Transparent vaginal hydrating & lubricating gel contains : Aqua q.s to 100%, Glycerin 14.5%, Sodium Hydroxide 3%, Carbomer 1.09%, Microcare SB 1% (Containing Sodium Benzoate and Potassium Sorbate), Hyaluronic Acid 0.05%.

Transparent Vaginal Hydrating & Lubricating Gel containing Hyaluronic Acid 0.05%

Pelvik Gel is a comprehensive approach with moisturising & visco-elastic properties, which reduces irritating, recurring vaginal dryness associated with itching, burning, dyspareunia, rash & inflammation in women.

Pelvik Gel :

1) Lubricates & repairs vaginal epithelium

2) Reduces vaginal dryness

3) Soothes the genital mucosa

4) Increases vaginal tissue elasticity

5) Maintains female sexual health

6) Does not alter the Vaginal Microenvironment & pH

DOSE :

Apply intra-vaginally 5 gm daily or SOS or as directed by the Physician.

In supine position Pelvik Gel should be administered intra-vaginally by means of a calibrated applicator.

Instructions for use for the patients

1. Remove cap from the tube & then remove aluminium tagger seal from the tube completely before fixing applicator on the tube mouth. Screw the end of the applicator on tube. Make sure the plunger is fully inserted in the barrel.

2. Gently squeeze the tube to fill the applicator with the 5 gm gel or as directed by the Physician (upto the mark).

3. Unscrew applicator from the tube and close the tube with cap. To apply gel, lie down in supine position, insert end of applicator deep into the vagina and slowly push plunger to ensure complete delivery of contents.

4. After use, pull plunger out of barrel and wash both in warm soapy water. Do not use detergents. Do not put the applicator in hot or boiling water. Rinse well afterwards.

5. The applicator can be reassembled by fully inserting the plunger into the barrel beyond the point where resistance is felt.

6. Put the applicator into the box for future use

7. Discard the applicator and tube after complete use.

Store in a cool and dry place. Protect from light.

Keep out of reach of children.

Keep the tube tightly closed after use with the cap.

For Topical Use Only.

Tested under Dermatological control for no side effects and the product is Bio-compatible.

Refer on the pack.

A tube of 50 gm with an applicator.

Data on file

Pegclear Concentrate for Oral Solution

Each 25 ml contains:

Polyethylene Glycol 3350 USP 13.125 gm

Sodium Chloride IP 0.3507 gm

Sodium Bicarbonate IP 0.1785 gm

Potassium Chloride IP 0.0466 gm

Concentrate for oral solution, clear and colourless liquid.

4.1. Therapeutic indication

For the treatment of chronic constipation.

For bowel cleansing prior to colonoscopy in adult patients only.

4.2. Posology and method of administration

Posology

A course of treatment for constipation with Pegclear should not normally exceed 2 weeks, although this can be repeated if required. As for all laxatives, prolonged use is not usually recommended. Extended use may be necessary in the case of patients with severe chronic or resistant constipation secondary to multiple sclerosis or parkinson's disease, or induced by regular constipating medication in particular opioids and antimuscarinics.

Adults, adolescents & elderly :

25 ml (13.125 gm) of solution diluted in 100 ml of water 1-3 times daily in divided doses, according to individual’s response. For extended use, the dose can be adjusted down to 1 or 2 doses per day of 25 ml of solution diluted in 100 ml of water.

Children :

2 to 6 years : usual starting daily dose is 12.5 ml solution diluted in 50 ml of water.

7 to 11 years : Usual starting daily dose is 25 ml solution diluted in 100 ml of water. The dose should be adjusted up or down as required to produce regular soft stools. If the dose needs increasing, this is best done every second day. The maximum dose of PEG 3350 does not normally exceed 26.252 gm per day.

Geriatric use

Can be administered to elderly patients in the same dosage as recommended for adults

Method of administration

Pegclear must not be taken undiluted and may only be diluted in water. Dilute required dose (volume) of Pegclear with water as recommended under dosage. Any unused solution should be discarded within 24 hours.

4.3. Contraindications

Hypersensitivity to the active substances or to any of the excipients of the formulation; intestinal perforation or obstruction due to structural or functional disorder of the gut wall, ileus; severe inflammatory conditions of the intestinal tract, such as crohn's disease and ulcerative colitis; toxic megacolon.

4.4. Special warnings and precautions for use

If patients develop any symptoms indicating shifts of fluids/electrolytes like oedema, shortness of breath, increasing fatigue, dehydration, cardiac failure; PEG 3350 should be stopped immediately, electrolytes should be measured and any abnormality should be treated appropriately.

PEG 3350 increases gastro-intestinal transit rate which may transiently reduce absorption of other medicinal products. The sodium content should be taken into consideration when administering the product to patients on a controlled sodium diet. No dosage change is necessary for the treatment of constipation in patients with renal insufficiency.

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

Polyethylene glycol raises the solubility of medicinal products that are soluble in alcohol and relatively insoluble in water. PEG 3350 increases gastro-intestinal transit rate which may transiently reduce absorption of other medicinal products. There have been isolated reports of decreased efficacy with some concomitantly administered medicinal products, e.g. anti-epileptics.

4.6. Fertility, pregnancy and lactation

Pregnancy

There is limited data on the use of PEG 3350 in pregnant women. Studies in animals have shown indirect reproductive toxicity like reduction in fetal and placental weights, reduced fetal viability, increased limb and paw hyperflexion and abortions. Clinically, no effects during pregnancy are anticipated, since systemic exposure to PEG 3350 is negligible. PEG 3350 can be used during pregnancy.

Lactation

As systemic exposure of the breast-feeding woman to PEG 3350 is negligible, no effects on the breastfed newborn/infant are anticipated, and PEG 3350 can be used during breast-feeding.

Fertility

There are no data on the effects of PEG 3350 on fertility in humans. There were no effects on fertility in studies in male and female rats.

4.7. Effects on ability to drive and use machines

Pegclear concentrate for oral solution has no influence on the ability to drive and use machines.

4.8. Undesirable effects

Gastrointestinal tract related reactions occur most commonly. These reactions may occur as a consequence of expansion of the contents of the gastrointestinal tract, and an increase in motility due to the pharmacologic effects of PEG 3350. Mild diarrhoea usually responds to dose reduction.

Other adverse reactions which may occur are : Immune system disorders: allergic reactions, including anaphylaxis, angioedema, dyspnoea, rash, erythema, urticaria, and pruritis.

Metabolism and nutrition disorders: electrolyte disturbances, particularly hyperkalaemia and hypokalaemia.

Nervous system disorders: headache

Gastrointestinal disorders: abdominal pain, diarrhoea, vomiting, nausea, dyspepsia, abdominal distension, borborygmi, flatulence, and anal discomfort.

General disorders and administration site conditions: peripheral oedema.

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

Severe pain or distension, diarrhoea, vomiting may occur in case of overdosage.

Severe pain or distention can be treated by nasogastric aspiration.

Extensive fluid loss by diarrhoea or vomiting may require correction of electrolyte disturbances.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group : osmotically acting laxative.

Polyethylene glycol 3350 acts by virtue of its osmotic action in the gut, which induces a laxative effect. PEG 3350 increases the stool volume, triggering the colon motility via neuromuscular pathways leading to an improved propulsive colonic transportation of the softened stools and a facilitation of the defecation. Electrolytes combined with PEG 3350 are exchanged across the intestinal barrier (mucosa) with serum electrolytes and excreted in faecal water without net gain or loss of sodium, potassium and water.

5.2 Pharmacokinetic properties

PEG 3350 passes unchanged along the gut. It is virtually unabsorbed from the gastro- intestinal tract. Any polyethylene glycol 3350 that is absorbed is excreted via the urine.

Preclinical studies provide evidence that macrogol or PEG 3350 has no significant systemic toxicity potential, based on conventional studies of pharmacology, repeated dose toxicity and genotoxicity.

There were no direct embryotoxic or teratogenic effects in rats even at maternally toxic levels that are a multiple of 66 x the maximum recommended dose in humans for chronic constipation and 25 x for faecal impaction. Indirect embryofetal effects, including reduction in fetal and placental weights, reduced fetal viability, increased limb and paw hyperflexion and abortions, were noted in the rabbit at a maternally toxic dose that was 3.3 x the maximum recommended dose in humans for treatment of chronic constipation and 1.3 x for faecal impaction. Rabbits are a sensitive animal test species to the effects of GI-acting substances and the studies were conducted under exaggerated conditions with high dose volumes administered, which are not clinically relevant. The findings may have been a consequence of an indirect effect of PEG 3350 related to poor maternal condition as the result of an exaggerated pharmacodynamic response in the rabbit. There was no indication of a teratogenic effect.

There are long-term animal toxicity and carcinogenicity studies involving macrogol 3350. Results from these and other toxicity studies using high levels of orally administered high molecular weight macrogols provide evidence of safety at the recommended therapeutic dose.

Polyethylene glycols or Macrogols are addition polymers of ethylene oxide and water, represented by the chemical formula H(OCH CH ) OH, where n represents the average 2 2 n number of oxyethylene groups. Each macrogol is usually designated by a number that corresponds approximately to its average molecular weight. The chemical structure of PEG is given below:

n represents average no. of oxyethylene groups

Polyethylene glycol (PEG) 3350, a white or almost white solid with a waxy or paraffin like appearance has an approximate average molecular weight of 3350 daltons. Pegclear contains PEG 3350, Sodium Chloride, Sodium Bicarbonate and Potassium Chloride. When a 25 ml dose of Pegclear is made up to 125 ml of solution, it provides 65 mmol/l of Sodium, 53 mmol/l of Chloride, 5.4 mmol/I of Potassium & 17 mmol/l of Bicarbonate which corresponds to 8.125 mmol of Sodium, 6.625 mmol of Chloride, 0.675 mmol of Potassium and 2.125 mmol of Bicarbonate in each diluted dose of 125 ml.

8.1. Incompatibilities

Not applicable.

8.2. Shelf-life

24 months

8.3. Packaging information

A bottle of 200 ml

8.4. Storage and handing instructions

Store at a temperature not exceeding 30°C.

Do not refrigerate or freeze.

Keep out of reach of children.

Discard product 30 days after first opening. The diluted solution should be kept covered. Throw away any solution not used within a 24 hour period

Advise the patient to read the Patient Information Leaflet Instruct. patients:

• To reconstitute Pegclear oral solution with water prior to ingestion.
• Not to take other laxatives while they are taking Pegclear oral solution.
• Not to take oral medications within 1 hour before the start or during the administration of Pegclear oral solution.
• To take only clear liquids but avoid red and purple liquids.
• To consume water or other clear liquids during the bowel preparation and after completion of the bowel preparation up until 2 hours before the time of the colonoscopy.
• To follow the directions in the Instructions for Use on how to prepare and administer the product.
• If they experience severe bloating, distention or abdominal pain, to slow or temporarily discontinue drinking the solution and to contact their healthcare provider.
• To contact their healthcare provider if they develop signs and symptoms of dehydration or if they experience altered consciousness or seizures.
• To discontinue administration of the solution and contact their healthcare provider if they develop symptoms of a hypersensitivity reaction

12th June 2024

Pantoprazole for Injection IP 40 mg

Each vial contains :

Pantoprazole Sodium IP (Sterile)

(As Lyophilized Bulk)

equivalent to Pantoprazole  40 mg

This pack contains 10 ml ampoule of Sodium Chloride Injection IP (0.9% w/v).

Lyophilized Powder for solution for injection 40mg / Vial

4.1 Therapeutic indication

Duodenal ulcer, gastric ulcer, moderate and severe reflux oesophagitis.

4.2 Posology and method of administration

Pantoprazole Sodium IP is available in 40mg strength vial.

This medicine should be administered by a healthcare professional and under appropriate medical supervision.

Intravenous administration of Pansa IV is recommended only if oral administration is not appropriate. Data are available on intravenous use for up to 7 days. Therefore, as soon as oral therapy is possible, treatment with Pansa IV should be discontinued and 40 mg pantoprazole p.o. should be administered instead.

Gastric and duodenal ulcer, reflux oesophagitis : The recommended intravenous dose is one vial of Pansa IV (40 mg pantoprazole) per day.

In case a rapid acid control is required, a starting dose of 2 x 80 mg Pansa IV is sufficient to manage a decrease of acid output into the target range (<10 mEq/h) within one hour in the majority of patients.

Hepatic Impairment : A daily dose of 20 mg pantoprazole (half a vial of 40 mg pantoprazole) should not be exceeded in patients with severe liver impairment.

Renal Impairment : No dose adjustment is necessary in patients with impaired renal function.

Elderly : No dose adjustment is necessary in elderly patients.

Paediatric population : Pansa IV is not recommended for use in patients below 18 years of age.

For IV Injection : Reconstitute the contents of the vial with 10 ml of Sodium Chloride Injection IP (0.9% w/v) & administer by slow injection over 2 to 5 minutes.

For IV Infusion : After reconstitution with 10 ml of Sodium Chloride Injection IP (0.9% w/v). Further dilute to 100 ml with 0.9% w/v Sodium Chloride Injection IP or 5% w/v Dextrose Injection IP & administer by infusion over 15 minutes.

4.3 Contraindications

Hypersensitivity to the active substance, substituted benzimidazoles, or to any of the excipients listed in the formulation.

4.4 Special warnings and precautions for use

Gastric malignancy : Symptomatic response to pantoprazole may mask the symptoms of gastric malignancy and may delay diagnosis. In the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis, anaemia or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded. Further investigation is to be considered if symptoms persist despite adequate treatment.

Hepatic impairment : In patients with severe liver impairment, the liver enzymes should be monitored during therapy. In the case of a rise of the liver enzymes, the treatment should be discontinued.

Co-administration with HIV protease inhibitors : Co-administration of pantoprazole is not recommended with HIV protease inhibitors for which absorption is dependent on acidic intragastric pH such as Atazanavir due to significant reduction in their bioavailability.

Gastrointestinal infections caused by bacteria : Treatment with Pansa IV may lead to a slightly increased risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter or C. difficile.

Hypomagnesaemia : Severe hypomagnesaemia has been reported in patients treated with PPIs like pantoprazole for at least three months, and in most cases for a year. Healthcare professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment.

Bone fractures : Proton pump inhibitors, especially if used in high doses and over long durations (>1 year), may modestly increase the risk of hip, wrist and spine fracture, predominantly in the elderly or in presence of other recognised risk factors. Patients at risk of osteoporosis should receive care according to current clinical guidelines and they should have an adequate intake of vitamin D and calcium.

Subacute cutaneous lupus erythematosus (SCLE) : Proton pump inhibitors are associated with very infrequent cases of SCLE. If lesions occur, especially in sun-exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and the health care professional should consider stopping Pansa IV. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.

Interference with laboratory tests : Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To avoid this interference, Pansa IV treatment should be stopped for at least 5 days before CgA measurements. If CgA and gastrin levels have not returned to reference range after initial measurement, measurements should be repeated 14 days after cessation of proton pump inhibitor treatment.

4.5 Drug interactions

Medicinal products with pH dependent absorption pharmacokinetics :

Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with the absorption of other medicinal products where gastric pH is an important determinant of oral bioavailability, e.g. some azole antifungals such as ketoconazole, itraconazole, posaconazole and other medicine such as erlotinib.

HIV protease inhibitors

Co-administration of pantoprazole is not recommended with HIV protease inhibitors for which absorption is dependent on acidic intragastric pH such as atazanavir due to significant reduction in their bioavailability. If the combination of HIV protease inhibtiors with a proton pump inhibitor is judged unavoidable, close clinical monitoring (e.g. virus load) is recommended. A pantoprazole dose of 20 mg per day should not be exceeded. Dosage of the HIV protease inhibitor may need to be adjusted.

Coumarin anticoagulants (phenprocoumon or warfarin)

Co-administration of pantoprazole with warfarin or phenprocoumon did not affect the pharmacokinetics of warfarin, phenoprocoumon or INR. However, there have been reports of increased INR and prothrombin time in patients receiving PPIs and war farin or phenoprocoumon concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding, and even death. Patients treated with pantoprazole and warfarin or phenprocoumon may need to be monitored for increase in INR and prothrombin time.

Methotrexate

Concomitant use of high dose methotrexate (e.g. 300 mg) and proton-pump inhibitors has been repor ted to increase methotrexate levels in some patients. Therefore, in settings where high-dose methotrexate is used, for example cancer and psoriasis, a temporary withdrawal of pantoprazole may need to be considered.

Other interactions studies

Pantoprazole is extensively metabolized in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation by CYP2C19 and other metabolic pathways include oxidation by CYP3A4.

Medicinal products that inhibit or induce CYP2C19

Inhibitors of CYP2C19 such as fluvoxamine could increase the systemic exposure of pantoprazole. A dose reduction may be considered for patients treated long-term with high doses of pantoprazole, or those with hepatic impairment.

Enzyme inducers affecting CYP2C19 and CYP3A4 such as rifampicin and St John´s wort (Hypericum perforatum) may reduce the plasma concentrations of PPIs that are metabolized through these enzyme systems.

4.6 Use in special populations

Pregnancy

A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative or feto / neonatal toxicity of Pantoprazole 40 mg Powder for Solution for Injection. As a precautionary measure, it is preferable to avoid the use of Pantoprazole 40 mg Powder for Solution for Injection during pregnancy.

Breast-feeding

There is insufficient information on the excretion of pantoprazole in human milk but excretion into human milk has been reported. A risk to the newborns/infants cannot be excluded. Therefore, a decision on whether to discontinue breast-feeding or to discontinue/abstain from Pansa IV therapy should take into account the benefit of breast-feeding for the child, and the benefit for the woman.

Fertility

There was no evidence of impaired fertility following the administration of pantoprazole in animal studies.

4.7 Effects on the ability to drive and use machines

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

Adverse drug reactions such as dizziness and visual disturbances may occur. If affected, patients should not drive or operate machines.

4.8 Undesirable effects

Adverse drug reaction reports show that Proton Pump Inhibitors like Pantoprazole, are associated with acute kidney injury.

The table below lists adverse reactions reported with pantoprazole, ranked under the following frequency classification : 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), not known (cannot be estimated from the available data).

Reporting of side effects

Reporting suspected adverse reactions after authorization 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 : http://www.zuventus.co.in/safety.aspx

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

4.9 Overdose

There are no known symptoms of overdose in man. Systemic exposure with up to 240 mg administered intravenously over 2 minutes were well tolerated. As pantoprazole is extensively protein bound, it is not readily dialysable. In the case of an overdose with clinical signs of intoxication, apart from symptomatic and supportive treatment, no specific therapeutic recommendations can be made.

5.1 Mechanism of action

Pantoprazole is a substituted benzimidazole which inhibits the secretion of hydrochloric acid in the stomach by specific blockade of the proton pumps of the parietal cells.

Pantoprazole is converted to its active form in the acidic environment in the parietal cells where it inhibits the H+, K+-ATPase enzyme, i.e. the final stage in the production of hydrochloric acid in the stomach. The inhibition is dose-dependent and affects both basal and stimulated acid secretion. In most patients, freedom from symptoms is achieved within 2 weeks. As with other proton pump inhibitors and H2 receptor inhibitors, treatment with pantoprazole reduces acidity in the stomach and thereby increases gastrin in proportion to the reduction in acidity. The increase in gastrin is reversible. Since pantoprazole binds to the enzyme distal to the cell receptor level, it can inhibit hydrochloric acid secretion independently of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same whether the product is given orally or intravenously.

5.2 Pharmacodynamic properties

The fasting gastrin values increase under pantoprazole. On short-term use, in most cases they do not exceed the upper limit of normal. During long-term treatment, gastrin levels double in most cases. An excessive increase, however, occurs only in isolated cases. As a result, a mild to moderate increase in the number of specific endocrine (ECL) cells in the stomach is observed in a minority of cases during long-term treatment (simple to adenomatoid hyperplasia). However, according to the studies conducted so far, the formation of carcinoid precursors (atypical hyperplasia) or gastric carcinoids as were found in animal experiments have not been observed in humans.

During treatment with antisecretory medicinal products, serum gastrin increases in response to the decreased acid secretion. Also CgA increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumours. Available published evidence suggests that proton pump inhibitors should be discontinued between 5 days and 2 weeks prior to CgA measurements. This is to allow CgA levels that might be spuriously elevated following PPI treatment to return to reference range. An influence of a long term treatment with pantoprazole exceeding one year cannot be completely ruled out on endocrine parameters of the thyroid according to results in animal studies.

5.3 Pharmacokinetic properties

Pharmacokinetics do not vary after single or repeated administration. In the dose range of 10 to 80 mg, the plasma kinetics of pantoprazole are linear after both oral and intravenous administration.

Distribution

Pantoprazole's serum protein binding is about 98%. Volume of distribution is about 0.15 l/kg.

Biotransformation

The substance is almost exclusively metabolized in the liver. The main metabolic pathway is demethylation by CYP2C19 with subsequent sulphate conjugation, other metabolic pathways include oxidation by CYP3A4.

Elimination

Terminal half-life is about 1 hour and clearance is about 0.1 l/h/kg. There were a few cases of subjects with delayed elimination. Because of the specific binding of pantoprazole to the proton pumps of the parietal cell the elimination half-life does not correlate with the much longer duration of action (inhibition of acid secretion).

Renal elimination represents the major route of excretion (about 80%) for the metabolites of pantoprazole, the rest is excreted with the faeces. The main metabolite in both the serum and urine is desmethylpantoprazole which is conjugated with sulphate. The half-life of the main metabolite (about 1.5 hours) is not much longer than that of pantoprazole.

6.1 Animal Toxicology or Pharmacology

Nonclinical data reveal no special hazard to humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. Studies also revealed no evidence of impaired fertility or teratogenic effects.

A slight increase of neoplastic changes of the thyroid was observed in the group of rats receiving the highest dose (200 mg/kg). As the therapeutic dose in man is low, no harmful effects on the thyroid glands are expected.

The active ingredient, Pantoprazole Sodium IP, a PPI, is a substituted benzimidazole, sodium 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl] sulfinyl]- 1H-benzimidazole, a compound that inhibits gastric acid secretion. Its empirical formula is C16H14F2N3NaO4S, with a molecular weight of 405.4.

The structural formula is :

8.1 Incompatibilities

This medicinal product must not be mixed with other medicinal products except for :

• 0.9% Sodium chloride solution
• Glucose 5% solution

It should not be prepared or mixed with solvents other than those stated above.

8.2 Shelf-life

Refer on the pack.

8.3 Packaging Information

A vial of 40 mg with Sodium Chloride Injection IP 10 ml.

8.4 Storage and handling instructions

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

Keep out of reach of children.

After reconstitution, do not use in case any foreign particulate matter is observed inside the vial.

Adverse reactions

Advise patients to report to their healthcare provider if they experience any signs or symptoms consistent with:

• Injection Site Reactions
• Acute Tubulointerstitial Nephritis
• Clostridium difficile- Associated Diarrhea
• Bone Fracture
• Severe Cutaneous Adverse Reactions
• Cutaneous and Systemic Lupus Erythematosus 
• Hepatic Effects
• Hypomagnesemia and Mineral Metabolism

Drug interactions

Advise patients to report to their healthcare provider before they start treatment with any of the following:

• Rilpivirine-containing products
• High-dose methotrexate

Pregnancy

Advise a pregnant woman of the potential risk to a fetus. Advise females of reproductive potential to inform their prescriber of a known or suspected pregnancy.

05 June 2024

Pantoprazole Gastro-resistant Tablets IP 40 mg

Each Gastro-resistant tablet contains :

Pantoprazole Sodium IP

equivalent to Pantoprazole 40 mg

Excipients q.s.

Colours : Yellow Oxide of Iron &

Titanium Dioxide IP

Gastro-resistant Tablet 40 mg

4.1 Therapeutic indication

For the treatment of gastric ulcer, duodenal ulcer, moderate and severe reflux oesophagitis.

4.2 Posology and method of administration Adults and adolescents 12 years of age and above Reflux oesophagitis

One tablet of Pantoprazole per day. In individual cases the dose may be doubled (increase to 2 tablets Pantoprazole daily) especially when there has been no response to other treatment. A 4-week period is usually required for the treatment of reflux oesophagitis. If this is not sufficient, healing will usually be achieved within a further 4 weeks.

Treatment of gastric ulcer

One tablet of Pantoprazole per day. In individual cases the dose may be doubled (increase to 2 tablets of Pantoprazole daily) especially when there has been no response to other treatment. A 4-week period is usually required for the treatment of gastric ulcers. If this is not sufficient, healing will usually be achieved within a further 4 weeks.

Treatment of duodenal ulcer

One tablet of Pantoprazole per day. In individual cases the dose may be doubled (increase to 2 tablets of Pantoprazole daily) especially when there has been no response to other treatment. A duodenal ulcer generally heals within 2 weeks. If a 2-week period of treatment is not sufficient, healing will be achieved in almost all cases within a further 2 weeks.

Special populations

Patients with hepatic impairment

A daily dose of 20 mg Pantoprazole (1 tablet of 20 mg Pantoprazole) should not be exceeded in patients with severe liver impairment.

Patients with renal impairment

No dose adjustment is necessary in patients with impaired renal function

Elderly

No dose adjustment is necessary in the elderly

Paediatric population

Pantoprazole is not recommended for use in children below 12 years of age because of limited data on safety and efficacy in this age group.

Method of administration

Oral use. The tablets should not be chewed or crushed, and should be swallowed whole 1 hour before a meal with some water

4.3 Contraindications

Hypersensitivity to the active substance, substituted Benzimidazoles, or to any of the excipients listed in the formulation

4.4 Warning and precautions

Hepatic impairment

In patients with severe liver impairment, the liver enzymes should be monitored regularly during treatment with Pantoprazole, particularly on long-term use. In the case of a rise of the liver enzymes, the treatment should be discontinued.

Gastric malignancy

Symptomatic response to Pantoprazole may mask the symptoms of gastric malignancy and may delay diagnosis. In the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis, anaemia or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded. Further investigation is to be considered if symptoms persist despite adequate treatment.

Co-administration with HIV protease inhibitors

Co-administration of Pantoprazole is not recommended with HIV protease inhibitors for which absorption is dependent on acidic intragastric pH such as Atazanavir, due to significant reduction in their bioavailability.

Long-term treatment

In long-term treatment, especially when exceeding a treatment period of 1 year, patients should be kept under regular surveillance

Gastrointestinal infections caused by bacteria

Treatment with Pantoprazole may lead to a slightly increased risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter or C. difficile.

Hypomagnesaemia

Severe hypomagnesaemia has been rarely reported in patients treated with proton pump inhibitors (PPIs) like Pantoprazole for at least three months, and in most cases for a year. Serious manifestations of hypomagnesaemia such as fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmia can occur but they may begin insidiously and be overlooked. Hypomagnesaemia may lead to hypocalcaemia and/or hypokalaemia. In most affected patients, hypomagnesaemia (and hypomagnesaemia associated hypocalcaemia and/or hypokalaemia) improved after magnesium replacement and discontinuation of the PPI.

For patients expected to be on prolonged treatment or who take PPIs with digoxin or medicinal products that may cause hypomagnesaemia (e.g. diuretics), health care professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment.

Bone fractures

Proton pump inhibitors, especially if used in high doses and over long durations (> 1 year), may modestly increase the risk of hip, wrist and spine fracture, predominantly in the elderly or in the presence of other recognised risk factors. Observational studies suggest that proton pump inhibitors may increase the overall risk of fracture by 10 - 40%. Some of this increase may be due to other risk factors. Patients at risk of osteoporosis should receive care according to current clinical guidelines and they should have an adequate intake of vitamin D and calcium

Sub-acute cutaneous lupus erythematosus (SCLE)

Proton pump inhibitors are associated with very infrequent cases of SCLE. If lesions occur, especially in sun exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and the healthcare professional should consider stopping Pantoprazole. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.

Interference with laboratory tests

Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To avoid this interference, Pantoprazole treatment should be stopped for at least 5 days before CgA measurements. If CgA and gastrin

levels have not returned to reference range after initial measurement, measurements should be repeated 14 days after cessation of proton pump inhibitor treatment.

4.5 Drug interactions

Medicinal products with pH-dependent absorption pharmacokinetics

Because of profound and long-lasting inhibition of gastric acid secretion, Pantoprazole may interfere with the absorption of medicinal products where gastric pH is an important determinant of oral bioavailability, e.g. some azole antifungals such as Ketoconazole, Itraconazole, Posaconazole and other medicines such as Erlotinib.

HIV protease inhibitors

Co-administration of Pantoprazole is not recommended with HIV protease inhibitors for which absorption is dependent on acidic intragastric pH such as Atazanavir due to significant reduction in their bioavailability. If the combination of HIV protease inhibitors with a proton pump inhibitor is judged unavoidable, close clinical monitoring (e.g. virus load) is recommended. A Pantoprazole dose of 20 mg per day should not be exceeded. Dosage of the HIV protease inhibitor may need to be adjusted.

Coumarin anticoagulants (Phenprocoumon or Warfarin)

Co-administration of Pantoprazole with Warfarin or Phenprocoumon did not affect the pharmacokinetics of Warfarin, Phenprocoumon or INR. However, there have been reports of increased INR and prothrombin time in patients receiving PPIs and Warfarin or Phenprocoumon concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding, and even death. Patients treated with Pantoprazole and Warfarin or Phenprocoumon may need to be monitored for increase in INR and prothrombin time.

Methotrexate

Concomitant use of high-dose Methotrexate (e.g. 300 mg) and proton pump inhibitors has been reported to increase Methotrexate levels in some patients. Therefore, in settings where high-dose Methotrexate is used, for example cancer and psoriasis, a temporary withdrawal of Pantoprazole may need to be considered.

Other interactions studies

Pantoprazole is extensively metabolised in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation by CYP2C19 and other metabolic pathways include oxidation by CYP3A4. Interaction studies with medicinal products also metabolised with these pathways, like Carbamazepine, Diazepam, Glibenclamide, Nifedipine, and an oral contraceptive containing Levonorgestrel and Ethinyl Oestradiol, did not reveal clinically significant interactions

An interaction of Pantoprazole with other medicinal products or compounds, which are metabolised using the same enzyme system, cannot be excluded.

Results from a range of interaction studies demonstrate that Pantoprazole does not affect the metabolism of active substances metabolised by CYP1A2 (such as Caffeine, Theophylline), CYP2C9 (such as Piroxicam, Diclofenac, Naproxen), CYP2D6 (such as Metoprolol), CYP2E1 (such as Ethanol), or does not interfere with p-glycoprotein related absorption of Digoxin.

There were no interactions with concomitantly administered antacids. Interaction studies have also been performed by concomitantly administering Pantoprazole with the respective antibiotics (Clarithromycin, Metronidazole, Amoxicillin). No clinically relevant interactions were found.

Medicinal products that inhibit or induce CYP2C19

Inhibitors of CYP2C19 such as fluvoxamine could increase the systemic exposure of Pantoprazole. A dose reduction may be considered for patients treated long-term with high doses of Pantoprazole, or those with hepatic impairment. Enzyme inducers affecting CYP2C19 and CYP3A4 such as Rifampicin and St John´s wort (Hypericum perforatum) may reduce the plasma concentrations of PPIs that are metabolised through these enzyme systems.

4.6 Special populations

Pregnancy

A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative or fetal/ neonatal toxicity of Pantoprazole. Animal studies have shown reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of Pantoprazole during pregnancy.

Breast-feeding

Animal studies have shown excretion of Pantoprazole in breast milk. There is insufficient information on the excretion of Pantoprazole in human milk but excretion into human milk has been reported. A risk to the new-borns / infants cannot be excluded. Therefore, a decision on whether to discontinue breast-feeding or to discontinue/abstain from Pantoprazole therapy taking into account the benefit of breast-feeding for the child, and the benefit of Pantoprazole therapy for the woman.

Fertility

There was no evidence of impaired fertility following the administration of Pantoprazole in animal studies

4.7 Effects on ability to drive and use machines

Pantoprazole has no or negligible influence on the ability to drive and use machines. Adverse drug reactions, such as dizziness and visual disturbances may occur. If affected, patients should not drive or operate machines.

4.8 Undesirable effects

1. Hypocalcemia and/or hypokalaemia may be related to the occurrence of hypomagnesaemia in association with hypomagnesemia.

2. Muscle spasm as a consequence of electrolyte disturbance.

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

There are no known symptoms of overdose in man. Systemic exposure with up to 240 mg administered intravenously over 2 minutes, were well tolerated. As Pantoprazole is extensively protein bound, it is not readily dialysable. In the case of an overdose with clinical signs of intoxication, apart from symptomatic and supportive treatment, no specific therapeutic recommendations can be made.

5.1 Mechanism of action

Pantoprazole is a substituted Benzimidazole which inhibits the secretion of Hydrochloric acid in the stomach by specific blockade of the proton pumps of the parietal cells. Pantoprazole is converted to its active form in the acidic environment in the parietal cells where it inhibits the H+, K+-ATPase enzyme, i.e. the final stage in the production of hydrochloric acid in the stomach. The inhibition is dose-dependent and affects both basal and stimulated acid secretion. In most patients, freedom from symptoms is achieved within 2 weeks. As with other proton pump inhibitors and H2 receptor inhibitors, treatment with Pantoprazole reduces acidity in the stomach and thereby increases gastrin in proportion to the reduction in acidity. The increase in gastrin is reversible. Since Pantoprazole binds to the enzyme distal to the cell receptor level, it can inhibit hydrochloric acid secretion independently of stimulation by other substances (Acetylcholine, Histamine, Gastrin). The effect is the same whether the product is given orally or intravenously.

5.2 Pharmacodynamic properties

The fasting gastrin values increase under Pantoprazole. On short-term use, in most cases they do not exceed the upper limit of normal. During long-term treatment, gastrin levels double in most cases. An excessive increase, however, occurs only in isolated cases. As a result, a mild to moderate increase in the number of specific endocrine (ECL) cells in the stomach is observed in a minority of cases during long-term treatment (simple to adenomatoid hyperplasia). However, according to the studies conducted so far, the formation of carcinoid precursors (atypical hyperplasia) or gastric carcinoids as were found in animal experiments have not been observed in humans. An influence of a long term treatment with Pantoprazole exceeding one year cannot be completely ruled out on endocrine parameters of the thyroid according to results in animal studies. During treatment with antisecretory medicinal products, serum gastrin increases in response to the decreased acid secretion. Also CgA increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumours. Available published evidence suggests that proton pump inhibitors should be discontinued between 5 days and 2 weeks prior to CgA measurements. This is to allow CgA levels that might be spuriously elevated following PPI treatment to return to reference range.

5.3 Pharmacokinetic properties

Absorption

Pantoprazole is rapidly absorbed and the maximal plasma concentration is achieved even after one single 40 mg oral dose. On average at about 2.5 h p.a. the maximum serum concentrations of about 2 - 3 µg/mL are achieved, and these values remain constant after multiple administration. Pharmacokinetics does not vary after single or repeated administration. In the dose range of 10 to 80 mg, the plasma kinetics of Pantoprazole are linear after both oral and intravenous administration. The absolute bioavailability from the tablet was found to be about 77%. Concomitant intake of food had no influence on AUC, maximum serum concentration and thus bioavailability. Only the variability of the lag-time will be increased by concomitant food intake.

Distribution

Pantoprazole's serum protein binding is about 98%. Volume of distribution is about 0.15 L/kg.

Biotransformation

The substance is almost exclusively metabolised in the liver. The main metabolic pathway is demethylation by CYP2C19 with subsequent sulphate conjugation; other metabolic pathway includes oxidation by CYP3A4.

Elimination

Terminal half-life is about 1 hour and clearance is about 0.1 L/h/kg. There were a few cases of subjects with delayed elimination. Because of the specific binding of Pantoprazole to the proton pumps of the parietal cell the elimination half-life does not correlate with the much longer duration of action (inhibition of acid secretion). Renal elimination represents the major route of excretion (about 80%) for the metabolites of Pantoprazole, the rest is excreted with the faeces. The main metabolite in both the serum and urine is desmethylpantoprazole which is conjugated with sulphate. The half-life of the main metabolite (about 1.5 hours) is not much longer than that of Pantoprazole.

6.1 Animal toxicology or pharmacology

Non-clinical data reveal no special hazard to humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. In the two-year carcinogenicity studies in rats neuroendocrine neoplasms were found. In addition, squamous cell papillomas were found in the fore stomach of rats. The mechanism leading to the formation of gastric carcinoids by substituted Benzimidazoles has been carefully investigated and allows the conclusion that it is a secondary reaction to the massively elevated serum gastrin levels occurring in the rat during chronic high-dose treatment. In the two-year rodent

studies an increased number of liver tumours was observed in rats and in female mice and was interpreted as being due to Pantoprazole's high metabolic rate in the liver. A slight increase of neoplastic changes of the thyroid was observed in the group of rats receiving the highest dose (200 mg/kg). The occurrence of these neoplasms is associated with the pantoprazole-induced changes in the breakdown of thyroxine in the rat liver. As the therapeutic dose in man is low, no harmful effects on the thyroid glands are expected. In a peri-postnatal rat reproduction study designed to assess bone development, signs of offspring toxicity (mortality, lower mean body weight, lower mean body weight gain and reduced bone growth) were observed at exposures (Cmax) approximately 2x the human clinical exposure. By the end of the recovery phase, bone parameters were similar across groups and body weights were also trending toward reversibility after a drug-free recovery period. The increased mortality has only been reported in pre-weaning rat pups (up to 21 days age) which is estimated to correspond to infants up to the age of 2 years old. The relevance of this finding to the paediatric population is unclear. A previous peri-postnatal study in rats at slightly lower doses found no adverse effects at 3 mg/kg compared with a low dose of 5 mg/kg in this study. Investigations revealed no evidence of impaired fertility or teratogenic effects. Penetration of the placenta was investigated in the rat and was found to increase with advanced gestation. As a result, concentration of Pantoprazole in the foetus is increased shortly before birth.

Pantoprazole is a proton pump inhibitor (PPI) that suppresses the final step in gastric acid production by covalently binding to the (H+, K+)-ATPase enzyme system at the secretory surface of the gastric parietal cell. It is a substituted benzimidazole, a compound that inhibits gastric acid secretion. Its chemical name is sodium 5-(difluoromethoxy)-2-[[(3,4-dimethoxy2-pyridinyOmethyl] sulfinyl] 1H-benzimidazole sesquihydrate. Its empirical formula is C16H14F2N3NaO4S. 1.5 H2O, with a molecular weight of 432.4 g/mol.

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

PVC/PVDC-Alu blister strip of 15 tablets.

8.4 Storage and handing instructions

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

Keep out of reach of children.

Do not take Pantoprazole

If you are allergic to Pantoprazole or to any of the other ingredients of this medicine.

If you are allergic to medicines containing other proton pump inhibitors.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking Pantoprazole.

• If you have severe liver problems. Please tell your doctor if you have ever had problems with your liver in the past. Your doctor will check your liver enzymes more frequently, especially when you are taking Pantoprazole as a long-term treatment. In the case of a rise of liver enzymes the treatment should be stopped.

• If you have reduced body stores or risk factors for reduced Vitamin B12 and receive long-term treatment with Pantoprazole. As with all acid reducing agents, pantoprazole may lead to a reduced absorption of Vitamin B12.

• If you are taking HIV protease inhibitors such as Atazanavir (for the treatment of HIV-infection) at the same time as Pantoprazole, ask your doctor for specific advice.

• Taking a proton pump inhibitor like Pantoprazole, especially over a period of more than one year, may slightly increase your risk of fracture in the hip, wrist or spine. Tell your doctor if you have osteoporosis (reduced bone density) or if you have been told that you are at risk of getting osteoporosis (for example, if you are taking steroids).

• If you are on Pantoprazole for more than three months it is possible that the levels of Magnesium in your blood may fall. Low levels of magnesium can be seen as fatigue, involuntary muscle contractions, disorientation, convulsions, dizziness, increased heart rate. If you get any of these symptoms, please tell your doctor promptly. Low levels of magnesium can also lead to a reduction in Potassium or Calcium levels in the blood. Your doctor may decide to perform regular blood tests to monitor your levels of Magnesium.

• If you have ever had a skin reaction after treatment with a medicine similar to Pantoprazole that reduces stomach acid.

• If you get a rash on your skin, especially in areas exposed to the sun tell your doctor as soon as you can, as you may need to stop your treatment with Pantoprazole. Remember to also mention any other ill-effects like pain in your joints.

• If you are due to have a specific blood test (Chromogranin A).

Tell your doctor immediately, before or after taking this medicine, if you notice any of the following symptoms, which could be a sign of another, more serious, disease :

• An unintentional loss of weight.

• Vomiting, particularly if repeated.

• Vomiting blood; this may appear as dark coffee grounds in your vomit.

• You notice blood in your stools; which may be black or tarry in appearance.

• Difficulty in swallowing or pain when swallowing.

• You look pale and feel weak (anaemia)

• Chest pain

• Stomach pain

• Severe and/or persistent diarrhoea, because this medicine has been associated with a small increase in infectious diarrhoea

Your doctor may decide that you need some tests to rule out malignant disease because Pantoprazole also alleviates the symptoms of cancer and could cause delay in diagnosing it. If your symptoms continue in spite of your treatment, further investigations will be considered. If you take Pantoprazole on a long-term basis (longer than 1 year) your doctor will probably keep you under regular surveillance. You should report any new and exceptional symptoms and circumstances whenever you see your doctor.

Children and adolescents

Pantoprazole is not recommended for use in children as it has not been proven to work in children below 12 years of age.

Other medicines and Pantoprazole

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription.

This is because Pantoprazole may influence the effectiveness of other medicines, so tell your doctor if you are taking :

• Medicines such as Ketoconazole, Itraconazole and Posaconazole (used to treat fungal infections) or Erlotinib (used for certain types of cancer) because Pantoprazole may stop these and other medicines from working properly.

• Warfarin and Phenprocoumon, which affect the thickening, or thinning of the blood. You may need further checks.

• Medicines used to treat HIV-infection, such as Atazanavir.

• Methotrexate (used to treat rheumatoid arthritis, psoriasis, and cancer) - if you are taking Methotrexate your doctor may temporarily stop your Pantoprazole treatment because Pantoprazole can increase levels of Methotrexate in the blood.

• Fluvoxamine (used to treat depression and other psychiatric diseases) if you are taking Fluvoxamine your doctor may reduce the dose.

• Rifampicin (used to treat infections).

• St John’s wort (Hypericum perforatum) (used to treat mild depression).

Each film coated sustained release tablet contains :

Linezolid IP 1200 mg

Excipients q.s.

Colours : Ferric Oxide USP-NF (Yellow) & Titanium Dioxide IP

Linezolid, which is a synthetic antibacterial agent of the oxazolidinone class.

Molecular formula : C₁₆H₂₀ FN₃O₄

Molecular weight : 337.35 g/mol

IUPAC Name : (S)-N-({3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide.

Pharmacodynamics

Linezolid is a synthetic, antibacterial agent that belongs to a new class of antimicrobials, the oxazolidinones. It has in vitro activity against aerobic Gram positive bacteria and anaerobic micro-organisms. Linezolid selectively inhibits bacterial protein synthesis via a unique mechanism of action. Specifically, it binds to a site on the bacterial ribosome (23S of the 50S subunit) and prevents the formation of a functional 70S initiation complex which is an essential component of the translation process.

Pharmacokinetics

Linezolid is extensively absorbed after oral dosing. Maximum plasma concentrations are reached approximately 1 to 2 hours after dosing, and the absolute bioavailability is approximately 100%. Absorption is not significantly affected by food. Linezolid is primarily metabolised by oxidation of the morpholine ring resulting mainly in the formation of two inactive open-ring carboxylic acid derivatives; the aminoethoxyacetic acid metabolite and the hydroxyethyl glycine metabolite. In patients with normal renal function or mild to moderate renal insufficiency, Linezolid is primarily excreted under steady-state conditions in the urine.

Bioequivalence Testing :

A crossover, comparative bioavailability study of Ozolid SR 1200 given as a single dose (Linezolid 1200 mg Sustained Release Tablet from Zuventus Healthcare Limited) was compared with Linezolid Immediate Release 600 mg x 2 tablet [1 tablet each at 12 hourly and each tablet containing Linezolid 600 mg] to determine the systemic exposure of Linezolid in plasma over a period of 24 hours. It was observed that the Area under the curve of the two formulations was similar proving their bioequivalence as shown in table 1.

The safety and efficacy of Linezolid in children aged (< 18 years old) has not been established.

Most common adverse reactions (>5% of adult and/or pediatric patients treated with Linezolid) include : diarrhea, vomiting, headache, nausea, and anemia

The following undesirable effects have been observed and reported during treatment with Linezolid with the following frequencies : Infections and infestations : Common- candidiasis, oral candidiasis, vaginal candidiasis, fungal infections; Uncommon- vaginitis; Rareantibiotic-associated colitis, including pseudomembranous colitis. Blood and the lymphatic system disorders : Common- anaemia; Uncommon- leucopenia, neutropenia, thrombocytopenia, eosinophilia; Rare-pancytopenia; Frequency not known- myelosuppression, sideroblastic anaemia. Immune system disorders : Frequency not known- anaphylaxis. Metabolism and nutrition disorders : Uncommonhyponatraemia; Frequency not known- lactic acidosis. Psychiatric disorders : Common- insomnia. Nervous system disorders : Commonheadache, taste perversion (metallic taste), dizziness; Uncommon- convulsions, hypoaesthesia, paraesthesia; Frequency not known- serotonin syndrome, peripheral neuropathy. Eye disorders : Uncommon- blurred vision; Rare- changes in visual field defect; Frequency not known- optic neuropathy, optic neuritis, loss of vision, changes in visual acuity, changes in colour vision. Ear and labyrinth disorders : Uncommon- tinnitus. Cardiac disorders : Uncommon- arrhythmia (tachycardia). Vascular disorders : Common-hypertension; Uncommon-transient ischaemic attacks, phlebitis, thrombophlebitis. Gastrointestinal disorders : Common- diarrhoea, nausea, vomiting, localised or general abdominal pain, constipation, dyspepsia; Uncommon- pancreatitis, gastritis, abdominal distention, dry mouth, glossitis, loose stools, stomatitis, tongue discolouration or disorder; Rare- superficial tooth discolouration. Hepato-biliary disorders : Common- abnormal liver function test; increased AST, ALT or alkaline phosphatase; Uncommon- increased total bilirubin. Skin and subcutaneous tissue disorders : Common- pruritus, rash; Uncommon- urticaria, dermatitis, diaphoresis; Frequency not known- bullous disorders such as those described as Stevens-Johnson syndrome and toxic epidermal necrolysis, angioedema, alopecia. Renal and urinary disorders : Common- increased BUN; Uncommon- renal failure, increased creatinine, polyuria. Reproductive system and breast disorders : Uncommon- vulvovaginal disorder. General disorders and administration site conditions : Common- fever, localised pain; Uncommon-chills, fatigue, injection site pain, increased thirst. Investigations : Common- Chemistry- Increased LDH, creatine kinase, lipase, amylase or non fasting glucose. Decreased total protein, albumin, sodium or calcium. Increased or decreased potassium or bicarbonate; Haematology- Increased neutrophils or eosinophils. Decreased haemoglobin, haematocrit or red blood cell count. Increased or decreased platelet or white blood cell counts. Uncommon- Chemistry-Increased sodium or calcium. Decreased non fasting glucose. Increased or decreased chloride. Haematology- Increased reticulocyte count. Decreased neutrophils.

Pregnancy

Pregnancy Category C : Linezolid should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers: It is not known whether Linezolid is excreted in human milk.

Caution should be exercised when Ozolidisadm in istered to an ursing woman.

Usage in pediatrics : Pediatric patients exhibit wider variability in Linezolid clearance and systemic exposure (AUC) compared with adults. In pediatric patients with a sub-optimal clinical response, particularly those with pathogens with MIC of 4 mcg/mL, lower systemic exposure, site and severity of infection, and the underlying medical condition should be considered when assessing clinical response.

Usage in geriatrics : No overall differences in safety or effectiveness were obser ved between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Severe renal impairment (i.e. CLCR < 30 ml/min) : No dose adjustment is required. Linezolid should be used with special caution in patients with severe renal insufficiency who are undergoing dialysis and only when the anticipated benefit is considered to outweigh the theoretical risk.

Hepatic impairment : No dose adjustment is required. However, there are limited clinical data and it is recommended that Linezolid should be used in such patients only when the anticipated benefit is considered to outweigh the theoretical risk.

Monoamine Oxidase Inhibitors

Linezolid is a reversible, nonselective inhibitor of monoamine oxidase.

Adrenergic and Serotonergic Agents

Linezolid has the potential for interaction with adrenergic and serotonergic agents.

WARNINGS AND PRECAUTIONS :

Myelosuppression

Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported in patients receiving Linezolid. Discontinuation of therapy with Linezolid should be considered in patients who develop or have worsening myelosuppression.

Peripheral and Optic Neuropathy

Peripheral and optic neuropathies have been reported in patients treated with Linezolid, primarily in those patients treated for longer than the maximum recommended duration of 28 days. If patients experience symptoms of visual impairment, such as changes in visual acuity, changes in color vision, blurred vision, or visual field defect, prompt ophthalmic evaluation is recommended. Visual function should be monitored in all patients taking Linezolid for extended periods (≥ 3 months) and in all patients reporting new visual symptoms regardless of length of therapy with Linezolid. If peripheral or optic neuropathy occurs, the continued use of Linezolid in these patients should be weighed against the potential risks.

Serotonin Syndrome

Patients taking serotonergic antidepressants should receive Linezolid only if no other therapies

are available. Discontinue serotonergic antidepressants and monitor patients for signs and symptoms of both serotonin syndrome and antidepressant discontinuation.

Mortality Imbalance in an Investigational Study in

Patients with Catheter-Related Bloodstream

Linezolid is not approved and should not be used for the treatment of

patients with catheter-related bloodstream infections or catheter-site infections.

Clostridium difficile Associated Diarrhea

• Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Linezolid, and may range in severity from mild diarrhea to fatal colitis.
• Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
• If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued.
• Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Potential Interactions Producing Elevation of Blood Pressure

Unless patients are monitored for potential increases in blood pressure, Linezolid should not be administered to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis and/or patients taking any of the following types of medications: directly and indirectly acting sympathomimetic agents (e.g., pseudoephedrine), vasopressive agents (e.g., epinephrine, norepinephrine), dopaminergic agents (e.g., dopamine, dobutamine).

Lactic Acidosis

Lactic acidosis has been reported with the use of Linezolid. In reported cases, patients experienced repeated episodes of nausea and vomiting. Patients who develop recurrent nausea or vomiting, unexplained acidosis, or a low bicarbonate level while receiving Linezolid should receive immediate medical evaluation.

Convulsions

ConvulsionshavebeenreportedinpatientswhentreatedwithLinezolid.

Insomeofthesecases, ahistoryof seizuresorrisk factors for seizureswas reported.

Hypoglycemia

Postmarketing cases of symptomatic hypoglycemia have been reported in patients with diabetes mellitus receiving insulin or oral hypoglycemic agents when treated with Linezolid, a reversible, nonselective MAO inhibitor. If hypoglycemia occurs, a decrease in the dose of insulin or oral hypoglycemic agent, or discontinuation of oral hypoglycemic agent, insulin, or Linezolid may be required.

Development of Drug-Resistant Bacteria

Prescribing Linezolid in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

In the event of overdosage, supportive care is advised, with maintenance of glomerular filtration. To remove any unabsorbed Linezolid gastric lavage, administration of activated charcoal are recommended. Hemodialysis may facilitate more rapid elimination of Linezolid. In a Phase 1 clinical trial, approximately 30% of a dose of Linezolid was removed during a 3-hour hemodialysis session beginning 3 hours after the dose of Linezolid was administered. Data are not available for removal of Linezolid with peritoneal dialysis or hemoperfusion. Clinical signs of acute toxicity in animals were decreased activity and ataxia in rats and vomiting and tremors in dogs treated with 3000 mg/kg/day and 2000 mg/kg/day, respectively

Store in a dry place at a temperature not exceeding 30°C.

Protect from light.

Keep out of reach of children.

Refer on the pack.

Alu-Alu blister strip of 5 tablets.

Aviptadil Injection 150 µg/10 ml

Each ml contains :

Aviptadil 15 µg

Water for Injections IP q.s.

Injection 150 µg / 10 ml

4.1 Therapeutic indication

For treatment of patients with severe COVID-19 with Acute Respiratory Distress Syndrome (ARDS).

4.2 Posology and method of administration

Aviptadil intravenous infusion is administered by infusion pump in escalating doses for 3 successive days

• Day 1 : Aviptadil 0.166 mcg/kg/hr (equivalent to 1 vial of Aviptadil Injection)
• Day 2 : Aviptadil 0.332 mcg/kg/hr (equivalent to 2 vials of Aviptadil Injection)
• Day 3 : Aviptadil 0.498 mcg/kg/hr (equivalent to 3 vials of Aviptadil Injection)

Duration of infusion depends on the patient's body weight

• Body weight < 60 kg - 14 hour infusions of Aviptadil at escalating doses on 3 successive days.
• Body weight 60 - 90 kg - 12 hour infusions of Aviptadil at escalating doses on 3 successive days.
• Body weight > 90 kg - 10 hour infusions of Aviptadil at escalating doses on 3 successive days.

4.3 Contraindications

Aviptadil is contraindicated in patients who are hypersensitive to any component of this product.

4.4 Special warnings and precautions for use

Mild transient flushing of the face or trunk occurs commonly. This is rarely associated with discomfort and palpitations or tachycardia in which cases patients may be withdrawn from treatment. Aviptadil must be used with caution in patients with severe cardiovascular or cerebrovascular conditions.

4.5 Drugs interactions

No clinically relevant interaction was observed concomitantly to anti-hypertensive drugs or other cardiovascular drugs.

4.6 Use in special populations

No specific studies in special patient populations have been performed so far

4.7 Effects on ability to drive and use machines

No trials on the effect on the ability to drive a car or use machines have been carried out

4.8 Undesirable effects

Gastrointestinal Disorders e.g. Diarrhea, Vascular disorders - Hypotension, cutaneous flushing, facial flushing and Infusion related reactions.

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

No case of overdose has been reported

5.1 Mechanism of action

Aviptadil is a synthetic form of Human Vasoactive Intestinal Polypeptide (VIP). VIP is highly concentrated in the lung and it blocks apoptosis, caspase-3 activation in the lung, inhibits inflammatory cytokines like IL6 and TNF alpha production and reverses CD4/CD8 ratio. VIP increases surfactant production by up regulation of choline phosphate cytidylyltransferase, which increase the incorporation of methyl choline to phosphatidylcholine, the major components of pulmonary surfactant. It also up regulate C Fos protein expression in type II alveolar cells, which increase the synthesis of pulmonary surfactant phospholipids and induce surfactant protein A expression. VIP reduces ischemia-reperfusion injury in animal models. It reduces cell death by inhibiting activation induced perforin, granzyme B and caspase activity. VIP reduces pulmonary inflammation by reducing the production of pro inflammatory cytokines. It inhibits the synthesis and activation of NF-kB, which block the production of TNF alpha. In addition to that VIP blocks SARS-CoV-2 replication in the lungs and monocyte. VIP and pituitary adenylate cyclase activating polypeptide (PACAP) inhibit SARS CoV-2 RNA synthesis in human lung epithelial cell (by 41%) and human primary monocytes (by 33-45%). It also blocks viral cytopathic effect demonstrated by reduced LDH release (by 40%). SARS CoV-2 attack mainly type II cells and results in the death of alveolar type II (AT 11) cells which produces surfactant, resulting in profound defect in oxygenation, leading to hypoxia. Aviptadil a synthetic form of VIP results in rapid clinical recovery in patients with SARS-CoV-2 infection.

5.2 Pharmacodynamic properties

Pulmonary circulation

After intravenous infusion of Aviptadil an increase of heart rate, stroke volume and cardiac output was reported. Right atrial and pulmonary wedge pressure remained unchanged while pulmonary vascular resistance significantly decreased as well as pulmonary arterial systolic pressure. Aviptadil vasodilating properties are 50 times more potent than prostacyclin and independent of the endothelium.

Immunotolerogenic response

In Pulmonary Sarcoidosis, the presumed primary therapeutic mechanism of action of inhaled Aviptadil is a combination of anti-inflammatory properties and induction of tolerogenic immune response of immune cells localized in the lungs.

Systemic circulation

In healthy volunteers intravenous Aviptadil reduced systemic vascular resistance due to its potent vasodilatory effects, followed by increase of heart rate and decrease of blood pressure.

Airway responses

During intravenous infusion (20 ng Aviptadil /kg/min, 30 min), ventilation - perfusion relationships of the lungs (VA/Q) were significantly changed. VA/Q distributions determined by inert gas elimination technique

were shifted to lower values but arterial oxygen tension remained unchanged. Therefore, Aviptadil alters the ventilation - perfusion distributions but generates no shunt and does not cause hypoxia.

5.3 Pharmacokinetic properties

Absorption

Studies with radiolabeled Aviptadil (single intravenous bolus injection of 300 pmol [1 µg]) demonstrate that after the initial rapid clearance from the circulation, the lung is the primary site of peptide binding. Within 30 min., about 45% of the radioactivity is found in the lungs. Only minimal activity was found in the gastrointestinal tract, and almost no activity was seen in normal liver or spleen during the observation period of 24 hours. The radioactivity in the lungs decreased at 4 hours to 25%, and after 24 hours to 10%. Radioactivity was excreted into the urine (35% of the injected dose after 4 hours, and 90% after 24 hours). Half-life of Aviptadil in blood was 1 minute, the metabolic clearance rate was 9 ml/kg/min and the apparent volume of distribution for Aviptadil was about 14 ml/kg.

Distribution

Aviptadil binding to its receptors occurs in discrete locations within the gastrointestinal, respiratory, and genital tracts. Aviptadil is localized on respiratory epithelium, smooth muscles of the airways, blood vessels and alveolar walls.

Elimination

After injection of 1 µg radioactively labelled Aviptadil as bolus to patients a very rapid tissue distribution was observed. Within 30 minutes about 45% of the radioactivity was found in the lungs. Over an observation period of 24 hours only minimal activity was detected in the gastrointestinal tract and almost no activity was found in the liver or spleen. Radioactivity in the lungs decreased within four hours to 25% and within 24 hours to 10%. The half-life of Aviptadil in plasma is about 1-2 minutes. After injection of radiolabelled Aviptadil radioactivity was almost completely eliminated by the kidneys, 35% within 4 hours, and 90% within 24 hours.

6.1 Animal toxicology or pharmacology

In a battery of toxicological tests including repeated dose toxicity in rats and dogs, cardiopulmonary tests in dogs and functional behavioural assays in rats, no adverse side effects were observed with NAP concentrations that were ∼ 500-fold higher than the biologically active dose.

Effect of aviptadil on fertility and early embryonal development

• Aviptadil infusions in rabbits can increase plasma progesterone from both the basal levels of estrus and from the peak levels preceding ovulation.

• Infusions of Aviptadil at the time of the preovulatory steroid surge or during ovulation have little effect upon fertility or gamete transport in the rabbit.

• Endogenous VIP may play a role in the regulation of progesterone secretion in the rabbit.

Effect of aviptadil on embryogenesis

In rats, Aviptadil binding sites in the embryo were analysed during embryonic days E10-E13. Aviptadil binding was almost exclusively located to the brain and spinal cord. The investigation of expression of Aviptadil mRNA from embryo in this stage (E11) revealed totally negative results, indicating extraembryonic, maternal Aviptadil supply to the embryo. Indeed, beginning at day E9, there is an enormous increase of Aviptadil concentration in maternal blood, 6-10 times greater than later on during pregnancy. Data indicate that Aviptadil from maternal tissues may be the source of Aviptadil acting on the embryonic tissues, transferred to the embryo undegraded. On day E17, Aviptadil mRNA expression was easily detectable all over the embryo, and maternal Aviptadil concentration in the blood decreased to very low levels. Aviptadil is required for embryonic development.

Genotoxicity

No evidence of genotoxic potential has been found in in vitro and in vivo studies.

Non-proprietary name : Aviptadil

Other name : VIP (Vasoactive Intestinal Peptide)

Structure of Aviptadil

Aviptadil (VIP) is a linear, 28-AA peptide with an amidated C-terminus. All amino acids of Aviptadil are in Lconfiguration.

Chemical name : H-His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-ValLys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH2

Molecular formula : C₁₄₇H₂₃₈N₄₄O₄2S

Molecular weight : 3325.8 g/mol

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

A vial of 10 ml.

8.4 Storage and handing instructions

Store in a refrigerator (2°C - 8°C). Do not freeze.

Keep out of reach of children.

Do not use in case any foreign particulate matter is observed inside the vial.

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

Olmesartan Medoxomil Tablets 20 mg/40 mg

OLBET-20

Each film coated tablet contains:

Olmesartan Medoxomil Tablets 20 mg

Excipients q.s.

Colour: Titanium Dioxide IP

OLBET-40

Each film coated tablet contains:

Olmesartan Medoxomil Tablets 40 mg

Excipients q.s.

Colour: Titanium Dioxide IP

Film coated tablet

20/ 40 mg

4.1 Therapeutic Indication

Anti- Hypertension

Olmesartan is indicated for the management of Essential hypertension

4.2 Posology and method of administration

Posology

Adults

The recommended starting dose of olmesartan medoxomil is 10 mg once daily. In patients whose blood pressure is not adequately controlled at this dose, the dose of olmesartan medoxomil may be increased to 20 mg once daily as the optimal dose. If additional blood pressure reduction is required, olmesartan medoxomil dose may be increased to a maximum of 40 mg daily or hydrochlorothiazide therapy may be added.

The antihypertensive effect of olmesartan medoxomil is substantially present within 2 weeks of initiating therapy and is maximal by about 8 weeks after initiating therapy. This should be borne in mind when considering changing the dose regimen for any patient.

Older people (65 years or older)

No adjustment of dosage is generally required in older people (see below for dose recommendations in patients with renal impairment). If up-titration to the maximum dose of 40 mg daily is required, blood pressure should be closely monitored.

Patients with 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. The use of olmesartan medoxomil in patients with severe renal impairment (creatinine clearance < 20 ml/min) is not recommended, since there is only limited experience in this patient group.

Patients with hepatic impairment

No adjustment of dosage recommendations is required for patients with mild hepatic impairment. In patients with 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. There is no experience of olmesartan medoxomil in patients with severe hepatic impairment, therefore use is not recommended in this patient group. Olmesartan medoxomil should not be used in patients with biliary obstruction.

Paediatric population

Children and adolescents from 6 to less than 18 years of age. The recommended starting dose of olmesartan medoxomil in children from 6 to less than 18 years of age is 10 mg olmesartan medoxomil once daily. In children whose blood pressure is not adequately controlled at this dose, the dose of olmesartan medoxomil may be increased to 20 mg once daily. If additional blood pressure reduction is required, in children who weigh > 35 kg, the olmesartan medoxomil dose may be increased to a maximum of 40 mg. In children who weigh < 35 kg, the daily dose should not exceed 20 mg.

Other paediatric population

The safety and efficacy of olmesartan medoxomil in children aged 1 to 5 years old have not yet been established.

Olmesartan medoxomil should not be used in children below 1 years of age because of safety concerns and lack of data in this age group.

Method of administration

In order to assist compliance, it is recommended that Olmesartan tablets be taken at about the same time each day, with or without food, for example at breakfast time. The tablet should be swallowed with a sufficient amount of fluid (e.g. one glass of water). The tablet should be swallowed whole without chewing.

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients.
• Second and third trimesters of pregnancy.
• Biliary obstruction.
• The concomitant use of Olmesartan with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2)

4.4 Special warnings and precautions for use

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). 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.

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 older people, 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.

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.

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, exclude other etiologies. Consider discontinuation of olmesartan medoxomil in cases where no other etiology is identified. In cases where symptoms disappear and sprue-like enteropathy is confirmed by biopsy, treatment with olmesartan medoxomil should not be restarted.

Ethnic differences:

As with all other angiotensin II antagonists, the blood pressure lowering effect of olmesartan medoxomil is somewhat less in black patients than in non-black patients, possibly because of a higher prevalence of low-renin status in the black hypertensive population.

Pregnancy:

Angiotensin II receptor antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately and, if appropriate, alternative therapy should be started.

Other:

As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic heart disease or ischaemic cerebrovascular disease could result in a myocardial infarction or stroke.

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.

Olmesartan contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Drugs interactions

Paediatric population:

Interaction studies have only been performed in adults.

It is not known if the interactions in children are similar to those in adults.

Effects of other medicinal products on olmesartan medoxomil:

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.

Other antihypertensive medications:

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

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.

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

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.

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.

4.6 Use in special populations

Pregnancy

The use of AIIRAs is not recommended during the first trimester of pregnancy. The use of AIIRAs is contraindicated during the second and third trimester of pregnancy.

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however, a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with AIIRAs, similar risks may exist for this class of drugs. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to AIIRA therapy during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).

Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.

Infants whose mothers have taken AIIRAs should be closely observed for hypotension.

Breastfeeding

Olmesartan is excreted in the milk of lactating rats but it is not known whether olmesartan is excreted in human milk. Because no information is available regarding the use of Olmesartan during breastfeeding, Olmesartan is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile:

The most commonly reported adverse reactions during treatmentwith olmesartan medoxomil 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%).

Tabulated list of adverse reactions:

Adverse reactions from olmesartan medoxomil in clinical trials, post-authorisation safety studies and spontaneous reporting are summarized in the below table.

They are listed by System Organ Class and ranked under headings of frequency using the following convention: 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); not known (cannot be estimated from available data).

*Cases of autoimmune hepatitis with a latency of few months to years have been reported post-marketing, that were reversible after the withdrawal of olmesartan.

Single cases of rhabdomyolysis have been reported in temporal association with the intake of angiotensin II receptor blockers.

Additional information on special populations

In older people the frequency of hypotension is slightly increased from rare to uncommon.

Paediatric population:

The safety of olmesartan medoxomil was monitored in 361 children and adolescents, aged 1-17 years old during 2 clinical trials. Whilst the nature and severity of the adverse events are similar to that of the adults, the frequency of the following is higher in the children:

- Epistaxis is a common adverse event in children (i.e. ≥ 1/100 to < 1/10) that has not been reported in adults.

- During the 3 weeks of double blind study, the incidence of treatment emergent dizziness and headache nearly doubled in children 6-17 years of age in the high olmesartan medoxomil dose group.

The overall safety profile for olmesartan medoxomil in paediatric patients does not differ significantly from the safety profile in 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.co.in/drug-safety-reporting

4.9 Overdose

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.

5.1 Mechanism of Action/ Pharmacodynamic properties

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. 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.

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.

Clinical efficacy and safety

In hypertension, olmesartan medoxomil causes a dose-dependent, long-lasting reduction in arterial blood pressure. There has been no evidence of first-dose hypotension, of tachyphylaxis during long-term treatment, or of rebound hypertension after cessation of therapy.

Once daily dosing with olmesartan medoxomil provides an effective and smooth reduction in blood pressure over the 24-hour dose interval. Once daily dosing produced similar decreases in blood pressure as twice daily dosing at the same total daily dose.

With continuous treatment, maximum reductions in blood pressure are achieved by 8 weeks after the initiation of therapy, although a substantial proportion of the blood pressure lowering effect is already observed after 2 weeks of treatment. When used together with hydrochlorothiazide, the reduction in blood pressure is additive and coadministration is well tolerated.

The effect of olmesartan on mortality and morbidity is not yet known.

The Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study in 4447 patients with type 2 diabetes, normo-albuminuria and at least one additional cardiovascular risk factor, investigated whether treatment with olmesartan could delay the onset of microalbuminuria. During the median follow-up duration of 3.2 years, patients received either olmesartan or placebo in addition to other antihypertensive agents, except ACE inhibitors or ARBs.

For the primary endpoint, the study demonstrated a significant risk reduction in the time to onset of microalbuminuria, in favour of olmesartan. After adjustment for BP differences this risk reduction was no longer statistically significant. 8.2% (178 of 2160) of the patients in the olmesartan group and 9.8% (210 of 2139) in the placebo group developed microalbuminuria.

For the secondary endpoints, cardiovascular events occurred in 96 patients (4.3%) with olmesartan and in 94 patients (4.2%) with placebo. The incidence of cardiovascular mortality was higher with olmesartan compared to placebo treatment (15 patients (0.7%) vs. 3 patients (0.1%)), despite similar rates for non-fatal stroke (14 patients (0.6%) vs. 8 patients (0.4%)), non-fatal myocardial infarction (17 patients (0.8%) vs. 26 patients (1.2%)) and non-cardiovascular mortality (11 patients (0.5%) vs. 12 patients (0.5%)). Overall mortality with olmesartan was numerically increased (26 patients (1.2%) vs. 15 patients (0.7%)), which was mainly driven by a higher number of fatal cardiovascular events.

The Olmesartan Reducing Incidence of End-stage Renal Disease in Diabetic Nephropathy Trial (ORIENT) investigated the effects of olmesartan on renal and cardiovascular outcomes in 577 randomized Japanese and Chinese type 2 diabetic patients with overt nephropathy. During a median follow-up of 3.1 years, patients received either olmesartan or placebo in addition to other antihypertensive agents including ACE inhibitors.

The primary composite endpoint (time to first event of the doubling of serum creatinine, end-stage renal disease, all-cause death) occurred in 116 patients in the olmesartan group (41.1%) and 129 patients in the placebo group (45.4%) (HR 0.97 (95% CI 0.75 to 1.24); p=0.791). The composite secondary cardiovascular endpoint occurred in 40 olmesartan-treated patients (14.2%) and 53 placebo-treated patients (18.7%). This composite cardiovascular endpoint included cardiovascular death in 10 (3.5%) patients receiving olmesartan versus 3 (1.1%) receiving placebo, overall mortality 19 (6.7%) versus 20 (7.0%), non-fatal stroke 8 (2.8%) versus 11 (3.9%) and non-fatal myocardial infarction 3 (1.1%) versus 7 (2.5%), respectively.

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.

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

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.

Paediatric population:

The antihypertensive effects of olmesartan medoxomil in the paediatric population were evaluated in a randomized, double-blind, placebo-controlled study in 302 hypertensive patients aged 6 to 17 years. The study population consisted of an all-black cohort of 112 patients and a mixed racial cohort of 190 patients, including 38 blacks. The aetiology of the hypertension was predominantly essential hypertension (87% of the black cohort and 67% of the mixed cohort). Patients who weighed 20 to <35 kg were randomized to 2.5 mg (low dose) or 20 mg (high dose) of olmesartan medoxomil once daily and patients who weighed ≥ 35 kg were randomized to 5 mg (low dose) or 40 mg (high dose) of olmesartan medoxomil once daily. Olmesartan medoxomil significantly reduced both systolic and diastolic blood pressure in a weight-adjusted dose-dependent manner. Olmesartan medoxomil at both low and high doses significantly reduced systolic blood pressure by 6.6 and 11.9 mmHg from the baseline, respectively. This effect was also observed during the 2 weeks randomized withdrawal phase, whereby both mean systolic and diastolic blood pressures demonstrated a statistically significant rebound in the placebo group compared to olmesartan medoxomil group. The treatment was effective in both, paediatric patients with primary and secondary hypertension. As observed in adult populations, the blood pressure reductions were smaller in black patients.

In the same study, 59 patients aged 1 to 5 years who weighed ≥ 5 kg received 0.3 mg/kg of olmesartan medoxomil once daily for three weeks in an open label phase and then were randomized to receiving olmesartan medoxomil or placebo in a double-blind phase. At the end of the second week of withdrawal, the mean systolic/diastolic blood pressure at trough was 3/3 mmHg lower in the group randomized to olmesartan medoxomil; this difference in blood pressure was not statistically significant (95% C.I. -2 to 7/-1 to 7).

5.3 Pharmacokinetic properties

Absorption and distribution

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 co-administered 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).

Biotransformation and elimination

Total plasma clearance was typically 1.3 l/h (CV, 19%) and was relatively slow compared to hepatic blood flow (ca 90 l/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.

Pharmacokinetics in special populations

Older people (age 65 years or older):

In hypertensive patients, the AUC at steady state was increased by ca 35% in older people (65 – 75 years old) and by ca 44% in very old people (≥ 75 years old) compared with the younger age group. This may be at least in part related to a mean decrease in renal function in this group of patients.

Renal impairment:

In renally impaired patients, the AUC at steady state increased by 62%, 82% and 179% in patients with mild, moderate and severe renal impairment, respectively, compared to healthy controls.

Hepatic impairment:

After single oral administration, olmesartan AUC values were 6% and 65% higher in mildly and moderately hepatically impaired patients, respectively, than in their corresponding matched healthy controls. The unbound fraction of olmesartan at 2 hours post-dose in healthy subjects, in patients with mild hepatic impairment and in patients with moderate hepatic impairment was 0.26%, 0.34% and 0.41%, respectively. Following repeated dosing in patients with moderate hepatic impairment, olmesartan mean AUC was again about 65% higher than in matched healthy controls. Olmesartan mean Cmax values were similar in hepatically-impaired and healthy subjects. Olmesartan medoxomil has not been evaluated in patients with severe hepatic impairment.

Paediatric population:

The pharmacokinetics of olmesartan was studied in paediatric hypertensive patients aged 1 to16 years. The clearance of olmesartan in paediatric patients was similar to that in adult patients when adjusted by the body weight.

There is no pharmacokinetic information available in renally impaired paediatric subjects.

Drug interactions

Bile acid sequestering agent colesevelam:

Concomitant administration of 40 mg olmesartan medoxomil and 3750 mg colesevelam hydrochloride in healthy subjects resulted in 28% reduction in Cmax and 39% reduction in AUC of olmesartan. Lesser effects, 4% and 15% reduction in Cmaxand AUC respectively, were observed when olmesartan medoxomil was administered 4 hours prior to colesevelam hydrochloride. Elimination half-life of olmesartan was reduced by 50 – 52% irrespectively of whether administered concomitantly or 4 hours prior to colesevelam hydrochloride.

6.1 Animal Toxicology or Pharmacology

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.

Olmesartan medoxomil, a prodrug, is hydrolyzed to olmesartan during absorption from the gastrointestinal tract. Olmesartan is a selective AT1 subtype angiotensin II receptor antagonist.

Chemical name: 2,3-dihydroxy-2-butenyl 4 (1-hydroxy-1-methylethyl)-2-propyl-1-[p-(o-1H-tetrazol-5-ylphenyl) benzyl] imidazole-5-carboxylate, cyclic 2,3-carbonate

Molecular formula: C₂₉H₃₀N₆O₆

Molecular mass: 558.59 g/mol

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

Refer on pack

8.3 Packaging information

10 blister strips of 10 tablets each

8.4 Storage and handing instructions

• Store below 25°C. Protected from light & moisture.
• Keep out of reach of children.

• Pregnancy: Advise female patients of childbearing age about the consequences of exposure to Olbet during pregnancy. Discuss treatment options with women planning to become pregnant. Tell patients to report pregnancies to their physicians as soon as possible.
• Lactation: Advise nursing women not to breastfeed during treatment with Olbet.
• Hyperkalemia: Advise patients not to use potassium supplements or salt substitutes that contain potassium without consulting their healthcare provider.

10/10/2024

Olmesartan Medoxomil, Chlorthalidone and Amlodipine Tablets

Olbet TRIO 20

Each film coated tablet contains:

Olmesartan Medoxomil IP…………….20 mg

Chlorthalidone IP……………………12.5 mg

Amlodipine Besylate IP

equivalent to Amlodipine………………5 mg

Excipients………………………………...q.s.

Olbet TRIO 40

Each film coated tablet contains:

Olmesartan Medoxomil IP…………….40 mg

Chlorthalidone IP……………………12.5 mg

Amlodipine Besylate IP

equivalent to Amlodipine……………………………..5 mg

Excipients…………………………………q.s.

Film-coated tablet. (Olmesartan Medoxomil, Chlorthalidone and Amlodipine)

20mg/12.5mg/5mg, 40mg/12.5mg/5mg.

4.1 Therapeutic Indication

For the treatment of essential hypertension

4.2 Posology and method of administration

Adults

The recommended dose is 1 tablet per day.

Renal impairment

The maximum dose in patients with mild to moderate renal impairment (creatinine clearance of 30 - 60 mL/min) is Olbet Trio 20 mg/5 mg/12.5 mg, owing to limited experience of the 40 mg Olmesartan Medoxomil dosage in this patient group. Monitoring of serum concentrations of potassium and creatinine is advised in patients with moderate renal impairment.

The use of Olbet Trio in patients with severe renal impairment (creatinine clearance < 30 mL/min) is contraindicated.

Hepatic impairment

In patients with moderate hepatic impairment the maximum dose should not exceed 20 mg/5 mg/12.5 mg once daily.

Method of administration

The table should be swallowed with a sufficient amount of fluid (e.g. one glass of water). The tablet should not be chewed and should be taken at the same time each day. It can be taken with or without food.

4.3 Contraindications

• Hypersensitivity to Olmesartan medoxomil, chlorthalidone, amlodipine or to any of the excipients.
• Severe renal impairment.
• Refractory hypokalemia, hypercalcemia, hyponatremia and symptomatic hyperuricemia.
• Severe hepatic insufficiency, cholestasis and biliary obstructive disorders.
• Pregnancy.
• Anuria
• Concomitant use of Olbet Trio with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m2)
• Due to the Amlodipine component, it is contraindicated in patients with:
  • Shock (including cardiogenic shock).
  • Severe hypotension.
  • Obstruction of the outflow tract of the left ventricle (e.g. high grade aortic stenosis).
  • Haemodynamically unstable heart failure after acute myocardial infarction.

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.

Amlodipine

The safety and efficacy of amlodipine in hypertensive crisis has not been established.

Patients with cardiac failure:

Patients with heart failure should be treated with caution. In a long-term, placebo controlled study in patients with severe heart failure (NYHA class III and IV) the reported incidence of pulmonary oedema was higher in the amlodipine treated group than in the placebo group.

Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

Patients with hepatic impairment:

The half life of amlodipine is prolonged and AUC values are higher in patients with impaired liver function; dosage recommendations have not been established. Amlodipine should therefore be initiated at the lower end of the dosing range and caution should be used, both on initial treatment and when increasing the dose. Slow dose titration and careful monitoring may be required in patients with severe hepatic impairment.

Elderly patients:

In the elderly increase of the dosage should take place with care (see sections 4.2 and 5.2).

Patients with renal impairment:

Amlodipine may be used in such patients at normal doses. Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment. Amlodipine is not dialysable.

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.

Amlodipine

Effects of other medicinal products on amlodipine

CYP3A4 inhibitors

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine exposure resulting in an increased risk of hypotension. The clinical translation of these PK variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required.

CYP3A4 inducers

Upon co-administration of known inducers of the CYP3A4, the plasma concentration of amlodipine may vary. Therefore, blood pressure should be monitored and dose regulation considered both during and after concomitant medication particularly with strong CYP3A4 inducers (e.g. rifampicin, hypericum perforatum).

Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients resulting in increased blood pressure lowering effects.

Dantrolene (infusion)

In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalaemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalaemia, it is recommended that the co-administration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.

Effects of amlodipine on other medicinal products

The blood pressure lowering effects of amlodipine adds to the blood pressure-lowering effects of other medicinal products with antihypertensive properties.

Tacrolimus

There is a risk of increased tacrolimus blood levels when co-administered with amlodipine but the pharmacokinetic mechanism of this interaction is not fully understood. In order to avoid toxicity of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.

Mechanistic Target of Rapamycin (mTOR) Inhibitors

mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. With concomitant use of mTOR inhibitors, amlodipine may increase exposure of mTOR inhibitors.

Cyclosporin

No drug interaction studies have been conducted with cyclosporin and amlodipine in healthy volunteers or other populations with the exception of renal transplant patients, where variable trough concentration increases (average 0% - 40%) of cyclosporin were observed.

Consideration should be given for monitoring cyclosporin levels in renal transplant patients on amlodipine, and ciclosporin dose reductions should be made as necessary.

Simvastatin

Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.

In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin or warfarin.

4.6 Use in special populations

Pregnancy

Use of Olbet TRIO is Not recommended in pregnancy.

Breast-feeding

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

4.7 Effects on ability to drive and use machines

Olbet-TRIO can have minor or moderate influence on the ability to drive and use machines.

Dizziness, headache, nausea or fatigue may occasionally occur in patients taking antihypertensive therapy, which may impair the ability to react. Caution is recommended especially at the start of treatment.

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.

Amlodipine

The most commonly reported adverse reactions during treatment are somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle swelling, oedema and fatigue.

The following adverse reactions have been observed and reported during treatment with amlodipine:

• Blood and lymphatic system disorders: Leukocytopenia, thrombocytopenia
• Immune system disorders: Allergic reactions
• Metabolism and nutrition disorders: Hyperglycaemia
• Psychiatric disorders: Depression, mood changes (including anxiety), insomnia, Confusion
• Nervous system disorders: Somnolence, dizziness, headache (especially at the beginning of the treatment), Tremor, dysgeusia, syncope, hypoesthesia, paresthesia, Hypertonia, peripheral neuropathy, Extrapyramidal disorder
• Eye disorders: Visual disturbance (including diplopia)
• Ear and labyrinth disorders: Tinnitus
• Cardiac disorders: Palpitations, Arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), Myocardial infarction.
• Vascular disorders: Flushing, Hypotension, Vasculitis
• Respiratory, thoracic and mediastinal disorders: Dyspnoea, Cough, rhinitis.
• Gastrointestinal disorders: Abdominal pain, nausea, dyspepsia, altered bowel habits (including diarrhoea and constipation), Vomiting, dry mouth, Pancreatitis, gastritis, gingival hyperplasia.
• Hepatobiliary disorders: Hepatitis, jaundice, hepatic enzymes increased
• Skin and subcutaneous tissue disorders: Alopecia, purpura, skin discolouration, hyperhidrosis, pruritus, rash, exanthema, urticaria, Angioedema, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke oedema, photosensitivity, Toxic Epidermal Necrolysis
• Musculoskeletal and connective tissue disorders: Ankle swelling, muscle cramps, Arthralgia, myalgia, back pain
• Renal and urinary disorders: Micturition disorder, nocturia, increased urinary frequency
• Reproductive system and breast disorders: Impotence, gynaecomastia
• General disorders and administration site conditions: Oedema, Fatigue, asthenia

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

Symptoms:

The most likely effect of Olbet Trio overdosage is hypotension.

The most likely effects of Olmesartan Medoxomil overdosage is hypotension. Amlodipine overdosage can be expected to lead to excessive peripheral vasodilatation with marked hypotension and possibly a reflex tachycardia. Marked and potentially prolonged systemic hypotension, up to and including shock with fatal outcome, has been reported.

In poisoning due to an overdosage the following signs and symptoms may occur : dizziness, nausea, somnolence, hypovolemia, hypotension and electrolyte disturbances associated with cardiac arrhythmias and muscle spasms.

Treatment

In the event of overdosage with Olbet Trio, treatment should be symptomatic and supportive. Management depends upon the time since ingestion and the severity of the symptoms.

If intake is recent, gastric lavage may be considered. In healthy subjects, the administration of activated charcoal immediately or up to 2 hours after ingestion of Amlodipine has been shown to reduce substantially the absorption of Amlodipine.

Clinically significant hypotension due to an overdose of Olbet Trio requires active support of the cardiovascular system, including close monitoring of heart and lung function, elevation of the extremities, and attention to circulating fluid volume and urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous Calcium gluconate may be beneficial in reversing the effects of Calcium channel blockade.

The dialyzability of Olmesartan or Chlorthalidone is unknown. The degree to which Olmesartan and Chlorthalidone are removed by haemodialysis has not been established.

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.

Amlodipine

Amlodipine is a calcium channel blocker that inhibits the transmembrane influx of calcium ions through the potential-dependent L-type channels into the heart and smooth muscle. Experimental data indicate that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites. Amlodipine is relatively vessel-selective, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. The antihypertensive effect of amlodipine derives from a direct relaxant effect on arterial smooth muscle, which leads to a lowering of peripheral resistance and hence of blood pressure.

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.

Amlodipine

In hypertensive patients, amlodipine causes a dose-dependent, long-lasting reduction in arterial blood pressure. There has been no evidence of first-dose hypotension, of tachyphylaxis during long-term treatment, or of rebound hypertension after abrupt cessation of therapy.

Following administration of therapeutic doses to patients with hypertension, amlodipine produces an effective reduction in blood pressure in the supine, sitting and standing positions. Chronic use of amlodipine is not associated with significant changes in heart rate or plasma catecholamine levels. In hypertensive patients with normal renal function, therapeutic doses of amlodipine reduce renal vascular resistance and increase glomerular filtration rate and effective renal plasma flow, without changing filtration fraction or proteinuria.

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.

Amlodipine

After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 80%. The volume of distribution is approximately 21 l/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.

The absorption of amlodipine is unaffected by the concomitant intake of food.

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.

Amlodipine

The terminal plasma elimination half-life is about 35-50 hours and is consistent with once daily dosing. Amlodipine is extensively metabolised by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted 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.

Amlodipine

Reproductive toxicology

Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of labour and decreased pup survival at dosages approximately 50 times greater than the maximum recommended dosage for humans based on mg/kg.

Impairment of fertility

There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females 14 days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum recommended human dose of 10 mg on a mg/m2 basis). In another rat study in which male rats were treated with amlodipine besilate for 30 days at a dose comparable with the human dose based on mg/kg, decreased plasma follicle-stimulating hormone and testosterone were found as well as decreases in sperm density and in the number of mature spermatids and Sertoli cells.

Carcinogenesis, mutagenesis

Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of carcinogenicity. The highest dose (for mice, similar to, and for rats twice* the maximum recommended clinical dose of 10 mg on a mg/m2 basis) was close to the maximum tolerated dose for mice but not for rats.

Mutagenicity studies revealed no drug related effects at either the gene or chromosome levels.

*Based on patient weight of 50 kg

Olbet™ - TRIO tablet contains combination of Olmesartan Medoxomil, Chlorthalidone and Amlodipine.

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.

The structural formula for olmesartan medoxomil is:

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.

The structural formula for Chlorthalidone is:

Amlodipine is a Calcium ion influx inhibitor of the Dihydropyridine group (slow channel blocker or calcium ion antagonist). The amlodipine besylate is chemically described as 3-ethyl-5-methyl (±)-2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl) -1,4-dihydro- 6-methyl- 3,5-pyridine dicarboxylate, monobenzenesulphonate.

The structural formula for amlodipine besylate is:

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

Refer on pack

8.3 Packaging information

10 blister strips of 10 tablets each

8.4 Storage and handing instructions

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

Keep out of reach of children.

• Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to Olbet TRIO during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.
• Symptomatic Hypotension: A patient receiving Olbet TRIO should be cautioned that light-headedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician. Tell patients that if syncope occurs, Olbet TRIO should be discontinued until the physician has been consulted.
• Caution patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of light-headedness and possible syncope

29/11/2024

Amlodipine and Olmesartan Medoxomil Tablets IP

Olbet AM 20

Each film-coated tablet contains:

Amlodipine Besilate IP equivalent to Amlodipine 5 mg

Olmesartan Medoxomil IP 20 mg

Excipients q.s.

Colours: Lake of Quinoline Yellow WS & Titanium Dioxide IP

Olbet-AM 40

Each film-coated tablet contains:

Amlodipine Besilate IP equivalent to Amlodipine 5 mg

Olmesartan Medoxomil IP 40 mg

Excipients q.s.

Colours: Lake of Quinoline Yellow WS & Titanium Dioxide IP

Film-coated tablet.

5mg/20mg and 5mg/40mg

4.1 Therapeutic Indications

Olbet AM 20:

1. For the treatment of mild to moderate hypertension.

Olbet-AM 40:

1. For the treatment of hypertension alone or with other antihypertensive agents
2. To use as initial therapy in patients who are likely to need multiple antihypertensive agents to achieve their blood pressure goals.

4.2 Posology and Method of Administration

Adults

The recommended dosage of Olbet-AM is one tablet per day.

Olbet-AM 5 mg/20 mg may be administered in patients whose blood pressure is not adequately controlled by 20 mg olmesartan medoxomil or 5 mg amlodipine alone.

Olbet-AM 5 mg/ 40 mg may be administered in patients whose blood pressure is not adequately controlled by Olbet-AM 20 mg/5 mg.

A stepwise titration of the dosage of the individual components is recommended before changing to the fixed combination. When clinically appropriate, direct change from monotherapy to the fixed combination may be considered. For convenience, patients receiving olmesartan medoxomil and amlodipine from separate tablets may be switched to Olbet-AM tablets containing the same component doses. Olbet-AM can be taken with or without food.

Older people (age 65 years or over)

No adjustment of the recommended dose is generally required for older people but increase of the dosage should take place with care. Blood pressure should be closely monitored If up titration to the maximum dose of 40 mg olmesartan daily is required.

Renal impairment

The maximum dose of olmesartan medoxomil 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. The use of Olbet-AM in patients with severe renal impairment (creatinine clearance < 20 mL/min) is not recommended. Monitoring of potassium levels and creatinine is advised in patients with moderate renal impairment.

Hepatic impairment

Olbet-AM should be used with caution in patients with mild to moderate hepatic impairment. In patients with 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. As with all calcium antagonists, amlodipine's half life is prolonged in patients with impaired liver function and dosage recommendations have not been established. Olbet-AM should therefore be administered with caution in these patients. Use of Olbet-AM in patients with severe hepatic impairment is contraindicated.

Paediatric population

The safety and efficacy of Olbet-AM in children and adolescents below 18 years has not been established.

Method of administration

The tablet should be swallowed with a sufficient amount of fluid (e.g. one glass of water). The tablet should not be chewed and should be taken at the same time each day.

4.3 Contraindications

• Hypersensitivity to the active substances, to dihydropyridine derivatives or to any of the excipients
• Second and third trimesters of pregnancy.
• Severe hepatic insufficiency and biliary obstruction.
• The concomitant use of Olbet-AM with aliskiren containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m2).

Due to the component amlodipine, Olbet-AM is also contraindicated in patients with:

• Severe hypotension.
• Shock (including cardiogenic shock).
• Obstruction of the outflow tract of the left ventricle (e.g. aortic stenosis).
• Hemodynamically unstable heart failure after acute myocardial infarction

4.4 Special Warnings and Precautions for Use

Patients with hypovolaemia or sodium depletion:

Symptomatic hypotension may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, and diarrhoea or vomiting, especially after the first dose. Correction of this condition prior to administration of Olbet-AM or close medical supervision at the start of the treatment is recommended.

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 medicinal products that affect this system, such as angiotensin II receptor antagonists, has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure.

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

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 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.

Hepatic impairment:

Exposure to amlodipine and olmesartan medoxomil is increased in patients with hepatic impairment. Care should be taken when Olbet-AM is administered in patients with mild to moderate hepatic impairment. In moderately impaired patients, the dose of olmesartan medoxomil should not exceed 20 mg. In patients with impaired hepatic function, amlodipine should be initiated at the lower end of the dosing range and caution should be used, both on initial treatment and when increasing the dose. Use of Olbet-AM in patients with severe hepatic impairment is contraindicated.

Hyperkalaemia:

As with other angiotensin II antagonists and ACE inhibitors, hyperkalaemia may occur during treatment, especially in the presence of renal impairment and/or heart failure. Close monitoring of serum potassium levels in at-risk patients is recommended.

Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other medicinal products that may increase potassium levels (heparin, etc.) should be undertaken with caution and with frequent monitoring of potassium levels.

Lithium:

As with other angiotensin II receptor antagonists, the concomitant use of Olbet-AM and lithium is not recommended.

Aortic or mitral valve stenosis; obstructive hypertrophic cardiomyopathy:

Due to the amlodipine component of Olbet-AM, as with all 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 medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of Olbet-AM is not recommended in such patients.

Heart failure:

As a consequence of the inhibition of the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotaemia and (rarely) with acute renal failure and/or death.

Patients with heart failure should be treated with caution. In a long-term, placebo controlled study of amlodipine in patients with severe heart failure (NYHA III and IV), the reported incidence of pulmonary oedema was higher in the amlodipine group than in the placebo group. Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

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.

Ethnic differences:

As with all other angiotensin II antagonists, the blood pressure lowering effect of Olbet-AM can be somewhat less in black patients than in non-black patients, possibly because of a higher prevalence of low-renin status in the black hypertensive population.

Elderly

In the elderly, increase of the dosage should take place with care.

Pregnancy:

Angiotensin II antagonists should not be initiated during pregnancy. Unless continued angiotensin II antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.

Other:

As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic heart disease or ischaemic cerebrovascular disease could result in a myocardial infarction or stroke.

4.5 Drugs interactions

Potential interactions related to the Olbet-AM combination:

To be taken into account with concomitant use

Other antihypertensive agents:

The blood pressure lowering effect of Olbet-AM can be increased by concomitant use of other antihypertensive medicinal products (e.g. alpha-blockers, diuretics).

Potential interactions related to the olmesartan medoxomil component of Olbet-AM:

Concomitant use not recommended

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.

Medicinal products affecting potassium levels:

Concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase serum potassium levels (e.g. heparin, ACE inhibitors) may lead to increases in serum potassium. If medicinal products, which affect potassium levels, are to be prescribed in combination with Olbet-AM, monitoring of serum potassium levels is recommended.

Lithium:

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

Concomitant use requiring caution

Non-steroidal anti-inflammatory medicinal products (NSAIDs) including selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs:

When angiotensin II antagonists are administered simultaneously with NSAIDs, attenuation of the antihypertensive effect may occur. Furthermore, concomitant use of angiotensin II antagonists and NSAIDs may increase the risk of worsening of renal function and may lead to an increase in serum potassium. Therefore monitoring of renal function at the beginning of such concomitant therapy is recommended, as well as adequate hydration of the patient.

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.

Additional information

After treatment with antacid (aluminium magnesium hydroxide), a modest reduction in bioavailability of olmesartan was observed.

Olmesartan medoxomil had no significant effect on the pharmacokinetics or pharmacodynamics of warfarin or the pharmacokinetics of digoxin. Coadministration of olmesartan medoxomil with pravastatin had no clinically relevant effects on the pharmacokinetics of either component in healthy subjects.

Olmesartan had no clinically relevant inhibitory effects on human cytochrome P450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1 and 3A4 in vitro, and had no or minimal inducing effects on rat cytochrome P450 activities. No clinically relevant interactions between olmesartan and medicinal products metabolised by the above cytochrome P450 enzymes are expected.

Potential interactions related to the amlodipine component of Olbet-AM:

Effects of other medicinal products on amlodipine

CYP3A4 inhibitors:

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine exposure. The clinical translation of these PK variations may be more pronounced in the elderly. There is an increased risk of hypotension. Close observation of patients is recommended and dose adjustment may thus be required.

CYP3A4 inducers:

Upon co-administration of known inducers of the CYP3A4, the plasma concentration of amlodipine may vary. Therefore, blood pressure should be monitored and dose regulation considered both during and after concomitant medication particularly with strong CYP3A4 inducers (e.g. rifampicin, hypericum perforatum).

Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients resulting in increased blood pressure lowering effects.

Dantrolene (infusion): In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalaemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalaemia, it is recommended that the co-administration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.

Effects of amlodipine on other medicinal products

The blood pressure lowering effects of amlodipine adds to the blood pressure-lowering effects of other antihypertensive agents.

In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin or warfarin.

Simvastatin: Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.

Tacrolimus: There is a risk of increased tacrolimus blood levels when co-administered with amlodipine. In order to avoid toxicity of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.

Mechanistic Target of Rapamycin (mTOR) Inhibitors: mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. With concomitant use of mTOR inhibitors, amlodipine may increase exposure of mTOR inhibitors.

Cyclosporine: In a prospective study in renal transplant patients, an average 40% increase in trough cyclosporine levels was observed when used concomitantly with amlodipine. The co-administration of Olbet-AM with cyclosporine may increase exposure to cyclosporine. Monitor trough cyclosporine levels during concomitant use and cyclosporine dose reductions should be made as necessary.

4.6 Use in special populations

Pregnancy

There are no data about the use of Olbet-AM in pregnant patients. Animal reproductive toxicity studies with Olbet-AM have not been performed.

Olmesartan medoxomil

The use of angiotensin II antagonists is not recommended during the first trimester of pregnancy. The use of angiotensin II antagonists is contraindicated during the 2nd and 3rd trimesters of pregnancy.

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with angiotensin II antagonists, similar risks may exist for this class of drugs. Unless continued angiotensin II antagonists therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to angiotensin II antagonists therapy during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).

Should exposure to angiotensin II antagonists have occurred from the second trimester on, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken angiotensin II antagonists should be closely observed for hypotension.

Amlodipine

Data on a limited number of exposed pregnancies do not indicate that amlodipine or other calcium receptor antagonists have a harmful effect on the health of the fetus. However, there may be a risk of prolonged delivery.

Therefore, Olbet-AM is not recommended during the first trimester of pregnancy and is contraindicated during the second and third trimesters of pregnancy.

Breastfeeding

Olmesartan is excreted into the milk of lactating rats. However, it is not known whether olmesartan passes into human milk.

Amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3 – 7%, with a maximum of 15%. The effect of amlodipine on infants is unknown.

During breast-feeding, Olbet-AM is not recommended and alternative treatments with better-established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

4.7 Effects on Ability to Drive and Use Machines

Olbet-AM can have minor or moderate influence on the ability to drive and use machines.

Dizziness, headache, nausea or fatigue may occasionally occur in patients taking antihypertensive therapy, which may impair the ability to react. Caution is recommended especially at the start of treatment.

4.8 Undesirable Effects

The most commonly reported adverse reactions during treatment with Olbet AM are peripheral oedema (11.3%), headache (5.3%) and dizziness (4.5%).

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), not known (cannot be estimated from the available data)

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

Symptoms:

There is no experience of overdose with Olbet-AM. The most likely effects of olmesartan medoxomil overdosage are hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurred. Amlodipine overdosage can be expected to lead to excessive peripheral vasodilatation with marked hypotension and possibly a reflex tachycardia. Marked and potentially prolonged systemic hypotension up to and including shock with fatal outcome has been reported.

Non-cardiogenic pulmonary oedema has rarely been reported as a consequence of amlodipine overdose that may manifest with a delayed onset (24-48 hours post-ingestion) and require ventilatory support. Early resuscitative measures (including fluid overload) to maintain perfusion and cardiac output may be precipitating factors.

Treatment:

If intake is recent, gastric lavage may be considered. In healthy subjects, the administration of activated charcoal immediately or up to 2 hours after ingestion of amlodipine has been shown to reduce substantially the absorption of amlodipine.

Clinically significant hypotension due to an overdose of Olbet-AM requires active support of the cardiovascular system, including close monitoring of heart and lung function, elevation of the extremities, and attention to circulating fluid volume and urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade.

Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit. The dialysability of olmesartan is unknown.

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Angiotensin II antagonists and calcium channel blockers, ATC code C09DB02.

Mechanism of action

Olbet-AM is a combination of an angiotensin II receptor antagonist, olmesartan medoxomil, and a calcium channel blocker, amlodipine besilate. The combination of these active ingredients has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.

The antihypertensive effect of Olbet-AM was similar irrespective of age and gender, and was similar in patients with and without diabetes.

Olmesartan medoxomil

The olmesartan medoxomil component of Olbet-AM is a selective angiotensin II type 1 (AT1) receptor antagonist. Olmesartan medoxomil is rapidly converted to the pharmacologically active metabolite, olmesartan. Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a significant role in the pathophysiology of hypertension. The effects of angiotensin II include vasoconstriction, stimulation of the synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by blocking its binding to the AT1 receptor in tissues including vascular smooth muscle and the adrenal gland. The action of olmesartan is independent of the source or route of synthesis of angiotensin II. The selective antagonism of the angiotensin II (AT1) receptors by olmesartan results in increases in plasma renin levels and angiotensin I and II concentrations, and some decrease in plasma aldosterone concentrations.

In hypertension, olmesartan medoxomil causes a dose-dependent, long-lasting reduction in arterial blood pressure. There has been no evidence of first-dose hypotension, of tachyphylaxis during long-term treatment, or of rebound hypertension after abrupt cessation of therapy.

Following once daily administration to patients with hypertension, olmesartan medoxomil produces an effective and smooth reduction in blood pressure over the 24 hour dose interval. Once daily dosing produced similar decreases in blood pressure as twice daily dosing at the same total daily dose.

With continuous treatment, maximum reductions in blood pressure are achieved by 8 weeks after the initiation of therapy, although a substantial proportion of the blood pressure lowering effect is already observed after 2 weeks of treatment.

The effect of olmesartan medoxomil on mortality and morbidity is not yet known.

Amlodipine

The amlodipine component of Olbet-AM is a calcium channel blocker that inhibits the transmembrane influx of calcium ions through the potential-dependent L-type channels into the heart and smooth muscle. Experimental data indicate that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites. Amlodipine is relatively vessel-selective, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. The antihypertensive effect of amlodipine derives from a direct relaxant effect on arterial smooth muscle, which leads to a lowering of peripheral resistance and hence of blood pressure.

In hypertensive patients, amlodipine causes a dose-dependent, long-lasting reduction in arterial blood pressure. There has been no evidence of first-dose hypotension, of tachyphylaxis during long-term treatment, or of rebound hypertension after abrupt cessation of therapy.

Following administration of therapeutic doses to patients with hypertension, amlodipine produces an effective reduction in blood pressure in the supine, sitting and standing positions. Chronic use of amlodipine is not associated with significant changes in heart rate or plasma catecholamine levels. In hypertensive patients with normal renal function, therapeutic doses of amlodipine reduce renal vascular resistance and increase glomerular filtration rate and effective renal plasma flow, without changing filtration fraction or proteinuria.

In haemodynamic studies in patients with heart failure and in clinical studies based on exercise tests in patients with NYHA class II-IV heart failure, amlodipine was found not to cause any clinical deterioration, as measured by exercise tolerance, left ventricular ejection fraction and clinical signs and symptoms.

5.2 Pharmacokinetic Properties

Olbet-AM

Following oral intake of Olbet-AM, peak plasma concentrations of olmesartan and amlodipine are reached at 1.5 – 2 h and 6 – 8 hours, respectively. The rate and extent of absorption of the two active substances from Olbet-AM are equivalent to the rate and extent of absorption following intake of the two components as separate tablets. Food does not affect the bioavailability of olmesartan and amlodipine from Olbet-AM.

Olmesartan medoxomil

Absorption and distribution:

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 active substances 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).

Biotransformation and elimination:

Total plasma clearance of olmesartan was typically 1.3 L/h (CV, 19%) and was relatively slow compared to hepatic blood flow (ca 90 L/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 is between 10 and 15 hours after multiple oral dosing. Steady state is reached after the first few doses and no further accumulation is evident after 14 days of repeated dosing. Renal clearance is approximately 0.5 – 0.7 L/h and is independent of dose.

Drug interactions

Bile acid sequestering agent colesevelam:

Concomitant administration of 40 mg olmesartan medoxomil and 3750 mg colesevelam hydrochloride in healthy subjects resulted in 28% reduction in Cmax and 39% reduction in AUC of olmesartan. Lesser effects, 4% and 15% reduction in Cmax and AUC respectively, were observed when olmesartan medoxomil was administered 4 hours prior to colesevelam hydrochloride. Elimination half-life of olmesartan was reduced by 50 – 52% irrespectively of whether administered concomitantly or 4 hours prior to colesevelam hydrochloride.

Amlodipine

Absorption and distribution:

After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 80%. The volume of distribution is approximately 21 l/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.

The absorption of amlodipine is unaffected by the concomitant intake of food.

Biotransformation and elimination:

The terminal plasma elimination half-life is about 35-50 hours and is consistent with once daily dosing. Amlodipine is extensively metabolised by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine.

Olmesartan medoxomil and amlodipine

Special populations

Paediatric population (age below 18 years):

No pharmacokinetic data in paediatric patients are available.

Elderly (age 65 years or over):

In hypertensive patients, the olmesartan AUC at steady state is increased by ca 35% in elderly people (65 – 75 years old) and by ca 44% in very elderly people (≥ 75 years old) compared with the younger age group (see section 4.2). This may be at least in part related to a mean decrease in renal function in this group of patients. The recommended dosage regimen for elderly people is, however, the same, although caution should be exercised when increasing the dosage.

The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger subjects. Amlodipine clearance tends to be decreased with resulting increases in AUC and elimination half-life in elderly people. Increases in AUC and elimination half-life in patients with congestive heart failure were as expected for the patient age group in this study.

Renal impairment:

In renally impaired patients, the olmesartan AUC at steady state increased by 62%, 82% and 179% in patients with mild, moderate and severe renal impairment, respectively, compared to healthy controls.

Amlodipine is extensively metabolised to inactive metabolites. Ten percent of the substance is excreted unchanged in the urine. Changes in amlodipine plasma concentration are not correlated with the degree of renal impairment. In these patients, amlodipine may be administered at the normal dosage. Amlodipine is not dialysable.

Hepatic impairment:

After single oral administration, olmesartan AUC values are 6% and 65% higher in mildly and moderately hepatically impaired patients, respectively, than in their corresponding matched healthy controls. The unbound fraction of olmesartan at 2 hours post-dose in healthy subjects, in patients with mild hepatic impairment and in patients with moderate hepatic impairment is 0.26%, 0.34% and 0.41%, respectively. Following repeated dosing in patients with moderate hepatic impairment, olmesartan mean AUC is again about 65% higher than in matched healthy controls. Olmesartan mean Cmax values are similar in hepatically impaired and healthy subjects. Olmesartan medoxomil has not been evaluated in patients with severe hepatic impairment.

Very limited clinical data are available regarding amlodipine administration in patients with hepatic impairment. The clearance of amlodipine is decreased and the half-life is prolonged in patients with impaired hepatic function, resulting in an increase in AUC of about 40% – 60%.

6.1 Animal Toxicology or Pharmacology

Based on the non-clinical toxicity profile of each substance, no exacerbation of toxicities for the combination is expected, because each substance has different targets, i.e. the kidneys for olmesartan medoxomil and the heart for amlodipine. In a 3-month, repeat-dose toxicity study of orally administered olmesartan medoxomil/amlodipine combination in rats, and the following changes were observed:

• Decreases in red blood cell count-related parameters and kidney alterations, which may be attributed to the olmesartan medoxomil component.
• Intestinal changes including luminal dilatation and diffuse mucosal thickening in the ileum and colon, which may be related to the amlodipine component.
• Adrenal alterations, such as hypertrophy of the glomerular cortical cells and vacuolation of the fascicular cortical cells, which could be induced by amlodipine.
• Hypertrophy of the mammary gland ducts, possibly induced by the amlodipine component.

These findings suggest that both components of the combination may contribute to specific organ changes, with olmesartan medoxomil primarily affecting blood cells and kidneys, and amlodipine influencing the intestines, adrenals, and mammary glands.

Amlodipine and Olmesartan Medoxomil Tablets provided, as a tablet for oral administration, is a combination of the calcium channel blocker (CCB) amlodipine besylate and the angiotensin II receptor blocker (ARB) olmesartan medoxomil.

The amlodipine besylate is chemically described as 3-ethyl-5-methyl (±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulphonate.

Its empirical formula is C₂₀H₂₅CIN₂O₅•C₆H₆O₃S.

The molecular weight of amlodipine besylate is 567.1.

The structural formula for amlodipine besylate is:

Olmesartan medoxomil, a prodrug, is hydrolyzed to olmesartan during absorption from the gastrointestinal tract.

The olmesartan medoxomil is chemically described as 2,3-dihydroxy-2-butenyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-carboxylate, cyclic 2,3-carbonate.

Its empirical formula is C₂₉H₃₀N₆O₆.

The molecular weight of olmesartan medoxomil is 558.59.

The structural formula for olmesartan medoxomil is:

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

Refer on pack

8.3 Packaging information

A Blister strip of 10 tablets each.

8.4 Storage and handing instructions

• Store below 30°C. Protected from light & moisture.
• Keep out of reach of children.

Pregnancy: Advise female patients of childbearing age about the consequences of exposure to Amlodipine and Olmesartan Medoxomil Tablets during pregnancy. Discuss treatment options with women planning to become pregnant. Tell patients to report pregnancies to their physicians as soon as possible.

Lactation: Advise nursing women not to breastfeed during treatment with Amlodipine and Olmesartan Medoxomil Tablets.

Potassium Supplements: Advise patients not to use potassium supplements or salt substitutes containing potassium without consulting their healthcare provider.

29/11/2024