypercholesterolaemic subjects.A pharmacodynamic interaction, in terms of adverse effects, between Revostat and ezetimibe cannot be ruled out.

Antacid: The simultaneous dosing of Revostat with an antacid suspension containing aluminium and magnesium hydroxide resulted in a decrease in rosuvastatin plasma concentration of approximately 50%. This effect was mitigated when the antacid was dosed 2 hours after Revostat. The clinical relevance of this interaction has not been studied.

Erythromycin: Concomitant use of Revostat and erythromycin resulted in a 20% decrease in AUC and a 30% decrease in Cmax of rosuvastatin. This interaction may be caused by the increase in gut motility caused by erythromycin.

Ticagrelor: Ticagrelor might affect renal excretion of rosuvastatin, increasing the risk for rosuvastatin accumulation. Although the exact mechanism is not known, in some cases, concomitant use of ticagrelor and rosuvastatin led to renal function decrease, increased CPK level and rhabdomyolysis.

Cytochrome P450 enzymes: Results from in vitro and in vivo studies show that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a poor substrate for these isoenzymes. Therefore, drug interactions resulting from cytochrome P450-mediated metabolism are not expected. No clinically relevant interactions have been observed between rosuvastatin and either fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4).

Interactions requiring rosuvastatin dose adjustments (see also Table 1): When it is necessary to co-administer Revostat with other medicinal products known to increase exposure to rosuvastatin, doses of Revostat should be adjusted. Start with a 5 mg once daily dose of Revostat if the expected increase in exposure (AUC) is approximately 2-fold or higher. The maximum daily dose of Revostat should be adjusted so that the expected rosuvastatin exposure would not likely exceed that of a 40 mg daily dose of Revostat taken without interacting medicinal products, for example a 20 mg dose of Revostat with gemfibrozil (1.9-fold increase), and a 10 mg dose of Revostat with combination ritonavir/atazanavir (3.1-fold increase).

If medicinal product is observed to increase rosuvastatin AUC less than 2-fold, the starting dose need not be decreased but caution should be taken if increasing the Revostat dose above 20mg.

The following medical product/combinations did not have a clinically significant effect on the AUC ratio of rosuvastatin at coadministration:

Aleglitazar 0.3 mg 7 days dosing; Fenofibrate 67 mg 7 days TID dosing; Fluconazole 200mg 11 days OD dosing; Fosamprenavir 700 mg/ritonavir 100 mg 8 days BID dosing; Ketoconazole 200 mg 7 days BID dosing; Rifampin 450 mg 7 days OD dosing; Silymarin 140 mg 5 days TID dosing. Effect of rosuvastatin on co-administered medicinal products

Vitamin K antagonists: As with other HMG-CoA reductase inhibitors, the initiation of treatment or dosage up-titration of Revostat in patients treated concomitantly with vitamin K antagonists (e.g. warfarin or another coumarin anticoagulant) may result in an increase in International Normalised Ratio (INR). Discontinuation or down-titration of Revostat may result in a decrease in INR. In such situations, appropriate monitoring of INR is desirable.

Oral contraceptive/hormone replacement therapy (HRT): Concomitant use of Revostat and an oral contraceptive resulted in an increase in ethinyl estradiol and norgestrel AUC of 26% and 34%, respectively. These increased plasma levels should be considered when selecting oral contraceptive doses. There are no pharmacokinetic data available in subjects taking concomitant Revostat and HRT, therefore, a similar effect cannot be excluded. However, the combination has been extensively used in women in clinical trials and was well tolerated.

Other medicinal products:

Digoxin: Based on data from specific interaction studies no clinically relevant interaction with digoxin is expected.

Fusidic Acid: Interaction studies with rosuvastatin and fusidic acid have not been conducted. The risk of myopathy, including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. The mechanism of this interaction (whether it is pharmacodynamic or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination.

If treatment with systemic fusidic acid is necessary, Revostat treatment should be discontinued throughout the duration of the fusidic acid treatment. Also see section 4.4.

Paediatric population: Interaction studies have only been performed in adults. The extent of interactions in the paediatric population is not known.

4.6 Fertility, pregnancy and lactation

Revostat is contraindicated in pregnancy and lactation.

Women of child bearing potential should use appropriate contraceptive measures.

Since cholesterol and other products of cholesterol biosynthesis are essential for the development of the foetus, the potential risk from inhibition of HMG-CoA reductase outweighs the advantage of treatment during pregnancy. Animal studies provide limited evidence of reproductive toxicity . If a patient becomes pregnant during use of this product, treatment should be discontinued immediately.

Rosuvastatin is excreted in the milk of rats. There are no data with respect to excretion in milk in humans .

4.7 Effects on ability to drive and use machines

Studies to determine the effect of Revostat on the ability to drive and use machines have not been conducted. However, based on its pharmacodynamic properties, Revostat is unlikely to affect this ability. When driving vehicles or operating machines, it should be taken into account that dizziness may occur during treatment.

4.8 Undesirable effects

The adverse reactions seen with Revostat are generally mild and transient. In controlled clinical trials, less than 4% of Revostat-treated patients were withdrawn due to adverse reactions.

Tabulated list of adverse reactions Based on data from clinical studies and extensive post-marketing experience, the following table presents the adverse reaction profile for rosuvastatin. Adverse reactions listed below are classified according to frequency and system organ class (SOC).

The frequencies of adverse reactions are ranked according to the following convention: Common (≥ 1/100 to <1/10); Uncommon (≥ 1/1,000 to <1/100); Rare (≥ 1/10,000 to <1/1000); Very rare (<1/10,000); Not known (cannot be estimated from the available data).

Table 2. Adverse reactions based on data from clinical studies and post-marketing experience

As with other HMG-CoA reductase inhibitors, the incidence of adverse drug reactions tends to be dose dependent.

Renal effects: Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients treated with Revostat. Shifts in urine protein from none or trace to ++ or more were seen in <1% of patients at some time during treatment with 10 and 20 mg, and in approximately 3% of patients treated with 40 mg. A minor increase in shift from none or trace to + was observed with the 20 mg dose. In most cases, proteinuria decreases or disappears spontaneously on continued therapy. Review of data from clinical trials and post-marketing experience to date has not identified a causal association between proteinuria and acute or progressive renal disease.

Haematuria has been observed in patients treated with Revostat and clinical trial data show that the occurrence is low.

Skeletal muscle effects: Effects on skeletal muscle e.g. myalgia, myopathy (including myositis) and, rarely, rhabdomyolysis with and without acute renal failure have been reported in Revostat-treated patients with all doses and in particular with doses > 20 mg.

A dose-related increase in CK levels has been observed in patients taking rosuvastatin; the majority of cases were mild, asymptomatic and transient. If CK levels are elevated (>5xULN), treatment should be discontinued.

Liver effects: As with other HMG-CoA reductase inhibitors, a dose-related increase in transaminases has been observed in a small number of patients taking rosuvastatin; the majority of cases were mild, asymptomatic and transient.

The following adverse events have been reported with some statins:

Sexual dysfunction. Exceptional cases of interstitial lung disease, especially with long term therapy .

The reporting rates for rhabdomyolysis, serious renal events and serious hepatic events (consisting mainly of increased hepatic transaminases) is higher at the 40 mg dose.

Paediatric population: Creatine kinase elevations >10xULN and muscle symptoms following exercise or increased physical activity were observed more frequently in a 52-week clinical trial of children and adolescents compared to adults .In other respects, the safety profile of rosuvastatin was similar in children and adolescents compared to adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website: https://www.zuventus.com/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

There is no specific treatment in the event of overdose. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Liver function and CK levels should be monitored. Haemodialysis is unlikely to be of benefit.

5.1 Mechanism of action

Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor for cholesterol. The primary site of action of rosuvastatin is the liver, the target organ for cholesterol lowering.

Rosuvastatin increases the number of hepatic LDL receptors on the cell-surface, enhancing uptake and catabolism of LDL and it inhibits the hepatic synthesis of VLDL, thereby reducing the total number of VLDL and LDL particles.

5.2 Pharmacodynamic effects

Revostat reduces elevated LDL-cholesterol, total cholesterol and triglycerides and increases HDL-cholesterol. It also lowers ApoB, non-HDL-C, VLDL-C, VLDL-TG and increases ApoA-I (see Table 3). Revostat also lowers the LDL-C/HDL-C, total C/HDL-C and non-HDL-C/HDL-C and the ApoB/ApoA-I ratios.

Table 3 Dose response in patients with primary hypercholesterolaemia (type IIa and IIb) (adjusted mean percent change from baseline)

A therapeutic effect is obtained within 1 week following treatment initiation and 90% of maximum response is achieved in 2 weeks. The maximum response is usually achieved by 4 weeks and is maintained after that.

5.3 Pharmacokinetic properties

Absorption: Maximum rosuvastatin plasma concentrations are achieved approximately 5 hours after oral administration. The absolute bioavailability is approximately 20%.

Distribution: Rosuvastatin is taken up extensively by the liver which is the primary site of cholesterol synthesis and LDL-C clearance. The volume of distribution of rosuvastatin is approximately 134 L. Approximately 90% of rosuvastatin is bound to plasma proteins, mainly to albumin.

Metabolism: Rosuvastatin undergoes limited metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a poor substrate for cytochrome P450-based metabolism. CYP2C9 was the principal isoenzyme involved, with 2C19, 3A4 and 2D6 involved to a lesser extent. The main metabolites identified are the N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin whereas the lactone form is considered clinically inactive. Rosuvastatin accounts for greater than 90% of the circulating HMG-CoA reductase inhibitor activity.

Excretion: Approximately 90% of the rosuvastatin dose is excreted unchanged in the faeces (consisting of absorbed and non-absorbed active substance) and the remaining part is excreted in urine. Approximately 5% is excreted unchanged in urine. The plasma elimination half-life is approximately 19 hours. The elimination half-life does not increase at higher doses. The geometric mean plasma clearance is approximately 50 litres/hour (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, the hepatic uptake of rosuvastatin involves the membrane transporter OATP-C. This transporter is important in the hepatic elimination of rosuvastatin.

Linearity: Systemic exposure of rosuvastatin increases in proportion to dose. There are no changes in pharmacokinetic parameters following multiple daily doses.

6.1 Animal Toxicology or Pharmacology

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenicity potential. Specific tests for effects on hERG have not been evaluated. Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels were as follows: In repeated-dose toxicity studies histopathologic liver changes likely due to the pharmacologic action of rosuvastatin were observed in mouse, rat, and to a lesser extent with effects in the gall bladder in dogs, but not in monkeys. In addition, testicular toxicity was observed in monkeys and dogs at higher dosages. Reproductive toxicity was evident in rats, with reduced litter sizes, litter weight and pup survival observed at maternally toxic doses, where systemic exposures were several times above the therapeutic exposure level.

CRESTOR (rosuvastatin) is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA)-reductase inhibitor

Chemical Name: s bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino] pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]

Molecular Formula: (C22H27FN3O6S)2Ca a

Molecular Weight: 1,001.14.

Structure:

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

Refer on pack.

8.3 Packaging information

3 Blister strips of 10 tablets each

8.4 Storage and handing instructions

Store below 30°C. Protect from light & moisture.

Keep out of reach of children.

Patients should be instructed not to take 2 doses of rosuvastatin calcium within 12 hours of each other.

Skeletal Muscle Effects

Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing rosuvastatin calcium.

Concomitant Use of Antacids

When taking rosuvastatin calcium with an aluminum and magnesium hydroxide combination antacid, the antacid should be taken at least 2 hours after rosuvastatin calcium administration.

Embryo fetal Toxicity

Advise females of reproductive potential of the risk to a fetus, to use effective contraception during treatment, and to inform their healthcare provider of a known or suspected pregnancy.

Lactation

Advise women not to breastfeed during treatment with rosuvastatin

Liver Enzymes

It is recommended that liver enzyme tests be performed before the initiation of rosuvastatin calcium and if signs or symptoms of liver injury occur. All patients treated with rosuvastatin calcium should be advised to promptly report any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.

10th October 2024

Deflazacort Tablets 6 mg/12mg/24 mg/30 mg

Each uncoated tablet contains

Deflazacort 6 mg/12 mg/24 mg/30 mg.

Excipients q.s.

Tablets for oral administration.

6 mg/12 mg/24 mg/30 mg

4.1. Therapeutic indication

For asthma, rheumatoid arthritis when glucocorticosteriod therapy is warranted.

4.2.Posology and method of administration

Deflazacort is a glucocorticoid derived from prednisolone and 6mg of deflazacort has approximately the same anti-inflammatory potency as 5mg prednisolone or prednisone. Doses vary widely in different diseases and different patients. In more serious and lifethreatening conditions, high doses of deflazacort may need to be given. When deflazacort is used long term in relatively benign chronic diseases, the maintenance dose should be kept as low as possible. Dosage may need to be increased during periods of stress or in exacerbation of illness. The dosage should be individually titrated according to diagnosis, severity of disease and patient response and tolerance. The lowest dose that will produce an acceptable response should be used.

Adults

For acute disorders, up to 120 mg/day deflazacort may need to be given initially. Maintenance doses in most conditions are within the range 3-18 mg/day. The following regimens are for guidance only

Rheumatoid arthritis: The maintenance dose is usually within the range 3 - 18 mg/day. The smallest effective dose should be used and increased if necessary.

Bronchial asthma: In the treatment of an acute attack, high doses of 48-72 mg/day may be needed depending on severity and gradually reduced once the attack has been controlled. For maintenance in chronic asthma, doses should be titrated to the lowest dose that controls symptoms.

Other conditions: The dose of deflazacort depends on clinical need titrated to the lowest effective dose for maintenance. Starting doses may be estimated on the basis of ratio of 5mg prednisone or prednisolone to 6mg deflazacort.

Hepatic Impairment

In patients with hepatic impairment, blood levels of deflazacort may be increased. Therefore, the dose of deflazacort should be carefully monitored and adjusted to the minimum effective dose.

Renal Impairment

In renally impaired patients, no special precautions other than those usually adopted in patients receiving glucocorticoid therapy are necessary.

Elderly

In elderly patients, no special precautions other than those usually adopted in patients receiving glucocorticoid therapy are necessary. The common adverse effects of systemic corticosteroids may be associated with more serious consequences in old age.

Paediatric Population

There has been limited exposure of children to deflazacort in clinical trials. In children, the indications for glucocorticoids are the same as for adults, but it is important that the lowest effective dosage is used. Alternate day administration may be appropriate.

Doses of deflazacort usually lie in the range 0.25 - 1.5 mg/kg/day. The following ranges provide general guidance:

Juvenile chronic arthritis: The usual maintenance dose is between 0.25 - 1.0 mg/kg/day

Nephrotic syndrome: Initial dose of usually 1.5 mg/kg/day followed by down titration according to clinical need.

Bronchial asthma: On the basis of the potency ratio, the initial dose should be between 0.25 - 1.0 mg/kg deflazacort on alternate days.

Deflazacort withdrawal

In patients who have received more than physiological doses of systemic corticosteroids (approximately 9mg per day or equivalent) for greater than 3 weeks, 3 withdrawal should not be abrupt. How dose reduction should be carried out depends largely on whether the disease is likely to relapse as the dose of systemic corticosteroids is reduced. Clinical assessment of disease activity may be needed during withdrawal. If the disease is unlikely to relapse on withdrawal of systemic corticosteroids but there is uncertainty about HPA suppression, the dose of systemic corticosteroids may be reduced rapidly to physiological doses. Once a daily dose equivalent to 9mg deflazacort is reached, dose reduction should be slower to allow the HPA-axis to recover. Abrupt withdrawal of systemic corticosteroid treatment, which has continued up to 3 weeks is appropriate if it is considered that the disease is unlikely to relapse. Abrupt withdrawal of doses up to 48 mg daily of deflazacort, or equivalent for 3 weeks is unlikely to lead to clinically relevant HPA-axis suppression, in the majority of patients. In the following patient groups, gradual withdrawal of systemic corticosteroid therapy should be considered even after courses lasting 3 weeks or less:

•  Patients who have had repeated courses of systemic corticosteroids, particularly if taken for greater than 3 weeks.
• When a short course has been prescribed within one year of cessation of long-term therapy (months or years).
• Patients who may have reasons for adrenocortical insufficiency other than exogenous corticosteroid therapy.
• Patients receiving doses of systemic corticosteroid greater than 48 mg daily of deflazacort (or equivalent),
• Patients repeatedly taking doses in the evening

4.3.Contraindications

Systemic infection unless specific anti-infective therapy is employed. Hypersensitivity to the active substance, deflazacort or any of the excipients. Patients receiving live virus immunisation.

4.4.Special warnings and precautions for use

Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine. Undesirable effects may be minimised by using the lowest effective dose for the minimum period, and by administering the daily requirement as a single morning dose or whenever possible as a single morning dose on alternate days. Frequent patient review is required to appropriately titrate the dose against disease activity.

Adrenal suppression

Adrenal cortical atrophy develops during prolonged therapy and may persist for years after stopping treatment. Withdrawal of corticosteroids after prolonged therapy must therefore always be gradual to avoid acute adrenal insufficiency which could be fatal, being tapered off over weeks or months according to the dose and duration of treatment. During prolonged therapy, any intercurrent illness, trauma or surgical procedure will require a temporary increase in dosage; if corticosteroids have been stopped following prolonged therapy, they may need to be temporarily re-introduced. Patients should carry 'Steroid treatment' cards which give clear guidance on the precautions to be taken to minimise risk and which provide details of prescriber, drug, dosage and the duration of treatment.

Anti-inflammatory/immunosuppressive effects and infection

Suppression of the inflammatory response and immune function increases the susceptibility to infections and their severity. The clinical presentation may often be atypical and serious infections such as septicaemia and tuberculosis may be masked and may reach an advanced stage before being recognised. Chickenpox is of particular concern since this normally minor illness may be fatal in immunosuppressed patients. Patients (or parents of children) without a definite history of chicken pox should be advised to avoid close personal contact with chickenpox or herpes zoster and, if exposed, they should seek urgent medical attention. Passive immunisation with varicella zoster immunoglobulin (VZIG) is needed by exposed non-immune patients who are receiving systemic corticosteroids or who have used them within the previous 3 months; this should be given within 10 days of exposure to chickenpox. If a diagnosis of chickenpox is confirmed, the illness warrants specialist care and urgent treatment. Corticosteroids should not be stopped and the dose may need to be increased. Patients should be advised to take particular care to avoid exposure to measles and to seek immediate medical advice if exposure occurs. Prophylaxis with intramuscular normal immunoglobulin may be needed. Live vaccines should not be given to individuals with impaired responsiveness. The antibody response to other vaccines may be diminished.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids. Prolonged use of glucocorticoids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves and may enhance the establishment of secondary ocular infections due to fungi or viruses. Use in active tuberculosis should be restricted to those cases of fulminating and disseminated tuberculosis in which deflazacort is used for management with appropriate antituberculosis regimen. If glucocorticoids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged glucocorticoid therapy, these patients should receive chemoprophylaxis. Tendonitis and tendon rupture are known class effect of glucocorticoids. The risk of such reactions may be increased by co-administration of quinolones. Pheochromocytoma crisis, which can be fatal, has been reported after administration of systemic corticosteroids. Corticosteroids should only be administered to patients with suspected or identified pheochromocytoma after an appropriate risk/benefit evaluation.

Special precautions

The following clinical conditions require special caution and frequent patient monitoring is necessary: -

• Cardiac disease or congestive heart failure (except in the presence of active rheumatic carditis), hypertension, thromboembolic disorders. Glucocorticoids can cause salt and water retention and increased excretion of potassium. Dietary salt restriction and potassium supplementation may be necessary.
• Gastritis or oesophagitis, diverticulitis, ulcerative colitis if there is probability of impending perforation, abscess or pyogenic infections, fresh intestinal anastomosis, active or latent peptic ulcer.
• Diabetes mellitus or a family history, osteoporosis, myasthenia gravis, renal insufficiency.
• Emotional instability or psychotic tendency, epilepsy. 
• Previous corticosteroid-induced myopathy.
• Liver failure.
• Hypothyroidism and cirrhosis, which may increase glucocorticoid effect.
• Ocular herpes simplex because of possible corneal perforation.

Patients and/or carers should be warned that potentially severe psychiatric adverse reactions may occur with systemic steroids. Symptoms typically emerge within a few days or weeks of starting the treatment. Risks may be higher with high doses/systemic exposure, although dose levels do not allow prediction of the onset, type, severity or duration of reactions. Most reactions recover after either dose reduction or withdrawal, although specific treatment may be necessary. Patients/carers should be encouraged to seek medical advice if worrying psychological symptoms develop, especially if depressed mood or suicidal ideation is suspected. Patients/carers should also be alert to possible psychiatric disturbances that may occur either during or immediately after dose tapering/withdrawal of systemic steroids, although such reactions have been reported infrequently.

Particular care is required when considering the use of systemic corticosteroids in patients with existing or previous history of severe affective disorders in themselves or in their first degree relatives. These would include depressive or manic-depressive illness and previous steroid psychosis. Glucocorticoids are known to cause irregular menstruation and leukocytosis, care should be taken with deflazacort.

Paediatric population

Corticosteroids cause dose-related growth retardation in infancy, childhood and adolescence which may be irreversible. Hypertrophic cardiomyopathy has been reported after systemic administration of glucocorticosteroids in preterm infants. In infants receiving administration of systemic glucocorticosteroids, echocardiograms should be performed to monitor myocardial structure and function.

Use in Elderly

The common adverse effects of systemic corticosteroids may be associated with more serious consequences in old age, especially osteoporosis, hypertension, hypokalaemia, diabetes, susceptibility to infection and thinning of the skin. Close clinical supervision is required to avoid life-threatening reactions. Since complications of glucocorticoid therapy are dependent on dose and duration of therapy, the lowest possible dose must be given and a risk/benefit decision must be made as to whether intermittent therapy should be used.

4.5.Interaction with other medicinal products and other forms of interaction

• The same precautions should be exercised as for other glucocorticoids. Deflazacort is metabolised in the liver. It is recommended to increase the maintenance dose of deflazacort if drugs which are liver enzyme inducers are co-administered, e.g. rifampicin, rifabutin, carbamazepine, phenobarbitone, phenytoin, primidone and aminoglutethimide. For drugs which inhibit liver enzymes, e.g. ketoconazole it may be possible to reduce the maintenance dose of deflazacort.
• In patients taking estrogens, corticosteroid requirements may be reduced.
• The desired effects of hypoglycaemic agents (including insulin), anti-hypertensives and diuretics are antagonised by corticosteroids and the hypokalaemic effects of acetazolamide, loop diuretics, thiazide diuretics, beta 2-agonists, xanthines and carbenoxolone are enhanced.
• The efficacy of coumarin anticoagulants may be enhanced by concurrent corticosteroid therapy and close monitoring of the INR or prothrombin time is required to avoid spontaneous bleeding.
• In patients treated with systemic corticosteroids, use of non-depolarising muscle relaxants can result in prolonged relaxation and acute myopathy. Risk factors for this include prolonged and high dose corticosteroid treatment, and prolonged duration of muscle paralysis. This interaction is more likely following prolonged ventilation (such as in the ITU setting).
• The renal clearance of salicylates is increased by corticosteroids and steroid withdrawal may result in salicylate intoxication.
• As glucocorticoids can suppress the normal responses of the body to attack by micro-organisms, it is important to ensure that any anti-infective therapy is effective and it is recommended to monitor patients closely. Concurrent use of glucocorticoids and oral contraceptives should be closely monitored as plasma levels of glucocorticoids may be increased. This effect may be due to a change in metabolism or binding to serum proteins. Antacids may reduce bioavailability; leave at least 2 hours between administration of deflazacort and antacids. 8
• Co-treatment with CYP3A inhibitors, including cobicistat-containing products, is expected to increase the risk of systemic side-effects. The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects.

4.6.Fertility, pregnancy and lactation

Pregnancy

The ability of corticosteroids to cross the placenta varies between individual drugs, however, deflazacort does cross the placenta. Administration of corticosteroids to pregnant animals can cause abnormalities of foetal development including cleft palate, intra-uterine growth retardation and effects on brain growth and development. There is no evidence that corticosteroids result in an increased incidence of congenital abnormalities, such as cleft palate/lip in man. However, when administered for prolonged periods or repeatedly during pregnancy, corticosteroids may increase the risk of intra-uterine growth retardation. Hypoadrenalism may, in theory, occur in the neonate following prenatal exposure to corticosteroids but usually resolves spontaneously following birth and is rarely clinically important. As with all drugs, corticosteroids should only be prescribed when the benefits to the mother and child outweigh the risks. When corticosteroids are essential however, patients with normal pregnancies may be treated as though they were in the non-gravid state.

Breast-feeding

Corticosteroids are excreted in breast milk, although no data are available for deflazacort. Doses of up to 50 mg daily of deflazacort are unlikely to cause systemic effects in the infant. Infants of mothers taking higher doses than this may have a degree of adrenal suppression but the benefits of breast feeding are likely to outweigh any theoretical risk.

Fertility

No data is available on Deflazacort and its effects on fertility.

4.7.Effects on ability to drive and use machines

The effect of corticosteroids on the ability to drive or use machinery has not been systematically evaluated. Vertigo is a possible undesirable effect after treatment with deflazacort. If affected, patients should not drive or operate machinery.

4.8.Undesirable effects

The incidence of predictable undesirable effects, including hypothalamic-pituitaryadrenal suppression correlates with the relative potency of the drug, dosage; timing of administration and the duration of treatment. The following CIOMS frequency rating is used: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000), not known (cannot be estimated from the available data).

Endocrine disorders

Uncommon: Suppression of the hypothalamic-pituitary-adrenal axis, amenorrhoea, Cushingoid facies. Not known: Growth suppression in infancy, childhood and adolescence.

Metabolism and nutrition disorders

Common: Weight gain. Uncommon: impaired carbohydrate tolerance with increased requirement for antidiabetic therapy, sodium and water retention with hypertension, potassium loss and hypokalaemic alkalosis when co-administered with beta 2-agonist and xanthines. Not known: Negative protein and calcium balance, increased appetite.

Infections and Infestations

Uncommon: Increased susceptibility and severity of infections with suppression of clinical symptoms and signs, opportunistic infections, recurrence of dormant tuberculosis. Not known: candidiasis.

Musculoskeletal and connective tissue disorders

Uncommon: Osteoporosis, vertebral and long bone fractures. Rare: Muscle wasting. Not known: avascular osteonecrosis, tendonitis and tendon rupture when coadministered with quinolones, myopathy (acute myopathy may be precipitated by nondepolarising muscle relaxants, negative nitrogen balance.

Reproductive system and breast disorders

Not known: Menstrual irregularity.

Cardiac disorders

Not known: Heart failure, hypertrophic cardiomyopathy in preterm infants.

Nervous system disorders

Uncommon: Headache, vertigo.

Not known: restlessness, Increased intra-cranial pressure with papilloedema in children (pseudotumour cerebri), usually after treatment withdrawal, aggravation of epilepsy.

Psychiatric disorders

A wide range of psychiatric reactions including affective disorders such as: Uncommon: depressed and labile mood. Not known: irritable, euphoric, suicidal thoughts. Psychotic reactions including: Not known: mania, delusions, hallucinations, aggravation of schizophrenia Other reactions including: Uncommon: behavioural disturbances. Not known: anxiety, sleep disturbances, and cognitive dysfunction including confusion and amnesia have been reported. Reactions are common and may occur in both adults and children. In adults, the frequency of severe reactions has been estimated to be 5-6%. Psychological effects have been reported on withdrawal of corticosteroids; the frequency is unknown.

Eye disorders

Not known: Vision blurred, increased intra-ocular pressure, glaucoma, papilloedema, posterior subcapsular cataracts especially in children, chorioretinopathy, corneal or scleral thinning, exacerbation of ophthalmic viral or fungal diseases.

Gastrointestinal disorders

Uncommon: Dyspepsia, peptic ulceration, haemorrhage, nausea. Not known: perforation of peptic ulcer, acute pancreatitis (especially in children), candidiasis.

Skin and subcutaneous tissue disorders

Uncommon: hirsutism, striae, acne.

Rare: bruising.

Not known: Skin atrophy, telangiectasia.

General disorders and administration site conditions

Uncommon: Oedema.

Not known: impaired healing.

Immune system disorders

Uncommon: Hypersensitivity including anaphylaxis has been reported.

Blood and lymphatic system disorders

Not known: Leukocytosis.

Vascular disorders

Not known: Thromboembolism in particular in patients with underlying conditions associated with increased thrombotic tendency, rare incidence of benign intracranial hypertension.

Withdrawal symptoms and signs

Not known: Too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to acute adrenal insufficiency, hypotension and death. A 'withdrawal syndrome' may also occur including fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and loss of weight. This may occur in patients even without evidence of adrenal insufficiency.

Class effect

Pheochromocytoma crisis has been reported with other systemic corticosteroids and is a known class effect.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com By reporting side effects, you can help provide more information on the safety of this medicine.

4.9. Overdose

It is unlikely that treatment is needed in cases of acute overdosage. The LD50 for the oral dose is greater than 4000 mg/kg in laboratory animals.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: corticosteroids for systemic use; Glucocorticoids. ATC code: H02AB13. Deflazacort is a glucocorticoid. Its anti-inflammatory and immunosuppressive effects are used in treating a variety of diseases and are comparable to other antiinflammatory steroids. Clinical studies have indicated that the average potency ratio of deflazacort to prednisolone is 0.69-0.89.

5.2 Pharmacokinetic properties

Absorption: Orally administered deflazacort appears to be well absorbed.

Distribution: The active metabolite D 21-OH achieves peak plasma concentrations in 1.5 to 2 hours. It is 40% protein-bound and has no affinity for corticosteroid-binding-globulin (transcortin).

Biotransformation: Orally administered deflazacort is immediately converted by plasma esterases to the pharmacologically active metabolite (D 21-OH). Metabolism of D 21-OH is extensive. The metabolite of D 21-OH is deflazacort 6- beta-OH.

Elimination: Its elimination plasma half-life is 1.1 to 1.9 hours. Elimination takes place primarily through the kidneys; 70% of the administered dose is excreted in the urine. The remaining 30% is eliminated in the faeces. Metabolism of D 21-OH is extensive; only 18% of urinary excretion represents D 21-OH. The metabolite of D 21-OH, deflazacort 6-beta-OH, represents one third of the urinary elimination.

Safety studies have been carried out in the rat, dog, mouse and monkey. The findings are consistent with other glucocorticoids at comparable doses. Teratogenic effects demonstrated in rodents and rabbits are typical of those caused by other glucocorticoids. Deflazacort was not found to be carcinogenic in the mouse, but studies in the rat produced carcinogenic findings consistent with the findings with other glucocorticoids.

Deflazacort, is an oxaline derivative of Prednisolone.

Figure: Structure of Deflazacort

IUPAC Name: (11β,16β)-21-(acetyloxy)-11-hydroxy-2'-methyl-5'H-pregna-1,4- dieno[17,16-d]oxazole-3,20-dione Molecular Formula: C₂₅H₃₁NO₆ Molecular Weight: 441.5 g/mol

1. Incompatibilities Not applicable.

2. Shelf-life

3. Packaging information

4. Storage and handing instructions

• Keep out of reach of children. Keep out of the sight and reach of children. Store in a dry place at a temperature not exceeding 25°C.

A patient information leaflet is available for this product.

Administration

Warn patients and/or caregivers to not stop taking Cortimax abruptly or without first checking with their healthcare providers as there may be a need for gradual dose reduction to decrease the risk of adrenal insufficiency.

Cortimax may be taken with or without food. Do not take Cortimax with grapefruit juice.

Tablets

Cortimax Tablets may be taken whole or crushed and taken immediately after mixing with applesauce.

Increased Risk of Infection

Tell patients and/or caregivers to inform their healthcare provider if the patient has had recent or ongoing infections or if they have recently received a vaccine. Medical advice should be sought immediately if the patient develops fever or other signs of infection. Patients and/or caregivers should be made aware that some infections can potentially be severe and fatal. Warn patients who are on corticosteroids to avoid exposure to chickenpox or measles and to alert their healthcare provider immediately if they are exposed.

Alterations in Cardiovascular/Renal Function

Inform patients and/or caregivers that Cortimax can cause an increase in blood pressure and water retention. If this occurs, dietary salt restriction and potassium supplementation may be needed.

Behavioral and Mood Disturbances

Advise patients and/or caregivers about the potential for severe behavioral and mood changes with Cortimax and encourage them to seek medical attention if psychiatric symptoms develop.

Decreases in Bone Mineral Density

Advise patients and/or caregivers about the risk of osteoporosis with prolonged use of Cortimax, which can predispose the patient to vertebral and long bone fractures.

Ophthalmic Effects

Inform patients and/or caregivers that Cortimax may cause cataracts or glaucoma and advise monitoring if corticosteroid therapy is continued for more than 6 weeks.

Vaccination

Advise patients and/or caregivers to bring immunizations up-to-date according to immunization guidelines prior to starting therapy with Cortimax. Live-attenuated or live vaccines should be administered at least 4 to 6 weeks prior to starting Cortimax. Inform patients and/or caregivers that they may receive concurrent vaccinations with use of Cortimax, except for live-attenuated or live vaccines.

Serious Skin Rashes

Instruct patients and/or caregivers to seek medical attention at the first sign of a rash.

Drug Interactions

Certain medications can cause an interaction with Cortimax. Advise patients and/or caregivers to inform their healthcare provider of all the medicines the patient is taking, including over-the-counter medicines (such as insulin, aspirin or other NSAIDS), dietary supplements, and herbal products. Inform patients and/or caregivers that alternate therapy, dosage adjustment, and/or special test(s) may be needed during the treatment.

Fiber Powder

Contains Wheat Dextrin, Guar Gum, Resistant Maltodextrin, Inulin

Each sachet of 10 grams (per serve) contains:

Dietary fiber (Soluble fiber) …………………. 6.67 gram

Ingredients:

Wheat Dextrin, Resistant Maltodextrin, Inulin, Guar Gum

Sachets (10 gm powder)

4.1 Therapeutic Indication

Dietary Management of Diabetes

4.2 Posology and method of administration

Recommended Usage: 10 g (1 sachet) a day or as suggested by a healthcare professional.

Recommended duration of use: Depends upon physiological condition of the individual.

Instructions for Use: Add whole sachet of 10 g powder in 200 ml water. Stir well and use promptly. Consume whole sachet at once.

NOT FOR MEDICINAL USE

Flavour: Orange Flavour

Individual clinical data of components of “Fibrelite” is promising to promote a healthy lifestyle and prevent metabolic diseases, e.g. diabetes mellitus, obesity, and dyslipidaemia.

4.3 Contraindications

Hypersensitivity to active ingredients or to any of the excipients.

4.4 Special warnings and precautions for use

Allergens: Contains Wheat. It may contain Milk, Soy and Nuts.

The product should not be taken dry and should always be taken mixed with fluid.

4.5 Drugs interactions

4.6 Use in special populations

Pregnant / lactating women, children and people with medical conditions should consult a healthcare professional before use.

4.7 Effects on ability to drive and use machines

Fibrelite has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Polyols (non-digestible carbohydrates in Fibrelite) may have laxative effects.

Common side effects include: GI discomfort or nausea, Bloating, Gas, Stomach Cramps, Diarrhea. Gradually increasing fiber intake and drinking plenty of water can help minimize these side effects.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com Website: Website: https://www.zuventus.com/drug-safety-reporting

4.9 Overdose

Symptoms: Overdose with soluble fibres may cause abdominal discomfort, flatulence and intestinal obstruction.

Management: Adequate fluid intake should be maintained and management should be symptomatic.

5.1 Mechanism of Action

Resistant Maltodextrin

Resistant Maltodextrin (resistant starch) is a starch fraction that is indigestible in the small intestine but is fermented in the colon by colonic microbiota (bacteria), resulting in enhanced short-chain fatty acid (SCFA) production. Several health benefits are obtained from the fermentation of resistant starch in the colon, e.g. weight control, blood glucose reduction, insulin sensitivity, triacylglycerol reduction, and appetite regulation.

Resistant maltodextrin helps to maintain blood and lipid profiles as well as promote satiety and reducing food intake. Studies have demonstrated the beneficial effects of resistant maltodextrin on body weight, body composition, satiety, and food intake.

Inulin

Inulin is a water soluble storage polysaccharide belong to a class of dietary fibers known as fructans (non-digestible carbohydrates). Inulin functions as a prebiotic, promote the proliferation of the beneficial lactic acid-producing Bifidobacteria and Lactobacillus species in gut.

Inulin have been found to be effective in the stabilization of glycemic response and have positive effects on lipid metabolism by absorbing bile salts from small intestine. Inulin is a soluble fiber which is not digested by human enzymes and produces distinctive fiber-alike results on the effectiveness of the gut, thus, lowering the pH of intestine, providing assistance in relieving constipation and increasing stool load or rate (bulking effect).

Wheat Dextrin

It is a carbohydrate, which is not digested in small intestine but slowly fermented in the large intestine, does not raise blood sugar or insulin levels. Wheat dextrin aids in reducing the glycemic load of a meal containing carbohydrates.

Through the production of SCFAs, wheat dextrin stimulates pancreatic insulin release and affect liver control of glycogen breakdown, and effective in decreasing glucose and insulin levels and improving glycemic and insulinemic indices. Long-term assessment of wheat dextrin supplementation demonstrated a trend towards better weight maintenance compared with baseline. Also wheat dextrin increases the fecal/stool output.

Hydrolysed Guar Gum

The fermentation of partially hydrolyzed guar gum in colon produces Short Chain Fatty Acids (SCFA), which is responsible for their clinical effects. Several SCFA have shown their growth stimulatory effects on lactic acid bacteria and Bifidobacterium spp. Usefulness of partially hydrolysed guar gum has been studied in many clinical situations, e.g. diabetes, hypercholesterolemia, bacterial overgrowth etc. with promising results.

Administration of partially hydrolysed guar gum (PHGG) induces beneficial impact on hyperglycaemia, hyperlipidaemia and incretins metabolic hormones. It reduces LDL cholesterol, whereas HDL level was significantly increased therefore reducing the risk of metabolic syndrome. Partially hydrolyzed guar gum can also act as a prebiotic.

5.2 Pharmacodynamic properties

Fibrelite is a special blend, which slows down digestion and provides satiety for a longer period. It is a low-calorie formula, which provides the required fibre important for digestive health. Proposed usage are for dietary management of prediabetes and diabetes. Evidence from clinical trials demonstrate that the individual components of Fibrelite e.g. resistant maltodextrin, inulin, wheat dextrin, hydrolyzed guar gum have been shown to be a promising alternative that can help promote a healthy lifestyle and prevent metabolic diseases, e.g. Diabetes Mellitus, Obesity, Dyslipidaemia and Constipation.

5.3 Pharmacokinetic properties

Absorption and Digestion: Soluble fiber is not digested in the small intestine. Instead, it absorbs water and forms a gel-like substance, which slows down digestion and helps regulate blood sugar levels.

Fermentation: In the large intestine, soluble fiber is fermented by gut bacteria. This process produces short-chain fatty acids (SCFAs) like acetate, propionate, and butyrate, which have various health benefits, including anti-inflammatory effects and improved gut health.

Metabolism: The SCFAs produced during fermentation are absorbed into the bloodstream and can be used as an energy source by the body. They also play a role in regulating metabolism and appetite.

Excretion: Any unfermented fiber is excreted in the stool, contributing to bulk and aiding in regular bowel movements. These properties make soluble fiber beneficial for managing blood sugar levels, cholesterol, and overall digestive health.

6.1 Animal Toxicology or Pharmacology

Not available

Fibrelite is a “Nutraceutical” a substance that may be considered food or part of a food which provides health benefits, encompassing prevention and treatment of disease. Fibrelite is 100% natural soluble fiber from plant origin (vegan). Fibrelite is a blend of soluble fibres, which helps in improving the health and overall well-being. It comprises of Resistant Maltodextrin, Inulin, Wheat Dextrin and Partially Hydrolysed Guar Gum that is formulated to improve the colon health and support the good bacteria in the digestive system.

8.1 Incompatibilities

None

8.2 Shelf-life

Refer on pack.

8.3 Packaging information

10 tablets in each blister strip

8.4 Storage and handing instructions

Storage: Store below 30°C.

Protect from light and moisture Keep out of reach of children.

• Fiber helps to restore normal digestive health.
• Polyols, present in Fibrelite may have laxative effects.
• Pregnant / lactating women, children and people with medical conditions should consult a healthcare professional before use.
• This product is not intended to diagnose, treat, cure or prevent any disease(s).

15th October 2024

Rosuvastatin Tablet IP 10mg/20mg/40mg

Revostat 10mg

Each film-coated tablet contains:

Rosuvastatin Calcium IP equivalent to Rosuvastatin 10mg

Excipients q.s.

Revostat 20mg

Each film-coated tablet contains:

Rosuvastatin Calcium IP equivalent to Rosuvastatin 20mg

Excipients q.s.

Revostat 40mg

Each film-coated tablet contains:

Rosuvastatin Calcium IP equivalent to Rosuvastatin 40mg

Excipients q.s.

Tablet 10/20/40mg

4.1 Therapeutic indication

1) As an adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia.

2) As an adjunctive therapy to diet to slow the progression of atherosclerosis in adult patients as part of a treatment strategy to lower Total-C and LDL-C

3) Risk reduction of MI stroke and arterial evascularisation procedure in patients without clinically evident CHD but with multiple risk factor

4.2 Posology and method of administration

Before treatment initiation the patient should be placed on a standard cholesterol-lowering diet that should continue during treatment. The dose should be individualised according to the goal of therapy and patient response, using current consensus guidelines.

Revostat may be given at any time of day, with or without food.

Treatment of hypercholesterolaemia

The recommended start dose is 5 or 10 mg orally once daily in both statin naï ve or patients switched from another HMG CoA reductase inhibitor. The choice of start dose should take into account the individual patient's cholesterol level and future cardiovascular risk as well as the potential risk for adverse reactions (see below). A dose adjustment to the next dose level can be made after 4 weeks, if necessary.

Prevention of cardiovascular events

In the cardiovascular events risk reduction study, the dose used was 20 mg daily

Paediatric population

Paediatric use should only be carried out by specialists.

Children and adolescents 6 to 17 years of age (Tanner Stage< II-V)

Heterozygous familial hypercholesterolaemia

In children and adolescents with heterozygous familial hypercholesterolaemia the usual start dose is 5 mg daily.

• In children 6 to 9 years of age with heterozygous familial hypercholesterolaemia, the usual dose range is 5-10 mg orally once daily. Safety and efficacy of doses greater than 10 mg have not been studied in this population.
• In children 10 to 17 years of age with heterozygous familial hypercholesterolaemia, the usual dose range is 5-20 mg orally once daily. Safety and efficacy of doses greater than 20 mg have not been studied in this population.

Titration should be conducted according to the individual response and tolerability in paediatric patients, as recommended by the paediatric treatment recommendations (see section 4.4). Children and adolescents should be placed on standard cholesterol-lowering diet before rosuvastatin treatment initiation; this diet should be continued during rosuvastatin treatment.

Homozygous familial hypercholesterolaemia

In children 6 to 17 years of age with homozygous familial hypercholesterolaemia, the recommended maximum dose is 20 mg once daily.

A starting dose of 5 to 10 mg once daily depending on age, weight and prior statin use is advised. Titration to the maximum dose of 20 mg once daily should be conducted according to the individual response and tolerability in paediatric patients, as recommended by the paediatric treatment recommendations (see section 4.4). Children and adolescents should be placed on standard cholesterol-lowering diet before rosuvastatin treatment initiation; this diet should be continued during rosuvastatin treatment.

There is limited experience with doses other than 20 mg in this population.

The 40 mg tablet is not suitable for use in paediatric patients.

Children younger than 6 years

The safety and efficacy of use in children younger than 6 years has not been studied. Therefore, Revostat is not recommended for use in children younger than 6 years.

Use in the elderly

A start dose of 5 mg is recommended in patients>70 years. No other dose adjustment is necessary in relation to age.

Dosage in patients with renal insufficiency

No dose adjustment is necessary in patients with mild to moderate renal impairment. The recommended start dose is 5 mg in patients with moderate renal impairment (creatinine clearance <60 ml/min). The use of Revostat in patients with severe renal impairment is contraindicated for all doses.

Dosage in patients with hepatic impairment

There was no increase in systemic exposure to rosuvastatin in subjects with Child-Pugh scores of 7 or below. However, increased systemic exposure has been observed in subjects with Child-Pugh scores of 8 and 9 (see section 5.2). In these patients an assessment of renal function should be considered (see section 4.4). There is no experience in subjects with Child-Pugh scores above 9. Revostat is contraindicated in patients with active liver disease.

4.3 Contraindications

Contraindicated:

• Patients with hypersensitivity to rosuvastatin or to any of the excipients.
• Patients with active liver disease including unexplained, persistent elevations of serum transaminases and any serum transaminase elevation exceeding 3 times the upper limit of normal (ULN).
• Patients with severe renal impairment (creatinine clearance <30 ml/min).
• Patients with myopathy.
• Patients receiving concomitant combination of sofosbuvir/velpatasvir/voxilaprevir
• Patients receiving concomitant ciclosporin.
• Pregnancy and lactation and in women of childbearing potential not using appropriate contraceptive measures.

4.4 Special warnings and precautions for use

Renal Effects

Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients treated with higher doses of Revostat, in particular 40 mg, where it was transient or intermittent in most cases. Proteinuria has not been shown to be predictive of acute or progressive renal disease.The reporting rate for serious renal events in post-marketing use is higher at the 40 mg dose.

Skeletal Muscle Effects

Effects on skeletal muscle e.g. myalgia, myopathy and, rarely, rhabdomyolysis have been reported in Revostat-treated patients with all doses and in particular with doses > 20 mg. Very rare cases of rhabdomyolysis have been reported with the use of ezetimibe in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be excluded (see section 4.5) and caution should be exercised with their combined use. As with other HMG-CoA reductase inhibitors, the reporting rate for rhabdomyolysis associated with Revostat in post-marketing use is higher at the 40 mg dose.

Creatine Kinase Measurement

Creatine Kinase (CK) should not be measured following strenuous exercise or in the presence of a plausible alternative cause of CK increase which may confound interpretation of the result. If CK levels are significantly elevated at baseline (>5xULN) a confirmatory test should be carried out within 5 – 7 days. If the repeat test confirms a baseline CK >5xULN, treatment should not be started.

Before Treatment

Revostat, as with other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with pre-disposing factors for myopathy/rhabdomyolysis. Such factors include:

• renal impairment
• hypothyroidism
• personal or family history of hereditary muscular disorders
• previous history of muscular toxicity with another HMG-CoA reductase inhibitor or fibrate
• alcohol abuse
• age >70 years
• situations where an increase in plasma levels may occur
• concomitant use of fibrates.

In such patients the risk of treatment should be considered in relation to possible benefit and clinical monitoring is recommended. If CK levels are significantly elevated at baseline (>5xULN) treatment should not be started.

Whilst on Treatment

Patients should be asked to report inexplicable muscle pain, weakness or cramps immediately, particularly if associated with malaise or fever. CK levels should be measured in these patients. Therapy should be discontinued if CK levels are markedly elevated (>5xULN) or if muscular symptoms are severe and cause daily discomfort (even if CK levels are ≤ 5xULN). If symptoms resolve and CK levels return to normal, then consideration should be given to re-introducing Revostat or an alternative HMG-CoA reductase inhibitor at the lowest dose with close monitoring. Routine monitoring of CK levels in asymptomatic patients is not warranted. There have been very rare reports of an immune-mediated necrotising myopathy (IMNM) during or after treatment with statins, including rosuvastatin. IMNM is clinically characterised by proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment.

In few cases, statins have been reported to induce de novo or aggravate pre-existing myasthenia gravis or ocular myasthenia (see section 4.8). Revostat should be discontinued in case of aggravation of symptoms. Recurrences when the same or a different statin was (re-) administered have been reported.

In clinical trials, there was no evidence of increased skeletal muscle effects in the small number of patients dosed with Revostat and concomitant therapy. However, an increase in the incidence of myositis and myopathy has been seen in patients receiving other HMG-CoA reductase inhibitors together with fibric acid derivatives including gemfibrozil, ciclosporin, nicotinic acid, azole antifungals, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when given concomitantly with some HMG-CoA reductase inhibitors. Therefore, the combination of Revostat and gemfibrozil is not recommended. The benefit of further alterations in lipid levels by the combined use of Revostat with fibrates or niacin should be carefully weighed against the potential risks of such combinations.

Revostat must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination .Patients should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness. Statin therapy may be re-introduced seven days after the last dose of fusidic acid. In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g. for the treatment of severe infections, the need for co-administration of Revostat and fusidic acid should only be considered on a case by case basis and under close medical supervision.

Revostat should not be used in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g. sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders; or uncontrolled seizures).

Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which could be life-threatening or fatal, have been reported with rosuvastatin .At the time of prescription, patients should be advised of the signs and symptoms of severe skin reactions and be closely monitored. If signs and symptoms suggestive of this reaction appear, Revostat should be discontinued immediately and an alternative treatment should be considered.

If the patient has developed a serious reaction such as SJS or DRESS with the use of Revostat, treatment with Revostat must not be restarted in this patient at any time.

Liver Effects

As with other HMG-CoA reductase inhibitors, Revostat should be used with caution in patients who consume excessive quantities of alcohol and/or have a history of liver disease.

It is recommended that liver function tests be carried out prior to, and 3 months following, the initiation of treatment. Revostat should be discontinued or the dose reduced if the level of serum transaminases is greater than 3 times the upper limit of normal. The reporting rate for serious hepatic events (consisting mainly of increased hepatic transaminases) in post-marketing use is higher at the 40 mg dose.

In patients with secondary hypercholesterolaemia caused by hypothyroidism or nephrotic syndrome, the underlying disease should be treated prior to initiating therapy with Revostat.

Race

Pharmacokinetic studies show an increase in exposure in Asian subjects compared with Caucasians.

Protease Inhibitors

Increased systemic exposure to rosuvastatin has been observed in subjects receiving rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Consideration should be given both to the benefit of lipid lowering by use of Revostat in HIV patients receiving protease inhibitors and the potential for increased rosuvastatin plasma concentrations when initiating and up titrating Revostat doses in patients treated with protease inhibitors. The concomitant use with certain protease inhibitors is not recommended unless the dose of Revostat is adjusted.

Lactose Intolerance

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Interstitial Lung Disease

Exceptional cases of interstitial lung disease have been reported with some statins, especially with long-term therapy.Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

Diabetes Mellitus

Some evidence suggests that statins as a class raise blood glucose and in some patients, at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/l, BMI >30 kg/m2, raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.

In the JUPITER study, the reported overall frequency of diabetes mellitus was 2.8% in rosuvastatin and 2.3% in placebo, mostly in patients with fasting glucose 5.6 to 6.9 mmol/l.

Paediatric Population

The evaluation of linear growth (height), weight, BMI (body mass index), and secondary characteristics of sexual maturation by Tanner staging in paediatric patients 6 to 17 years of age taking rosuvastatin is limited to a two-year period. After two years of study treatment, no effect on growth, weight, BMI or sexual maturation was detected (see section 5.1).

In a clinical trial of children and adolescents receiving rosuvastatin for 52 weeks, CK elevations >10xULN and muscle symptoms following exercise or increased physical activity were observed more frequently compared to observations in clinical trials in adults.

4.5 Interaction with other medicinal products and other forms of interaction

Effect of co-administered medicinal products on rosuvastatin

Transporter protein inhibitors: Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake transporter OATP1B1 and efflux transporter BCRP. Concomitant administration of Revostat with medicinal products that are inhibitors of these transporter proteins may result in increased rosuvastatin plasma concentrations and an increased risk of myopathy

Ciclosporin: During concomitant treatment with Revostat and ciclosporin, rosuvastatin AUC values were on average 7 times higher than those observed in healthy volunteers (see Table 1). Revostat is contraindicated in patients receiving concomitant ciclosporin.Concomitant administration did not affect plasma concentrations of ciclosporin.

Protease inhibitors: Although the exact mechanism of interaction is unknown, concomitant protease inhibitor use may strongly increase rosuvastatin exposure. For instance, in a pharmacokinetic study, co-administration of 10 mg rosuvastatin and a combination product of two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers was associated with an approximately three-fold and seven-fold increase in rosuvastatin AUC and Cmax respectively. The concomitant use of Revostat and some protease inhibitor combinations may be considered after careful consideration of Revostat dose adjustments based on the expected increase in rosuvastatin exposure.

Gemfibrozil and other lipid-lowering products: Concomitant use of Revostat and gemfibrozil resulted in a 2-fold increase in rosuvastatin C_max and AUC.

Based on data from specific interaction studies no pharmacokinetic relevant interaction with fenofibrate is expected, however a pharmacodynamic interaction may occur. Gemfibrozil, fenofibrate, other fibrates and lipid lowering doses (> or equal to 1 g/day) of niacin (nicotinic acid) increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors, probably because they can produce myopathy when given alone. The 40 mg dose is contraindicated with concomitant use of a fibrate (see sections 4.3 and 4.4). These patients should also start with the 5 mg dose.

Ezetimibe: Concomitant use of 10 mg Revostat and 10 mg ezetimibe resulted in a 1.2-fold increase in AUC of rosuvastatin in hypercholesterolaemic subjects.A pharmacodynamic interaction, in terms of adverse effects, between Revostat and ezetimibe cannot be ruled out.

Antacid: The simultaneous dosing of Revostat with an antacid suspension containing aluminium and magnesium hydroxide resulted in a decrease in rosuvastatin plasma concentration of approximately 50%. This effect was mitigated when the antacid was dosed 2 hours after Revostat. The clinical relevance of this interaction has not been studied.

Erythromycin: Concomitant use of Revostat and erythromycin resulted in a 20% decrease in AUC and a 30% decrease in Cmax of rosuvastatin. This interaction may be caused by the increase in gut motility caused by erythromycin.

Ticagrelor: Ticagrelor might affect renal excretion of rosuvastatin, increasing the risk for rosuvastatin accumulation. Although the exact mechanism is not known, in some cases, concomitant use of ticagrelor and rosuvastatin led to renal function decrease, increased CPK level and rhabdomyolysis.

Cytochrome P450 enzymes: Results from in vitro and in vivo studies show that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a poor substrate for these isoenzymes. Therefore, drug interactions resulting from cytochrome P450-mediated metabolism are not expected. No clinically relevant interactions have been observed between rosuvastatin and either fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4).

Interactions requiring rosuvastatin dose adjustments (see also Table 1): When it is necessary to co-administer Revostat with other medicinal products known to increase exposure to rosuvastatin, doses of Revostat should be adjusted. Start with a 5 mg once daily dose of Revostat if the expected increase in exposure (AUC) is approximately 2-fold or higher. The maximum daily dose of Revostat should be adjusted so that the expected rosuvastatin exposure would not likely exceed that of a 40 mg daily dose of Revostat taken without interacting medicinal products, for example a 20 mg dose of Revostat with gemfibrozil (1.9-fold increase), and a 10 mg dose of Revostat with combination ritonavir/atazanavir (3.1-fold increase).

If medicinal product is observed to increase rosuvastatin AUC less than 2-fold, the starting dose need not be decreased but caution should be taken if increasing the Revostat dose above 20mg.

The following medical product/combinations did not have a clinically significant effect on the AUC ratio of rosuvastatin at coadministration:

Aleglitazar 0.3 mg 7 days dosing; Fenofibrate 67 mg 7 days TID dosing; Fluconazole 200mg 11 days OD dosing; Fosamprenavir 700 mg/ritonavir 100 mg 8 days BID dosing; Ketoconazole 200 mg 7 days BID dosing; Rifampin 450 mg 7 days OD dosing; Silymarin 140 mg 5 days TID dosing. Effect of rosuvastatin on co-administered medicinal products

Vitamin K antagonists: As with other HMG-CoA reductase inhibitors, the initiation of treatment or dosage up-titration of Revostat in patients treated concomitantly with vitamin K antagonists (e.g. warfarin or another coumarin anticoagulant) may result in an increase in International Normalised Ratio (INR). Discontinuation or down-titration of Revostat may result in a decrease in INR. In such situations, appropriate monitoring of INR is desirable.

Oral contraceptive/hormone replacement therapy (HRT): Concomitant use of Revostat and an oral contraceptive resulted in an increase in ethinyl estradiol and norgestrel AUC of 26% and 34%, respectively. These increased plasma levels should be considered when selecting oral contraceptive doses. There are no pharmacokinetic data available in subjects taking concomitant Revostat and HRT, therefore, a similar effect cannot be excluded. However, the combination has been extensively used in women in clinical trials and was well tolerated.

Other medicinal products:

Digoxin: Based on data from specific interaction studies no clinically relevant interaction with digoxin is expected.

Fusidic Acid: Interaction studies with rosuvastatin and fusidic acid have not been conducted. The risk of myopathy, including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. The mechanism of this interaction (whether it is pharmacodynamic or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination.

If treatment with systemic fusidic acid is necessary, Revostat treatment should be discontinued throughout the duration of the fusidic acid treatment. Also see section 4.4.

Paediatric population: Interaction studies have only been performed in adults. The extent of interactions in the paediatric population is not known.

4.6 Fertility, pregnancy and lactation

Revostat is contraindicated in pregnancy and lactation.

Women of child bearing potential should use appropriate contraceptive measures.

Since cholesterol and other products of cholesterol biosynthesis are essential for the development of the foetus, the potential risk from inhibition of HMG-CoA reductase outweighs the advantage of treatment during pregnancy. Animal studies provide limited evidence of reproductive toxicity . If a patient becomes pregnant during use of this product, treatment should be discontinued immediately.

Rosuvastatin is excreted in the milk of rats. There are no data with respect to excretion in milk in humans .

4.7 Effects on ability to drive and use machines

Studies to determine the effect of Revostat on the ability to drive and use machines have not been conducted. However, based on its pharmacodynamic properties, Revostat is unlikely to affect this ability. When driving vehicles or operating machines, it should be taken into account that dizziness may occur during treatment.

4.8 Undesirable effects

The adverse reactions seen with Revostat are generally mild and transient. In controlled clinical trials, less than 4% of Revostat-treated patients were withdrawn due to adverse reactions.

Tabulated list of adverse reactions Based on data from clinical studies and extensive post-marketing experience, the following table presents the adverse reaction profile for rosuvastatin. Adverse reactions listed below are classified according to frequency and system organ class (SOC).

The frequencies of adverse reactions are ranked according to the following convention: Common (≥ 1/100 to <1/10); Uncommon (≥ 1/1,000 to <1/100); Rare (≥ 1/10,000 to <1/1000); Very rare (<1/10,000); Not known (cannot be estimated from the available data).

Table 2. Adverse reactions based on data from clinical studies and post-marketing experience

As with other HMG-CoA reductase inhibitors, the incidence of adverse drug reactions tends to be dose dependent.

Renal effects: Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients treated with Revostat. Shifts in urine protein from none or trace to ++ or more were seen in <1% of patients at some time during treatment with 10 and 20 mg, and in approximately 3% of patients treated with 40 mg. A minor increase in shift from none or trace to + was observed with the 20 mg dose. In most cases, proteinuria decreases or disappears spontaneously on continued therapy. Review of data from clinical trials and post-marketing experience to date has not identified a causal association between proteinuria and acute or progressive renal disease.

Haematuria has been observed in patients treated with Revostat and clinical trial data show that the occurrence is low.

Skeletal muscle effects: Effects on skeletal muscle e.g. myalgia, myopathy (including myositis) and, rarely, rhabdomyolysis with and without acute renal failure have been reported in Revostat-treated patients with all doses and in particular with doses > 20 mg.

A dose-related increase in CK levels has been observed in patients taking rosuvastatin; the majority of cases were mild, asymptomatic and transient. If CK levels are elevated (>5xULN), treatment should be discontinued.

Liver effects: As with other HMG-CoA reductase inhibitors, a dose-related increase in transaminases has been observed in a small number of patients taking rosuvastatin; the majority of cases were mild, asymptomatic and transient.

The following adverse events have been reported with some statins:

Sexual dysfunction. Exceptional cases of interstitial lung disease, especially with long term therapy .

The reporting rates for rhabdomyolysis, serious renal events and serious hepatic events (consisting mainly of increased hepatic transaminases) is higher at the 40 mg dose.

Paediatric population: Creatine kinase elevations >10xULN and muscle symptoms following exercise or increased physical activity were observed more frequently in a 52-week clinical trial of children and adolescents compared to adults .In other respects, the safety profile of rosuvastatin was similar in children and adolescents compared to adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website: https://www.zuventus.com/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

There is no specific treatment in the event of overdose. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Liver function and CK levels should be monitored. Haemodialysis is unlikely to be of benefit.

5.1 Mechanism of action

Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor for cholesterol. The primary site of action of rosuvastatin is the liver, the target organ for cholesterol lowering.

Rosuvastatin increases the number of hepatic LDL receptors on the cell-surface, enhancing uptake and catabolism of LDL and it inhibits the hepatic synthesis of VLDL, thereby reducing the total number of VLDL and LDL particles.

5.2 Pharmacodynamic effects

Revostat reduces elevated LDL-cholesterol, total cholesterol and triglycerides and increases HDL-cholesterol. It also lowers ApoB, non-HDL-C, VLDL-C, VLDL-TG and increases ApoA-I (see Table 3). Revostat also lowers the LDL-C/HDL-C, total C/HDL-C and non-HDL-C/HDL-C and the ApoB/ApoA-I ratios.

Table 3 Dose response in patients with primary hypercholesterolaemia (type IIa and IIb) (adjusted mean percent change from baseline)

A therapeutic effect is obtained within 1 week following treatment initiation and 90% of maximum response is achieved in 2 weeks. The maximum response is usually achieved by 4 weeks and is maintained after that.

5.3 Pharmacokinetic properties

Absorption: Maximum rosuvastatin plasma concentrations are achieved approximately 5 hours after oral administration. The absolute bioavailability is approximately 20%.

Distribution: Rosuvastatin is taken up extensively by the liver which is the primary site of cholesterol synthesis and LDL-C clearance. The volume of distribution of rosuvastatin is approximately 134 L. Approximately 90% of rosuvastatin is bound to plasma proteins, mainly to albumin.

Metabolism: Rosuvastatin undergoes limited metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a poor substrate for cytochrome P450-based metabolism. CYP2C9 was the principal isoenzyme involved, with 2C19, 3A4 and 2D6 involved to a lesser extent. The main metabolites identified are the N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin whereas the lactone form is considered clinically inactive. Rosuvastatin accounts for greater than 90% of the circulating HMG-CoA reductase inhibitor activity.

Excretion: Approximately 90% of the rosuvastatin dose is excreted unchanged in the faeces (consisting of absorbed and non-absorbed active substance) and the remaining part is excreted in urine. Approximately 5% is excreted unchanged in urine. The plasma elimination half-life is approximately 19 hours. The elimination half-life does not increase at higher doses. The geometric mean plasma clearance is approximately 50 litres/hour (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, the hepatic uptake of rosuvastatin involves the membrane transporter OATP-C. This transporter is important in the hepatic elimination of rosuvastatin.

Linearity: Systemic exposure of rosuvastatin increases in proportion to dose. There are no changes in pharmacokinetic parameters following multiple daily doses.

6.1 Animal Toxicology or Pharmacology

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenicity potential. Specific tests for effects on hERG have not been evaluated. Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels were as follows: In repeated-dose toxicity studies histopathologic liver changes likely due to the pharmacologic action of rosuvastatin were observed in mouse, rat, and to a lesser extent with effects in the gall bladder in dogs, but not in monkeys. In addition, testicular toxicity was observed in monkeys and dogs at higher dosages. Reproductive toxicity was evident in rats, with reduced litter sizes, litter weight and pup survival observed at maternally toxic doses, where systemic exposures were several times above the therapeutic exposure level.

CRESTOR (rosuvastatin) is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA)-reductase inhibitor

Chemical Name: s bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino] pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]

Molecular Formula: (C22H27FN3O6S)2Ca a

Molecular Weight: 1,001.14.

Structure:

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

Refer on pack.

8.3 Packaging information

3 Blister strips of 10 tablets each

8.4 Storage and handing instructions

Store below 30°C. Protect from light & moisture.

Keep out of reach of children.

Patients should be instructed not to take 2 doses of rosuvastatin calcium within 12 hours of each other.

Skeletal Muscle Effects

Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing rosuvastatin calcium.

Concomitant Use of Antacids

When taking rosuvastatin calcium with an aluminum and magnesium hydroxide combination antacid, the antacid should be taken at least 2 hours after rosuvastatin calcium administration.

Embryo fetal Toxicity

Advise females of reproductive potential of the risk to a fetus, to use effective contraception during treatment, and to inform their healthcare provider of a known or suspected pregnancy.

Lactation

Advise women not to breastfeed during treatment with rosuvastatin

Liver Enzymes

It is recommended that liver enzyme tests be performed before the initiation of rosuvastatin calcium and if signs or symptoms of liver injury occur. All patients treated with rosuvastatin calcium should be advised to promptly report any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.

10th October 2024

Voglibose, Glimepiride & Metformin Hydrochloride (SR) tablets

Zuvog ^® Trio-1

Each uncoated bilayered tablet contains:

Voglibose IP........................................... 0.2mg

Glimepiride IP..........................................1mg

Metformin hydrochloride IP.................... 500mg

(in sustained release form)

Excipients q.s.

Colours: Quinoline Yellow Lake and Brilliant Blue

Zuvog ^® Trio-2

Each uncoated bilayered tablet contains:

Voglibose IP................................................ 0.2mg

Glimepiride IP............................................... 2mg

Metformin hydrochloride IP

(in sustained release form) ...........................500mg

Excipients q.s.

Colours: Quinoline Yellow Lake and Brilliant Blue

Tablets

Voglibose (0.2mg), Glimepiride IP 1mg/2mg, Metformin 500mg

4.1 Therapeutic Indication

As 3rd line treatment of type 2 diabetes mellitus when diet, exercise and the single agents and second line therapy with two drugs do not result in adequate glycemic control.

4.2 Posology and method of administration

The usual recommended dose for adults is one tablet of Zuvog ^® Trio-1/2, twice a day before meals.

Additionally, voglibose tablets may be taken before the remaining meal, as prescribed by the physician.

Special Populations:

Children

Data are insufficient to recommend pediatric use of Zuvog ® Trio-1/2.

Renal impairment

A GFR should be assessed before initiation of treatment with metformin containing products and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months. The maximum daily dose of metformin should preferably be divided into 2-3 daily doses. Factors that may increase the risk of lactic acidosis should be reviewed before considering initiation of metformin in patients with GFR<60 mL/min. If no adequate strength of Zuvog trio is available, individual mono components should be used instead of the fixed dose combination.

Method of administration

Due to sustained release formulation, Zuvog trio must be swallowed whole and not crushed or chewed.

4.3 Contraindications

• Patients hypersensitive to glimepiride, voglibose, metformin, other sulfonylureas, other sulfonamides, or any of the excipients
• Pregnant women
• Breast-feeding women
• Any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis, diabetic pre-coma).
• Severe renal failure (GFR˂ 30ml/min)
• Hepatic insufficiency
• Acute alcohol intoxication, alcoholism
• Severe infections, before or after operation or with severe trauma
• Gastrointestinal obstruction or predisposed to it
• Acute conditions with the potential to alter renal function such as:
  • dehydration
  • severe infection
  • shock
  • intravascular administration of iodinated contrast agents
• Acute or chronic disease which may cause tissue hypoxia such as:
  • cardiac or respiratory failure
  • recent myocardial infarction
  • shock

4.4 Special warnings and precautions for use

Warnings

Glimepiride: In exceptional stress situations (e.g. trauma, surgery, febrile infections) blood glucose regulation may deteriorate, and a temporary change to insulin may be necessary to maintain good metabolic control.

For Metformin:

Lactic acidosis: Metformin accumulation occurs at acute worsening of renal function and increases the risk of lactic acidosis. In case of dehydration (severe diarrhoea or vomiting, fever or reduced fluid intake), Metformin should be temporarily discontinued and contact with a health care professional is recommended. Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs) should be initiated with caution in metformin-treated patients. Diagnosis: Patients and/or care-givers should be informed of the risk of lactic acidosis. In case of suspected symptoms, the patient should stop taking metformin and seek immediate medical attention Diagnostic laboratory findings are decreased blood pH (˂7.35), plasma lactate levels (˃5 mmol/L), and an increased anion gap and lactate/pyruvate ratio.

Precautions

Zuvog trio should be administered carefully in patients who are receiving other antidiabetic drugs because hypoglycemia may occur.

For Glimepiride:

In the initial weeks of treatment, the risk of hypoglycaemia may be increased and necessitates especially careful monitoring. Factors favouring hypoglycaemia include:

• unwillingness or (more commonly in older patients) incapacity of the patient to cooperate.
• under nourishment, irregular mealtimes or skipped meals.
• imbalance between physical exertion and carbohydrate intake.
• alterations of diet.
• consumption of alcohol, especially in combination with skipped meals.
• impaired renal function.
• severe impairment of liver function.
• overdosage with glimepiride.
• certain uncompensated disorders of the endocrine system affecting carbohydrate metabolism or counter-regulation of hypoglycaemia (as for example in certain disorders of thyroid function and in anterior pituitary or cortico-adrenal insufficiency).
• concurrent administration of certain other medicines.
• treatment with glimepiride in the absence of any indication.

If such risk factors for hypoglycaemia are present, it may be necessary to adjust the dosage of glimepiride or the entire therapy. This also applies whenever illness occurs during therapy or the patient's life-style changes. Those symptoms of hypoglycaemia which reflect the body's adrenergic counter regulation may be milder or absent where hypoglycaemia develops gradually, in the elderly, and where there is autonomic neuropathy or where the patient is receiving concurrent treatment with beta-blockers, clonidine, reserpine, guanethidine or other sympatholytic drugs. Hypoglycaemia can almost always be promptly controlled by immediate intake of carbohydrates (glucose or sugar).

It is known from other sulfonylureas that, despite initially successful counter measures, hypoglycaemia may recur. Patients must, therefore, remain under close observation. Severe hypoglycaemia further requires immediate treatment and follow-up by a physician and, in some circumstances, in-patient hospital care. Treatment of patients with G6PD-deficiency with sulfonylurea agents can lead to haemolytic anaemia. Since glimepiride belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD-deficiency and a non-sulfonylurea alternative should be considered.

For Metformin:

Regular monitoring of thyroid-stimulating hormone (TSH) levels is recommended in patients with hypothyroidism. Long-term treatment with metformin has been associated with a decrease in vitamin B12 serum levels which may cause peripheral neuropathy. Monitoring of the vitamin B12 level is recommended.

Other precautions:

• All patients should continue their diet with a regular distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet.
• The usual laboratory tests for diabetes monitoring should be performed regularly.
• Metformin alone never causes hypoglycaemia, although caution is advised when it is used in combination with insulin or sulfonylureas.

Voglibose:

Voglibose should be administered with caution to the following patients: patients with history of laparotomy or ileus; patients with chronic intestinal disease accompanied by disturbance in digestion and absorption; patients with aggravating symptoms due to increased generation of intestinal gas (eg, Roemheld syndrome, severe hernia, and stenosis and ulcer of the large intestine) and patients with serious hepatic or renal disorders.

Other precautions

• All patients should continue their dietary restriction with a regular distribution of carbohydrate intake during the day. Overweight patients should continue their energy restricted diet.
• The usual laboratory tests for diabetes monitoring should be performed regularly.
• Patients should be instructed and explained to recognize hypoglycemic symptoms and its management.
• When patients with diabetes are exposed to unusual stress such as fever, trauma, infection, or surgery, a temporary loss of control of blood glucose may occur. At such times insulin therapy may be necessary for some time.

4.5 Drugs interactions

For Glimepiride:

Based on experience with glimepiride and on what is known of other sulfonylureas, the following interactions must be considered:

Glimepiride is metabolized by cytochrome P450 2C9 (CYP2C9). This should be taken into account when glimepiride is coadministered with inducers (e.g. rifampicin) or inhibitors (e.g. fluconazole) of CYP2C9. Potentiation of the blood-glucose-lowering effect and, thus, in some instances hypoglycaemia may occur when one of the following drugs is taken, for example: insulin and other oral antidiabetics; ACE inhibitors; anabolic steroids and male sex hormones; chloramphenicol; coumarin derivatives; cyclophosphamide; disopyramide; fenfluramine; fenyramidol; fibrates; fluoxetine; guanethidine; ifosfamide; MAO inhibitors; miconazole; fluconazole; paraaminosalicylic acid; pentoxifylline (high dose parenteral); phenylbutazone; azapropazone; oxyphenbutazone; probenecid; quinolones; salicylates; sulfinpyrazone; clarithromycin; sulfonamide antibiotics; tetracyclines; tritoqualine; trofosfamide. Weakening of the blood-glucose-lowering effect and, thus raised blood glucose levels may occur when one of the following drugs is taken, for example: acetazolamide; barbiturates; corticosteroids; diazoxide; diuretics; epinephrine (adrenaline) and other sympathomimetic agents; glucagon; laxatives (after protracted use); nicotinic acid (in high doses); oestrogens and progestogens; phenothiazines; phenytoin; rifampicin; thyroid hormones. H2 receptor antagonists, beta-blockers, clonidine and reserpine may lead to either potentiation or weakening of the blood glucose-lowering effect. Under the influence of sympatholytic drugs such as beta-blockers, clonidine, guanethidine and reserpine, the signs of adrenergic counter-regulation to hypoglycaemia may be reduced or absent. Both acute and chronic alcohol intake may potentiate or weaken the blood glucose-lowering action of glimepiride in an unpredictable fashion. The effect of coumarin derivatives may be potentiated or weakened.

Bile acid sequestrant: Colesevelam binds to glimepiride and reduces glimepiride absorption from the gastro-intestinal tract. No interaction was observed when glimepiride was taken at least 4 hours before colesevelam. Therefore glimepiride should be administered at least 4 hours prior to colesevelam

For Metformin:

Concomitant use not recommended:

Alcohol: Alcohol intoxication, particularly in case of fasting, malnutrition or hepatic insufficiency. Avoid consumption of alcohol and alcohol-containing medications.

Combinations requiring precautions for use:

Some medicinal products can adversely affect renal function which may increase the risk of lactic acidosis, e.g. NSAIDs, including selective cyclo-oxygenase (COX) II inhibitors, ACE inhibitors, angiotensin II receptor antagonists and diuretics, especially loop diuretics. When starting or using such products in combination with metformin, close monitoring of renal function is necessary. Glucocorticoids (systemic and local routes), beta-2-agonists and diuretics have intrinsic hyperglycaemic activity. Inform the patient and perform more frequent blood glucose monitoring, especially at the beginning of treatment. If necessary, adjust the dosage of the antidiabetic drug during therapy with the other drug and upon its discontinuation. ACE-inhibitors may decrease the blood glucose levels. If necessary, adjust the dosage of the antidiabetic drug during therapy with the other drug and upon its discontinuation.

Metformin may decrease the anticoagulant effect of phenprocoumon. Therefore, a close monitoring of the INR is recommended. Levothyroxine can reduce the hypoglycemic effect of metformin. Monitoring of blood glucose levels is recommended, especially when thyroid hormone therapy is initiated or stopped, and the dosage of metformin must be adjusted if necessary.

Organic cation transporters (OCT)

Metformin is a substrate of both transporters OCT1 and OCT2.

Co-administration of metformin with

• Inhibitors of OCT1 (such as verapamil) may reduce efficacy of metformin.
• Inducers of OCT1 (such as rifampicin) may increase gastrointestinal absorption and efficacy of metformin.
• Inhibitors of OCT2 (such as cimetidine, dolutegravir, ranolazine, trimethoprime, vandetanib, isavuconazole) may decrease the renal elimination of metformin and thus lead to an increase in metformin plasma concentration.
• Inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may alter efficacy and renal elimination of metformin.

Caution is therefore advised, especially in patients with renal impairment, when these drugs are co-administered with metformin, as metformin plasma concentration may increase. If needed, dose adjustment of metformin may be considered as OCT inhibitors/inducers may alter the efficacy of metformin

For Voglibose

When voglibose is used in combination with derivative(s) of sulfonylamide, sulfonylurea or biguanide, or with insulin, hypoglycemic symptoms may occur. Therefore, when used in combination with any of these drugs, care should be taken, such as starting the administration at a low dose. Voglibose does not affect the pharmacokinetics of warfarin, hence it can be safely administered along with warfarin.

4.6 Use in special populations

Pregnancy

Zuvog Trio must not be taken during pregnancy. Otherwise there is risk of harm to the child. The patient must change over to insulin during pregnancy.

Lactation

To prevent possible ingestion with the breast milk and possible harm to the child, Zuvog Trio must not be taken by breast-feeding women. If necessary the patient must change over to insulin, or must stop breast-feeding.

4.7 Effects on ability to drive and use machines

Alertness and reactions may be impaired due to hypo- or hyperglycemia, especially when beginning or after altering treatment or when Zuvog-TRIO is not taken regularly. This may, for example, affect the ability to drive or to operate machinery.

4.8 Undesirable effects

Zuvog Trio should be administered carefully in patients who are receiving other antidiabetic drugs because hypoglycemia may occur.

Glimepiride

Metabolism and nutrition disorders: As a result of the blood-glucose-lowering action of glimepiride, hypoglycaemia may occur, which may also be prolonged. Possible symptoms of hypoglycaemia include headache, ravenous hunger, nausea, vomiting, lassitude, sleepiness, disordered sleep, restlessness, aggressiveness, impaired concentration, impaired alertness and reactions, depression, confusion, speech disorders, aphasia, visual disorders, tremor, pareses, sensory disturbances, dizziness, helplessness, loss of self-control, delirium, cerebral convulsions, somnolence and loss of consciousness up to and including coma, shallow respiration and bradycardia. In addition, signs of adrenergic counter-regulation may be present such as sweating, clammy skin, anxiety, tachycardia, hypertension, palpitations, angina pectoris, and cardiac arrhythmias. The clinical picture of a severe hypoglycaemic attack may resemble that of a stroke. The symptoms nearly always subside when hypoglycaemia is corrected; Eye disorders: Especially at the start of treatment, there may be temporary visual impairment due to the change in blood glucose levels. The cause is a temporary alteration in the turgidity and hence the refractive index of the lens, this being dependent on blood glucose level; Gastrointestinal disorders: Occasionally, gastrointestinal symptoms such as nausea, vomiting, sensations of pressure or fulness in the epigastrium, abdominal pain and diarrhoea may occur. In isolated cases, there may be hepatitis, elevation of liver enzyme levels and/or cholestasis and jaundice, which may progress to life-threatening liver failure but can regress after withdrawal of glimepiride, dysgeusia (frequency not known); Blood and lymphatic system disorders: Changes in the blood picture may occur: Rarely, thrombocytopenia and, in isolated cases, leucopenia, haemolytic anaemia, erythrocytopenia, granulocytopenia, agranulocytosis or pancytopenia may develop. Cases of severe thrombocytopenia with platelet count less than 10,000/μl and thrombocytopenic purpura have been reported in post-marketing experience (frequency not known); Skin and subcutaneous tissue disorders:Alopecia (frequency not known); General disorders: Occasionally, allergic or pseudoallergic reactions may occur, e.g. in the form of itching, urticaria or rashes. Such mild reactions may develop into serious reactions with dyspnoea and a fall in blood pressure, sometimes progressing to shock. In the event of urticaria a physician must therefore be notified immediately. In isolated cases, a decrease in serum sodium concentration and allergic vasculitis or hypersensitivity of the skin to light may occur.

For Metformin:

Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite (>10%) are very common: these occur most frequently during initiation of therapy and resolve spontaneously in most cases. To prevent these gastrointestinal symptoms, it is recommended that metformin be taken in 2 or 3 daily doses during or after meals. A slow increase of the dose may also improve gastrointestinal tolerability.

• Metallic taste (3%) is common.
• Mild erythema has been reported in some hypersensitive individuals. The incidence of such effects is regarded as very rare (<0.01%).
• A decrease of vitamin B12 absorption with decrease of serum levels has been observed in patients treated long-term with metformin and appears generally to be without clinical significance (<0.01%).
• However, cases of peripheral neuropathy in patients with vitamin B12 deficiency have been reported in post-marketing experience (frequency not known) • Lactic acidosis (0.03 cases/1000 patient-years) is very rare.
• Hemolytic anemia (frequency unknown)
• Reduction of thyrotropin level in patients with hypothyroidism (frequency unknown)
• Hypomagnesemia in the context of diarrhea (frequency unknown)
• Encephalopathy (frequency unknown)
• Photosensitivity (frequency unknown)
• Hepatobiliary disorders: Reports of liver function tests abnormalities and hepatitis resolving upon metformin discontinuation

For Voglibose:

Gastrointestinal adverse effects such as diarrhoea, loose stools, abdominal pain, constipation, anorexia, nausea, vomiting, or heartburn may occur with the use of Voglibose. Also abdominal distention, increased flatus, and intestinal obstruction like symptoms due to an increase in intestinal gas, may occur with use of Voglibose.

When Voglibose is administered to patients with serious liver cirrhosis, hyperammonia may worsen with the development of constipation followed by disturbance of consciousness. Elevation of GOT (glutamate oxaloacetate), GPT (glutamatepyruvate transaminase), LDH (lactate dehydrogenase), alpha GPT (alpha glutamate pyruvate) or alkaline phosphatase may infrequently occur. When Voglibose is used in combination with other antidiabetic drugs, hypoglycemia may occur (0.1% to <5%).

Hypersensitivity: Rash and pruritus may rarely occur. In such a case, Voglibose tablets should be discontinued.

Psychoneurologic: Headache may rarely occur.

Hematologic: Anemia; thrombocytopenia, and leucopenia may rarely occur.

Others: Numbness, edema of face, blurred vision, hot flushes, malaise, weakness, hyperkalemia, increased serum amylase, decreased HDL cholesterol, diaphoresis or alopecia, and perspiration.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website: https://www.zuventus.com/drug-safety-reporting

4.9 Overdose

For Glimepiride:

Signs and Symptoms: Acute overdosage as well as long-term treatment with too high a dose of glimepiride may lead to severe life-threatening hypoglycaemia. Management: As soon as an overdose of glimepiride has been discovered, a physician must be notified without delay. The patient must immediately take sugar, if possible in the form of glucose, unless a physician has already undertaken responsibility for treating the overdose. Careful monitoring is essential until the physician is confident that the patient is out of danger. It must be remembered that hypoglycaemia may recur after initial recovery. Admission to hospital may sometimes be necessary - even as a precautionary measure. In particular, significant overdoses and severe reactions with signs such as loss of consciousness or other serious neurological disorders are medical emergencies and require immediate treatment and admission to hospital. If, for example, the patient is unconscious, an intravenous injection of concentrated glucose

solution is indicated (for adults starting with 40 ml of 20% solution, for example). Alternatively, in adults, administration of glucagon, e.g. in doses of 0.5 to 1 mg i.v., s.c. or i.m. may be considered. In particular, when treating hypoglycaemia due to accidental intake of glimepiride in infants and young children, the dose of glucose given must be very carefully adjusted in view of the possibility of producing dangerous hyperglycaemia, and must be controlled by close monitoring of blood glucose. Patients who have ingested life-threatening amounts of glimepiride require detoxification (e.g. by gastric lavage and medicinal charcoal).

After acute glucose replacement has been completed it is usually necessary to give an intravenous glucose infusion in lower concentration so as to ensure that the hypoglycaemia does not recur. The patient's blood glucose level should be carefully monitored for at least 24 hours. In severe cases with a protracted course, hypoglycaemia, or the danger of slipping back into hypoglycaemia, may persist for several days.

Metformin: Hypoglycaemia has not been seen with metformin doses of up to 85 g, although lactic acidosis has occurred in such circumstances. High overdose or concomitant risks of metformin may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in hospital. The most effective method to remove lactate and metformin is haemodialysis. Pancreatitis may occur in the context of a metformin overdose

Voglibose: Voglibose competitively and reversibly inhibits the alpha glucosidase enzymes (glucoamylase, sucrase, maltase and isomaltase) in the brush border in the small intestine, which delays the hydrolysis of complex carbohydrates. It is unlikely to produce hypoglycemia in overdose, but abdominal discomfort and diarrhea may occur.

5.1 Mechanism of Action

The administration of vildagliptin results in a rapid and complete inhibition of DPP-4 activity, resulting in increased fasting and postprandial endogenous levels of the incretin hormones GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide).

5.2 Pharmacodynamic properties

Voglibose

Voglibose is an alpha glucosidase inhibitor which inhibits the activity of alpha glucosidases that catalyse the decomposition of disaccharides into monosaccharides in the intestine, thereby delaying the digestion and absorption of carbohydrates, resulting in improvement of postprandial hyperglycaemia.

Metformin hydrochloride

Metformin improves glucose tolerance in patients with type 2 diabetes (NIDDM), lowering both basal and postprandial plasma glucose. Metformin is not chemically or pharmacologically related to sulphonylureas, thiazolidinediones, or alpha-glucosidase inhibitors. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulphonylureas, metformin does not produce hypoglycaemia in either patients with type 2 diabetes or normal subjects and does not cause hyperinsulinaemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

Glimepiride

Glimepiride is an orally active hypoglycaemic substance belonging to the sulphonylurea group. It may be used in non-insulin dependent (type 2) diabetes mellitus.

Glimepiride acts mainly by stimulating insulin release from pancreatic beta cells. As with other sulfonylureas this effect is based on an increase of responsiveness of the pancreatic beta cells to the physiological glucose stimulus. In addition, glimepiride seems to have pronounced extrapancreatic effects also postulated for other sulfonylureas.

5.3 Pharmacokinetic properties

Absorption& Distribution

Voglibose

Voglibose is poorly absorbed after oral doses. Plasma concentrations after oral doses have usually been undetectable. After an 80 mg dose (substantially higher than recommended dose), peak plasma levels of about 20 ng/mL were observed in 1-1.5 hours.

Metformin Hydrochloride

The absolute bioavailability of a metformin 500-mg tablet given under fasting conditions is approximately 50-60%. Studies using single oral doses of metformin 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35 minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850-mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.

The apparent volume of distribution (V/F) of metformin following single oral doses of metformin immediate-release 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulphonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metforminimmediate-release, steady state plasma concentrations of metformin are reached within 24-48 hours and are generally <1 µg/mL.

Glimepiride

The bioavailability of glimepiride after oral administration is complete. Food intake has no relevant influence on absorption, only the absorption rate is slightly diminished. Maximum serum concentrations (Cmax) are reached approx 2.5 hours after oral intake (mean 0.3 μg/ml during multiple dosing of 4 mg/daily) and there is a linear relationship between dose and both Cmax and AUC (area under the time concentration curve).

Glimepiride has a very low distribution volume (approx. 8.8 litres), which is roughly equal to the albumin distribution space, high protein binding (>99%) and a low clearance (approx. 48 ml/min).

Metabolism & Excretion

Voglibose

Voglibose is metabolized negligibly and rapidly excreted. When voglibose tablets were repeatedly administered to healthy male adults in a single dose of 0.2 mg, three times a day, for 7 consecutive days, voglibose was not detected in plasma or urine. Also, on administration of voglibose to 10 healthy male subjects in a single dose of 2 mg, voglibose was not detected in plasma or urine.

Metformin Hydrochloride

Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance of metformin is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Mean dominant serum half-life, which is of relevance for the serum concentrations under multiple-dose conditions, is about 5 to 8 hours. After high doses, slightly longer half-lives were noted.

Glimepiride

After a single dose of radiolabelled glimepiride, 58% of the radioactivity was recovered in the urine, and 35% in the faeces. No unchanged substance was detected in the urine. Two metabolites most probably resulting from hepatic metabolism (major enzyme is CYP2C9) were identified both in urine and faeces: the hydroxy derivative and the carboxy derivative. After oral administration of glimepiride, the terminal half-lives of these metabolites were 3 to 6 and 5 to 6 hours respectively.

Comparison of single and multiple once-daily dosing revealed no significant differences in pharmacokinetics, and the intra individual variability was very low. There was no relevant accumulation.

6.1 Animal Toxicology or Pharmacology

Not available

Glimepiride

Glimepiride is a long-acting, third-generation sulfonylurea with hypoglycemic activity. Compared to other generations of sulfonylurea compounds, glimepiride is very potent and has a longer duration of action.

Chemical Name - 4-ethyl-3-methyl-N-[2-[4-[(4 methylcyclohexyl)carbamoylsulfamoyl]phenyl]ethyl]-5-oxo-2Hpyrrole-1-carboxamide

Molecular Weight- 490.6 g/mol

Molecular Formula- C₂₄H₃₄N₄O₅S

Metformin

Metformin is an agent belonging to the biguanide class of antidiabetics with anti-hyperglycemic activity. Metformin is associated with a very low incidence of lactic acidosis

Chemical Name - 3-(diaminomethylidene)-1,1-dimethylguanidine

Molecular Weight- 129.16 g/mol

Molecular Formula- C₄H₁₁N₅

Structure-

Voglibose

Voglibose is an alpha-glucosidase inhibitor used for lowering post-prandial blood glucose levels in people with diabetes mellitus.

Chemical Name - (1S,2S,3R,4S,5S)-5-(1,3-dihydroxypropan-2-ylamino)-1- (hydroxymethyl)cyclohexane-1,2,3,4-tetrol

Molecular Weight- 267.28 g/mol

Molecular Formula- C₁₀H₂₁NO₇

Structure:

8.1 Incompatibilities

None

8.2 Shelf-life

Refer on pack.

8.3 Packaging information

10 tablets in each blister strip

8.4 Storage and handing instructions

Store protect from moisture, at a temperature not exceeding 25°C.

Keep out of reach of children.

Hypoglycemia

Explain the symptoms and treatment of hypoglycemia as well as conditions that predispose to hypoglycemia. Inform patients that their ability to concentrate and react may be impaired as a result of hypoglycemia and that this may present a risk in situations where these abilities are especially important, such as driving or operating other machinery.

Hypersensitivity Reactions

Inform patients that hypersensitivity reactions may occur with glimepiride tablets and that if a reaction occurs to seek medical treatment and discontinue glimepiride tablets.

Pregnancy

Advise females of reproductive potential to inform their prescriber of a known or suspected pregnancy.

Lactation

Advise breastfeeding women taking glimepiride tablets to monitor breastfed infants for signs of hypoglycemia (e.g., jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, seizures).

Lactic Acidosis

Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its development. Advise patients to discontinue metformin hydrochloride extended-release tablets immediately and to promptly notify their healthcare provider if unexplained hyperventilation, myalgias, malaise, unusual somnolence or other nonspecific symptoms occur. Counsel patients against excessive alcohol intake and inform patients about importance of regular testing of renal function while receiving metformin hydrochloride extended-release tablets. Instruct patients to inform their doctor that they are taking metformin hydrochloride extended-release tablets prior to any surgical or radiological procedure, as temporary discontinuation may be required.

Vitamin B12 Deficiency

Inform patients about importance of regular haematological parameters while receiving metformin hydrochloride extended-release tablets.

Females of Reproductive Age:

Inform females that treatment with metformin hydrochloride extended-release tablets may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy.

Metformin SR Tablets Administration Information:

Inform patients that metformin SR tablets must be swallowed whole and not crushed, cut, or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.

14/10/2024

Voglibose, Glimepiride & Metformin Hydrochloride (SR) tablets

Zuvog ^® Trio-1

Each uncoated bilayered tablet contains:

Voglibose IP........................................... 0.2mg

Glimepiride IP..........................................1mg

Metformin hydrochloride IP.................... 500mg

(in sustained release form)

Excipients q.s.

Colours: Quinoline Yellow Lake and Brilliant Blue

Zuvog ^® Trio-2

Each uncoated bilayered tablet contains:

Voglibose IP................................................ 0.2mg

Glimepiride IP............................................... 2mg

Metformin hydrochloride IP

(in sustained release form) ...........................500mg

Excipients q.s.

Colours: Quinoline Yellow Lake and Brilliant Blue

Tablets

Voglibose (0.2mg), Glimepiride IP 1mg/2mg, Metformin 500mg

4.1 Therapeutic Indication

As 3rd line treatment of type 2 diabetes mellitus when diet, exercise and the single agents and second line therapy with two drugs do not result in adequate glycemic control.

4.2 Posology and method of administration

The usual recommended dose for adults is one tablet of Zuvog ^® Trio-1/2, twice a day before meals.

Additionally, voglibose tablets may be taken before the remaining meal, as prescribed by the physician.

Special Populations:

Children

Data are insufficient to recommend pediatric use of Zuvog ® Trio-1/2.

Renal impairment

A GFR should be assessed before initiation of treatment with metformin containing products and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months. The maximum daily dose of metformin should preferably be divided into 2-3 daily doses. Factors that may increase the risk of lactic acidosis should be reviewed before considering initiation of metformin in patients with GFR<60 mL/min. If no adequate strength of Zuvog trio is available, individual mono components should be used instead of the fixed dose combination.

Method of administration

Due to sustained release formulation, Zuvog trio must be swallowed whole and not crushed or chewed.

4.3 Contraindications

• Patients hypersensitive to glimepiride, voglibose, metformin, other sulfonylureas, other sulfonamides, or any of the excipients
• Pregnant women
• Breast-feeding women
• Any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis, diabetic pre-coma).
• Severe renal failure (GFR˂ 30ml/min)
• Hepatic insufficiency
• Acute alcohol intoxication, alcoholism
• Severe infections, before or after operation or with severe trauma
• Gastrointestinal obstruction or predisposed to it
• Acute conditions with the potential to alter renal function such as:
  • dehydration
  • severe infection
  • shock
  • intravascular administration of iodinated contrast agents
• Acute or chronic disease which may cause tissue hypoxia such as:
  • cardiac or respiratory failure
  • recent myocardial infarction
  • shock

4.4 Special warnings and precautions for use

Warnings

Glimepiride: In exceptional stress situations (e.g. trauma, surgery, febrile infections) blood glucose regulation may deteriorate, and a temporary change to insulin may be necessary to maintain good metabolic control.

For Metformin:

Lactic acidosis: Metformin accumulation occurs at acute worsening of renal function and increases the risk of lactic acidosis. In case of dehydration (severe diarrhoea or vomiting, fever or reduced fluid intake), Metformin should be temporarily discontinued and contact with a health care professional is recommended. Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs) should be initiated with caution in metformin-treated patients. Diagnosis: Patients and/or care-givers should be informed of the risk of lactic acidosis. In case of suspected symptoms, the patient should stop taking metformin and seek immediate medical attention Diagnostic laboratory findings are decreased blood pH (˂7.35), plasma lactate levels (˃5 mmol/L), and an increased anion gap and lactate/pyruvate ratio.

Precautions

Zuvog trio should be administered carefully in patients who are receiving other antidiabetic drugs because hypoglycemia may occur.

For Glimepiride:

In the initial weeks of treatment, the risk of hypoglycaemia may be increased and necessitates especially careful monitoring. Factors favouring hypoglycaemia include:

• unwillingness or (more commonly in older patients) incapacity of the patient to cooperate.
• under nourishment, irregular mealtimes or skipped meals.
• imbalance between physical exertion and carbohydrate intake.
• alterations of diet.
• consumption of alcohol, especially in combination with skipped meals.
• impaired renal function.
• severe impairment of liver function.
• overdosage with glimepiride.
• certain uncompensated disorders of the endocrine system affecting carbohydrate metabolism or counter-regulation of hypoglycaemia (as for example in certain disorders of thyroid function and in anterior pituitary or cortico-adrenal insufficiency).
• concurrent administration of certain other medicines.
• treatment with glimepiride in the absence of any indication.

If such risk factors for hypoglycaemia are present, it may be necessary to adjust the dosage of glimepiride or the entire therapy. This also applies whenever illness occurs during therapy or the patient's life-style changes. Those symptoms of hypoglycaemia which reflect the body's adrenergic counter regulation may be milder or absent where hypoglycaemia develops gradually, in the elderly, and where there is autonomic neuropathy or where the patient is receiving concurrent treatment with beta-blockers, clonidine, reserpine, guanethidine or other sympatholytic drugs. Hypoglycaemia can almost always be promptly controlled by immediate intake of carbohydrates (glucose or sugar).

It is known from other sulfonylureas that, despite initially successful counter measures, hypoglycaemia may recur. Patients must, therefore, remain under close observation. Severe hypoglycaemia further requires immediate treatment and follow-up by a physician and, in some circumstances, in-patient hospital care. Treatment of patients with G6PD-deficiency with sulfonylurea agents can lead to haemolytic anaemia. Since glimepiride belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD-deficiency and a non-sulfonylurea alternative should be considered.

For Metformin:

Regular monitoring of thyroid-stimulating hormone (TSH) levels is recommended in patients with hypothyroidism. Long-term treatment with metformin has been associated with a decrease in vitamin B12 serum levels which may cause peripheral neuropathy. Monitoring of the vitamin B12 level is recommended.

Other precautions:

• All patients should continue their diet with a regular distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet.
• The usual laboratory tests for diabetes monitoring should be performed regularly.
• Metformin alone never causes hypoglycaemia, although caution is advised when it is used in combination with insulin or sulfonylureas.

Voglibose:

Voglibose should be administered with caution to the following patients: patients with history of laparotomy or ileus; patients with chronic intestinal disease accompanied by disturbance in digestion and absorption; patients with aggravating symptoms due to increased generation of intestinal gas (eg, Roemheld syndrome, severe hernia, and stenosis and ulcer of the large intestine) and patients with serious hepatic or renal disorders.

Other precautions

• All patients should continue their dietary restriction with a regular distribution of carbohydrate intake during the day. Overweight patients should continue their energy restricted diet.
• The usual laboratory tests for diabetes monitoring should be performed regularly.
• Patients should be instructed and explained to recognize hypoglycemic symptoms and its management.
• When patients with diabetes are exposed to unusual stress such as fever, trauma, infection, or surgery, a temporary loss of control of blood glucose may occur. At such times insulin therapy may be necessary for some time.

4.5 Drugs interactions

For Glimepiride:

Based on experience with glimepiride and on what is known of other sulfonylureas, the following interactions must be considered:

Glimepiride is metabolized by cytochrome P450 2C9 (CYP2C9). This should be taken into account when glimepiride is coadministered with inducers (e.g. rifampicin) or inhibitors (e.g. fluconazole) of CYP2C9. Potentiation of the blood-glucose-lowering effect and, thus, in some instances hypoglycaemia may occur when one of the following drugs is taken, for example: insulin and other oral antidiabetics; ACE inhibitors; anabolic steroids and male sex hormones; chloramphenicol; coumarin derivatives; cyclophosphamide; disopyramide; fenfluramine; fenyramidol; fibrates; fluoxetine; guanethidine; ifosfamide; MAO inhibitors; miconazole; fluconazole; paraaminosalicylic acid; pentoxifylline (high dose parenteral); phenylbutazone; azapropazone; oxyphenbutazone; probenecid; quinolones; salicylates; sulfinpyrazone; clarithromycin; sulfonamide antibiotics; tetracyclines; tritoqualine; trofosfamide. Weakening of the blood-glucose-lowering effect and, thus raised blood glucose levels may occur when one of the following drugs is taken, for example: acetazolamide; barbiturates; corticosteroids; diazoxide; diuretics; epinephrine (adrenaline) and other sympathomimetic agents; glucagon; laxatives (after protracted use); nicotinic acid (in high doses); oestrogens and progestogens; phenothiazines; phenytoin; rifampicin; thyroid hormones. H2 receptor antagonists, beta-blockers, clonidine and reserpine may lead to either potentiation or weakening of the blood glucose-lowering effect. Under the influence of sympatholytic drugs such as beta-blockers, clonidine, guanethidine and reserpine, the signs of adrenergic counter-regulation to hypoglycaemia may be reduced or absent. Both acute and chronic alcohol intake may potentiate or weaken the blood glucose-lowering action of glimepiride in an unpredictable fashion. The effect of coumarin derivatives may be potentiated or weakened.

Bile acid sequestrant: Colesevelam binds to glimepiride and reduces glimepiride absorption from the gastro-intestinal tract. No interaction was observed when glimepiride was taken at least 4 hours before colesevelam. Therefore glimepiride should be administered at least 4 hours prior to colesevelam

For Metformin:

Concomitant use not recommended:

Alcohol: Alcohol intoxication, particularly in case of fasting, malnutrition or hepatic insufficiency. Avoid consumption of alcohol and alcohol-containing medications.

Combinations requiring precautions for use:

Some medicinal products can adversely affect renal function which may increase the risk of lactic acidosis, e.g. NSAIDs, including selective cyclo-oxygenase (COX) II inhibitors, ACE inhibitors, angiotensin II receptor antagonists and diuretics, especially loop diuretics. When starting or using such products in combination with metformin, close monitoring of renal function is necessary. Glucocorticoids (systemic and local routes), beta-2-agonists and diuretics have intrinsic hyperglycaemic activity. Inform the patient and perform more frequent blood glucose monitoring, especially at the beginning of treatment. If necessary, adjust the dosage of the antidiabetic drug during therapy with the other drug and upon its discontinuation. ACE-inhibitors may decrease the blood glucose levels. If necessary, adjust the dosage of the antidiabetic drug during therapy with the other drug and upon its discontinuation.

Metformin may decrease the anticoagulant effect of phenprocoumon. Therefore, a close monitoring of the INR is recommended. Levothyroxine can reduce the hypoglycemic effect of metformin. Monitoring of blood glucose levels is recommended, especially when thyroid hormone therapy is initiated or stopped, and the dosage of metformin must be adjusted if necessary.

Organic cation transporters (OCT)

Metformin is a substrate of both transporters OCT1 and OCT2.

Co-administration of metformin with

• Inhibitors of OCT1 (such as verapamil) may reduce efficacy of metformin.
• Inducers of OCT1 (such as rifampicin) may increase gastrointestinal absorption and efficacy of metformin.
• Inhibitors of OCT2 (such as cimetidine, dolutegravir, ranolazine, trimethoprime, vandetanib, isavuconazole) may decrease the renal elimination of metformin and thus lead to an increase in metformin plasma concentration.
• Inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may alter efficacy and renal elimination of metformin.

Caution is therefore advised, especially in patients with renal impairment, when these drugs are co-administered with metformin, as metformin plasma concentration may increase. If needed, dose adjustment of metformin may be considered as OCT inhibitors/inducers may alter the efficacy of metformin

For Voglibose

When voglibose is used in combination with derivative(s) of sulfonylamide, sulfonylurea or biguanide, or with insulin, hypoglycemic symptoms may occur. Therefore, when used in combination with any of these drugs, care should be taken, such as starting the administration at a low dose. Voglibose does not affect the pharmacokinetics of warfarin, hence it can be safely administered along with warfarin.

4.6 Use in special populations

Pregnancy

Zuvog Trio must not be taken during pregnancy. Otherwise there is risk of harm to the child. The patient must change over to insulin during pregnancy.

Lactation

To prevent possible ingestion with the breast milk and possible harm to the child, Zuvog Trio must not be taken by breast-feeding women. If necessary the patient must change over to insulin, or must stop breast-feeding.

4.7 Effects on ability to drive and use machines

Alertness and reactions may be impaired due to hypo- or hyperglycemia, especially when beginning or after altering treatment or when Zuvog-TRIO is not taken regularly. This may, for example, affect the ability to drive or to operate machinery.

4.8 Undesirable effects

Zuvog Trio should be administered carefully in patients who are receiving other antidiabetic drugs because hypoglycemia may occur.

Glimepiride

Metabolism and nutrition disorders: As a result of the blood-glucose-lowering action of glimepiride, hypoglycaemia may occur, which may also be prolonged. Possible symptoms of hypoglycaemia include headache, ravenous hunger, nausea, vomiting, lassitude, sleepiness, disordered sleep, restlessness, aggressiveness, impaired concentration, impaired alertness and reactions, depression, confusion, speech disorders, aphasia, visual disorders, tremor, pareses, sensory disturbances, dizziness, helplessness, loss of self-control, delirium, cerebral convulsions, somnolence and loss of consciousness up to and including coma, shallow respiration and bradycardia. In addition, signs of adrenergic counter-regulation may be present such as sweating, clammy skin, anxiety, tachycardia, hypertension, palpitations, angina pectoris, and cardiac arrhythmias. The clinical picture of a severe hypoglycaemic attack may resemble that of a stroke. The symptoms nearly always subside when hypoglycaemia is corrected; Eye disorders: Especially at the start of treatment, there may be temporary visual impairment due to the change in blood glucose levels. The cause is a temporary alteration in the turgidity and hence the refractive index of the lens, this being dependent on blood glucose level; Gastrointestinal disorders: Occasionally, gastrointestinal symptoms such as nausea, vomiting, sensations of pressure or fulness in the epigastrium, abdominal pain and diarrhoea may occur. In isolated cases, there may be hepatitis, elevation of liver enzyme levels and/or cholestasis and jaundice, which may progress to life-threatening liver failure but can regress after withdrawal of glimepiride, dysgeusia (frequency not known); Blood and lymphatic system disorders: Changes in the blood picture may occur: Rarely, thrombocytopenia and, in isolated cases, leucopenia, haemolytic anaemia, erythrocytopenia, granulocytopenia, agranulocytosis or pancytopenia may develop. Cases of severe thrombocytopenia with platelet count less than 10,000/μl and thrombocytopenic purpura have been reported in post-marketing experience (frequency not known); Skin and subcutaneous tissue disorders:Alopecia (frequency not known); General disorders: Occasionally, allergic or pseudoallergic reactions may occur, e.g. in the form of itching, urticaria or rashes. Such mild reactions may develop into serious reactions with dyspnoea and a fall in blood pressure, sometimes progressing to shock. In the event of urticaria a physician must therefore be notified immediately. In isolated cases, a decrease in serum sodium concentration and allergic vasculitis or hypersensitivity of the skin to light may occur.

For Metformin:

Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite (>10%) are very common: these occur most frequently during initiation of therapy and resolve spontaneously in most cases. To prevent these gastrointestinal symptoms, it is recommended that metformin be taken in 2 or 3 daily doses during or after meals. A slow increase of the dose may also improve gastrointestinal tolerability.

• Metallic taste (3%) is common.
• Mild erythema has been reported in some hypersensitive individuals. The incidence of such effects is regarded as very rare (<0.01%).
• A decrease of vitamin B12 absorption with decrease of serum levels has been observed in patients treated long-term with metformin and appears generally to be without clinical significance (<0.01%).
• However, cases of peripheral neuropathy in patients with vitamin B12 deficiency have been reported in post-marketing experience (frequency not known) • Lactic acidosis (0.03 cases/1000 patient-years) is very rare.
• Hemolytic anemia (frequency unknown)
• Reduction of thyrotropin level in patients with hypothyroidism (frequency unknown)
• Hypomagnesemia in the context of diarrhea (frequency unknown)
• Encephalopathy (frequency unknown)
• Photosensitivity (frequency unknown)
• Hepatobiliary disorders: Reports of liver function tests abnormalities and hepatitis resolving upon metformin discontinuation

For Voglibose:

Gastrointestinal adverse effects such as diarrhoea, loose stools, abdominal pain, constipation, anorexia, nausea, vomiting, or heartburn may occur with the use of Voglibose. Also abdominal distention, increased flatus, and intestinal obstruction like symptoms due to an increase in intestinal gas, may occur with use of Voglibose.

When Voglibose is administered to patients with serious liver cirrhosis, hyperammonia may worsen with the development of constipation followed by disturbance of consciousness. Elevation of GOT (glutamate oxaloacetate), GPT (glutamatepyruvate transaminase), LDH (lactate dehydrogenase), alpha GPT (alpha glutamate pyruvate) or alkaline phosphatase may infrequently occur. When Voglibose is used in combination with other antidiabetic drugs, hypoglycemia may occur (0.1% to <5%).

Hypersensitivity: Rash and pruritus may rarely occur. In such a case, Voglibose tablets should be discontinued.

Psychoneurologic: Headache may rarely occur.

Hematologic: Anemia; thrombocytopenia, and leucopenia may rarely occur.

Others: Numbness, edema of face, blurred vision, hot flushes, malaise, weakness, hyperkalemia, increased serum amylase, decreased HDL cholesterol, diaphoresis or alopecia, and perspiration.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website: https://www.zuventus.com/drug-safety-reporting

4.9 Overdose

For Glimepiride:

Signs and Symptoms: Acute overdosage as well as long-term treatment with too high a dose of glimepiride may lead to severe life-threatening hypoglycaemia. Management: As soon as an overdose of glimepiride has been discovered, a physician must be notified without delay. The patient must immediately take sugar, if possible in the form of glucose, unless a physician has already undertaken responsibility for treating the overdose. Careful monitoring is essential until the physician is confident that the patient is out of danger. It must be remembered that hypoglycaemia may recur after initial recovery. Admission to hospital may sometimes be necessary - even as a precautionary measure. In particular, significant overdoses and severe reactions with signs such as loss of consciousness or other serious neurological disorders are medical emergencies and require immediate treatment and admission to hospital. If, for example, the patient is unconscious, an intravenous injection of concentrated glucose

solution is indicated (for adults starting with 40 ml of 20% solution, for example). Alternatively, in adults, administration of glucagon, e.g. in doses of 0.5 to 1 mg i.v., s.c. or i.m. may be considered. In particular, when treating hypoglycaemia due to accidental intake of glimepiride in infants and young children, the dose of glucose given must be very carefully adjusted in view of the possibility of producing dangerous hyperglycaemia, and must be controlled by close monitoring of blood glucose. Patients who have ingested life-threatening amounts of glimepiride require detoxification (e.g. by gastric lavage and medicinal charcoal).

After acute glucose replacement has been completed it is usually necessary to give an intravenous glucose infusion in lower concentration so as to ensure that the hypoglycaemia does not recur. The patient's blood glucose level should be carefully monitored for at least 24 hours. In severe cases with a protracted course, hypoglycaemia, or the danger of slipping back into hypoglycaemia, may persist for several days.

Metformin: Hypoglycaemia has not been seen with metformin doses of up to 85 g, although lactic acidosis has occurred in such circumstances. High overdose or concomitant risks of metformin may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in hospital. The most effective method to remove lactate and metformin is haemodialysis. Pancreatitis may occur in the context of a metformin overdose

Voglibose: Voglibose competitively and reversibly inhibits the alpha glucosidase enzymes (glucoamylase, sucrase, maltase and isomaltase) in the brush border in the small intestine, which delays the hydrolysis of complex carbohydrates. It is unlikely to produce hypoglycemia in overdose, but abdominal discomfort and diarrhea may occur.

5.1 Mechanism of Action

The administration of vildagliptin results in a rapid and complete inhibition of DPP-4 activity, resulting in increased fasting and postprandial endogenous levels of the incretin hormones GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide).

5.2 Pharmacodynamic properties

Voglibose

Voglibose is an alpha glucosidase inhibitor which inhibits the activity of alpha glucosidases that catalyse the decomposition of disaccharides into monosaccharides in the intestine, thereby delaying the digestion and absorption of carbohydrates, resulting in improvement of postprandial hyperglycaemia.

Metformin hydrochloride

Metformin improves glucose tolerance in patients with type 2 diabetes (NIDDM), lowering both basal and postprandial plasma glucose. Metformin is not chemically or pharmacologically related to sulphonylureas, thiazolidinediones, or alpha-glucosidase inhibitors. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulphonylureas, metformin does not produce hypoglycaemia in either patients with type 2 diabetes or normal subjects and does not cause hyperinsulinaemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

Glimepiride

Glimepiride is an orally active hypoglycaemic substance belonging to the sulphonylurea group. It may be used in non-insulin dependent (type 2) diabetes mellitus.

Glimepiride acts mainly by stimulating insulin release from pancreatic beta cells. As with other sulfonylureas this effect is based on an increase of responsiveness of the pancreatic beta cells to the physiological glucose stimulus. In addition, glimepiride seems to have pronounced extrapancreatic effects also postulated for other sulfonylureas.

5.3 Pharmacokinetic properties

Absorption& Distribution

Voglibose

Voglibose is poorly absorbed after oral doses. Plasma concentrations after oral doses have usually been undetectable. After an 80 mg dose (substantially higher than recommended dose), peak plasma levels of about 20 ng/mL were observed in 1-1.5 hours.

Metformin Hydrochloride

The absolute bioavailability of a metformin 500-mg tablet given under fasting conditions is approximately 50-60%. Studies using single oral doses of metformin 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35 minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850-mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.

The apparent volume of distribution (V/F) of metformin following single oral doses of metformin immediate-release 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulphonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metforminimmediate-release, steady state plasma concentrations of metformin are reached within 24-48 hours and are generally <1 µg/mL.

Glimepiride

The bioavailability of glimepiride after oral administration is complete. Food intake has no relevant influence on absorption, only the absorption rate is slightly diminished. Maximum serum concentrations (Cmax) are reached approx 2.5 hours after oral intake (mean 0.3 μg/ml during multiple dosing of 4 mg/daily) and there is a linear relationship between dose and both Cmax and AUC (area under the time concentration curve).

Glimepiride has a very low distribution volume (approx. 8.8 litres), which is roughly equal to the albumin distribution space, high protein binding (>99%) and a low clearance (approx. 48 ml/min).

Metabolism & Excretion

Voglibose

Voglibose is metabolized negligibly and rapidly excreted. When voglibose tablets were repeatedly administered to healthy male adults in a single dose of 0.2 mg, three times a day, for 7 consecutive days, voglibose was not detected in plasma or urine. Also, on administration of voglibose to 10 healthy male subjects in a single dose of 2 mg, voglibose was not detected in plasma or urine.

Metformin Hydrochloride

Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance of metformin is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Mean dominant serum half-life, which is of relevance for the serum concentrations under multiple-dose conditions, is about 5 to 8 hours. After high doses, slightly longer half-lives were noted.

Glimepiride

After a single dose of radiolabelled glimepiride, 58% of the radioactivity was recovered in the urine, and 35% in the faeces. No unchanged substance was detected in the urine. Two metabolites most probably resulting from hepatic metabolism (major enzyme is CYP2C9) were identified both in urine and faeces: the hydroxy derivative and the carboxy derivative. After oral administration of glimepiride, the terminal half-lives of these metabolites were 3 to 6 and 5 to 6 hours respectively.

Comparison of single and multiple once-daily dosing revealed no significant differences in pharmacokinetics, and the intra individual variability was very low. There was no relevant accumulation.

6.1 Animal Toxicology or Pharmacology

Not available

Glimepiride

Glimepiride is a long-acting, third-generation sulfonylurea with hypoglycemic activity. Compared to other generations of sulfonylurea compounds, glimepiride is very potent and has a longer duration of action.

Chemical Name - 4-ethyl-3-methyl-N-[2-[4-[(4 methylcyclohexyl)carbamoylsulfamoyl]phenyl]ethyl]-5-oxo-2Hpyrrole-1-carboxamide

Molecular Weight- 490.6 g/mol

Molecular Formula- C₂₄H₃₄N₄O₅S

Metformin

Metformin is an agent belonging to the biguanide class of antidiabetics with anti-hyperglycemic activity. Metformin is associated with a very low incidence of lactic acidosis

Chemical Name - 3-(diaminomethylidene)-1,1-dimethylguanidine

Molecular Weight- 129.16 g/mol

Molecular Formula- C₄H₁₁N₅

Structure-

Voglibose

Voglibose is an alpha-glucosidase inhibitor used for lowering post-prandial blood glucose levels in people with diabetes mellitus.

Chemical Name - (1S,2S,3R,4S,5S)-5-(1,3-dihydroxypropan-2-ylamino)-1- (hydroxymethyl)cyclohexane-1,2,3,4-tetrol

Molecular Weight- 267.28 g/mol

Molecular Formula- C₁₀H₂₁NO₇

Structure:

8.1 Incompatibilities

None

8.2 Shelf-life

Refer on pack.

8.3 Packaging information

10 tablets in each blister strip

8.4 Storage and handing instructions

Store protect from moisture, at a temperature not exceeding 25°C.

Keep out of reach of children.

Hypoglycemia

Explain the symptoms and treatment of hypoglycemia as well as conditions that predispose to hypoglycemia. Inform patients that their ability to concentrate and react may be impaired as a result of hypoglycemia and that this may present a risk in situations where these abilities are especially important, such as driving or operating other machinery.

Hypersensitivity Reactions

Inform patients that hypersensitivity reactions may occur with glimepiride tablets and that if a reaction occurs to seek medical treatment and discontinue glimepiride tablets.

Pregnancy

Advise females of reproductive potential to inform their prescriber of a known or suspected pregnancy.

Lactation

Advise breastfeeding women taking glimepiride tablets to monitor breastfed infants for signs of hypoglycemia (e.g., jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, seizures).

Lactic Acidosis

Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its development. Advise patients to discontinue metformin hydrochloride extended-release tablets immediately and to promptly notify their healthcare provider if unexplained hyperventilation, myalgias, malaise, unusual somnolence or other nonspecific symptoms occur. Counsel patients against excessive alcohol intake and inform patients about importance of regular testing of renal function while receiving metformin hydrochloride extended-release tablets. Instruct patients to inform their doctor that they are taking metformin hydrochloride extended-release tablets prior to any surgical or radiological procedure, as temporary discontinuation may be required.

Vitamin B12 Deficiency

Inform patients about importance of regular haematological parameters while receiving metformin hydrochloride extended-release tablets.

Females of Reproductive Age:

Inform females that treatment with metformin hydrochloride extended-release tablets may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy.

Metformin SR Tablets Administration Information:

Inform patients that metformin SR tablets must be swallowed whole and not crushed, cut, or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.

14/10/2024

Olmesartan Medoxomil and Chlorthalidone tablets 20mg/12.5mg, 40mg/12.5mg

Olbet-CT 20 Tablets

Each film coated bilayered tablets contains:

Olmesartan Medoxomil IP ………. 20mg

Chlorthalidone IP …………………………..12.5 mg

Excipients……………………………………..q.s.

Olbet-CT 40 Tablets

Each film coated bilayered tablets contains:

Olmesartan Medoxomil IP ………. 40mg

Chlorthalidone IP ………………………..12.5 mg

Excipients……………………………………..q.s.

Film-coated tablet.

4.1 Therapeutic Indication

For the treatment of essential hypertension

4.2 Posology and method of administration

The dose of Olbet-CT is one tablet once daily.

Renal impairment

The maximum dose in patients with mild to moderate renal impairment (creatinine clearance of 20-60 ml/min) is 20 mg olmesartan medoxomil once daily, owing to limited experience of higher dosages in this patient group.

Olbet-CT is not recommended in patients with severe renal failure.

Hepatic impairment

Mild hepatic impairment:

No dose adjustment. Should be used with caution due to the chlorthalidone component, as in patients with impaired hepatic function or progressive liver disease, minor alterations in fluid and electrolyte balance may precipitate hepatic coma.

Moderate hepatic impairment:

An initial dose of 10 mg olmesartan medoxomil once daily is recommended and the maximum dose should not exceed 20 mg once daily. Close monitoring of blood pressure and renal function is advised in hepatically-impaired patients who are already receiving diuretics and/or other antihypertensive agents. Should be used with caution.

Severe hepatic impairment:

NOT recommended in this patient group.

Olmesartan medoxomil should not be used in patients with biliary obstruction.

Elderly patients

No adjustment of dosage is generally required in elderly people. If up-titration of Olmesartan medoxomil to the maximum dose of 40 mg daily is required, blood pressure should be closely monitored.

Paediatric population

Safety and effectiveness of Olbet CT in children have not been established.

4.3 Contraindications

• Hypersensitivity to Olmesartan medoxomil, chlorthalidone or other sulfonamide-derived drugs
• Pregnancy
• Biliary obstruction
• The concomitant use of Olmesartan Tablets with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2)
• Anuria

4.4 Special warnings and precautions for use

Olmesartan medoxomil

Intravascular volume depletion

Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of olmesartan medoxomil.

Other conditions with stimulation of the renin-angiotensin-aldosterone system

In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with other drugs that affect this system has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure. The possibility of similar effects cannot be excluded with angiotensin II receptor antagonists.

Renovascular hypertension

There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system.

Renal impairment and kidney transplantation

When olmesartan medoxomil is used in patients with impaired renal function, periodic monitoring of serum potassium and creatinine levels is recommended. Use of olmesartan medoxomil is not recommended in patients with severe renal impairment (creatinine clearance < 20 ml/min) (see sections 4.2 and 5.2). There is no experience of the administration of olmesartan medoxomil in patients with a recent kidney transplant or in patients with end-stage renal impairment (i.e. creatinine clearance < 12 ml/min).

Hepatic impairment

There is no experience in patients with severe hepatic impairment and therefore use of olmesartan medoxomil in this patient group is not recommended (see section 4.2 for dosage recommendations in patients with mild or moderate hepatic impairment).

Hyperkalaemia

The use of medicinal products that affect the renin-angiotensin-aldosterone system may cause hyperkalaemia.

The risk, that may be fatal, is increased in elderly, in patients with renal insufficiency and in diabetic patients, in patients concomitantly treated with other medicinal products that may increase potassium levels, and/or in patients with intercurrent events.

Before considering the concomitant use of medicinal products that affect the renin-angiotensin-aldosterone system, the benefit risk ratio should be evaluated and other alternatives considered. (see also below section “Dual blockade of the renin-angiotensin-aldosterone system (RAAS)”).

The main risk factors for hyperkalaemia to be considered are:

-Diabetes, renal impairment, age (> 70 years)

-Combination with one or more other medicinal products that affect the renin-angiotensin-aldosterone system and/or potassium supplements. Some medicinal products or therapeutic class of medicinal products may provoke a hyperkalaemia: salt substitutes containing potassium, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptors antagonists, non steroidal anti-inflammatory drugs (including selective COX-2 inhibitors), heparin, immunosuppressor as ciclosporin or tacrolimus, trimethoprim

-Intercurrent events, in particular dehydration, acute cardiac decompensation, metabolic acidosis, worsening of renal function, sudden worsening of the renal condition (e.g. infectious diseases), cellular lysis (e.g. acute limb ischemia, rhabdomyolysis, extended trauma).

Close-monitoring of serum potassium in at risk patients is recommended

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended.

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Lithium

As with other angiotensin-II receptor antagonists, the combination of lithium and olmesartan medoxomil is not recommended.

Aortic or mitral valve stenosis; obstructive hypertrophic cardiomyopathy

As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy.

Primary aldosteronism

Patients with primary aldosteronism generally will not respond to antihypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of olmesartan medoxomil is not recommended in such patients.

Sprue-like enteropathy

In very rare cases severe, chronic diarrhoea with substantial weight loss has been reported in patients taking olmesartan few months to years after drug initiation, possibly caused by a localized delayed hypersensitivity reaction. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, and in the absence of other apparent etiologies, olmesartan treatment should be immediately discontinued and should not be restarted. If diarrhoea does not improve during the week after the discontinuation, further specialist (e.g. a gastro-enterologist) advice should be considered.

Chlorthalidone

Hypotension

Chlorthalidone may cause symptomatic hypotension. Patients with impaired sympathetic response, volume-depletion or who are salt restricted may be at increased risk for developing hypotension. If hypotension occurs, place the patient in the supine position and, if necessary, give intravenous normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

Impaired Renal Function

Changes in renal function including acute renal failure can be caused by diuretics. Patients with chronic kidney disease, heart failure, or volume depletion may be at particular risk of developing acute renal failure on Chlorthalidone. Monitor renal function periodically. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Chlorthalidone.

Electrolyte Abnormalities

Chlorthalidone can cause hypokalemia, hyponatremia, hypochloremic alkalosis, and hypomagnesemia.

Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion. Monitor serum electrolytes periodically.

If hypokalemia is accompanied by clinical signs (e.g., muscular weakness, paresis, or ECG alterations),

Chlorthalidone should be discontinued. Correction of hypokalemia and any coexisting hypomagnesemia is recommended prior to the initiation of thiazides.

Metabolic Disturbances

Chlorthalidone may alter glucose tolerance.

Chlorthalidone may raise serum levels of cholesterol and triglycerides.

Chlorthalidone may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients.

Chlorthalidone decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels in patients with hypercalcemia receiving Chlorthalidone

4.5 Drugs interactions

Olmesartan medoxomil

Other antihypertensive medications:

The blood pressure lowering effect of olmesartan medoxomil can be increased by concomitant use of other antihypertensive medications.

ACE-inhibitors, angiotensin II receptor blockers or aliskiren

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent

Potassium supplements and potassium sparing diuretics:

Based on experience with the use of other drugs that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other drugs that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium. Such concomitant use is therefore not recommended.

Non-steroidal anti-inflammatory drugs (NSAIDs):

NSAIDs (including acetylsalicylic acid at doses> 3 g/day and also COX-2 inhibitors) and angiotensin II receptor antagonists may act synergistically by decreasing glomerular filtration. The risk of the concomitant use of NSAIDs and angiotensin II antagonists is the occurrence of acute renal failure. Monitoring of renal function at the beginning of treatment should be recommended as well as regular hydration of the patient.

Additionally, concomitant treatment can reduce the antihypertensive effect of angiotensin II receptor antagonists, leading to their partial loss of efficacy.

Bile acid sequestering agent colesevelam

Concurrent administration of the bile acid sequestering agent colesevelam hydrochloride reduces the systemic exposure and peak plasma concentration of olmesartan and reduces t1/2. Administration of olmesartan medoxomil at least 4 hours prior to colesevelam hydrochloride decreased the drug interaction effect. Administering olmesartan medoxomil at least 4 hours before the colesevelam hydrochloride dose should be considered.

Other compounds:

After treatment with antacid (aluminium magnesium hydroxide), a modest reduction in bioavailability of olmesartan was observed. Coadministration of warfarin and digoxin had no effect on the pharmacokinetics of olmesartan.

Effects of olmesartan medoxomil on other medicinal products:

Lithium:

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors and angiotensin II antagonists. Therefore, use of olmesartan medoxomil and lithium in combination is not recommended. If use of the combination proves necessary, careful monitoring of serum lithium levels is recommended.

Other compounds:

Compounds which have been investigated in specific clinical studies in healthy volunteers include warfarin, digoxin, an antacid (magnesium aluminium hydroxide), hydrochlorothiazide and pravastatin. No clinically relevant interactions were observed and in particular olmesartan medoxomil had no significant effect on the pharmacokinetics or pharmacodynamics of warfarin or the pharmacokinetics of digoxin.

Olmesartan had no clinically relevant inhibitory effects on in vitro human cytochrome P450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1 and 3A4, and had no or minimal inducing effects on rat cytochrome P450 activities. Therefore, in vivo interaction studies with known cytochrome P450 enzyme inhibitors and inducers were not conducted, and no clinically relevant interactions between olmesartan and drugs metabolised by the above cytochrome P450 enzymes are expected.

Chlorthalidone

Chlorthalidone may add to or potentiate the action of other antihypertensive drugs. Chlorthalidone and related drugs may increase the responsiveness to tubocurarine. Lithium renal clearance is reduced by chlorthalidone, increasing the risk of lithium toxicity. Monitor serum lithium levels during concomitant use.

4.6 Use in special populations

Pregnancy

Use of Olbet CT is Not recommended in pregnancy.

Breast-feeding

Use of Olbet CT is Not recommended in breast-feeding.

4.7 Effects on ability to drive and use machines

Olmesartan medoxomil has minor or moderate influence on the ablility to drive and use machines. Dizziness or fatigue may occasionally occur in patients taking antihypertensive therapy, which may impair the ablility to react.

4.8 Undesirable effects

Olmesartan medoxomil

The most commonly reported adverse reactions during treatment with olmesartan are headache (7.7%), influenza-like symptoms (4.0%) and dizziness (3.7%).

In placebo-controlled monotherapy studies, the only adverse drug reaction that was unequivocally related to treatment was dizziness (2.5% incidence on olmesartan medoxomil and 0.9% on placebo).

The incidence was also somewhat higher on olmesartan medoxomil compared with placebo for hypertriglyceridaemia (2.0% versus 1.1%) and for raised creatine phosphokinase (1.3% versus 0.7%).

The following terminologies have been used in order to classify the occurrence of adverse reactions very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

• Blood and lymphatic system disorders: Thrombocytopenia (Uncommon)
• Immune system disorders: Anaphylactic reaction (Uncommon)
• Metabolism and nutrition disorders: Hypertriglyceridaemia, Hyperuricaemia (Common), Hyperkalaemia (Rare)
• Nervous system disorders: Dizziness, Headache (Common)
• Ear and labyrinth disorders: Vertigo (Uncommon)
• Cardiac disorders: Angina pectoris (Uncommon)
• Vascular disorders: Hypotension (Rare)
• Respiratory, thoracic and mediastinal disorders: Bronchitis, Pharyngitis, Cough, Rhinitis (Common)
• Gastrointestinal disorders: Gastroenteritis, Diarrhoea, Abdominal pain, Nausea, Dyspepsia (Common), Vomiting (Uncommon), Sprue-like enteropathy (Very rare)
• Skin and subcutaneous tissue disorders: Exanthema, Allergic dermatitis, Urticaria, Rash, Pruritus, (Uncommon), Angioedema (Rare)
• Musculoskeletal and connective tissue disorders: Arthritis, Back pain, Skeletal pain, Myalgia, (Uncommon), Muscle spasm (Rare)
• Renal and urinary disorders: Haematuria, Urinary tract infection (common), Acute renal failure, Renal insufficiency (Rare)
• General disorders and administration site conditions: Pain, Chest pain, Peripheral oedema, Influenza-like symptoms, Fatigue (Common), Face oedema, Asthenia, Malaise (Uncommon), Lethargy (Rare)
• Investigations: Hepatic enzymes increased, Blood urea increased, Blood creatine phosphokinase increased (Common), Blood creatinine increased (Rare)

Chlorthalidone

• Hypotension
• Impaired Renal Function
• Electrolyte Abnormalities
• Metabolic Disturbances (see Warnings and Precautions for more information)

The following adverse reactions have been observed, but there is not enough systematic collection of data to support an estimate of their frequency.

Gastrointestinal System Reactions: anorexia, gastric irritation, nausea, vomiting, cramping, diarrhea, constipation, jaundice (intrahepatic cholestatic jaundice), pancreatitis.

Central Nervous System Reactions: dizziness, paresthesias, headache.

Hematologic Reactions: leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia.

Dermatologic-Hypersensitivity Reactions: purpura, photosensitivity, rash, urticaria, necrotizing angiitis (vasculitis) (cutaneous vasculitis), Lyell’s syndrome (toxic epidermal necrolysis).

Cardiovascular Reaction: Orthostatic hypotension.

Other Adverse Reactions: muscle spasm, weakness, restlessness, impotence, xanthopsia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

4.9 Overdose

Olmesartan medoxomil

Only limited information is available regarding overdosage in humans. The most likely effect of overdosage is hypotension. In the event of overdosage, the patient should be carefully monitored and treatment should be symptomatic and supportive.

No information is available regarding the dialysability of olmesartan.

Chlorthalidone

Symptoms of acute overdosage include nausea, weakness, dizziness and disturbances of electrolyte balance. The oral LD50 of the drug in the mouse and the rat is more than 25,000 mg/kg body weight. The minimum lethal dose (MLD) in humans has not been established. There is no specific antidote but gastric lavage is recommended, followed by supportive treatment. Where necessary, this may include intravenous dextrose-saline with potassium, administered with caution.

5.1 Mechanism of Action

Olmesartan medoxomil

Olmesartan medoxomil is a potent, orally active, selective angiotensin II receptor (type AT1) antagonist. It is expected to block all actions of angiotensin II mediated by the AT1 receptor, regardless of the source or route of synthesis of angiotensin II.

Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a significant role in the pathophysiology of hypertension via the type 1 (AT1) receptor.

Chlorthalidone

Chlorthalidone is a long-acting oral diuretic with antihypertensive activity. The diuretic effects of chlorthalidone and the benzothiadiazine (thiazide) diuretics appear to arise from similar mechanisms and the maximal effect of chlorthalidone and the thiazides appear to be similar. The site of the action appears to be the distal convoluted tubule of the nephron. Although the mechanism of action of chlorthalidone and related drugs is not wholly clear, sodium and water depletion appear to provide a basis for its antihypertensive effect.

5.2 Pharmacodynamic properties

Olmesartan medoxomil

The selective antagonism of the angiotensin II (AT1) receptors results in increases in plasma renin levels and angiotensin I and II concentrations, and some decrease in plasma aldosterone concentrations.

Chlorthalidone

The diuretic action of chlorthalidone commences a mean of 2.6 hours after dosing and continues for up to 72 hours. The drug produces diuresis with increased excretion of sodium and chloride. The diuretic effects of chlorthalidone lead to decreased extracellular fluid volume, plasma volume, cardiac output, total exchangeable sodium, glomerular filtration rate, and renal plasma flow. Chlorthalidone produces dose-related reductions in serum potassium levels, elevations in serum uric acid and blood glucose, and it can lead to decreased sodium and chloride levels.

5.3 Pharmacokinetic properties

Absorption and distribution

Olmesartan medoxomil

Olmesartan medoxomil is a prodrug. It is rapidly converted to the pharmacologically active metabolite, olmesartan, by esterases in the gut mucosa and in portal blood during absorption from the gastrointestinal tract.

No intact olmesartan medoxomil or intact side chain medoxomil moiety have been detected in plasma or excreta. The mean absolute bioavailability of olmesartan from a tablet formulation was 25.6 %.

The mean peak plasma concentration (Cmax) of olmesartan is reached within about 2 hours after oral dosing with olmesartan medoxomil, and olmesartan plasma concentrations increase approximately linearly with increasing single oral doses up to about 80 mg.

Food had minimal effect on the bioavailability of olmesartan and therefore olmesartan medoxomil may be administered with or without food.

No clinically relevant gender-related differences in the pharmacokinetics of olmesartan have been observed. Olmesartan is highly bound to plasma protein (99.7 %), but the potential for clinically significant protein binding displacement interactions between olmesartan and other highly bound coadministered drugs is low (as confirmed by the lack of a clinically significant interaction between olmesartan medoxomil and warfarin). The binding of olmesartan to blood cells is negligible. The mean volume of distribution after intravenous dosing is low (16 - 29 L).

Chlorthalidone

Absorption of chlorthalidone following oral dosing is consistent but incomplete (approximately 60%) with peak plasma concentrations occurring about 12 hours after dosing. The chlorthalidone blood levels are consistent and subject to little variability. In the blood, approximately 75% of the drug is bound to plasma proteins over a concentration range of 0.2 to 7.7 ug/mL.

Biotransformation and elimination

Olmesartan medoxomil

Total plasma clearance was typically 1.3 L/h (CV, 19 %) and was relatively slow compared to hepatic blood flow (ca 90L/h). Following a single oral dose of 14C-labelled olmesartan medoxomil, 10 - 16 % of the administered radioactivity was excreted in the urine (the vast majority within 24 hours of dose administration) and the remainder of the recovered radioactivity was excreted in the faeces. Based on the systemic availability of 25.6 %, it can be calculated that absorbed olmesartan is cleared by both renal excretion (ca 40 %) and hepato-biliary excretion (ca 60 %). All recovered radioactivity was identified as olmesartan. No other significant metabolite was detected. Enterohepatic recycling of olmesartan is minimal. Since a large proportion of olmesartan is excreted via the biliary route, use in patients with biliary obstruction is contraindicated.

The terminal elimination half-life of olmesartan varied between 10 and 15 hours after multiple oral dosing. Steady state was reached after the first few doses and no further accumulation was evident after 14 days of repeated dosing. Renal clearance was approximately 0.5 - 0.7 L/h and was independent of dose.

Chlorthalidone

The mean plasma half-life of chlorthalidone is about 40 to 60 hours. It is eliminated primarily as unchanged drug in the urine.

6.1 Animal Toxicology or Pharmacology

Olmesartan medoxomil

In chronic toxicity studies in rats and dogs, olmesartan medoxomil showed similar effects to other AT1 receptor antagonists and ACE inhibitors: raised blood urea (BUN) and creatinine (through functional changes to the kidneys caused by blocking AT1 receptors); reduction in heart weight; a reduction of red cell parameters (erythrocytes, haemoglobin, haematocrit); histological indications of renal damage (regenerative lesions of the renal epithelium, thickening of the basal membrane, dilatation of the tubules). These adverse effects caused by the pharmacological action of olmesartan medoxomil have also occurred in preclinical trials on other AT1 receptor antagonists and ACE inhibitors and can be reduced by simultaneous oral administration of sodium chloride.

In both species, increased plasma renin activity and hypertrophy/hyperplasia of the juxtaglomerular cells of the kidney were observed. These changes, which are a typical effect of the class of ACE inhibitors and other AT1 receptor antagonists, would appear to have no clinical relevance.

Like other AT1 receptor antagonists olmesartan medoxomil was found to increase the incidence of chromosome breaks in cell cultures in vitro. No relevant effects were observed in several in vivo studies using olmesartan medoxomil at very high oral doses of up to 2000 mg/kg. The overall data of a comprehensive genotoxicity testing suggest that olmesartan is very unlikely to exert genotoxic effects under conditions of clinical use.

Olmesartan medoxomil was not carcinogenic, neither in rats in a 2 year study nor in mice when tested in two 6 month carcinogenicity studies using transgenic models.

In reproductive studies in rats, olmesartan medoxomil did not affect fertility and there was no evidence of a teratogenic effect. In common with other angiotensin II antagonists, survival of offspring was reduced following exposure to olmesartan medoxomil and pelvic dilatation of the kidney was seen after exposure of the dams in late pregnancy and lactation. In common with other antihypertensive agents, olmesartan medoxomil was shown to be more toxic to pregnant rabbits than to pregnant rats, however, there was no indication of a fetotoxic effect.

Chlorthalidone

Reproduction studies have been performed in the rat and the rabbit at doses up to 420 times the human dose and have revealed no evidence of harm to the fetus due to chlorthalidone. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Carcinogenesis, Mutagenesis, Impairment of Fertility: No information is available.

Olmesartan medoxomil, a prodrug, is hydrolyzed to olmesartan during absorption from the gastrointestinal tract. Olmesartan is a selective AT 1 subtype angiotensin II receptor antagonist. Olmesartan medoxomil, USP is described chemically as 2,3-dihydroxy-2-butenyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[ p-(o-1 H-tetrazol-5-ylphenyl)benzyl]imidazole-5-carboxylate, cyclic 2,3-carbonate.

Chlorthalidone is an antihypertensive/diuretic supplied as 15 mg and 25 mg tablets for oral use. It is a monosulfamyl diuretic that differs chemically from thiazide diuretics in that a double ring system is incorporated in its structure. It is a racemic mixture of 2-chloro-5-(1-hydroxy-3-oxo-1-isoindolinyl) benzenesulfonamide

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

Refer on pack

8.3 Packaging information

10 blister strips of 10 tablets each

8.8 Storage and handing instructions

Store protected from light & moisture at a temperature not exceeding 30°C.

Keep out of reach of children.

Tablet should be swallowed whole & not to be broken, chewed or crushed.

• Advice patients not to take this medicine, if they are allergic to Olmesartan Medoxomil or Chlorthalidone
• Signs of an allergic reaction include a rash, itching or shortness of breath.
• Symptomatic hypotension and syncope: Advise patients that light headedness can occur, especially during the first days of therapy, and to report this symptom to a healthcare provider. Inform patients that dehydration from inadequate fluid intake, excessive perspiration, vomiting, or diarrhea may lead to an excessive fall in blood pressure. If syncope occurs advise patients, to contact their healthcare provider.
• Pregnancy: Tell female patients Olbet CT should not be given during pregnancy and lactation.
• Discuss treatment options with women planning to become pregnant. Tell patients to report pregnancies to their physicians as soon as possible.
• Tell the patients if they get any side effects, talk to the doctor or pharmacist. This includes any possible side effects not listed in this leaflet.
• Advice patients if they have any further questions, ask the doctor or pharmacist.

11/10/2024