Sucralfate Suspension

Composition:

Each 5 ml contains:

Sucralfate IP……………… 500 mg

Colour: Carmoisine

Suspension, 500mg/5ml

4.1 Therapeutic Indication

Indicated in the treatment of gastric, duodenal and benign ulcer.

4.2 Posology and Method of Administration

The recommended adult oral dosage for duodenal ulcer is 1 gram (10ml) four times per day.

Maximum daily dose: 8 grams.

Ancool®-SF suspension should be administered on an empty stomach on an empty stomach.

Four to six weeks’ treatment is usually needed for ulcer healing, but up to twelve weeks may be necessary in resistant cases.

Antacids may be used as required for relief of pain, but should not be taken half an hour before or after Ancool®-SF suspension.

Paediatric population: The safety and efficacy of Ancool®-SF suspension in children under 14 years of age has not been established.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients

4.4 Special warnings and precautions for use

• Ancool®-SF must not be administered intravenously. Inadvertent intravenous administration of insoluble sucralfate and its insoluble excipients may induce fatal complications, including pulmonary and cerebral emboli. Other severe complications including aluminium intoxication are reported after intravenous administration.
• The product should only be used with caution in patients with renal dysfunction, due to the possibility of increased aluminium absorption.
• Sucralfate is not recommended for use in individuals on dialysis.
• In patients with severe or chronic renal impairment, Ancool®-SF should be used with extreme caution and only for short-term treatment. Small amounts of aluminium are absorbed through the gastrointestinal tract and aluminium may accumulate. Aluminium osteodystrophy, osteomalacia, encephalopathy, and anaemia have been reported in patients with chronic renal impairment. For patients with impairment of renal function, laboratory testing such as aluminium, phosphate, calcium, and alkaline phosphatase is recommended to be periodically performed due to excretion impairment.
• The concomitant use of other aluminium containing medications is not recommended in view of the enhanced potential for aluminium absorption and toxicity. Bezoars have been reported after administration of sucralfate mainly to severely ill patients in intensive care units. The majority of these patients (including neonates in whom sucralfate is not recommended) had underlying conditions that may predispose to bezoar formation (such as delayed gastric emptying due to surgery, drug therapy or diseases that reduce motility), or were receiving concomitant enteral tube feeding.

4.5 Drugs interactions

• Concomitant administration of Ancool®-SF may reduce the bioavailability of certain drugs including fluoroquinolones such as ciprofloxacin and norfloxacin, tetracycline, ketoconazole, sulpiride, digoxin, warfarin, phenytoin, theophylline, levothyroxine, quinidine and H2 antagonists. The bioavailability of these agents may be restored by separating the administration of these agents from Ancool®-SF by two hours. This interaction appears to be non-systemic in origin presumably resulting from these agents being bound by Ancool®-SF in the gastrointestinal tract. Because of the potential of Ancool®-SF to alter the absorption of some drugs from the gastrointestinal tract, the separate administration of Ancool®-SF from that of other agents should be considered when alterations in bioavailability are felt to be critical for concomitantly administered drugs.
• Sucralfate should not be co-administered with citrate preparations. Co-administration of citrate preparations with sucralfate may increase the blood concentrations of aluminium. The mechanism may be due to chelation of aluminium, which is assumed to increase its absorption.
• The administration of Ancool®-SF and enteral feeds by nasogastric tube should be separated by one hour in patients receiving Ancool®-SF Suspension for the prophylaxis of stress ulceration. In rare cases bezoar formation has been reported when Ancool®-SF and enteral feeds have been given too closely together.

4.6 Use in special populations

Pregnancy

Teratogenicity studies in mice, rats and rabits at dose up to 50 times the human dose have revealed no evidence of harm to the foetus. Safety in pregnant women has not been established and Ancool®-SF should be used during pregnancy only if clearly needed.

Lactation:

It is not known whether this drug is excreted in human milk. Caution should be exercised when Ancool®-SF Suspension is administered to breast-feeding women.

4.7 Effects on ability to drive and use machines

There are no data on the effect of this product on driving capacity and use of machines. Do not drive if you feel dizzy or drowsy.

4.8 Undesirable effects

Tabulated list of adverse 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

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

4.9 Overdose

In a clinical trial on healthy men of overdose with sucralfate, most cases remained asymptomatic, but symptoms of abdominal pain, nausea, and vomiting were reported in a few cases.

Acute oral toxicity studies in animals, using doses up to 12 g/kg body weight, could not find a lethal dose. Risks associated with overdose, should, therefore, be minimal.

Pharmacotherapeutic group: Alimentary tract and metabolism, ATC code: A02B X02

5.1 Pharmacodynamic properties/ Mechanism of Action

Mechanism of action

The action of Ancool®-SF Suspension is non-systemic as the drug is only minimally absorbed from the gastro-intestinal tract. The small amounts that are absorbed are excreted primarily in the urine. Sucralfate exerts a generalised cytoprotective effect by preventing gastro-intestinal mucosal injury.

Studies in humans and animal models show that Sucralfate forms an ulcer adherent complex with the proteinaceous exudate of the ulcer site. This property enables sucralfate to form a protective barrier over the ulcer lesion giving sustained protection against the penetration and action of gastric acid, pepsin and bile. Studies both in humans and animals demonstrate that Sucralfate protects the gastric mucosa against various irritants such as alcohol, acetylsalicylic acid and sodium taurocholate.

Sucralfate also directly inhibits pepsin activity and absorbs bile salts. It has only weak antacid activity. It does not alter gastric emptying time, nor normal digestive function. Sucralfate has no demonstrated pharmacological effect on the cardiovascular or central nervous systems.

5.2 Pharmacokinetic properties

Sucralfate is only minimally absorbed from the gastro-intestinal tract. The small amounts that are absorbed are excreted primarily in the urine. Absorption of aluminium from sucralfate may be increased in patients on dialysis or with renal dysfunction.

6.1 Animal Toxicology or Pharmacology

There was no evidence of carcinogenesis in mice and rats receiving oral sucralfate in dosages of up to 1g/kg daily (12 times the usual human dosage) for 2 years. In animal studies there was no effect evidence of impaired fertility. The effect of sucralfate on human fertility is not known.

Ancool®-SF Suspension contain sucralfate and sucralfate is an α-D-glucopyranoside, β-Dfructofuranosyl-, octakis-(hydrogen sulfate), aluminum complex.

Ancool®-SF Suspension for oral administration contains 0.5 g of sucralfate per 5 mL. Therapeutic category: antiulcer.

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

Refer on the pack

8.3 Packaging information

200 ml bottle, Sugar free

8.4 Storage and handing instructions

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

Keep out of reach of children.

SHAKE WELL BEFORE USE

• Take Ancool®-SF Suspension on an empty stomach, preferably 1 hour before a meal.
• Do not take antacids 30 minutes before or after taking this medication.
• Use caution while driving or doing anything that requires concentration as Sucralfate can cause dizziness and sleepiness.
• It may take 4-6 weeks or more for the ulcers to heal completely. Do not stop taking the medicine until your doctor tells you to.
• Episodes of hyperglycemia have been reported in diabetic patients. Close monitoring of glycemia in diabetic patients treated with sucralfate suspension is recommended. Adjustment of the antidiabetic treatment dose during the use of sucralfate suspension might be necessary.

July 2024

Probiotic Culture Concentrate Not less than 2.5Billion CFU Capsules

Each veg capsule contains:

Probiotic Culture Concentrate not less than 2.5 Billion CFU.

[Lactobacillus Acidophillus (NCM),

Lactobacillus Paracasei (LPC-37),

Bifidobacterium Lactis (Bi-07),

Bifidobacterium Lactis (Bi-04)]

Capsule, 2.5 Billion CFU

4.1 Therapeutic indication

• Management and restoration of disturbed gut flora.

4.2 Posology and method of administration

• 1 - 2 capsules per day

4.3 Contraindications

• Subjects known to have shown a previous reaction, including anaphylaxis or an allergy to milk or to any component of Floristore.

4.4 Special warnings and precautions for use

• Avoid taking Floristore along with oral antibiotics; preferably keep a gap of 2 hours between antibiotics and Floristore capsule.
• Floristore should be taken during and continued for 1-2 weeks post antibiotic therapy to fully restore the gut microflora and minimize the opportunity for antibiotic-related side effects.

4.5 Drugs interactions

No known drug-drug interaction

4.6 Use in special populations

Usage in pregnancy & lactation

Floristore is generally considered as safe during pregnancy & lactation. However, pregnant and lactating women should consult physician before starting treatment with Floristore.

Usage in pediatrics

Safety and efficacy in children has not been established.

4.7 Effects on ability to drive and use machines

It is not known whether Floristore capsule alters the ability to drive. Do not drive if you experience any symptoms that affect your ability to concentrate and react.

4.8 Undesirable effects

During clinical studies patients reported less adverse events in Floristore group (4.2%) as compared to placebo (7.2%) The adverse events reported in both groups included: allergy to seafood, arrhythmia, fever, headache, left upper arm fracture, runny nose, and vomiting.

4.9 Overdose

No data on overdosage of this product. Available clinical studies demonstrate that floristore is safe and no significant adverse or toxic effects of Floristore are observed in humans.

5.1 Pharmacodynamic properties

Floristore may affects intestinal bacteria by increasing the populations of the beneficial anaerobic bacteria and decreasing the population of potentially pathogenic microorganisms.

Floristore affects the intestinal ecosystem by stimulating mucosal immune mechanisms and by stimulating nonimmune mechanisms through antagonism/competition with potential pathogens. These phenomena are thought to mediate most beneficial effects, including reduction of the incidence and severity of diarrhea, which is one of the most widely, recognized uses for probiotics.

5.2 Pharmacokinetic properties

Floristore provides a high concentration of live bacteria that survives the hostile gastric acid, bile and pancreatic secretions and colonizes the gastrointestinal lumen. Studies show that supplementation of Floristore promotes more rapid return to pre-antibiotic baseline faecal bacterial microbiota. Therefore, Floristore taken during and after antibiotic therapy minimizes the antibiotic induced disturbances of fecal microbiota. 

6.1 Animal Toxicology or Pharmacology

No known animal toxicology data

Floristore is a probiotic culture concentrate containing not less than 2.5 Billion CFU. The Floristore formulation is designed to provide 50% by count of those bacteria that are adapted to the upper intestine—specifically the Lactobacillus species: L. acidophilus NCFM and L. paracasei Lpc-37. The remaining 50% by count is provided by Bifidobacterium species, which are adapted to the lower intestinal tract. These strains are B. lactis Bi-07and B. lactis Bl-04. All the four strains are proportionate (25%).

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

24 months

8.3 Packaging information

1 blister strip of 10 capsules.

8.4 Storage and handing instructions

Store below 25^oC.

Keep out of reach of children.

• Not for medicinal use. This product is not intended to diagnose, treat, cure or prevent any disease.
• Not to exceed the stated recommended daily dose.
• If you are pregnant or nursing, please ask a healthcare professional.
• Use with caution in patients that may have a medical condition, are pregnant, lactating, trying to conceive, under the age of 18, or taking medications.

05.07.2024

Etoricoxib & Thiocolchicoside Tablets

Composition:

Each film coated tablet contains:

Etoricoxib IP 60 mg

Thiocolchicoside IP 4 mg

Colours: Red Oxide of Iron & Titanium Dioxide IP

Film coated tablet,

Etoricoxib (60 mg) &Thiocolchicoside (4 mg)

4.1 Therapeutic Indication

For the acute treatment of inflammatory musculoskeletal disorders associated with painful muscle spasm in adults.

4.2 Posology and Method of Administration

One table of ETOSPEED-MR one or two times daily or as prescribed by the healthcare professional depending on the severity of the condition being treated.

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients.
• Active peptic ulceration or active gastro-intestinal (GI) bleeding.
• Patients who, after taking acetylsalicylic acid or NSAIDs including COX-2 inhibitors, experience bronchospasm, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria, or allergic-type reactions.
• Pregnancy and lactation.
• Severe hepatic dysfunction (serum albumin <25 g/l or Child-Pugh score ≥10).
• Estimated renal creatinine clearance < 30 ml/min
• Children and adolescents under 16 years of age.
• Inflammatory bowel disease.
• Congestive heart failure (NYHA II-IV).
• Patients with hypertension whose blood pressure is persistently elevated above 140/90 mmHg and has not been adequately controlled.
• Established ischaemic heart disease, peripheral arterial disease, and cerebrovascular disease.
• In patients with flaccid paralysis, hypotone muscle.
• In women of childbearing potential not using contraception.

4.4 Special warnings and precautions for use

Etoricoxib

Gastrointestinal effects

Upper gastrointestinal complications [perforations, ulcers or bleedings (PUBs)], some of them resulting in fatal outcome, have occurred in patients treated with etoricoxib.

Caution is advised with treatment of patients most at risk of developing a gastrointestinal complication with NSAIDs; the elderly, patients using any other NSAID or acetylsalicylic acid concomitantly or patients with a prior history of gastrointestinal disease, such as ulceration and GI bleeding.

There is a further increase in the risk of gastrointestinal adverse effects (gastrointestinal ulceration or other gastrointestinal complications) when etoricoxib is taken concomitantly with acetylsalicylic acid (even at low doses). A significant difference in GI safety between selective COX-2 inhibitors + acetylsalicylic acid vs. NSAIDs + acetylsalicylic acid has not been demonstrated in long-term clinical trials.

Cardiovascular effects

Clinical trials suggest that the selective COX-2 inhibitor class of drugs may be associated with a risk of thrombotic events (especially myocardial infarction (MI) and stroke), relative to placebo and some NSAIDs. As the cardiovascular risks of etoricoxib may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically, especially in patients with osteoarthritis.

Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, and smoking) should only be treated with etoricoxib after careful consideration.

COX-2 selective inhibitors are not a substitute for acetylsalicylic acid for prophylaxis of cardiovascular Thrombo-embolic diseases because of their lack of antiplatelet effect. Therefore, antiplatelet therapies should not be discontinued

Renal effects

Renal prostaglandins may play a compensatory role in the maintenance of renal perfusion. Therefore, under conditions of compromised renal perfusion, administration of etoricoxib may cause a reduction in prostaglandin formation and, secondarily, in renal blood flow, and thereby impair renal function. Patients at greatest risk of this response are those with pre-existing significantly impaired renal function, uncompensated heart failure, or cirrhosis. Monitoring of renal function in such patients should be considered.

Fluid retention, oedema and hypertension

As with other medicinal products known to inhibit prostaglandin synthesis, fluid retention, oedema and hypertension have been observed in patients taking etoricoxib. All Nonsteroidal Anti-inflammatory Drugs (NSAIDs), including etoricoxib, can be associated with new onset or recurrent congestive heart failure. For information regarding a dose related response for etoricoxib. Caution should be exercised in patients with a history of cardiac failure, left ventricular dysfunction, or hypertension and in patients with pre-existing oedema from any other reason. If there is clinical evidence of deterioration in the condition of these patients, appropriate measures including discontinuation of etoricoxib should be taken.

Etoricoxib may be associated with more frequent and severe hypertension than some other NSAIDs and selective COX-2 inhibitors, particularly at high doses. Therefore, hypertension should be controlled before treatment with etoricoxib and special attention should be paid to blood pressure monitoring during treatment with etoricoxib. Blood pressure should be monitored within two weeks after initiation of treatment and periodically thereafter. If blood pressure rises significantly, alternative treatment should be considered.

Hepatic effects

Elevations of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials treated for up to one year with etoricoxib 30, 60 and 90 mg daily.

Any patients with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver function test has occurred, should be monitored. If signs of hepatic insufficiency occur, or if persistently abnormal liver function tests (three times the upper limit of normal) are detected, etoricoxib should be discontinued.

General

If during treatment, patients deteriorate in any of the organ system functions described above, appropriate measures should be taken and discontinuation of etoricoxib therapy should be considered. Medically appropriate supervision should be maintained when using etoricoxib in the elderly and in patients with renal, hepatic, or cardiac dysfunction.

Caution should be used when initiating treatment with etoricoxib in patients with dehydration. It is advisable to rehydrate patients prior to starting therapy with etoricoxib. Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs and some selective COX-2 inhibitors during post-marketing surveillance. Patients appear to be at highest risk for these reactions early in the course of therapy with the onset of the reaction occurring in the majority of cases within the first month of treatment. Serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported in patients receiving etoricoxib. Some selective COX-2 inhibitors have been associated with an increased risk of skin reactions in patients with a history of any drug allergy. Etoricoxib should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Etoricoxib may mask fever and other signs of inflammation.

Caution should be exercised when co-administering etoricoxib with warfarin or other oral anticoagulants.

The use of etoricoxib, as with any medicinal product known to inhibit cyclooxygenase / prostaglandin synthesis, is not recommended in women attempting to conceive.

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

Thiocolchicoside

The dose must be reduced in case of presence of diarrhoea following oral administration. After administration by intramuscular route episodes were observed of vasovagal syncope, thus the patient has to be monitored after being injected.

Post marketing cases of cytolytic hepatitis and cholestatic were reported with Thiocolchicoside.

The serious cases (for example fulminant hepatitis) were observed in patients that had taken FANS or paracetamol at the same time. The patients have to be informed to report any sign of hepatic toxicity.

Thiocolchicoside may precipitate seizures especially in epileptic patients or those at risk of convulsions.

The maximum daily oral dose of 16mg must not be exceeded and must be split in two doses at 12-hour interval.

In case you forget to take a dose take the next dose avoiding taking doses close to each other.

Preclinical studies showed that one of Thiocolchicoside metabolites (SL59.0955) induced aneuploidy (i.e. alterations in the number of chromosomes in dividing cells) at concentrations close to human exposure observed at doses 8 mg twice daily per os. Aneuploidy is considered as a risk factor for teratogenicity, embryo/foetotoxicity, spontaneous abortion, and impaired male fertility and a potential risk factor for cancer. As a precautionary measure, use of the product at doses exceeding the recommended dose or long-term use should be avoided.

Patients should be carefully informed about the potential risk of a possible pregnancy and about effective contraception measures to be followed.

4.5 Drugs interactions

Etoricoxib

Pharmacodynamic interactions

Oral anticoagulants: In subjects stabilised on chronic warfarin therapy, the administration of etoricoxib 120 mg daily was associated with an approximate 13% increase in prothrombin time International Normalised Ratio (INR). Therefore, patients receiving oral anticoagulants should be closely monitored for their prothrombin time INR, particularly in the first few days when therapy with etoricoxib is initiated or the dose of etoricoxib is changed.

Diuretics, ACE inhibitors and Angiotensin II Antagonists: NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function) the co-administration of an ACE inhibitor or Angiotensin II antagonist and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. These interactions should be considered in patients taking etoricoxib concomitantly with ACE inhibitors or angiotensin II antagonists. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy, and periodically thereafter.

Acetylsalicylic Acid: In a study in healthy subjects, at steady state, etoricoxib 120 mg once daily had no effect on the anti-platelet activity of acetylsalicylic acid (81 mg once daily). Etoricoxib can be used concomitantly with acetylsalicylic acid at doses used for cardiovascular prophylaxis (low-dose acetylsalicylic acid). However, concomitant administration of low-dose acetylsalicylic acid with etoricoxib may result in an increased rate of GI ulceration or other complications compared to use of etoricoxib alone. Concomitant administration of etoricoxib with doses of acetylsalicylic acid above those for cardiovascular prophylaxis or with other NSAIDs is not recommended.

Cyclosporin and tacrolimus: Although this interaction has not been studied with etoricoxib, coadministration of cyclosporin or tacrolimus with any NSAID may increase the nephrotoxic effect of cyclosporin or tacrolimus. Renal function should be monitored when etoricoxib and either of these drugs is used in combination.

Pharmacokinetic interactions

The effect of etoricoxib on the pharmacokinetics of other drugs.

Lithium: NSAIDs decrease lithium renal excretion and therefore increase lithium plasma levels. If necessary, monitor blood lithium closely and adjust the lithium dosage while the combination is being taken and when the NSAID is withdrawn.

Methotrexate: Two studies investigated the effects of etoricoxib 60, 90 or 120 mg administered once daily for seven days in patients receiving once-weekly methotrexate doses of 7.5 to 20 mg for rheumatoid arthritis. Etoricoxib at 60 and 90 mg had no effect on methotrexate plasma concentrations or renal clearance. In one study, etoricoxib 120 mg had no effect, but in the other study, etoricoxib 120 mg increased methotrexate plasma concentrations by 28% and reduced renal clearance of methotrexate by 13%.

Adequate monitoring for methotrexate-related toxicity is recommended when etoricoxib and methotrexate are administered concomitantly.

Oral contraceptives: Etoricoxib 60 mg given concomitantly with an oral contraceptive containing 35 micrograms ethinyl estradiol (EE) and 0.5 to 1 mg norethindrone for 21 days increased the steady state AUC0-24hr of EE by 37%. Etoricoxib 120 mg given with the same oral contraceptive concomitantly or separated by 12 hours, increased the steady state AUC0-24hr of EE by 50 to 60%. This increase in EE concentration should be considered when selecting an oral contraceptive for use with etoricoxib. An increase in EE exposure can increase the incidence of adverse events associated with oral contraceptives (e.g., venous Thrombo-embolic events in women at risk).

Hormone Replacement Therapy (HRT): Administration of etoricoxib 120 mg with hormone replacement therapy consisting of conjugated estrogens (0.625 mg) for 28 days, increased the mean steady state AUC0-24hr of unconjugated estrone (41%), equilin (76%), and 17-β-estradiol (22%). The effect of the recommended chronic doses of etoricoxib (30, 60, and 90 mg) has not been studied. The effects of etoricoxib 120 mg on the exposure (AUC0-24hr) to these estrogenic components of PREMARIN were less than half of those observed when PREMARIN was administered alone and the dose was increased from 0.625 to 1.25 mg. The clinical significance of these increases is unknown, and higher doses of PREMARIN were not studied in combination with etoricoxib. These increases in estrogenic concentration should be taken into consideration when selecting post-menopausal hormone therapy for use with etoricoxib because the increase in oestrogen exposure might increase the risk of adverse events associated with HRT.

Prednisone/prednisolone: In drug-interaction studies, etoricoxib did not have clinically important effects on the pharmacokinetics of prednisone/prednisolone.

Digoxin: Etoricoxib 120 mg administered once daily for 10 days to healthy volunteers did not alter the steady-state plasma AUC0-24hr or renal elimination of digoxin. There was an increase in digoxin Cmax (approximately 33%). This increase is not generally important for most patients. However, patients at high risk of digoxin toxicity should be monitored for this when etoricoxib and digoxin are administered concomitantly.

Effect of etoricoxib on drugs metabolised by sulfotransferases

Etoricoxib is an inhibitor of human sulfotransferase activity, particularly SULT1E1, and has been shown to increase the serum concentrations of ethinyl estradiol. While knowledge about effects of multiple sulfotransferases is presently limited and the clinical consequences for many drugs are still being examined, it may be prudent to exercise care when administering etoricoxib concurrently with other drugs primarily metabolised by human sulfotransferases (e.g., oral salbutamol and minoxidil).

Effect of etoricoxib on drugs metabolised by CYP isoenzymes

Based on in vitro studies, etoricoxib is not expected to inhibit cytochromes P450 (CYP) 1A2, 2C9, 2C19, 2D6, 2E1 or 3A4. In a study in healthy subjects, daily administration of etoricoxib 120 mg did not alter hepatic CYP3A4 activity as assessed by the erythromycin breath test.

Effects of other drugs on the pharmacokinetics of etoricoxib

The main pathway of etoricoxib metabolism is dependent on CYP enzymes. CYP3A4 appears to contribute to the metabolism of etoricoxib in vivo. In vitro studies indicate that CYP2D6, CYP2C9, CYP1A2 and CYP2C19 also can catalyse the main metabolic pathway, but their quantitative roles have not been studied in vivo.

Ketoconazole: Ketoconazole, a potent inhibitor of CYP3A4, dosed at 400 mg once a day for 11 days to healthy volunteers, did not have any clinically important effect on the single-dose pharmacokinetics of 60 mg etoricoxib (43% increase in AUC).

Voriconazole and Miconazole: Co-administration of either oral voriconazole or topical miconazole oral gel, strong CYP3A4 inhibitors, with etoricoxib caused a slight increase in exposure to etoricoxib, but is not considered to be clinically meaningful based on published data.

Rifampicin: Co-administration of etoricoxib with rifampicin, a potent inducer of CYP enzymes, produced a 65% decrease in etoricoxib plasma concentrations. This interaction may result in recurrence of symptoms when etoricoxib is co-administered with rifampicin. While this information may suggest an increase in dose, doses of etoricoxib greater than those listed for each indication have not been studied in combination with rifampicin and are therefore not recommended.

Antacids: Antacids do not affect the pharmacokinetics of etoricoxib to a clinically relevant extent.

Thiocolchicoside

No studies on interactions were carried out.

4.6 Use in special populations

Pregnancy

Etoricoxib

No clinical data on exposed pregnancies are available for etoricoxib. Studies in animals have shown reproductive toxicity. The potential for human risk in pregnancy is unknown. Etoricoxib, as with other medicinal products inhibiting prostaglandin synthesis, may cause uterine inertia and premature closure of the ductus arteriosus during the last trimester. Etoricoxib is contraindicated in pregnancy. If a woman becomes pregnant during treatment, etoricoxib must be discontinued.

Thiocolchicoside

There are limited data on the use of Thiocolchicoside in pregnant women. Therefore, the potential hazards for the embryo and foetus are unknown. Studies in animals have shown teratogenic effects.

Therefore, ETOSPEED-MR is contraindicated during pregnancy and in women of childbearing potential not using contraception

Lactation:

Etoricoxib

It is not known whether etoricoxib is excreted in human milk. Etoricoxib is excreted in the milk of lactating rats. Women who use etoricoxib must not breast feed.

Thiocolchicoside

Since it passes into the mother’s milk, the use of Thiocolchicoside is contraindicated during breastfeeding.

Therefore, ETOSPEED-MR is contraindicated during breastfeeding.

Fertility

The use of etoricoxib, as with any drug substance known to inhibit COX-2, is not recommended in women attempting to conceive.

In a fertility study performed in rats, no impairment of fertility was seen at doses up to 12 mg/kg, i.e. at dose levels inducing no clinical effect. Thiocolchicoside and its metabolites exert aneugenic activity at different concentration levels, which is a risk factor for impairment of human fertility.

Therefore, ETOSPEED-MR is contraindicated in women attempting to conceive.

4.7 Effects on ability to drive and use machines

Patients who experience dizziness, vertigo or somnolence while taking etoricoxib should refrain from driving or operating machinery. No studies were carried out on the ability to drive or use of machinery with Thiocolchicoside.

So if drowsiness occurs with ETOSPEED-MR, patients must refrain from driving or operating machinery.

4.8 Undesirable effects

Etoricoxib

Summary of the safety profile

In clinical trials, etoricoxib was evaluated for safety in 9,295 individuals, including 6,757 patients with OA, RA, chronic low back pain or ankylosing spondylitis (approx..600 patients with OA or RA were treated for one year or longer).

In clinical studies, the undesirable effects profile was similar in patients with OA or RA treated with etoricoxib for one year or longer.

In a clinical study for acute gouty arthritis, patients were treated with etoricoxib 120 mg once daily for eight days. The adverse experience profile in this study was generally similar to that reported in the combined OA, RA, and chronic low back pain studies.

In a cardiovascular safety outcomes programme of pooled data from three active comparator controlled trials, 17, 412 patients with OA or RA were treated with etoricoxib (60 mg or 90 mg) for a mean duration of approximately 18 months. The safety data and details from this programme.

In clinical studies for acute postoperative dental pain following surgery including 614 patients treated with etoricoxib (90 mg or 120 mg), the adverse experience profile in these studies was generally similar to that reported in the combined OA, RA, and chronic low back pain studies.

Tabulated list of adverse reactions

The following undesirable effects were reported at an incidence greater than placebo in clinical trials in patients with OA, RA, chronic low back pain or ankylosing spondylitis treated with etoricoxib 30 mg, 60 mg or 90 mg up to the recommended dose for up to 12 weeks; in the MEDAL Programme studies for up to 3½ years; in short term acute pain studies for up to 7 days; or in post-marketing experience:

The following serious undesirable effects have been reported in association with the use of NSAIDs and cannot be ruled out for etoricoxib: nephrotoxicity including interstitial nephritis and nephrotic syndrome.

Thiocolchicoside

Disturbances in immunity system

Anaphylactic reactions:

• Uncommon: pruritis,
• Rare: urticarial
• Very rare: hypotension
• Not noted: angiooedema and anaphylactic shock after intramuscular administration.

Pathology of the nervous system

• Common: drowsiness
• Rare: agitation and clouding
• Not noted: malaise associated or to a lesser extent vasovagal syncope in the minutes following intramuscular administration, convulsions.

Gastrointestinal pathology

• Common: diarrhoea (see paragraph 4.4), stomach pain
• Uncommon: nausea, vomiting
• Rare: heartburn after oral administration

Hepatobiliary pathology

• Not noted: cytolytic hepatitis and cholestatic.
• Pathology of the skin and subcutaneous tissue
• Uncommon: allergic skin 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
• Website link: https://www.zuventus.com/drug-safety-reporting

4.9 Overdose

Etoricoxib

In clinical studies, administration of single doses of etoricoxib up to 500 mg and multiple doses up to 150 mg/day for 21 days did not result in significant toxicity. There have been reports of acute overdosage with etoricoxib, although adverse experiences were not reported in the majority of cases. The most frequently observed adverse experiences were consistent with the safety profile for etoricoxib (e.g. gastrointestinal events, cardio renal events). In the event of overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the GI tract, employ clinical monitoring, and institute supportive therapy, if required. Etoricoxib is not dialysable by haemodialysis; it is not known whether etoricoxib is dialysable by peritoneal dialysis.

Thiocolchicoside

Overdosage was not noted or reported in any literature. In case of overdosage it is recommended to get medical attention and implement symptomatic measures.

5.1 Mechanism of Action

Etoricoxib

Etoricoxib is an oral, selective cyclo-oxygenase-2 (COX-2) inhibitor within the clinical dose range. Across clinical pharmacology studies, ETOSPEED-MR produced dose dependent inhibition of COX-2 without inhibition of COX-1 at doses up to 150 mg daily. Etoricoxib did not inhibit gastric prostaglandin synthesis and had no effect on platelet function. Cyclooxygenase is responsible for generation of prostaglandins. Two isoforms, COX-1 and COX-2, have been identified. COX-2 is the isoform of the enzyme that has been shown to be induced by pro-inflammatory stimuli and has been postulated to be primarily responsible for the synthesis of prostanoid mediators of pain, inflammation, and fever. COX-2 is also involved in ovulation, implantation and closure of the ductus arteriosus, regulation of renal function, and central nervous system functions (fever induction, pain perception and cognitive function). It may also play a role in ulcer healing. COX-2 has been identified in tissue around gastric ulcers in man but its relevance to ulcer healing has not been established.

Thiocolchicoside

Thiocolchicoside binds to GABA-A and strychnine sensitive glycine receptors. Thiocolchicoside acting as a GABA-A receptor antagonist, its myorelaxant effects could be exerted at the supra-spinal level, via complex regulatory mechanisms, although a glycinergic mechanism of action cannot be excluded. The characteristics of the interaction of Thiocolchicoside with GABA-A receptors are qualitatively and quantitatively shared by its main circulating metabolite, the glucuronidated derivative.

5.2 Pharmacodynamic properties

Etoricoxib

In patients with osteoarthritis (OA), etoricoxib 60 mg once daily provided significant improvements in pain and patient assessments of disease status. These beneficial effects were observed as early as the second day of therapy and maintained for up to 52 weeks. Studies with etoricoxib 30 mg once daily demonstrated efficacy superior to placebo over a 12-week treatment period (using similar assessments as the above studies). In a dose ranging study, etoricoxib 60 mg demonstrated significantly greater improvement than 30 mg for all 3 primary endpoints over 6 weeks of treatment. The 30 mg dose has not been studied in osteoarthritis of hands.

In patients with rheumatoid arthritis (RA), etoricoxib 60 mg and 90 mg once daily both provided significant improvements in pain, inflammation, and mobility. In studies evaluating the 60 mg and 90 mg dose, these beneficial effects were maintained over the 12-week treatment periods. In a study evaluating the 60 mg dose compared to the 90 mg dose, etoricoxib 60 mg once daily and 90 mg once daily were both more effective than placebo. The 90 mg dose was superior to the 60 mg dose for Patient Global Assessment of Pain (0-100 mm visual analogue scale), with an average improvement of -2.71 mm (95 % CI: -4.98 mm, -0.45 mm).

In patients experiencing attacks of acute gouty arthritis, etoricoxib 120 mg once daily over an eight-day treatment period, relieved moderate to extreme joint pain and inflammation comparable to indomethacin 50 mg three times daily. Pain relief was observed as early as four hours after initiation of treatment.

In patients with ankylosing spondylitis, etoricoxib 90 mg once daily provided significant improvements in spine pain, inflammation, stiffness and function. The clinical benefit of etoricoxib was observed as early as the second day of therapy after initiation of treatment and was maintained throughout the 52-week treatment period. In a second study evaluating the 60 mg dose compared to the 90 mg dose, etoricoxib 60 mg daily and 90 mg daily demonstrated similar efficacy compared to naproxen 1,000 mg daily. Among inadequate responders to 60 mg daily for 6 weeks, dose escalation to 90 mg daily improved spinal pain intensity score (0-100 mm visual analogue scale) compared to continuing on 60 mg daily, with an average improvement of -2.70 mm (95 % CI: -4.88 mm, -0.52 mm).

In a clinical study evaluating postoperative dental pain, etoricoxib 90 mg was administered once daily for up to three days. In the subgroup of patients with moderate pain at baseline, etoricoxib 90 mg demonstrated a similar analgesic effect to that of ibuprofen 600 mg (16.11 vs. 16.39; P = 0.722), and greater than that of paracetamol/codeine 600 mg/60 mg (11.00; P < 0.001) and placebo (6.84; P < 0.001) as measured by total pain relief over the first 6 hours (TOPAR6). The proportion of patients reporting rescue medication usage within the first 24 hours of dosing was 40.8 % for etoricoxib 90 mg, 25.5 % for ibuprofen 600 mg Q6h, and 46.7 % for paracetamol/codeine 600 mg/60 mg Q6h compared to 76.2 % for placebo. In this study, the median onset of action (perceptible pain relief) of 90 mg etoricoxib was 28 minutes after dosing.

Thiocolchicoside

Pharmacotherapeutic category: Other muscle relaxant with central action, ATC code: M03BX05

Thiocolchicoside is a semisynthetic sulphide derivative of colchicoside, showing muscle relaxant pharmacological activity.

In vitro thiocolchicoside binds solely with GABA receptors and glycinergic stricnine sensitive. From the moment that thiocolchicoside acts as an antagonist of the GABA receptors, its muscle relaxant effect may be exercised to a supraspinal level, through a regulatory mechanism even though the glycinergic mechanism of action cannot be excluded. The characteristics of interaction with the GABA receptors are qualitative and quantitative divided between thiocolchicoside and its main circulating metabolite, the derivative glucuronidated

In vivo the muscle relaxant properties of thiocolchicoside and its main metabolite have been shown in various predictive models of rat and rabbit.

The lack of muscle relaxant effect of thiocolchicoside in spineless rat suggests apredominant supraspinal activity.

Also electrocephalographic studies have shown that thiocolchicoside and its main metabolite are devoid of any sedative effect.

5.3 Pharmacokinetic properties

Etoricoxib

Absorption

Orally administered etoricoxib is well absorbed. The absolute bioavailability is approximately 100%. Following 120 mg once-daily dosing to steady state, the peak plasma concentration (geometric mean Cmax = 3.6 µg/ml) was observed at approximately 1 hour (Tmax) after administration to fasted adults. The geometric mean area under the curve (AUC0-24hr) was 37.8 µg•hr/ml. The pharmacokinetics of etoricoxib are linear across the clinical dose range.

Dosing with food (a high-fat meal) had no effect on the extent of absorption of etoricoxib after administration of a 120-mg dose. The rate of absorption was affected, resulting in a 36% decrease in Cmax and an increase in Tmax by 2 hours. These data are not considered clinically significant. In clinical trials, etoricoxib was administered without regard to food intake.

Distribution

Etoricoxib is approximately 92% bound to human plasma protein over the range of concentrations of 0.05 to 5 µg/ml. The volume of distribution at steady state (Vdss) was approximately 1,20l in humans.

Etoricoxib crosses the placenta in rats and rabbits, and the blood-brain barrier in rats.

Biotransformation

Etoricoxib is extensively metabolised with < 1% of a dose recovered in urine as the parent drug. The major route of metabolism to form the 6'-hydroxymethyl derivative is catalyzed by CYP enzymes. CYP3A4 appears to contribute to the metabolism of etoricoxib in vivo. In vitro studies indicate that CYP2D6, CYP2C9, CYP1A2 and CYP2C19 also can catalyse the main metabolic pathway, but their quantitative roles in vivo have not been studied. Five metabolites have been identified in man. The principal metabolite is the 6'-carboxylic acid derivative of etoricoxib formed by further oxidation of the 6'- hydroxymethyl derivative. These principal metabolites either demonstrate no measurable activity or are only weakly active as COX-2 inhibitors. None of these metabolites inhibit COX-1.

Elimination

Following administration of a single 25-mg radiolabelled intravenous dose of etoricoxib to healthy subjects, 70% of radioactivity was recovered in urine and 20% in faeces, mostly as metabolites. Less than 2% was recovered as unchanged drug.

Elimination of etoricoxib occurs almost exclusively through metabolism followed by renal excretion. Steady state concentrations of etoricoxib are reached within seven days of once daily administration of 120 mg, with an accumulation ratio of approximately 2, corresponding to a half-life of approximately 22 hours. The plasma clearance after a 25- mg intravenous dose is estimated to be approximately 50 ml/min.

Characteristics in patients

Elderly patients: Pharmacokinetics in the elderly (65 years of age and older) are similar to those in the young.

Gender: The pharmacokinetics of etoricoxib are similar between men and women.

Hepatic impairment: Patients with mild hepatic dysfunction (Child-Pugh score 5-6) administered etoricoxib 60 mg once daily had an approximately 16% higher mean AUC as compared to healthy subjects given the same regimen. Patients with moderate hepatic dysfunction (Child-Pugh score 7-9) administered etoricoxib 60 mg every other day had similar mean AUC to the healthy subjects given etoricoxib 60 mg once daily; etoricoxib 30 mg once daily has not been studied in this population. There are no clinical or pharmacokinetic data in patients with severe hepatic dysfunction (Child-Pugh score ≥10).

Renal impairment: The pharmacokinetics of a single dose of etoricoxib 120 mg in patients with moderate to severe renal insufficiency and patients with end-stage renal disease on haemodialysis were not significantly different from those in healthy subjects. Haemodialysis contributed negligibly to elimination (dialysis clearance approximately 50 ml/min).

Paediatric patients: The pharmacokinetics of etoricoxib in paediatric patients (60 kg given etoricoxib 90 mg once daily were similar to the pharmacokinetics in adults given etoricoxib 90 mg once daily. Safety and effectiveness of etoricoxib in paediatric patients have not been established.

Thiocolchicoside

Absorption

After oral administration, no thiocolchicoside is detected in plasma. Only two metabolites are observed: The pharmacologically active metabolite SL18.0740 and an inactive metabolite SL59.0955.

For both metabolites, maximum plasma concentrations occur 1hour after thiocolchicoside administration. After a single oral dose of 8 mg of thiocolchicoside the Cmax and AUC of SL18.0740 are about 60 ng/mL and 130 ng.h/mL respectively. For SL59.0955 these values are much lower: Cmax around 13 ng/mL and AUC ranging from 15.5 ng.h/mL (until 3h) to 39.7 ng.h/mL (until 24h).

Distribution

The apparent volume of distribution of thiocolchicoside is estimated around 42.7 L after an IM administration of 8 mg. No data are available for both metabolites.

Biotransformation

After oral administration, thiocolchicoside is first metabolized in the aglycon 3- demethyltiocolchicine or SL59.0955. This step mainly occurs by intestinal metabolism explaining the lack of circulating unchanged thiocolchicoside by this route of administration. SL59.0955 is then glucuroconjugated into SL18.0740 which has equipotent pharmacological activity to thiocolchicoside and thus supports the pharmacological activity after oral administration of thiocolchicoside. SL59.0955 is also demethylated into didemethyl-thiocolchicine.

Elimination

After oral administration of thiocolchicoside, the SL18.0740 metabolites is eliminated with an apparent t1/2 ranging from 3.2 to 7 hours and the metabolite SL59.0955 has a t 1/2 averaging 0.8h.

6.1 Animal Toxicology or Pharmacology

Etoricoxib

In reported preclinical studies, etoricoxib has been demonstrated not to be genotoxic. Etoricoxib was not carcinogenic in mice. Rats developed hepatocellular and thyroid follicular cell adenomas at >2-times the daily human dose [90 mg] based on systemic exposure when dosed daily for approximately two years. Hepatocellular and thyroid follicular cell adenomas observed in rats are considered to be a consequence of rat specific mechanism related to hepatic CYP enzyme induction. Etoricoxib has not been shown to cause hepatic CYP3A enzyme induction in humans.

In the rat, gastrointestinal toxicity of etoricoxib increased with dose and exposure time. In the 14-week toxicity study etoricoxib caused gastrointestinal ulcers at exposures greater than those seen in man at the therapeutic dose. In the 53- and 106-week toxicity study, gastrointestinal ulcers were also seen at exposures comparable to those seen in man at the therapeutic dose. In dogs, renal and gastrointestinal abnormalities were seen at high exposures.

Etoricoxib was not teratogenic in reproductive toxicity studies conducted in rats at 15 mg/kg/day (this represents approximately 1.5 times the daily human dose [90 mg] based on systemic exposure). In rabbits, a treatment related increase in cardiovascular malformations was observed at exposure levels below the clinical exposure at the daily human dose (90 mg). However, no treatment-related external or skeletal foetal malformations were observed. In rats and rabbits, there was a dose dependent increase in post implantation loss at exposures greater than or equal to 1.5 times the human exposure.

Etoricoxib is excreted in the milk of lactating rats at concentrations approximately twofold those in plasma. There was a decrease in pup body weight following exposure of pups to milk from dams administered etoricoxib during lactation.

Thiocolchicoside

Thiocolchicoside profile has been assessed in vitro, and in vivo following parenteral and oral administration. Thiocolchicoside was well tolerated following oral administration for periods of up to 6 months in both the rat and the non-human primate when administered at repeated doses of less than or equal to 2 mg/kg/day in the rat and less or equal to 2.5 mg/kg/day in non-human primate, and by the intramuscular route in the primate at repeated doses up to 0.5 mg/kg/day for 4 weeks. At high doses, thiocolchicoside induced emesis in dog, diarrhoea in rat and convulsions in both rodents and no rodents after acute administration by oral route. After repeated administration, thiocolchicoside induced gastro-intestinal disorders (enteritis, emesis) by oral route and emesis by IM route. Thiocolchicoside itself did not induce gene mutation in bacteria (Ames test), in vitro chromosomal damage (chromosome aberration test in human lymphocytes) and in vivo chromosomal damage (in vivo micronucleus in mouse bone marrow administered intraperitoneally). The major glucuro-conjugated metabolite SL18.0740 did not induce gene mutation in bacteria (Ames test); however, it induced in vitro chromosomal damage (in vitro micronucleus test on human lymphocytes) and in vivo chromosomal damage (in vivo micronucleus test in mouse bone marrow administered orally). The micronuclei predominantly resulted from chromosome loss (centromere positive micronuclei after FISH centromere staining), suggesting aneugenic properties. The aneugenic effect of SL18.0740 was observed at concentrations in the in vitro test and at AUC plasma exposures in the in vivo test higher (more than 10 fold based on AUC) than those observed in human plasma at therapeutic doses. The aglycon metabolite (3-demethylthiocolchicine-SL59.0955) formed mainly after oral administration induced in vitro chromosomal damage (in vitro micronucleus test on human lymphocytes) and in vivo chromosomal damage (in vivo oral micronucleus test in rat bone marrow administered orally). The micronuclei predominantly resulted from chromosome loss (centromere positive micronuclei after FISH or CREST centromere staining), suggesting aneugenic properties. The aneugenic effect of SL59.0955 was observed at concentrations in the in vitro test and at exposures in the in vivo test close to those observed in human plasma at therapeutic doses of 8 mg twice daily per os. Aneugenic effect in dividing cells may result in aneuploid cells. Aneuploidy is a modification in the number of chromosomes and loss of heterozygosity, which is recognized as a risk factor for teratogenicity, embryotoxicity/ spontaneous abortion, impaired male fertility, when impacting germ cells and a potential risk factor for cancer when impacting somatic cells. The presence of the aglycon metabolite (3-23 demethylthiocolchicine-SL59.0955) after intramuscular administration has never been assessed, therefore its formation using this route of administration cannot be excluded. In the rat, an oral dose of 12 mg/kg/day of thiocolchicoside caused major malformations along with fetotoxicity (retarded growth, embryo death, impairment of sex distribution rate). The dose without toxic effect was 3 mg/kg/day. In the rabbit, thiocolchicoside showed maternotoxicity starting from 24 mg/kg/day. Furthermore, minor abnormalities have been observed (supernumerary ribs, retarded ossification). In a fertility study performed in rats, no impairment of fertility was seen at doses up to 12 mg/kg/day, i.e. at dose levels inducing no clinical effect. Thiocolchicoside and its metabolites exert aneugenic activity at different concentration levels, which is recognised as a risk factor for impairment of human fertility. The carcinogenic potential was not evaluated.

Etoricoxib

Etoricoxib is 5-chloro-2-(6-methyl-3-pyridinyl)-3-(4-methylsufonylphenyl) pyridine having molecular weight of 358.5 and molecular formula is C18H15ClN2O2S and chemical structure is:

Thiocolchicoside

Thiocolchicoside is chemically N-[(7S)-1,2-dimethoxy-10-methylsulfanyl-9-oxo-3- [(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6,7-dihydro-5H- Page 25 of 33 benzo[a]heptalen-7-yl]acetamide having molecular weight of 563.6 g/mol and molecular formula is C27H33NO10S with the chemical structure as below:

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

Refer on the pack

8.3 Packaging information

ETOSPEED-MR is available in blister strip of 10 tablets.

8.4 Storage and handing instructions

Store protected from light & moisture, at a temperature not exceeding 30ºC.

Keep out of reach of children.

Patients should be informed of the following information before initiating therapy with ETOSPEED-MR and periodically during the course of ongoing therapy.

Cardiovascular Effects

Patients should be informed that celecoxib may cause serious CV side effects such as MI or stroke, which may result in hospitalization and even death. Patients should be informed of the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and to seek immediate medical advice if they observe any of these signs or symptoms. Patients should be informed that celecoxib can lead to the onset of new hypertension or worsening of pre-existing hypertension, and that etoricoxib may impair the response of some antihypertensive agents. Patients should be instructed on the proper follow up for monitoring of blood pressure.

Gastrointestinal Effects

Patients should be informed that celecoxib can cause gastrointestinal discomfort and more serious side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Patients should be informed of the signs and symptoms of ulcerations and bleeding, and to seek immediate medical advice if they observe any signs or symptoms that are indicative of these disorders, including epigastric pain, dyspepsia, melena, and hematemesis.

Hepatic Effects

Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). Patients should be instructed that they should stop therapy and seek immediate medical therapy if these signs and symptoms occur.

Adverse Skin Reactions

Patients should be informed that etoricoxib can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be informed of the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and seek immediate medical advice when observing any indicative signs or symptoms.

Patients should be advised to stop etoricoxib immediately if they develop any type of rash and contact their physician as soon as possible.

Weight Gain and Edema

Long-term administration of NSAIDs including etoricoxib has resulted in renal injury. Patients at greatest risk are those taking diuretics, ACE-inhibitors, angiotensin II antagonists, or with renal or liver dysfunction, heart failure, and the elderly.

Patients should be instructed to promptly report to their physicians signs or symptoms of unexplained weight gain or edema following treatment with etoricoxib.

Anaphylactoid Reactions

Patients should be informed of the signs and symptoms of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). Patients should be instructed to seek immediate emergency assistance if they develop any of these signs and symptoms.

Effects During Pregnancy

Patients should be informed that in late pregnancy celecoxib should be avoided because it may cause premature closure of the ductus arteriosus.

Pre-existing Asthma

Patients should be instructed to tell their physicians if they have a history of asthma or aspirin sensitive asthma because the use of NSAIDs in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Patients with this form of aspirin sensitivity should be instructed not to take celecoxib. Patients with pre-existing asthma should be instructed to seek immediate medical attention if their asthma worsens after taking etoricoxib.

July 2024

Nanocrystalline Silver Gel

Each gram of gel contains:

Silver as Nano particles 0.02 mg

Perfumed gel base q.s.

Colour: Carmoisine

0.02mg per g

Gel for external application

4.1 Therapeutic Indication

For the treatment of burns and wound infections.

4.2 Posology and method of administration

For cutaneous use only.

• Clean the wound using an appropriate wound cleaner.
• Apply a layer of Meganano gel to shallow wounds or completely fill deep wounds.
• Cover the gel with appropriate secondary dressing such as gauze, hydrocolloid foam or film, depending on wound drainage.
• The dressing should normally be changed daily (24 hrs) but for wounds which are less exudative, less frequent changes (every 48/72 hrs) may be acceptable, at the discretion of the treating physician. Cleansing and debriding should be performed before application.

4.3 Contraindications

• Meganano gel is contraindicated in patients with hypersensitivity to silver or any other ingredients of the preparation.
• Its utility is limited when used in heavily exudating wounds or wounds covered with thick eschar.

4.4 Special warnings and precautions for use

• Discontinue Meganano gel usage if signs of sensitivity appear
• Meganano gel should be removed and the wound should be thoroughly cleaned prior to hyperbaric oxygenation or any other therapy where the presence of metals is contraindicated.
• Meganano gel is for external use only and it should not be surgically implanted

4.5 Drugs interactions

As silver may inactivate enzymatic debriding agents, their concomitant use may be inappropriate.

4.6 Use in special populations

Pregnancy and lactation

There are no adequate and well controlled studies in pregnant women. Animal reproduction studies are not always predictive of human response. This drug should be used during pregnancy only if clearly justified. Caution should be exercised when used in nursing mothers. It is not known whether silver nano particles are excreted in human milk.

Children

Safety and effectiveness in pediatric patients have not been established.

4.7 Effects on ability to drive and use machines

Meganano gel have no influence on the ability to drive and use machines.

4.8 Undesirable effects

Meganano gel local applications are tolerated very well with some infrequently occurring side effects. These effects include skin necrosis, erythema multiforme, burning sensation, rashes, and interstitial nephritis.

Excessive use of silver preparations leads to an accumulation of silver in the human body. Silver-based products are contraindicated for people who are allergic to silver. The chronic use of silver products can result in an accumulation of silver particles in the hair, skin, kidneys, liver, heart and muscles due to high methionine- containing proteins, such as keratin, myosin, tropomyosin, troponin, and key dipeptide glutathione.

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

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

4.9 Overdose

Overdose is unlikely. If necessary, remove the medication by washing with warm water. If accidental ingestion occurs, an appropriate method of gastric emptying may be used if considered appropriate.

Mechanism of Action

Silver as nanoparticles in Meganano gel has a powerful & broad spectrum antimicrobial action owing to its ability to disrupt the bacterial cell wall & inhibition of bacterial cell respiration. It also prevents the bacterial cell multiplication by attacking the bacterial DNA. Silver as nanoparticles in Meganano gel exhibits good anti-inflammatory properties as indicated by inhibition of matrix metalloproteinases 2 and 9.

Meganano gel is a hydrophilic gel which retains skin moisture and thereby promotes healing. It has better rheological properties, spreadability and ease of application. It allows the vital gaseous exchange across its surface but does not allow entry of microbes in the wound, thus forming an antiseptic barrier.

Antimicrobial Spectrum

Silver nanoparticles in Meganano gel have a broad spectrum antimicrobial activity against bacteria, yeast and molds. Silver is highly effective against all the pathogens that may colonize the wound, most importantly:

Staphylococcus aureus (including methicillin resistant Staphylococcus aureus [MRSA]), Beta-hemolytic Streptococcus and other streptococcal spp., Proteus, E. coli, Klebsiella, Enterococci (including Vancomycin Resistant Enterococci [VRE]), Pseudomonas, Acinetobacter etc.

6.1 Animal Toxicology or Pharmacology

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development

Meganano gel is a clear, transparent gel with silver as nanoparticles synthesized by a proprietary biostabilization process, indicated for burn and wound care. Silver as nanoparticles is a broad spectrum antimicrobial without any reported resistance. It exhibits effective antibacterial and antifungal activity at 30 fold less silver concentration. It triggers cellular antioxidant system and prevents oxidative damage. When the interaction of silver nanoparticles with commonly used antibiotics was investigated, the observed effects were synergistic for Ceftazidime, additive for Streptomycin, Kanamycin, Ampiclox, Polymixin B and antagonistic for Chloramphenicol.

Sufficient data have been obtained to demonstrate that silver will inhibit bacteria that are resistant to other antimicrobial agents.

Silver nanoparticles in Meganano gel induce apoptosis which could favour scarless wound healing. Acute dermal toxicity studies on silver nanoparticles showed complete safety for topical application. Being a transparent gel it allows direct monitoring of the wound. It is least toxic to the tissues, non-irritating and non-staining.

Above mentioned properties make Meganano gel a safer and better alternative to conventional antimicrobial agents in the form of a topical antimicrobial formulation.

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on pack

8.3 Packaging information

• A tube of 15 gm
• A tube of 50 gm.
• A container of 200 gm

8.4 Storage and handing instructions

Store in a cool, dry & dark place. Do not freeze.

Keep out of reach of children.

Keep tube tightly closed after use.

• Meganano gel is used for the treatment of burns and wound infections.
• Advice patients not to take this medicine, if they are allergic to silver. Signs of an allergic reaction include a rash, or itching
• Advice patients to clean and dry the area before applying Meganano Gel and do not exceed the dose and frequency of application.
• Tell the patients if they get any side effects, talk to the doctor. This includes any possible side effects not listed in this leaflet.
• Advice patients if they have any further questions, ask the doctor or pharmacist.

01-07-2024

Nanocrystalline Silver Gel

Each gram of gel contains:

Silver as Nano particles 0.02 mg

Perfumed gel base q.s.

Colour: Carmoisine

0.02mg per g

Gel for external application

4.1 Therapeutic Indication

For the treatment of burns and wound infections.

4.2 Posology and method of administration

For cutaneous use only.

• Clean the wound using an appropriate wound cleaner.
• Apply a layer of Meganano gel to shallow wounds or completely fill deep wounds.
• Cover the gel with appropriate secondary dressing such as gauze, hydrocolloid foam or film, depending on wound drainage.
• The dressing should normally be changed daily (24 hrs) but for wounds which are less exudative, less frequent changes (every 48/72 hrs) may be acceptable, at the discretion of the treating physician. Cleansing and debriding should be performed before application.

4.3 Contraindications

• Meganano gel is contraindicated in patients with hypersensitivity to silver or any other ingredients of the preparation.
• Its utility is limited when used in heavily exudating wounds or wounds covered with thick eschar.

4.4 Special warnings and precautions for use

• Discontinue Meganano gel usage if signs of sensitivity appear
• Meganano gel should be removed and the wound should be thoroughly cleaned prior to hyperbaric oxygenation or any other therapy where the presence of metals is contraindicated.
• Meganano gel is for external use only and it should not be surgically implanted

4.5 Drugs interactions

As silver may inactivate enzymatic debriding agents, their concomitant use may be inappropriate.

4.6 Use in special populations

Pregnancy and lactation

There are no adequate and well controlled studies in pregnant women. Animal reproduction studies are not always predictive of human response. This drug should be used during pregnancy only if clearly justified. Caution should be exercised when used in nursing mothers. It is not known whether silver nano particles are excreted in human milk.

Children

Safety and effectiveness in pediatric patients have not been established.

4.7 Effects on ability to drive and use machines

Meganano gel have no influence on the ability to drive and use machines.

4.8 Undesirable effects

Meganano gel local applications are tolerated very well with some infrequently occurring side effects. These effects include skin necrosis, erythema multiforme, burning sensation, rashes, and interstitial nephritis.

Excessive use of silver preparations leads to an accumulation of silver in the human body. Silver-based products are contraindicated for people who are allergic to silver. The chronic use of silver products can result in an accumulation of silver particles in the hair, skin, kidneys, liver, heart and muscles due to high methionine- containing proteins, such as keratin, myosin, tropomyosin, troponin, and key dipeptide glutathione.

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

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

4.9 Overdose

Overdose is unlikely. If necessary, remove the medication by washing with warm water. If accidental ingestion occurs, an appropriate method of gastric emptying may be used if considered appropriate.

Mechanism of Action

Silver as nanoparticles in Meganano gel has a powerful & broad spectrum antimicrobial action owing to its ability to disrupt the bacterial cell wall & inhibition of bacterial cell respiration. It also prevents the bacterial cell multiplication by attacking the bacterial DNA. Silver as nanoparticles in Meganano gel exhibits good anti-inflammatory properties as indicated by inhibition of matrix metalloproteinases 2 and 9.

Meganano gel is a hydrophilic gel which retains skin moisture and thereby promotes healing. It has better rheological properties, spreadability and ease of application. It allows the vital gaseous exchange across its surface but does not allow entry of microbes in the wound, thus forming an antiseptic barrier.

Antimicrobial Spectrum

Silver nanoparticles in Meganano gel have a broad spectrum antimicrobial activity against bacteria, yeast and molds. Silver is highly effective against all the pathogens that may colonize the wound, most importantly:

Staphylococcus aureus (including methicillin resistant Staphylococcus aureus [MRSA]), Beta-hemolytic Streptococcus and other streptococcal spp., Proteus, E. coli, Klebsiella, Enterococci (including Vancomycin Resistant Enterococci [VRE]), Pseudomonas, Acinetobacter etc.

6.1 Animal Toxicology or Pharmacology

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development

Meganano gel is a clear, transparent gel with silver as nanoparticles synthesized by a proprietary biostabilization process, indicated for burn and wound care. Silver as nanoparticles is a broad spectrum antimicrobial without any reported resistance. It exhibits effective antibacterial and antifungal activity at 30 fold less silver concentration. It triggers cellular antioxidant system and prevents oxidative damage. When the interaction of silver nanoparticles with commonly used antibiotics was investigated, the observed effects were synergistic for Ceftazidime, additive for Streptomycin, Kanamycin, Ampiclox, Polymixin B and antagonistic for Chloramphenicol.

Sufficient data have been obtained to demonstrate that silver will inhibit bacteria that are resistant to other antimicrobial agents.

Silver nanoparticles in Meganano gel induce apoptosis which could favour scarless wound healing. Acute dermal toxicity studies on silver nanoparticles showed complete safety for topical application. Being a transparent gel it allows direct monitoring of the wound. It is least toxic to the tissues, non-irritating and non-staining.

Above mentioned properties make Meganano gel a safer and better alternative to conventional antimicrobial agents in the form of a topical antimicrobial formulation.

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on pack

8.3 Packaging information

• A tube of 15 gm
• A tube of 50 gm.
• A container of 200 gm

8.4 Storage and handing instructions

Store in a cool, dry & dark place. Do not freeze.

Keep out of reach of children.

Keep tube tightly closed after use.

• Meganano gel is used for the treatment of burns and wound infections.
• Advice patients not to take this medicine, if they are allergic to silver. Signs of an allergic reaction include a rash, or itching
• Advice patients to clean and dry the area before applying Meganano Gel and do not exceed the dose and frequency of application.
• Tell the patients if they get any side effects, talk to the doctor. This includes any possible side effects not listed in this leaflet.
• Advice patients if they have any further questions, ask the doctor or pharmacist.

Sitagliptin, Pioglitazone & Metformin Hydrochloride (Sustained Release) Tablets (15 mg + 100 mg + 500 mg)

Each lm coated bilayered tablet contains :

Sitagliptin Phosphate Monohydrate IP

equivalent to Sitagliptin 100 mg

Pioglitazone Hydrochloride IP

equivalent to Pioglitazone 15 mg

Metformin Hydrochloride IP 500 mg

(As sustained release form)

Colours : Indigo Carmine Lake

& Titanium Dioxide IP

Film coated tablet bilayered tablet, Sitagliptin 100 mg, Pioglitazone 15 mg, Metformin hydrochloride 500 mg

4.1 Therapeutic indication

For the treatment of type 2 diabetes mellitus.

4.2 Posology & method of administration

The usual recommended dose for adults is 1 tablet once daily or as directed by the Physician.

Geriatric use

In general, elderly patients often have physiological hypofunction; & therefore, Sitagliptin should be administered carefully. Start with lowest dose in elderly patients due to higher risks of lactic acidosis, poor renal & hepatic functions.

Pediatric use

Safety & effectiveness of Sitagliptin / Metformin hydrochloride tablets in paediatric patients under 18 years have not been established. Hence, Zensita MP tablet is not recommended in paediatric group. Method of administration : For oral administration only.

Zensita MP tablets must be swallowed whole & not to be chewed or crushed.

4.3 Contraindications

• Known hypersensitivity Pioglitazone, Sitagliptin & Metformin hydrochloride or to any other component of this product.
• Cardiac failure or history of cardiac failure (NYHA stages I-IV), hepatic impairment, diabetic ketoacidosis, current bladder cancer or a history of bladder cancer & un-investigated macroscopic haematuria.
• Renal impairment (e.g. serum creatinine levels ≥ 1.5 mg/dL for men, 1.4 mg/dL for women or abnormal creatinine clearance), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction & septicemia.
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin.

4.4 Special warnings & precautions for use

Sitagliptin

General

Sitagliptin should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Acute pancreatitis

Use of DPP-4 inhibitors has been associated with a risk of developing acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis : persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of Sitagliptin (with or without supportive treatment), but very rare cases of necrotising or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, Sitagliptin & other potentially suspect medicinal products should be discontinued; if acute pancreatitis is confirmed, Sitagliptin should not be restarted.

Caution should be exercised in patients with a history of pancreatitis Hypoglycaemia when used in combination with other anti-hyperglycaemic medicinal products.

In clinical trials of Sitagliptin as monotherapy & as part of combination therapy with medicinal products not known to cause hypoglycaemia (i.e. Metformin hydrochloride and/or a PPAR agonist), rates of hypoglycaemia reported with Sitagliptin were similar to rates in patients taking placebo. Hypoglycaemia has been observed when Sitagliptin was used in combination with insulin or a sulphonylurea. Therefore, to reduce the risk of hypoglycaemia, a lower dose of sulphonylurea or insulin may be considered.

Renal impairment

Sitagliptin is renally excreted. To achieve plasma concentrations of Sitagliptin similar to those in patients with normal renal function, lower dosages are recommended in patients with GFR < 45 mL/min, as well as in ESRD patients requiring haemodialysis or peritoneal dialysis When considering the use of Sitagliptin in combination with another anti-diabetic medicinal product, its conditions for use in patients with renal impairment should be checked.

Hypersensitivity reactions

Post-marketing reports of serious hypersensitivity reactions in patients treated with Sitagliptin have been reported.

These reactions include anaphylaxis, angioedema & exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment, with some reports occurring after the first dose. If a hypersensitivity reaction is 5 suspected, Sitagliptin should be discontinued. Other potential causes for the event should be assessed, & alternative treatment for diabetes initiated.

Bullous pemphigoid There have been post-marketing reports of bullous pemphigoid in patients taking DPP-4 inhibitors including Sitagliptin. If bullous pemphigoid is suspected, Sitagliptin should be discontinued.

Pioglitazone

Warning

Bladder cancer with Pioglitazone advice for healthcare practitioners :

Patients with active bladder cancer or with a history of bladder cancer & those with un-investigated haematuria, should not receive Pioglitazone.

Prescribers should review the safety & efficacy of Pioglitazone in individuals after 3 - 6 months of treatment to ensure that only patients who are deriving benefit continue to be treated. Pioglitazone should be stopped in patients who do not respond adequately to treatment (e.g. reduction in glycosylated haemoglobin, HbA1c).

Before starting Pioglitazone, the following known risk factors for development of bladder cancer should be assessed in individuals : age, current or past history of smoking, exposure to some occupational or chemotherapy agents such as cyclophosphamide or previous irradiation of the pelvic region.

Use in elderly patients should be considered carefully before & during treatment because the risk of bladder cancer increases with age. Elderly patients should start on the lowest possible dose & be regularly monitored because of the risks of bladder cancer & heart failure associated with Pioglitazone.

Fluid retention & cardiac failure

Pioglitazone can cause fluid retention, which may exacerbate or precipitate heart failure. When treating patients who have at least one risk factor for development of congestive heart failure (e.g. prior myocardial infarction or symptomatic coronary artery disease or the elderly), physicians should start with the lowest available dose & increase the dose gradually. Patients should be observed for signs & symptoms of heart failure; weight gain or oedema; particularly those with reduced cardiac reserve. There have been post-marketing cases of cardiac failure reported when Pioglitazone was used in combination with insulin or in patients with a history of cardiac failure.

Patients should be observed for signs & symptoms of heart failure, weight gain & oedema when Pioglitazone is used in combination with insulin. Since Insulin & Pioglitazone are both associated with fluid retention, concomitant administration may increase the risk of oedema. Post marketing cases of peripheral oedema & cardiac failure have also been reported in patients with concomitant use of Pioglitazone & nonsteroidal anti-inflammatory drugs, including selective COX-2 inhibitors. Pioglitazone should be discontinued if any deterioration in cardiac status occurs.

A cardiovascular outcome study of Pioglitazone has been performed in patients under 75 years with type 2 diabetes mellitus & pre-existing major macrovascular disease. Pioglitazone or placebo was added to existing antidiabetic & cardiovascular therapy for up to 3.5 years. This study showed an increase in reports of heart failure; however, this did not lead to an increase in mortality in this study. Significant fluid retention leading to the development / exacerbation of congestive heart failure has been reported with Pioglitazone - avoid its use in patients in heart failure or at risk of developing heart failure.

Elderly

Combination use with insulin should be considered with caution in the elderly because of increased risk of serious heart failure. In light of age- related risks (especially bladder cancer, fractures & heart failure), the balance of benefits & risks should be considered carefully both before & during treatment in the elderly.

Bladder cancer

Cases of bladder cancer were reported more frequently in a meta-analysis of controlled clinical trials with Pioglitazone (19 cases from 12,506 patients, 0.15%) than in control groups (7 cases from 10,212 patients, 0.07%) HR = 2.64 (95% CI 1.11 - 6.31, p = 0.029). After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 7 cases (0.06%) on Pioglitazone & 2 cases (0.02%) in control groups. Epidemiological studies have also suggested a small increased risk of bladder cancer in diabetic patients treated with Pioglitazone, although not all studies identified a statistically significant increased risk.

Risk factors for bladder cancer should be assessed before initiating Pioglitazone treatment (risks include age, smoking history, exposure to some occupational or chemotherapy agents e.g. cyclophosphamide or prior radiation treatment in the pelvic region). Any macroscopic haematuria should be investigated before starting Pioglitazone therapy. Patients should be advised to promptly seek the attention of their physician if macroscopic haematuria or other symptoms such as dysuria or urinary urgency develop during treatment.

There is some evidence that Pioglitazone may be associated with an increased risk of developing bladder cancer. Pioglitazone should not be used in patients with active bladder cancer & should be used with caution in patients with a history of bladder cancer.

Information for patients

Patients should be informed of the potential risks & benefits of Sitagliptin / Metformin Hydrochloride tablets & of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, & of regular testing of blood glucose, & glycated hemoglobin test.

During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change & patients should be advised to seek medical advice promptly.

The risks of lactic acidosis, its symptoms & conditions that predispose to its development, as noted in the Metformin hydrochloride sections, should be explained to patients.

Patients should be advised to discontinue Metformin hydrochloride immediately & to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of Metformin hydrochloride, gastrointestinal symptoms, which are common during initiation of Metformin hydrochloride therapy, are unlikely to recur. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

Patients should be informed about the importance of regular testing of renal function & hematological parameters when receiving treatment with Sitagliptin / Metformin hydrochloride.

Patients should be counselled against excessive alcohol intake, either acute or chronic, while receiving Sitagliptin / Metformin hydrochloride tablets.

Metformin (Metformin hydrochloride Sustained Release tablets) alone does not usually cause hypoglycemia, although it may occur when Metformin is used in conjunction with insulin secretagogues, such as sulfonylureas & insulin.

Patients should be informed that Sitagliptin / Metformin tablets must be swallowed whole & not crushed or chewed & that the inactive ingredients may occasionally be eliminated in the faeces as a soft mass that may resemble the original tablet.

Patients should be advised to notify their health practitioner immediately in case of Sitagliptin / Metformin hydrochloride overdose.

4.5 Drugs interactions

Sitagliptin

Effects of other medicinal products on Sitagliptin clinical data described below suggest that the risk for clinically meaningful interactions by co-administered medicinal products is low.

In vitro studies indicated that the primary enzyme responsible for the limited metabolism of Sitagliptin is CYP3A4, with contribution from CYP2C8. In patients with normal renal function, metabolism, including via CYP3A4, plays only a small role in the clearance of Sitagliptin. Metabolism may play a more significant role in the elimination of Sitagliptin in the setting of severe renal impairment or end-stage renal disease (ESRD). For this reason, it is possible that potent CYP3A4 inhibitors (i.e. Ketoconazole, Itraconazole, Ritonavir, Clarithromycin) could alter the pharmacokinetics of Sitagliptin in patients with severe renal impairment or ESRD. The effect of potent CYP3A4 inhibitors in the setting of renal impairment has not been assessed in a clinical study.

In vitro transport studies showed that Sitagliptin is a substrate for p-glycoprotein & organic anion transporter-3 (OAT3). OAT3 mediated transport of Sitagliptin was inhibited in vitro by probenecid, although the risk of clinically meaningful interactions is considered to be low. Concomitant administration of OAT3 inhibitors has not been evaluated in vivo.

Metformin hydrochloride

Co-administration of multiple twice-daily doses of 1,000 mg Metformin hydrochloride with 50 mg Sitagliptin did not meaningfully alter the pharmacokinetics of Sitagliptin in patients with type 2 diabetes.

Ciclosporin

A study was conducted to assess the effect of Ciclosporin, a potent inhibitor of p-glycoprotein, on the pharmacokinetics of Sitagliptin. Co-administration of a single 100 mg oral dose of Sitagliptin & a single 600 mg oral dose of Ciclosporin increased the AUC & Cmax of Sitagliptin by approximately 29% & 68%, respectively. These changes in Sitagliptin pharmacokinetics were not considered to be clinically meaningful. The renal clearance of Sitagliptin was not meaningfully altered. Therefore, meaningful interactions would not be expected with other p glycoprotein inhibitors.

Effects of Sitagliptin on other medicinal products

Digoxin

Sitagliptin had a small effect on plasma Digoxin concentrations. Following administration of 0.25 mg Digoxin concomitantly with 100 mg of Sitagliptin daily for 10 days, the plasma AUC of Digoxin was increased on average by 11%, & the plasma Cmax on average by 18%. No dose adjustment of Digoxin is recommended. However, patients at risk of Digoxin toxicity should be monitored for this when Sitagliptin & Digoxin are administered concomitantly. In vitro data suggest that Sitagliptin does not inhibit nor induce CYP450 isoenzymes. In clinical studies, Sitagliptin did not meaningfully alter the pharmacokinetics of Metformin hydrochloride, Glyburide, Simvastatin, Rosiglitazone, Warfarin, or oral contraceptives, providing in vivo evidence of a low propensity for causing interactions with substrates of CYP3A4, CYP2C8, CYP2C9, & organic cationic transporter (OCT). Sitagliptin may be a mild inhibitor of p-glycoprotein in vivo.

Pioglitazone

Interaction studies have shown that Pioglitazone has no relevant effect on either the pharmacokinetics or pharmacodynamics of Digoxin, Warfarin, Phenprocoumon & Metformin hydrochloride. Co-administration of Pioglitazone with sulphonylureas does not appear to affect the pharmacokinetics of the sulphonylurea. Studies in man suggest no induction of the main inducible cytochrome P450, 1A, 2C8/9 & 3A4. In vitro studies have shown no inhibition of any subtype of cytochrome P450. Interactions with substances metabolised by these enzymes, e.g. oral contraceptives, Cyclosporin, Calcium channel blockers, & HMGCoAreductase inhibitors are not to be expected. Co-administration of Pioglitazone with Gemfibrozil (an inhibitor of cytochrome P450 2C8) is reported to result in a 3-fold increase in AUC of Pioglitazone. Since there is a potential for an increase in dose- related adverse events, a decrease in the dose of Pioglitazone may be needed when Gembrozil is concomitantly administered. Close monitoring of glycaemic control should be considered. Co-administration of Pioglitazone with rifampicin (an inducer of cytochrome P450 2C8) is reported to result in a 54% decrease in AUC of Pioglitazone. The Pioglitazone dose may need to be increased when rifampicin is concomitantly administered. Close monitoring of glycaemic control should be considered.

Metformin hydrochloride

Carbonic anhydrase inhibitors

Topiramate or other carbonic anhydrase inhibitors (e.g. Zonisamide, Acetazolamide or Dichlorphenamide) frequently decrease serum bicarbonate & induce non-anion gap, hyperchloremic metabolic acidosis.

Concomitant use of these drugs may induce metabolic acidosis. Use these drugs with caution in patients treated with Metformin hydrochloride, as the risk of lactic acidosis may increase.

Cationic drugs

Cationic drugs (e.g. Amiloride, Digoxin, Morphine, Procainamide, Quinidine, Quinine, Ranitidine, Triamterene, Trimethoprim, or Vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with Metformin hydrochloride by competing for common renal tubular transport systems. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring & dose adjustment of Metformin hydrochloride and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

Drugs affecting glycemic control

Certain drugs tend to produce hyperglycemia & may lead to loss of glycemic control. These drugs include the Thiazides & other diuretics, Corticosteroids, Phenothiazines, Thyroid products, Estrogens, Oral contraceptives, Phenytoin, Nicotinic acid, Sympathomimetics, Calcium channel blockers, & Isoniazid. When such drugs are administered to a patient receiving Metformin hydrochloride, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving Metformin hydrochloride, the patient should be observed closely for hypoglycemia.

Concomitant use of Metformin hydrochloride not recommended.

Alcohol

Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in case of fasting or malnutrition or hepatic insufficiency.

Avoid consumption of Alcohol & Alcohol-containing medications.

Iodinated contrast agents

Metformin hydrochloride must be discontinued prior to, or at the time of the image procedure & not restarted until at least 48 hours after, provided that renal function has been re-evaluated & found to be stable.

Combinations requiring precautions for use

Some medicinal products can adversely affect renal function which may increase the risk of lactic acidosis, e.g. NSAIDs, including selective cyclo-oxygenase (COX) II inhibitors, ACE inhibitors, angiotensin II receptor antagonists & diuretics, especially loop diuretics. When starting or using such products in combination with Metformin hydrochloride, close monitoring of renal function is necessary.

Glucocorticoids (systemic & local routes), beta-2-agonists & diuretics have intrinsic hyperglycaemic activity. Inform the patient & perform more frequent blood glucose monitoring, especially at the beginning of treatment. If necessary, adjust the dosage of the antidiabetic drug during therapy with the other drug & upon its discontinuation. ACE-inhibitors may decrease the blood glucose levels. If necessary, adjust the dosage of the antidiabetic drug during therapy with the other drug & upon its discontinuation.

Metformin hydrochloride may decrease the anticoagulant effect of Phenprocoumon. Therefore, a close monitoring is recommended.

Levothyroxine can reduce the hypoglycemic effect of Metformin hydrochloride. Monitoring of blood glucose levels is recommended, especially when thyroid hormone therapy is initiated or stopped & the dosage of Metformin hydrochloride must be adjusted if necessary.

Organic cation transporters (OCT)

Metformin hydrochloride is a substrate of both transporters OCT1 & OCT2. Co-administration of Metformin hydrochloride with

• Inhibitors of OCT1 (such as Verapamil) may reduce efficacy of Metformin hydrochloride.
• Inducers of OCT1 (such as Rifampicin) may increase gastrointestinal absorption & efficacy of Metformin hydrochloride.
• Inhibitors of OCT2 (such as Cimetidine, Dolutegravir, Ranolazine, Trimethoprim, Vandetanib & Isavuconazole) may decrease the renal elimination of Metformin hydrochloride & thus lead to an increase in Metformin hydrochloride plasma concentration.
• Inhibitors of both OCT1 & OCT2 (such as Crizotinib, Olaparib) may alter efficacy & renal elimination of Metformin hydrochloride.

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

4.6 Use in special populations

This tablet must not be taken during pregnancy. The patient must change over to insulin during pregnancy. To prevent possible ingestion with the breast milk & possible harm to the child, this tablet must not be taken by breast-feeding women. If necessary the patient must change over to insulin, or must stop breast-feeding.

Pregnancy

Sitagliptin

There are no adequate data from the use of Sitagliptin in pregnant women. Studies in animals have shown reproductive toxicity at high doses. The potential risk for humans is unknown. Due to lack of human data, Sitagliptin should not be used during pregnancy.

Pioglitazone

There are no adequate human data to determine the safety of Pioglitazone during pregnancy. Foetal growth restriction was apparent in animal studies with Pioglitazone. This was attributable to the action of Pioglitazone in diminishing the maternal hyperinsulinaemia & increased insulin resistance that occurs during pregnancy thereby reducing the availability of metabolic substrates for foetal growth. The relevance of such a mechanism in humans is unclear & Pioglitazone should not be used in.

Metformin hydrochloride

Metformin hydrochloride was not teratogenic in rats & rabbits at doses up to 600 mg/kg/day, which represent 3 & 6 times the maximum recommended human daily dose of 2000 mg based on body surface area comparison for rats & rabbits, respectively. However, because animal reproduction studies are not always predictive of human response, Metformin hydrochloride should not be used during pregnancy unless clearly needed. The safety & effectiveness of Metformin hydrochloride used during labor & delivery has not been evaluated in human studies. Fertility of male or female rats was unaffected by Metformin hydrochloride when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons.

Lactation

It is unknown whether Sitagliptin is excreted in human breast milk. Animal studies have shown excretion of Sitagliptin in breast milk. Sitagliptin should not be used during breast-feeding. Breast-feeding must be discontinued during administration of Sitagliptin tablets in lactating women (transfer to milk in animal studies (rats) has been reported).

Studies in lactating rats show that Metformin hydrochloride is excreted into milk & reaches levels comparable to those in plasma.

Similar studies have not been conducted in nursing mothers. Thus, the potential for hypoglycemia in nursing infants after Metformin hydrochloride oral solution may exist. Metformin hydrochloride is excreted into human breast milk. No adverse effects were observed in breastfed new-borns / infants. However, as only limited data are available, breastfeeding is not recommended during Metformin hydrochloride treatment.

A decision on whether to discontinue breast-feeding should be made, taking into account the benefit of breast-feeding & the potential risk to adverse effect on the child.

Paediatric use

Safety & effectiveness of Sitagliptin in paediatric patients have not been established. The safety of Sitagliptin in low birth weight baby, new-born baby, infant, or little child has not been established. (No usage experience).

The safety & effectiveness in paediatric patients have not been established & Metformin hydrochloride is not recommended in paediatric patients below the age of 18 years. Thus, Sitagliptin / Metformin hydrochloride combination is not recommended in paediatric patients.

Geriatric use

Start with lowest dose in elderly patients due to higher risks of lactic acidosis, poor renal & hepatic functions & therefore, Sitagliptin should be administered carefully. Clinical studies of Metformin hydrochloride did not include sufcient numbers of subjects aged 65 & over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly & younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function & of concomitant disease or other drug therapy & the higher risk of lactic acidosis.

As Metformin hydrochloride is excreted via the kidney & elderly patients have a tendency to decreased renal function, elderly patients taking Sitagliptin / Metformin hydrochloride should have their renal function monitored regularly.

Patients with renal impairment

Sitagliptin / Metformin hydrochloride combination is not recommended in patients with renal impairment (e.g. serum creatinine levels greater than or equal to 1.5 mg/dL for men, greater than or equal to 1.4 mg/dL for women or abnormal creatinine clearance), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction & septicemia.

The single administration of Sitagliptin at 20 mg in patients with renal impairment revealed no remarkable changes in Cmax & t1/2 corresponding to the level of renal impairment. Compared with healthy adult subjects, the AUC0–∞ of subjects with mild renal impairment (50 ≤ creatinine clearance [Ccr] ≤ 80 mL/minute), moderate renal impairment (30 ≤ Ccr < 50 mL/minute), & severe renal impairment (Ccr < 30 mL/minute) was approximately 1.25 times, 1.68 times, & 1.49 times higher than that of healthy adult subjects, respectively. In addition, the AUC0–43h of patients with end-stage renal failure was approximately 1.16 times higher than that of healthy adult subjects. In addition, 15.6% of the total administration dose of Sitagliptin was eliminated via hemodialysis.

A GFR should be assessed before initiation of treatment with Metformin hydrochloride containing products & at least annually thereafter. In patients at an increased risk of further progression of renal impairment & in the elderly, renal function should be assessed more frequently e.g. every 3 - 6 months.

Patients with hepatic impairment

As determined from the pharmacokinetic characteristics of Sitagliptin, the extent of increase in the exposure level of Sitagliptin in patients with mild to moderate hepatic impairment will not pose any significant safety risk. Thus no dose adjustment is proposed in hepatic impaired patients. There was no clinical experience of Sitagliptin in severe degree hepatic dysfunction patient. The presence of liver disease is a risk-factor for the development of lactic acidosis during Metformin hydrochloride therapy & the drug should be avoided in patients with hepatic insufficiency.

A single administration of Sitagliptin 20 mg in patients with hepatic impairment revealed that the Cmax of subjects with mild hepatic impairment (Child-Pugh classification : total score 5 - 6) & moderate hepatic impairment (Child-Pugh classification : total score 7 - 9) was approximately 1.25 times & 1.38 times that of healthy adult subjects, respectively. Compared to healthy adult subjects, the AUC0–∞of subjects with mild & moderate hepatic impairments was approximately 1.46 times & 1.59 times higher than that of healthy adult subjects, respectively.

There have been no previous clinical studies using Sitagliptin in patients with severe hepatic impairment (Child-Pugh classification : total score was greater than 9). Thus, specific caution is required when the drug is administered to patients with severe hepatic impairment.

4.7 Effects on ability to drive & use machines

Sitagliptin has no or negligible influence on the ability to drive & use machines. However, when driving or using machines, it should be taken into account that dizziness & somnolence have been reported. In addition, patients should be alerted to the risk of hypoglycaemia when Sitagliptin is used in combination with a sulphonylurea or with insulin.

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

Pioglitazone has no or negligible influence on the ability to drive & use machines. However, patients who experience visual disturbance should be cautious when driving or using machines.

Metformin hydrochloride monotherapy does not cause hypoglycaemia & therefore has no effect on the ability to drive or to use machines. However, patients should be alerted to the risk of hypoglycaemia when Metformin hydrochloride is used in combination with other antidiabetic agents (Sulfonylureas, Insulin, & Repaglinide).

4.8 Undesirable effects

Sitagliptin

Dipeptidyl-peptidase-4 (DPP-4) inhibitors induced arthralgia : Dipeptidyl-peptidase-4 (DPP-4) inhibitors like Sitagliptin, Vildagliptin, Saxagliptin, Sitagliptin etc. induced arthralgia.

Summary of the safety proflle

Serious adverse reactions including pancreatitis & hypersensitivity reactions have been reported. Hypoglycaemia has been reported in combination with sulphonylurea (4.7% - 13.8%) & insulin (9.6%).

Tabulated list of adverse reactions

Adverse reactions are listed below (Table 1) by system organ class & frequency. Frequencies are dened as : 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).

Table 1 : The frequency of adverse reactions identified from placebo-controlled clinical studies of Sitagliptin monotherapy & post-marketing experience.

* Adverse reactions were identified through post-marketing surveillance.

† See TECOS Cardiovascular Safety Study below.

Description of selected adverse reactions

In addition to the drug-related adverse experiences described above, adverse experiences reported regardless of causal relationship to medication & occurring in at least 5% & more commonly in patients treated with Sitagliptin included upper respiratory tract infection & nasopharyngitis.

Additional adverse experiences reported regardless of causal relationship to medication that occurred more frequently in patients treated with Sitagliptin (not reaching the 5 % level, but occurring with an incidence of > 0.5 % higher with Sitagliptin than that in the control group) included osteoarthritis & pain in extremity.

Pioglitazone

Adverse reactions reported in excess (≥ 0.5%) of placebo & as more than an isolated case in patients receiving Pioglitazone in double-blind studies are listed below as MedDRA preferred term by system organ class & absolute frequency. Frequencies are defined as : 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). Within each system organ class, adverse reactions are presented in order of decreasing incidence followed by decreasing seriousness. Infections & infestations : common : upper respiratory tract infection, bronchitis. Uncommon : sinusitis.

Neoplasms benign, malignant & unspecified (including cysts & polyps) : uncommon bladder cancer.

Blood & lymphatic system disorders : anaemia.

Immune system disorders : not known : Hypersensitivity & allergic reactions ¹.

Metabolism & nutrition disorders : hypoglycaemia, appetite increased. Nervous system disorders : hypo-aesthesia, headache, dizziness, insomnia. Eye disorders : visual disturbance ², macular oedema

Ear & labyrinth disorders : vertigo

Cardiac disorders : heart failure ³

Respiratory, thoracic & mediastinal disorders: dyspnoea.

Gastrointestinal disorders : flatulence

Skin & subcutaneous tissue disorders : sweating

Musculoskeletal & connective tissue disorders : fracture bone, arthralgia, back pain

Renal & urinary disorders : haematuria, glycosuria, proteinuria

Reproductive system & breast disorders : erectile dysfunction. General disorders & administration site conditions: oedema ⁵, fatigue

Investigations : weight increased ⁶, blood creatine phospho-kinase increased, increased lactic dehydro- genase & alanine aminotransferase increased ⁷.

Description of selected adverse reactions :

1. Post-marketing reports of hypersensitivity reactions in patients treated with Pioglitazone have been reported. These reactions include anaphylaxis, angioedema, & urticaria.

2. Visual disturbance has been reported mainly early in treatment & is related to changes in blood glucose due to temporary alteration in the turgidity & refractive index of the lens as seen with other hypoglycaemic treatments.

3. In controlled clinical trials the incidence of reports of heart failure with Pioglitazone treatment was the same as in placebo, Metformin hydrochloride & sulphonylurea treatment groups, but was increased when used in combination therapy with insulin. In an outcome study of patients with pre-existing major macrovascular disease, the incidence of serious heart failure was 1.6% higher with Pioglitazone than with placebo, when added to therapy that included insulin. However, this did not lead to an increase in mortality in this study. In this study in patients receiving Pioglitazone & insulin, a higher percentage of patients with heart failure was observed in patients aged ≥ 65 years compared with those less than 65 years (9.7% compared to 4.0%). In patients on insulin with no Pioglitazone the incidence of heart failure was 8.2% in those ≥ 65 years compared to 4.0% in patients less than 65 years. Heart failure has been reported with marketing use of Pioglitazone, & more frequently when Pioglitazone was used in combination with insulin or in patients with a history of cardiac failure.

4. A pooled analysis was conducted of adverse reactions of bone fractures from randomised, comparator controlled, double blind clinical trials in over 8,100 patients in the Pioglitazone-treated groups & 7,400 in the comparatortreated groups of up to 3.5 years duration. A higher rate of fractures was observed in women taking Pioglitazone (2.6%) versus comparator (1.7%). No increase in fracture rates was observed in men treated with Pioglitazone (1.3%) versus comparator (1.5%).

5. In the 3.5 year PROactive study, 44/870 (5.1%) of Pioglitazone-treated female patients experienced fractures compared to 23/905 (2.5%) of female patients treated with comparator. No increase in fracture rates was observed in men treated with Pioglitazone (1.7%) versus comparator (2.1%). Post- marketing, bone fractures have been reported in both male & female patients.

6. Oedema was reported in 6 - 9% of patients treated with Pioglitazone over one year in controlled clinical trials. The oedema rates for comparator groups (sulphonylurea, Metformin hydrochloride) were 2 - 5%. The reports of oedema were generally mild to moderate & usually did not require discontinuation of treatment.

7. In active comparator controlled trials mean weight increase with Pioglitazone given as monotherapy was 2 - 3 kg over one year. This is similar to that seen in a sulphonylurea active comparator group. In combination trials Pioglitazone added to Metformin hydrochloride resulted in mean weight increase over one year of 1.5 kg & added to a sulphonylurea of 2.8 kg. In comparator group's addition of sulphonylurea to Metformin hydrochloride resulted in a mean weight gain of 1.3 kg & addition of Metformin hydrochloride to a sulphonylurea a mean weight loss of 1.0 kg.

8. In clinical trials with Pioglitazone the incidence of elevations of ALT greater than three times the upper limit of normal was equal to placebo but less than that seen in Metformin hydrochloride or sulphonylurea comparator groups. Mean levels of liver enzymes decreased with treatment with Pioglitazone. Rare cases of elevated liver enzymes & hepatocellular dysfunction have occurred in post-marketing experience. Although in very rare cases fatal outcome has been reported, causal relationship has not been established.

The following adverse reactions have been identified during post-approval use of Pioglitazone. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• New onset or worsening diabetic macular oedema with decreased visual acuity.
• Fatal & non-fatal hepatic failure.

Post-marketing reports of congestive heart failure have been reported in patients treated with Pioglitazone, both with & without previously known heart disease & both with & without concomitant insulin administration. In post-marketing experience, there have been reports of unusually rapid increases in weight & increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation & volume-related events such as excessive oedema & congestive heart failure.

Metformin hydrochloride

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

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

During treatment initiation, the most common adverse reactions are nausea, vomiting, diarrhoea, abdominal pain & loss of appetite, which resolve spontaneously in most cases.

Laboratory tests

Vitamin B₁₂ concentrations : Metformin hydrochloride may lower serum Vitamin B₁₂ concentrations. Measurement of hematologic parameters on an annual basis is advised in patients on Metformin hydrochloride & any apparent abnormalities should be appropriately investigated & managed.

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

Sitagliptin

During controlled clinical trials in healthy subjects, single doses of up to 800 mg Sitagliptin were administered.

Minimal increases in QTc, not considered to be clinically relevant, were observed in one study at a dose of 800 mg Sitagliptin. There is no experience with doses above 800 mg in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse reactions observed with Sitagliptin with doses of up to 600 mg per day for periods of up to 10 days & 400 mg per day for periods of up to 28 days. In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g. remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), & institute supportive therapy if required. Sitagliptin is modestly dialysable. In clinical studies, approximately 13.5 % of the dose was removed over a 3- to 4-hour haemodialysis session. Prolonged haemodialysis may be considered if clinically appropriate. It is not known if Sitagliptin is dialysable by peritoneal dialysis.

Pioglitazone

In clinical studies, patients have taken Pioglitazone at higher than the recommended highest dose of 45 mg daily. The maximum reported dose of 120 mg/day for four days, then 180 mg/day for seven days was not associated with any symptoms. Hypoglycaemia may occur in combination with sulphonylureas or insulin. Symptomatic & general supportive measures should be taken in case of overdose.

Metformin hydrochloride

No cases of overdose were reported during Metformin hydrochloride clinical trials. It would be expected that adverse reactions of a more intense character including epigastric discomfort, nausea, & vomiting followed by diarrhea, drowsiness, weakness, dizziness, malaise & headache might be seen. Should those symptoms persist, lactic acidosis should be excluded.

Overdose of Metformin hydrochloride has occurred, including ingestion of amounts greater than 50 g. Hypoglycemia was reported in approximately 10% of cases, but no causal association with Metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of Metformin hydrochloride overdose cases.

Metformin hydrochloride is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions.

Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom Metformin hydrochloride over dosage is suspected.

5.1 Mechanism of action / pharmacodynamic properties

Sitagliptin

Sitagliptin is a member of a class of oral anti-hyperglycaemic agents called dipeptidyl peptidase 4 (DPP-4) inhibitors.

The improvement in glycaemic control observed with this medicinal product may be mediated by enhancing the levels of active incretin hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) & glucose dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, & levels are increased in response to a meal. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 & GIP increase insulin synthesis & release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. Treatment with GLP-1 or with DPP-4 inhibitors in animal models of type 2 diabetes has been demonstrated to improve beta cell responsiveness to glucose & stimulate insulin biosynthesis & 9 release. With higher insulin levels, tissue glucose uptake is enhanced. In addition, GLP-1 lowers glucagon secretion from pancreatic alpha cells.

Decreased glucagon concentrations, along with higher insulin levels, lead to reduced hepatic glucose production, resulting in a decrease in blood glucose levels. The effects of GLP-1 & GIPare glucose-dependent such that when blood glucose concentrations are low, stimulation of insulin release & suppression of glucagon secretion by GLP-1 are not observed. For both GLP-1 & GIP, stimulation of insulin release is enhanced as glucose rises above normal concentrations. Further, GLP-1 does not impair the normal glucagon response to hypoglycaemia. The activity of GLP-1 & GIP is limited by the DPP-4 enzyme, which rapidly hydrolyzes the incretin hormones to produce inactive products. Sitagliptin prevents the hydrolysis of incretin hormones by DPP-4, thereby increasing plasma concentrations of the active forms of GLP-1 & GIP. By enhancing active incretin levels, Sitagliptin increases insulin release & decreases glucagon levels in a glucose-dependent manner. In patients with type 2 diabetes with hyperglycaemia, these changes in insulin & glucagon levels lead to lower haemoglobin A1c (HbA1c) & lower fasting & postprandial glucose concentrations. The glucose-dependent mechanism of Sitagliptin is distinct from the mechanism of sulphonylureas, which increase insulin secretion even when glucose levels are low & can lead to hypoglycaemia in patients with type 2 diabetes & in normal subjects. Sitagliptin is a potent & highly selective inhibitor of the enzyme DPP-4 & does not inhibit the closely-related enzymes DPP-8 or DPP-9 at therapeutic concentrations.

Pioglitazone

Pioglitazone is a selective agonist at peroxisome proliferator-activated receptor-gamma (PPARγ) in target tissues for insulin action such as adipose tissue, skeletal muscle, & liver. Activation of PPARγ increases the transcription of insulin-responsive genes involved in the control of glucose & lipid production, transport, & utilization. Through this mechanism, Pioglitazone both enhances tissue sensitivity to insulin & reduces the hepatic production of glucose (i.e. gluconeogenesis) - insulin resistance associated with type 2 diabetes mellitus is therefore improved without an increase in insulin secretion by pancreatic beta cells. Pioglitazone enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, & improves impaired glucose homeostasis. In patients with type 2 diabetes mellitus, these effects result in lower plasma glucose concentrations, lower plasma insulin concentrations, & lower HbA1c values.

Metformin hydrochloride

Metformin hydrochloride is a biguanide that improves glucose tolerance in patients with type 2 diabetes, lowering both basal & postprandial plasma glucose. Metformin hydrochloride decreases hepatic glucose production, decreases intestinal absorption of glucose, & improves insulin sensitivity by increasing peripheral glucose uptake & utilization. Metformin hydrochloride does not produce hypoglycemia in patients with type 2 diabetes or in healthy subjects except in special circumstances, & does not cause hyperinsulinemia. With Metformin hydrochloride therapy, insulin secretion remains unchanged while fasting insulin levels & daylong plasma insulin response may actually decrease.

5.2 Pharmacokinetic properties

Sitagliptin

Absorption

Following oral administration of a 100-mg dose to healthy subjects, Sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours post-dose, mean plasma AUC of Sitagliptin was 8.52 M•hr, Cmax was 950 nM. The absolute bioavailability of Sitagliptin is approximately 87 %. Since co-administration of a high-fat meal with Sitagliptin had no effect on the pharmacokinetics, Sitagliptin may be administered with or without food. Plasma AUC of Sitagliptin increased in a dose-proportional manner. Dose-proportionality was not established for Cmax & C24hr (Cmax increased in a greater than dose-proportional manner & C24hr increased in a less than dose-proportional manner).

Distribution

The mean volume of distribution at steady state following a single 100 mg intravenous dose of Sitagliptin to healthy subjects is approximately 198 litres. The fraction of Sitagliptin reversibly bound to plasma proteins is low (38%).

Biotransformation

Sitagliptin is primarily eliminated unchanged in urine, & metabolism is a minor pathway. Approximately 79% of Sitagliptin is excreted unchanged in the urine. Following a [14C] Sitagliptin oral dose, approximately 16 % of the radioactivity was excreted as metabolites of Sitagliptin. Six metabolites were detected at trace levels & are not expected to contribute to the plasma DPP-4 inhibitory activity of Sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of Sitagliptin was CYP3A4, with contribution from CYP2C8. In vitro data showed that Sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, & is not an inducer of CYP3A4 & CYP1A2.

Elimination

Following administration of an oral [14C] Sitagliptin dose to healthy subjects, approximately 100 % of the administered radioactivity was eliminated in faeces (13 %) or urine (87 %) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of Sitagliptin was approximately 12.4 hours. Sitagliptin accumulates only minimally with multiple doses. The renal clearance was approximately 350 mL/min.

Elimination of Sitagliptin occurs primarily via renal excretion & involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of Sitagliptin. The clinical relevance of hOAT-3 in Sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of Sitagliptin. However, Ciclosporin, a p-glycoprotein inhibitor, did not reduce the renal clearance of Sitagliptin. Sitagliptin is not a substrate for OCT2 or OAT1 or PEPT1/2 transporters. In vitro, Sitagliptin did not inhibit OAT3 (IC50=160 M) or p-glycoprotein (up to 250 M) mediated transport at therapeutically relevant plasma concentrations. In a clinical study Sitagliptin had a small effect on plasma digoxin concentrations indicating that Sitagliptin may be a mild inhibitor of p-glycoprotein.

Pioglitazone

Following oral administration, Pioglitazone is rapidly absorbed, & peak plasma concentrations of unchanged Pioglitazone are usually achieved 2 hours after administration. Proportional increases of the plasma concentration were observed for doses from 2–60 mg. Steady state is achieved after 4 - 7 days of dosing. Repeated dosing does not result in accumulation of the compound or metabolites. Absorption is not influenced by food intake. Absolute bioavailability is greater than 80%. The estimated volume of distribution in humans is 0.25 L/kg. Pioglitazone & all active metabolites are extensively bound to plasma protein (> 99%).

Pioglitazone undergoes extensive hepatic metabolism by hydroxylation of aliphatic methylene groups. This is predominantly via cytochrome P450 2C8 although other isoforms may be involved to a lesser degree. Three of the six identied metabolites are active (M-II, M-III, & M-IV). When activity, concentrations & protein binding is taken into account, Pioglitazone & metabolite M-III contribute equally to efcacy. On this basis M-IV contribution to efficacy is approximately three-fold that of Pioglitazone, whilst the relative efcacy of M-II is minimal.

In vitro studies have shown no evidence that Pioglitazone inhibits any subtype of cytochrome P450. There is no induction of the main inducible P450 isoenzymes 1A, 2C8/9, & 3A4 in man. Interaction studies have shown that Poglitazone has no relevant effect on either the pharmacokinetics or pharmacodynamics of Digoxin, Warfarin, Phenprocoumon & Metformin hydrochloride. Concomitant administration of Pioglitazone with Gembrozil (an inhibitor of cytochrome P450 2C8) or with Rifampicin (an inducer of cytochrome P450 2C8) is reported to increase or decrease, respectively, the plasma concentration of Pioglitazone.

Following oral administration of radiolabelled Pioglitazone to man, recovered label was mainly in faeces (55%) & a lesser amount in urine (45%). In animals, only a small amount of unchanged Pioglitazone can be detected in either urine or faeces. The mean plasma elimination half-life of unchanged Pioglitazone in man is 5 to 6 hours & for its total active metabolites 16 to 23 hours.

Metformin hydrochloride

Following a single oral dose of 1000 mg (2x500 mg tablets) Metformin hydrochloride after a meal, the time to reach maximum plasma Metformin hydrochloride concentration (T_max) is achieved at approximately 7 - 8 hours. In both single & multiple-dose studies in healthy subjects, once daily 1000 mg (2x500 mg tablets) dosing provides equivalent systemic exposure, as measured by areaunder-the-curve (AUC), & up to 35% higher C_max, of Metformin hydrochloride relative to the immediate release given as 500 mg twice daily.

Metformin hydrochloride sustained-release : The absolute bioavailability of a Metformin hydrochloride 500 mg tablet given under fasting conditions is approximately 50 - 60%. Following a single oral dose of Metformin hydrochloride sustained-release, Cmax is achieved within 4 - 8 hours. Peak plasma levels are approximately 20% lower compared to the same dose of Metformin hydrochloride immediate release. Both high & low fat meals had the same effect on the pharmacokinetics of sustained release. The apparent volume of distribution (V/F) of Metformin hydrochloride following single oral doses of 850 mg immediate release Metformin hydrochloride averaged 654 ± 358 L. Metformin hydrochloride is negligibly bound to plasma proteins. Metformin hydrochloride partitions into erythrocytes, most likely as a function of time. At usual clinical doses & dosing schedules of Metformin hydrochloride, steady state plasma concentrations of Metformin hydrochloride are reached within 24 - 48 hours & are generally < 1 µg/mL. During controlled clinical trials, which served as the basis of approval for Metformin hydrochloride, maximum Metformin hydrochloride plasma levels did not exceed 5 µg/mL, even at maximum doses.

Intravenous single-dose studies in healthy subjects demonstrate that Metformin hydrochloride is excreted unchanged in the urine & does not undergo hepatic metabolism (no metabolites have been identied in humans), nor biliary excretion.

Metabolism studies with extended-release Metformin hydrochloride tablets have not been conducted. Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of Metformin hydrochloride elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

6.1 Animal toxicology or pharmacology

Sitagliptin

Renal & liver toxicity was observed in rodents at systemic exposure values 58 times the human exposure level, while the no-effect level was found at 19 times the human exposure level. Incisor teeth abnormalities were observed in rats at exposure levels 67 times the clinical exposure level; the no-effect level for this nding was 58-fold based on the 14-week rat study. The relevance of these findings for humans is unknown. Transient treatment-related physical signs, some of which suggest neural toxicity, such as open-mouth breathing, salivation, white foamy emesis, ataxia, trembling, decreased activity, and/or hunched posture were observed in dogs at exposure levels approximately 23 times the clinical exposure level. In addition, very slight to slight skeletal muscle degeneration was also observed histologically at doses resulting in systemic exposure levels of approximately 23 times the human exposure level. A no-effect level for these findings was found at an exposure 6-fold the clinical exposure level. Sitagliptin has not been demonstrated to be genotoxic in preclinical studies. Sitagliptin was not carcinogenic in mice. In rats, there was an increased incidence of hepatic adenomas & carcinomas at systemic exposure levels 58 times the human exposure level. Since hepatotoxicity has been shown to correlate with induction of hepatic neoplasia in rats, this increased incidence of hepatic tumours in rats was likely secondary to chronic hepatic toxicity at this high dose.

Because of the high safety margin (19-fold at this no-effect level), these neoplastic changes are not considered relevant for the situation in humans. No adverse effects upon fertility were observed in male & female rats given Sitagliptin prior to & throughout mating. In a pre-/postnatal development study performed in rats Sitagliptin showed no adverse effects. Reproductive toxicity studies showed a slight treatment-related increased incidence of foetal rib malformations (absent, hypoplastic & wavy ribs) in the offspring of rats at systemic exposure levels more than 29 times the human exposure levels. Maternal toxicity was seen in rabbits at more than 29 times the human exposure levels. Because of the high safety margins, these findings do not suggest a relevant risk for human reproduction.

Sitagliptin is secreted in considerable amounts into the milk of lactating rats (milk / plasma ratio : 4:1).

Pioglitazone

Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg & above) & dogs (3 mg/kg) treated orally with Pioglitazone hydrochloride (approximately 11, 1, & 2 times the maximum 2 recommended human oral dose for mice, rats, & dogs, respectively, based on mg/m ). In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately 35 times the maximum recommended human oral dose based on mg/m²). Heart enlargement was seen in a 13-week study in monkeys at oral doses of 8.9 mg/kg & above (approximately four times the maximum recommended human oral dose based on mg/m²), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m²)

Metformin hydrochloride

Preclinical data reveal no special hazard for humans based on conventional studies on safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity reproduction.

This product (tablet) contains : Sitagliptin, Pioglitazone & Metformin hydrochloride as active ingredients. For the treatment of type 2 diabetes mellitus.

Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor which is used in combination with diet & exercise in the therapy of type 2 diabetes, either alone or in combination with other oral hypoglycemic agents.

Molecular formula : C₁₆H₁₅F₆N₅O

Molecular weight : 407.31 g/mol

 

Pioglitazone is an insulin sensitizing agent & thiazolidinedione that is indicated for the treatment of type 2 diabetes.

Molecular formula : C₁₉H₂₀N₂O₃S

Molecular weight : 356.40 g/mol

 

Metformin hydrochloride belong to the biguanide class of antidiabetics with antihyperglycemic activity.

Molecular formula : C₄H₁₁N₅

Molecular weight : 129.16 g/mol

 

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

Alu-Alu blister strip of 10 tablets.

8.4 Storage & handing instructions

Store below 30°C away from direct sunlight, heat & moisture.

Keep out of reach of children.

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

Read this entire leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

What Sitagliptin, Pioglitazone & Metformin hydrochloride Tablets is & what it is used for ?

This Product (tablet) contains : Sitagliptin, Pioglitazone & Metformin hydrochloride as active ingredients. For the treatment of type 2 diabetes mellitus.

What you need to know before you take Sitagliptin, Pioglitazone & Metformin hydrochloride Tablets ?

Do not take Sitagliptin, Pioglitazone & Metformin hydrochloride Tablet, if you are :

Having an allergy or hypersensitivity to any of the active ingredients or excipients present in this drug. Sitagliptin is contraindicated in patients with :

• Severe ketosis, diabetic coma (or history of diabetic coma) or pre-coma & also for immediate remedy in type 1 diabetes of hyperglycemias with infusion & insulin.
• Patients with severe infection, surgery, severe trauma (blood sugar control should preferably be done by insulin) are hypersensitive (allergic) to Pioglitazone or any of the other ingredients of Pioglitazone.
• Have heart failure or have had heart failure in the past.
• Have liver disease.
• Have had diabetic ketoacidosis (a complication of diabetes causing rapid weight loss, nausea or vomiting).
• Have or have ever had bladder cancer.
• Have blood in your urine that your doctor has not checked.

Metformin hydrochloride is contraindicated in patients with the following conditions :

• Renal impairment (e.g., serum creatinine levels ≥ 1.5 mg/dL for men, ≥ 1.4 mg/dL for women or abnormal creatinine clearance), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction & septicemia.
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin.

Warnings & precautions

Sitagliptin

Sitagliptin should be administered carefully in the following :

Patients with advanced liver failure (safety has not been established).

Patients with congestive heart failure (NYHA category III-IV) (safety has not been established). In patients with pituitary insufficiency or adrenal insufficiency, poor nutritional state, starvation, an irregular dietary intake, or debilitating condition, intense muscle movement or excessive alcohol intake (may cause low blood sugar).

Patients with history of abdominal surgery or with a history of bowel obstruction (may cause bowel obstruction).

In patients with arrhythmia, severe bradycardia or its history, patients with heart disease such as congestive heart failure or patients with low serum Potassium, congenital prolonged QT syndrome, & history of Torsade's de pointes or patients using antiarrhythmic drugs (may cause QT prolongation). Patients using insulin secretagogues (e.g., sulfonylurea) (risk of severe hypoglycaemia).

Acute pancreatitis

Acute pancreatitis has been observed in studies done outside Japan & since acute pancreatitis is also reported with similar molecules, it should not be used in patients with history of acute pancreatitis. In case a patient develops acute pancreatitis the drug should be withdrawn & immediate physician consultation should be done.

In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure while being treated with Sitagliptin compared with 3.7 cases per 10,000 patient year exposure while being treated with comparator (placebo & active comparator, sulfonylurea). Three additional cases of pancreatitis were reported following the last administered dose of Sitagliptin.

Hypoglycemia

Hypoglycemia may occur in patients with : Adrenal insufficiency; Malnutrition, starved state, irregular dietary intake, insufficient dietary intake or hyposthenia; Vigorous muscular movement; Patient with excessive alcohol consumption.

Important precautions

The points regarding hypoglycemia & its coping strategy should be sufficiently explained to the patient when using this product. Particularly, when co-administered with sulfonylurea or insulin formulation, there is a possibility of higher risk of hypoglycemia. In order to reduce the risk of hypoglycemia caused by sulfonylurea or insulin formulation, consider decreasing the dose of sulfonylurea or insulin formulation when given in combination with Sitagliptin.

Consider its application only to the patient diagnosed with Type 2 diabetes mellitus (T2DM). In addition to T2DM, pay attention to diseases having symptoms (such as renal glycosuria, thyroid dysfunction) similar to diabetes, such as abnormal glucose tolerance / positive urine sugar.

During administration of Sitagliptin, regularly check the blood sugar; check the effect of the drug. In case, the drug effect is insufficient even after taking this product for 3 months, then change to other treatment.

Metformin hydrochloride

Risk of lactic acidosis.

Metformin hydrochloride may cause a very rare, but very serious side effect called lactic acidosis, particularly if your kidneys are not working properly. The risk of developing lactic acidosis is also increased with uncontrolled diabetes, serious infections, prolonged fasting or alcohol intake, dehydration (see further information below), liver problems & any medical conditions in which a part of the body has a reduced supply of oxygen (such as acute severe heart disease).

If any of the above apply to you, talk to your doctor for further instructions.

Stop taking Metformin hydrochloride for a short time if you have a condition that may be associated with dehydration (significant loss of body fluids) such as severe vomiting, diarrhoea, fever, exposure to heat or if you drink less fluid than normal.

Talk to your doctor for further instructions. Stop taking Metformin hydrochloride & contact a doctor or the nearest hospital immediately if you experience some of the symptoms of lactic acidosis, as this condition may lead to coma.

Symptoms of lactic acidosis include :

• Vomiting
• Stomach ache (abdominal pain).
• Muscle cramps.
• A general feeling of not being well with severe tiredness.
• Difficulty in breathing.
• Reduced body temperature & heartbeat.

Lactic acidosis is a medical emergency & must be treated in a hospital.

If you need to have major surgery you must stop taking Metformin hydrochloride during & for some time after the procedure. Your doctor will decide when you must stop & when to restart your treatment with Metformin hydrochloride. During treatment with Metformin hydrochloride, your doctor will check your kidney function at least once a year or more frequently if you are elderly and/or if you have worsening kidney function. If you are older than 75 years, treatment with Metformin hydrochloride tablet should not be started to lower the risk of developing type 2 diabetes. You may see some remains of the tablets in your stools. Do not worry- this is normal for this type of tablet. You should continue to follow any dietary advice that your doctor has given you & you should make sure that you eat carbohydrates regularly throughout the day. Do not stop taking this medicine without speaking to your doctor.

Other medicines & Sitagliptin, Pioglitazone & Metformin hydrochloride tablets.

Sitagliptin

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. In particular, tell your doctor if you are taking Digoxin (a medicine used to treat irregular heartbeat & other heart problems). The level of digoxin in your blood may need to be checked if taking with Sitagliptin.

Pioglitazone

You can usually continue to take other medicines whilst you are being treated with Pioglitazone. However, certain medicines are especially likely to affect the amount of sugar in your blood :

• Gemfibrozil (used to lower cholesterol)
• Rifampicin (used to treat tuberculosis & other infections) Tell your doctor or pharmacist if you are taking any of these. Your blood sugar will be checked & your dose of Pioglitazone may need to be changed.

Metformin hydrochloride

Tell your doctor if you are taking, have recently taken or might take any other medicines. You may need more frequent blood glucose & kidney function tests, or your doctor may need to adjust the dosage of Metformin hydrochloride SR. It is especially important to mention the following :

• Steroids such as Prednisolone, Mometasone, Beclometasone.
• Medicines which increase urine production (diuretics (water tablets) such as Furosemide).
• Medicines used to treat pain & inflammation (NSAID & COX-2-inhibitors, such as Ibuprofen & Celecoxib)
• Certain medicines for the treatment of high blood pressure (ACE inhibitors & Angiotensin II receptor antagonists)
• Sympathomimetic medicines including epinephrine & dopamine used to treat heart attacks & low blood pressure. Epinephrine is also included in some dental anaesthetics.
• Medicines that may change the amount of Metformin hydrochloride in your blood, especially if you have reduced kidney function (such as Verapamil, Rifampicin, Cimetidine, Dolutegravir, Ranolazine, Trimethoprim, Vandetanib, Isavuconazole, Crizotinib, Olaparib).

Sitagliptin, Pioglitazone & Metformin hydrochloride Tablets with alcohol

Avoid excessive alcohol intake while taking Metformin hydrochloride (Sustained Release) since this may increase the risk of lactic acidosis.

Pregnancy & breast-feeding

Do not take Sitagliptin, Pioglitazone & Metformin hydrochloride Tablets if you are pregnant or breast feeding, think you may be pregnant or are planning to have a baby. Ask your doctor or pharmacist for advice before taking this medicine.

you think you might be or are planning to become pregnant.

• Are breast-feeding or if you are planning to breastfeed your baby. Your doctor will advise you to discontinue this medicine.

Driving & using machines tablets

Sitagliptin, Pioglitazone & Metformin hydrochloride Tablets taken on its own does not cause 'hypos' (symptoms of low blood sugar or hypoglycaemia, such as faintness, confusion & increased sweating) & therefore should not affect your ability to drive or use machinery. You should be aware, however, that this medicine has no or negligible influence on the ability to drive & use machines. However, dizziness & drowsiness have been reported, which may affect your ability to drive or use machines. Taking this medicine in combination with medicines called sulphonylureas or with insulin can cause hypoglycaemia, which may affect your ability to drive & use machines or work without safe foothold.

Pioglitazone will not affect your ability to drive or use machines but take care if you experience abnormal vision.

Metformin hydrochloride (Sustained Release) taken with other antidiabetic medicines can cause hypos, so in this case you should take extra care when driving or operating machinery.

How to take Sitagliptin, Pioglitazone & Metformin hydrochloride Tablets?

Always take Sitagliptin, Pioglitazone & Metformin hydrochloride tablets exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

Posology

The usual recommended dose for adults is 1 tablet once daily or as directed by the Physician.

Method of administration

For oral administration only.

Sitagliptin / Pioglitazone / Metformin hydrochloride tablets must be swallowed whole and not to be chewed or crushed.

Possible side effects

Sitagliptin

Like all medicines, this medicine can cause side effects, although not everybody gets them. STOP taking Sitagliptin & contact a doctor immediately if you notice any of the following serious side effects : Severe & persistent pain in the abdomen (stomach area) which might reach through to your back with or without nausea & vomiting, as these could be signs of an inflamed pancreas (pancreatitis). If you have a serious allergic reaction (frequency not known), including rash, hives, blisters on the skin / peeling skin & swelling of the face, lips, tongue, & throat that may cause difficulty in breathing or swallowing, stop taking this medicine & call your doctor right away. Your doctor may prescribe a medicine to treat your allergic reaction & a different medicine for your diabetes.

Some patients have experienced the following side effects after adding Sitagliptin to Metformin hydrochloride

Common (may affect up to 1 in 10 people) : Low blood sugar, Nausea, Flatulence, Vomiting.

Uncommon (may affect up to 1 in 100 people) : Stomach ache, Diarrhoea, Constipation, Drowsiness

Some patients have experienced different types of stomach discomfort when starting the combination of Sitagliptin & Metformin hydrochloride together (frequency is common).

Some patients have experienced the following side effects while taking Sitagliptin in combination with a sulphonylurea & Metformin hydrochloride :

Very common (may affect more than 1 in 10 people) : Low blood sugar.

Common : Constipation

Some patients have experienced the following side effects while taking Sitagliptin & Pioglitazone

Common : Flatulence, Swelling of the hands or legs.

Some patients have experienced the following side effects while taking Sitagliptin in combination with Pioglitazone & Metformin hydrochloride

Common : Swelling of the hands or legs.

Some patients have experienced the following side effects while taking Sitagliptin in combination with insulin (with or without Metformin hydrochloride)

Common : flu.

Uncommon : dry mouth Some patients have experienced the following side effects while taking.

Sitagliptin alone in clinical studies, or during post-approval use alone and/or with other diabetes medicines

Common : Low blood sugar, Headache, Upper respiratory infection, Stuffy or runny nose & sore throat, Osteoarthritis, Arm or leg pain.

Uncommon : Dizziness, Constipation, Itching.

Rare : Reduced number of platelets.

Frequency not known : Kidney problems (sometimes requiring dialysis), Vomiting, Joint pain, Muscle pain, Back pain, Interstitial lung disease, Bullous pemphigoid (a type of skin blister).

Pioglitazone

Like all medicines, Pioglitazone can cause side effects, although not everybody gets them. In particular, patients have experienced the following serious side effects : Heart failure has been experienced.

commonly (1 to 10 users in 100)

In patients taking Pioglitazone in combination with insulin. Symptoms are unusual shortness of breath or rapid increase in weight or localised swelling (oedema). If you experience any of these, especially if you are over the age of 65, seek medical advice straight away. Bladder cancer has been experienced uncommonly (1 to 10 users in 1000) in patients taking Pioglitazone. Signs & symptoms include blood in your urine, pain when urinating or a sudden need to urinate.

If you experience any of these, talk to your doctor as soon as possible. Localised swelling (oedema) has also been experienced very commonly in patients taking Pioglitazone in combination with insulin. If you experience this side effect, talk to your doctor as soon as possible.

Broken bones have been reported commonly (1 to 10 users in 100) in women patients taking Pioglitazone. If you experience this side effect, talk to your doctor as soon as possible. Blurred vision due to swelling (or fluid) at the back of the eye (frequency not known) has also been reported in patients taking Pioglitazone. If you experience this symptom for the first time, talk to your doctor as soon as possible. Also, if you already have blurred vision & the symptom gets worse, talk to your doctor as soon as possible. The other side effects that have been experienced by some patients taking Pioglitazone are :

Common (affects 1 to 10 users in 100)

• Weight gain
• Respiratory infection
• Numbness
• Abnormal vision
• Bone fracture

Uncommon (affects 1 to 10 users in 1,000)

• Inflammation of the sinuses (sinusitis).
• Difficulty sleeping (insomnia) Not known (frequency cannot be estimated from the available data).
• Blurred vision due to swelling (or fluid) in the back of the eye. If you experience these symptoms for the first time or if they get worse, tell your doctor as soon as possible.
• Increase in liver enzymes The other side effects that have been experienced by some patients when Pioglitazone is taken with other anti-diabetic medicines are :

Very common (affects more than 1 user in 10)

• Decreased blood sugar (hypoglycaemia)
• Localised swelling (oedema)

Common (affects 1 to 10 users in 100)

• Headache
• Dizziness
• Flatulence
• Joint pain
• Impotence
• Blood in urine
• Small reduction in red blood cell count
• Back pain
• Shortness of breath
• Heart failure (when taken with insulin)

Uncommon (affects 1 to 10 users in 1,000)

• Spinning sensation (vertigo)
• Sweating
• Tiredness
• Sugar in urine, proteins in urine
• Increased appetite
• Increase in enzymes

Metformin hydrochloride

Metformin hydrochloride may cause a very rare (may affect up to 1 user in 10,000), but very serious side effect called lactic acidosis. If this happens you must stop taking Metformin hydrochloride & contact a doctor or the nearest hospital immediately, as lactic acidosis may lead to coma. Metformin hydrochloride in may cause abnormal liver function tests & hepatitis (inflammation of the liver) which may result in jaundice (may affect up to 1 user in 10,000). If you develop yellowing of the eyes and/or skin contact your doctor immediately.

Other possible side effects are listed by frequency as follows :

Very common (affects more than 1 person in 10)

• Diarrhoea, nausea, vomiting, stomach ache or loss of appetite. If you get these, do not stop taking the tablets as these symptoms will normally go away in about 2 weeks. It helps if you take the tablets with or immediately after a meal.

Common (affects less than 1 person in 10, but more than 1 person in 100)

• Taste disturbance

Very rare (affects less than 1 person in 10,000)

• Decreased vitamin B12 levels.
• Skin rashes including redness, itching & hives.

How should I store Sitagliptin, Pioglitazone & Metformin hydrochloride Tablets ?

Keep this medicine out of the sight & reach of children.

Store below 30°C away from direct sunlight, heat & moisture.

Do not use this medicine after the expiry date, which is stated on the carton & the container after expiry. The expiry date refers to the last day of that month.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment.

Any other information

Keep this medicine out of the sight & reach of children

17 August 2023

Trypsin, Bromelain and Rutoside Trihydrate Tablets

Each enteric coated tablet contains :

Trypsin BP 48 mg

Bromelain 90 mg

Rutoside Trihydrate BP 100 mg

Excipients q.s.

Colour : Sunset Yellow Lake

Total proteolytic activity not less than 1095 FIP units per tablet (Papain method).

Appropriate overages of enzymes are added to compensate the probable loss on storage

Tablet

4.1 Therapeutic indication

For postoperative inflammation in subject undergoing minor surgery and dental procedure.

4.2 Posology and method of administration

• Adults : 1 to 2 tab b.i.d. or t.i.d. orally
• Children : 1 tab/10 kg body wt, taken daily in 2 - 4 partial doses

Tablets should be swallowed on empty stomach at least 30 min before meals or 2 h after meals.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

• Should not be used in known cases of hypersensitivity to any of its ingredients.
• Not recommended in patients with hereditary coagulation disorder (e.g. hemophilia) & liver disorder.
• The combination cannot replace an ongoing antibiotic therapy.
• Temporary reduction of dose advised if there is exacerbation of symptoms on initial therapy.

4.5 Drugs interactions

No evidence of incompatibility of Tibrolin with other concomitant medications has been reported.

4.6 Use in special populations

Pregnancy & Breastfeeding

Should be used with caution during pregnancy & breast feeding

4.7 Effects on ability to drive and use machines

It is not known whether Tibrolin tablet alters the ability to drive. Do not drive if you experience any symptoms that affect your ability to concentrate and react.

4.8 Undesirable effects

Generally, well tolerated, even during prolonged high doses were observed in most cases, side effects. Occasionally may appear insignificant change in consistency, colour and odour of stool. Rare side effects are: headache, hunger, and increased sweating. During high-dose were observed feelings of fullness, impoundment, occasional nausea. This feeling can be avoided by dividing the total dose during the day. Rarely occurring allergic reactions (skin rash) disappear after discontinuation

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

Even if long-term use of higher doses, there were no toxic effects, including possible light diarrhea that after discontinuing the plant disappears spontaneously.

5.1 Mechanism of action

Trypsin is a proteolytic enzyme found in the digestive system where it hydrolyses proteins. Trypsin breaks the fibrin barrier and restores circulation; resolves edema and hematoma; promotes phagocytosis to remove necrotic debris accumulated during injuries and burns; and inhibits necrotic damage and scarring.

Bromelain is a proteolytic enzyme, breaks peptide bonds inside protein molecules. Bromelain assists in removal of blood clot by supporting fibrinolysis, activation of plasmin, preventing aggregation of blood platelets. Bromelain reduces edemas; reduces blood level of plasma kinins to reduce pain; reduces the level of PGE2 and TXA2 in exudates during acute inflammation; induces secretion of interleukin (IL)-1, IL-6, IL-8 & TNF-α to promote re-epithelialization. Bromelain also increases tissue permeability of antibiotics.

Rutoside (also known as Rutin) is the glycoside, formed by combining a disaccharide and flavonol. It is a citrus flavonoid obtained from buckwheat & Pagoda Tree. Rutoside possesses antioxidant, antiinflammatory, antithrombotic, cytoprotective & vasoprotective properties. It promotes wound healing & augments tensile strength of scar tissue significantly. Rutoside also modulates respiratory burst of neutrophils, and inhibits TXA2 formation causing inhibition of platelet aggregation

5.2 Pharmacodynamic properties

The enzymes bromelain and trypsin reduce both edema of inflammatory origin, as well as swelling accompanying trauma or surgery. The enzymes show Fibrinolytic and thrombolytic effect, influence on rheological properties of blood, immunomodulatory effect, analgesic effect.

5.3 Pharmacokinetic properties

Trypsin : Pharmacokinetic study indicates that Trypsin is absorbed by enterocytes, probably through a transcellular route. Radio-labelled human Trypsin metabolism has been investigated in man. Serum half life of Trypsin varies from 17.5-24 minutes. Around 13-38% of the radio-labelled human trypsin injected was recovered from duodenal juice aspirated continuously over 300 minutes. After Radio-labelled Trypsin infusion, 11% of the total dose was found to be present in the circulation after 75 minutes. Metabolism of trypsin has not been well documented. Small amount may be excreted in the urine.

Bromelain : Bromelain is absorbed intact through the gastrointestinal tract. It is reported that about 40% of Bromelain is absorbed from the intestine. The highest concentration of bromelain is found in the blood one hour after administration; however, its proteolytic activity is rapidly deactivated.

Rutoside : Only about 17% of an ingested dose is absorbed. Absorption appears to occur mainly from the colon following the removal of the carbohydrate moiety by bacterial enzymes to form quercetin. Quercetin may undergo glucouronidation in the intestinal cells. Quercetin and glucuronide conjugates of quercetin are transported to the liver via the portal circulation, where they undergo significant first pass metabolism.

Gastric secretions can destroy the Trypsin, Rutoside and Bromelain. The high potency standardized Bromelain, Rutoside and Trypsin formulation is protected from stomach acid by a special enteric coating. This allows high levels of these activated proteolytic enzymes to be absorbed by the mucosal membrane of the intestine.

6.1 Animal toxicology or pharmacology

Acute median lethal dose after oral administration is too high, cannot be given. In vivo chromosomal analyzes :

No statistically significant increase in frequency was observed compared to the control group structural chromosomal aberrations in bone marrow cells.

Embryotoxicity, teratogenicity and impact on pregnancy :

There were no documented deviations from normal during pregnancy, there was no increase in the number intra uterine resorption or fetal death was observed and no malformation. There are changes in the development of organs and during ossification. There were no unexpected changes in the representation of gender or weight of the fruit.

Tibrolin is a combination of two proteases - Trypsin & Bromelain, and a bioflavonoid Rutoside.

Trypsin is a serine protease found in the digestive system, where it cleaves peptide chains, hydrolyses proteins. Trypsin is produced in the pancreas as the inactive proenzyme trypsinogen. Trypsin is obtained from the pancreas of pigs by repeated refining and subsequent activation of the proenzyme trypsinogen.

Bromelain is obtained from crude, aqueous extract from the stems and immature fruits of pineapples (Ananas comosus Merr.). Bromelain constitutes an unusually complex mixture of different thiol-endopeptidases and other components such as phosphatases, glucosidases, peroxidases, cellulases, glycoproteins and carbohydrates, among others. In addition, bromelain contains several proteinase inhibitors.

Rutin, also called rutoside, quercetin-3-rutinoside and sophorin, is a citrus flavonoid glycoside found in buckwheat, the leaves and petioles of Rheum species, and asparagus. Rutin is the glycoside between the flavonols quercetin and the disaccharide rutinose.

8.1 Incompatibilities

None

8.2 Shelf-life

24 Months.

8.3 Packaging information

A blister strip of 10 tablets.

8.4 Storage and handing instructions

• Store in a dry & dark place, at a temperature not exceeding 30°C.
• Keep out of reach of children.
• Tablet should be swallowed whole & not to be broken, crushed or chewed.

• Tibrolin should only be used : exactly as prescribed, at the lowest dose possible for your treatment for the shortest time needed,
• Do not take this medicine, if you are allergic to any ingredient of the Tibrolin
• Signs of an allergic reaction include a rash, itching or shortness of breath.
• Advice patients to talk to your doctor or pharmacist, if you get any side effects. This includes any possible side effects not listed in this leaflet.
• Advice patients If they have any further questions, ask doctor or pharmacist.

28 April 2021

Ferrous ascorbate, Folic acid & Methylcobalamin Suspension

Each 5 ml contains:

Ferrous Ascorbate equivalent to Elemental Iron…… 30 mg

Folic acid IP……500 mcg

Methylcobalamin IP…….500 mcg

200 ml bottle Suspension

[30 mg Ferrous ascorbate + 500 mcg Folic acid + 500 mcg Methylcobalamin] per 5 ml

4.1 Therapeutic indication

For the treatment of iron deficiency anaemia.

4.2 Posology and method of administration

1-2 teaspoonful daily (5-10 mL) or as directed by the physician.

Method of administration: Oral

4.3 Contraindications

• Patients hypersensitive to ferrous ascorbate, folic acid, methylcobalamin or to any other component of this formulation.
• Paroxysmal nocturnal haemoglobinuria, haemosiderosis, haemochromatosis.
• Repeated blood transfusions. Must not be used in anaemias other than those due to iron deficiency.

4.4 Special warnings and precautions for use

General

Do not exceed the recommended dose. The type of anaemia and the underlying cause or causes should be determined before starting therapy with this medication. Since the anaemia may be a result of a systemic disturbance, such as recurrent blood loss, the underlying cause or causes should be corrected, if possible.

• In general, people with a history of kidney disease, intestinal disease, peptic ulcer disease, enteritis, colitis, pancreatitis, hepatitis, who consume excessive alcohol, who plan to become pregnant, or who are over 55 years of age and have a family history of heart disease should consult a doctor and pharmacist before taking iron.
• Individuals with blood disorders who require frequent blood transfusions are also at risk of iron overload and should not take iron supplements without direction by a qualified healthcare provider. Long-term use of high doses of iron can cause haemosiderosis that clinically resembles haemochromatosis. Iron overload is associated with several genetic diseases, including haemochromatosis. Accumulation of excess iron is being investigated as a potential contributor to neurodegenerative diseases such as Alzheimer's and Parkinson's disease.
• Vitamin B12 deficiency that is allowed to progress for longer than 3 months may produce permanent degenerative lesions of the spinal cord.
• Folic acid in doses above 0.1 mg daily may obscure pernicious anaemia in that haematologic remission can occur while neurological manifestations remain progressive. This may result in severe nervous system damage before the correct diagnosis is made. Neurological manifestations will not be prevented with Folic acid, and if not treated with Vitamin B12, irreversible damage will result. Adequate doses of Vitamin B12 may prevent, halt, or improve the neurological changes caused by pernicious anaemia.
• Administration of Folic acid alone is improper therapy for pernicious anaemia and other megaloblastic anaemias in which Vitamin B12 is deficient. Doses of Cyanocobalamin exceeding 10 mcg daily may produce a hematologic response in patients with folate deficiency. Indiscriminate administration may mask the true diagnosis.
• Caution should be used in patients undergoing angioplasty since an intravenous loading dose of Folic acid, Vitamin B6, and Vitamin B12, followed by oral administration taken daily after coronary stenting, might actually increase restenosis rates. Due to the potential for harm, this combination of vitamins should not be recommended for patients receiving coronary stents.
• For pernicious anaemia, an adequate dose must be used and the blood picture must be examined regularly at least every three months for 18 months until stabilised, and then annually.
• Indiscriminate administration of this medicine may mask precise diagnosis.

Drug interactions

• The administration of the following with Iron salts results in decreased iron effectiveness : Aluminium Hydroxide, Aluminium Phosphate, Calcium, Aluminium Carbonate (basic), Chloramphenicol, Dihydroxyaluminium Aminoacetate, Dihydroxyaluminium Sodium Carbonate, Magaldrate, Magnesium Carbonate, Magnesium Hydroxide, Magnesium Oxide, Magnesium Trisilicate, Methacycline, Minocycline, Oxytetracycline, Rolitetracycline, Sodium Bicarbonate.
• The administration of the following with iron salts results in decreased effectiveness of the following molecules : Cefdinir, Cinoxacin, Ciprofloxacin, Enoxacin, Gatifloxacin, Gemifloxacin, Grepafloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Norfloxacin, Ofloxacin, Penicillamine, Sparfloxacin, Temafloxacin, Trovafloxacin Mesylate, Levothyroxine.
• The administration of the following with iron salts results in decreased effectiveness of the molecule as well as Iron : Zinc (with decreased gastrointestinal absorption), Acetohydroxamic acid, Trientine (with decreased gastrointestinal absorption).
• The administration of the following with iron salts results in reduced iron absorption/bioavailability : Esomeprazole, Desferrioxamine, Gossypol, Lansoprazole, Omeprazole, Pantoprazole, Rabeprazole, Soybean, Soy Protein, Vanadium, Cholestyramine, Colestipol, Pancrelipase.
• The administration of the following molecules with iron decreases the absorption of the molecules : Ciprofloxacin, Ofloxacin, Levofloxacin, Tiludronate, Risedronate, Alendronate, Etidronate, Ibandronate, Levodopa, Methyldopa, Levothyroxine, Mycophenolic acid, Minocycline, Doxycycline, Tetracycline, Demeclocycline.
• Allopurinol may increase iron storage in the liver and should not be used in combination with iron supplements.
• Aminosalicylic acid may cause a malabsorption syndrome (weight loss, iron and vitamin depletion, steatorrhoea).
• Aspirin and NSAIDs can cause mucosal damage and bleeding throughout the gastrointestinal tract. Chronic blood loss associated with the long-term use of these agents may contribute to iron deficiency anaemia. Since iron supplements may also irritate the gastrointestinal tract, patients should not use them concurrently with NSAIDs unless recommended by a Physician.
• Chloramphenicol can reduce the response to iron therapy in iron deficiency anaemia.
• Iron supplements and dimercaprol may combine in the body to form a harmful chemical.
• Adequate dietary iron intake is recommended when taking H2 blockers like Cimetidine, Ranitidine, Famotidine or Nizatidine. Iron supplements are not usually required unless they are being used for another indication.
• The administration of the following with Folic acids results in decreased effectiveness of the molecule : Fosphenytoin, Phenytoin, Pyrimethamine.
• The administration of the following with folate results in reduced folate absorption: Aminosalicylic acid, Antacids, Antibiotics, Aspirin, Carbamazepine, Cholestyramine, Colestipol, Cycloserine, Cimetidine, Famotidine, Nizatidine, Ranitidine, Pancrelipase, Sulfasalazine, Triamterene.
• The administration of the following with folate results in reduced serum folate levels: Oestrogens conjugated, Oral contraceptives pills, Methotrexate, Methylprednisolone Sodium Succinate (noted in people with multiple sclerosis), Intravenous pentamidine, Phenobarbital and Primidone, Pyrimethamine.
• Excessive use of Alcohol increases the requirement for Folic acid.
• Chloramphenicol may antagonize some effects of Folic acid on the blood (haematopoietic system). Limited data suggests that diuretics may increase excretion of Folic acid.
• Reduced Vitamin B12 and, to a lesser extent, folate levels occur in some people with diabetes and can contribute to hyperhomocysteinaemia, which adds to the already increased risk of cardiovascular disease. The reduced folate levels seen in diabetics have been linked to Metformin use in some cases, possibly as a result of reduced Folic acid absorption. Symptomatic folate deficiency is unlikely to occur with Metformin, but people with diabetes may need Folic acid supplements to reduce hyperhomocysteinaemia.
• Chronic cigarette smoking is associated with diminished folate status.
• Folate-dependent enzymes have been inhibited in laboratory experiments by Ibuprofen, Naproxen, Indomethacin and Sulindac.
• One study found that administration of Folic acid to pregnant women might not interfere with the protective effect of the sulphadoxine/pyrimethamine combination when used for intermittent preventative treatment of malaria.
• There is a general belief that Folic/folinic acid supplements do not interfere with the therapeutic effects of trimethoprim. However, this view has been challenged, and failure of trimethoprim therapy has occurred rarely when folinic acid is given concurrently.
• Absorption may be reduced by Para-aminosalicylic acid, Colchinine, Biguanides, Neomycin, Cholestyramine, Potassium Chloride, Methyldopa, and Cimetidine.
• Patients treated with Chloramphenicol may respond poorly to this medicine.
• Serum levels of this medicine may be lowered by oral contraceptives. These interactions are unlikely to have clinical significance.
• Anti-metabolities and most antibiotics invalidate Vitamins B12 assays by microbiological techniques.

Special populations

Pregnancy

Nutritional supplement doses of vitamins and minerals are generally considered safe during pregnancy.

Lactation

For the prevention and treatment of iron deficiency and to supply a maintenance dosage of folic acid.

4.7 Effects on ability to drive and use machines

There is no clinical study of Feronia Max Suspension in drive and use machines.

4.8 Undesirable effects

Adverse reactions with iron therapy are usually transient. Gastrointestinal upset, including nausea, vomiting, constipation, diarrhoea and dark stools, has been reported. Gastrointestinal side effects are relatively common and corrective bowel regimens such as increasing dietary fibre or over-the-counter medications might be recommended to balance these side effects.

Folate appears to be well-tolerated in recommended doses. Stomatitis, alopecia, myelosuppression and zinc depletion have been reported.

Erythema, urticaria, skin flushing, rash, itching, bloating, flatulence, cramps, bitter taste, and diarrhoea have been reported. The colour of the urine may become more intense. Irritability, excitability, general malaise, altered sleep patterns, vivid dreaming, overactivity, confusion, impaired judgment, increased seizure frequency, and psychotic behaviour have been reported. Very high doses can cause significant central nervous system side effects. Supplemental Folic acid might increase seizures in people with seizure disorders, particularly in very high doses.

Anaphylaxis and bronchospasm have also been reported.

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

The clinical course of acute iron overdosage can be variable. Initial symptoms may include abdominal pain, nausea, vomiting, diarrhoea, tarry stools, melena, haematemesis, hypotension, tachycardia, metabolic acidosis, hyperglycaemia, dehydration, drowsiness, pallor, cyanosis, lassitude, seizures, shock and coma.

Acute overdosage or iron accumulation symptoms may include arthritis, signs of gonadal failure (amenorrhoea, early menopause, loss of libido, impotence), and shortness of breath/dyspnoea. High doses may cause vomiting and diarrhoea, followed by cardiovascular or metabolic toxicity and death. It is unclear whether high levels are associated with cancer, coronary heart disease or myocardial infarction (MI or heart attack).

The stomach should be emptied by aspiration and gastric lavage if the patient reports immediately after overdosage.

Treatment should be symptomatic and supportive.

5.1 Mechanism of action / pharmacodynamic properties

Iron salts

Administration of iron in the form of Ferrous Ascorbate delivers maximum amount of Ferrous iron to the duodenal brush border and produces minimum GI adverse effects. Mechanism of action of Ferrous Ascorbate :

• With Ferrous Ascorbate iron absorption is facilitated by formation of soluble iron Ascorbate complexes and by inhibition of formation of insoluble iron complexes.
• It inhibits the conversion of Ferrous to Ferric iron which increases iron absorption.
• It also inhibits the effect of phytates, phosphates and oxalates on iron absorption.
• Iron is mobilized from the core ferritin to the sites of erythropoiesis and at the same time conversion of ferritin to hemosiderin (which cannot be utilized) is inhibited.
• In this way Ferrous Ascorbate allows rapid correction of haemoglobin.
• Inhibition of conversion of Ferrous to ferric iron reduces the amount of free radicals generated, thus, minimizing the GI adverse effects.

Folic acid

Folic acid is required to maintain normal erythropoiesis and nucleoprotein synthesis. Folic acid is reduced by enzymes folate reductase and Dihydrofolate reductase to form Dihydrofolic acid and Tetrahydrofolic acid respectively. Tetrahydrofolic acid acts as a coenzyme which mediates a number of one carbon transfer reactions by carrying a methyl group as an adduct. It involves a number of reactions such as :

• Conversion of homocysteine to methionine.
• Synthesis of thymidylate, which is an essential constituent of DNA, from Methylene-Tetrahydrofolic acid.
• Conversion of serine to glycine by Tetrahydrofolic acid and formation of Methylene-Tetrahydrofolic acid.
• To introduce carbon units at position 2 and 8 during de novo purine synthesis requires Formyl-Tetrahydrofolic acid and Methenyl Tetrahydrofolic acid.
• Generation and utilization of "formate pool".
• For mediating formino group transfer in histidine metabolism.

Methylcobalamin

Vitamin B12 is found only in foods of animal origin. Vitamin B12 is essential for cellular DNA synthesis and hence contributes to functions of various tissues of the body, formation of myelin sheath, more so the rapidly dividing and proliferating cellular systems such as blood and gastric epithelium. The absorbed inert form of cobalamin is converted into two important active forms. One is Methylcobalamin-involved in maturation of red blood corpuscles. The second active form is Adenosylcobalamin involved in healthy myelination and neuronal integrity.

5.2 Pharmacokinetic properties

Ferrous Ascorbate

The bioavailability of reference dose Ferrous Ascorbate has been reported in the range of 26.4% to 50.4%. Multiple studies have proven bioavailability of Ferrous Ascorbate to be better than other iron salts. Ferrous Ascorbate salt is more resistant to oxidation at alkaline pH and thus, delivers maximum amount of Ferrous iron to the duodenal brush border leading to increased iron absorption. Ferrous form is absorbed thrice as much as ferric form of iron. Following absorption, iron is transported in a transferrin bound form to bone marrow. Excretion is minimal.

Folic acid

Folic acid is absorbed rapidly from the small intestine, primarily from the proximal portion. It appears in the plasma approximately 15 to 30 minutes after an oral dose; peak levels are generally reached within 1 hour. Folic acid is metabolized in the liver to 7,8-dihydroFolic Acid and eventually to 5,6,7,8-tetrahydrofolic Acid with the aid of reduced diphosphopyridine nucleotide (DPNH) and folate reductases. Tetrahydrofolic Acid derivatives are distributed to all body tissues but are stored primarily in the liver. Folic acid has a half-life of 2 hours and is excreted mainly via urine.

Methylcobalamin

The absorption of cobalamins from the gut is dependent upon the glycoprotein intrinsic factor. Cobalamins are transported rapidly into the blood bound to protein, known as Transcobalamins. Cobalamins are stored in the liver and excreted in the bile. They are known to cross the placenta.

6.1 Animal toxicology or pharmacology

As per the toxicity reports, designed to determine the acute oral toxicity of Ferrous Ascorbate Complex to Sprague Dawley rats. No signs of intoxication were observed in animals treated at the dose level of 2000 mg/kg of the test substance. All animals survived through the study period of 14 days. Animals from control and 2000 mg/kg dose group exhibited normal body weight gain on day 7 and day 14. Gross pathological examination did not reveal any abnormalities attributable to the treatment.

Feronia Max Suspension is the combination of Ferrous Ascorbate, Folic acid and Methylcobalamin.

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

24 Months

8.3 Packaging information

1 x 200 ml

8.4 Storage and handing instructions

Store below 30°C. Protect from light. Do not freeze.

KEEP AWAY FROM THE REACH OF CHILDREN. Shake well before use.

• Ask the patient to report any adverse events.
• Not to exceed the stated recommended daily dose.

1st July 2024

Polyethylene Glycol 3350 Powder for Oral Solution

Composition:

Each 8.5 g (one measuring spoonful) contains:

Polyethylene Glycol 3350 USP-NF……………8.5 g

Dosage Form: Powder for Oral Solution

Dosage Strength: 8.5 g per one measuring spoonful

4.1 Therapeutic indication

For the treatment of occasional constipation.

This product should be used for 2 weeks or less or as directed by a physician.

4.2 Posology and method of administration

Dosage:

Adults: The usual dose is 17 grams (2 scoops) of powder per day. Take 2 scoops of powder & add water to make it to the mark of 125 ml/dose. It can be taken 1 to 3 times per day according to individual response.

Pediatrics:

Children 2 - 6 years - Take 1 scoop of Powder & add water to make it to the mark of 62.5 ml/dose.

Children 6 years & above - Take 2 scoops of Powder & add water to make it to the mark of 125 ml/dose. Dose should be adjusted up or down as required to produce regular soft stools. The maximum dose does not normally exceed 3 scoops per day for both pediatric age groups.

Directions for use:

Each Peclear^TM Jar is supplied with a measuring spoon to contain 8.5 grams of laxative powder when filled. Water/milk/fresh Juice can be used to dissolve the powder. Stir briskly and consume the contents immediately. 1 to 3 days may be required to produce a bowel movement.

4.3 Contraindications

Pegclear Powder for Oral Solution is contraindicated in patients with known or suspected bowel obstruction and patients known to be allergic to polyethylene glycol.

4.4 Special warnings and precautions for use

Warnings

Patients with symptoms suggestive of bowel obstruction (nausea, vomiting, abdominal pain or distention) should be evaluated to rule out this condition before initiating Pegclear^TM therapy.

Precautions

General: Patients presenting with complaints of constipation should have a thorough medical history and physical examination to detect associated metabolic, endocrine and neurogenic conditions, and medications. A diagnostic evaluation should include a structural examination of the colon. Patients should be educated about good defecatory and eating habits (such as high fiber diets) and lifestyle changes (adequate dietary fiber and fluid Intake, regular exercise) which may produce more regular bowel habits.

Laboratory Tests: No clinically significant effect on laboratory tests have been demonstrated.

4.5 Drug interactions

No specific drug Interactions have been demonstrated.

4.6 Use in special populations

Pregnancy:

There are limited amount of data from the use of Pegclear^TM in pregnant women. Studies in animals have shown indirect reproductive toxicity. Clinically, no effects during pregnancy are anticipated, since systemic exposure to polyethylene glycol 3350 is negligible. Pegclear^TM 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.

Geriatric Use:

There is no evidence for special considerations when Pegclear^TM is administered to elderly patients. In geriatric nursing home patients, a higher incidence of diarrhea occurred at the recommended 17 g dose. If diarrhea occurs Pegclear^TM should be discontinued.

4.7 Effects on ability to drive and use machines

Polyethylene Glycol 3350 Powder for Oral Solution has no influence on the ability to drive and use machines.

4.8 Undesirable effects

Nausea, abdominal bloating, cramping and flatulence may occur. High doses may produce diarrhea and excessive stool frequency, particularly in elderly nursing home patients.

Patients taking other medications containing polyethylene glycol have occasionally developed urticaria suggestive of an allergic reaction.

Reporting of suspected adverse reactions

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

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

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

4.9 Overdose

There have been no reports of accidental overdosage. In the event of overdosage diarrhea would be the expected major event. Severe pain or distension, diarrhoea, vomiting may occur in case of overdosage. Medication should be terminated and free water administered. Severe pain or distention can be treated by nasogastric aspiration. Extensive fluid loss by diarrhoea or vomiting may require correction of electrolyte disturbances.

The oral LD50 Is >50 gm/kg in mice, rats and rabbits.

5.1 Mechanism of Action

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.

5.2 Pharmacodynamic properties

Pharmacodynamic effect of PEG 3350 as a laxative is primarily due to its osmotic action, which increases water content in the stool, softens it, and facilitates easier passage of stool, thereby relieving constipation. In clinical studies an increase in frequency bowel movement and daily stool weight was observed.

In vitro study showed indirectly that PEG 3350 was not fermented into hydrogen or methane by the colonic microflora in human feces. PEG 3350 appears to have no effect on the active absorption or secretion of glucose or electrolytes. There is no evidence of tachyphylaxis.

6.1 Animal Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility: Long term carcinogenicity studies, genetic toxicity studies and reproductive toxicity studies in animal have not been performed with Pegclear^TM.

PEG 3350 is an osmotic agent for the treatment of constipation.

PegclearTM (polyethylene glycol 3350, NF) is a synthetic polyglycol having an average molecular weight of 3950.

The chemical formula is HO(C₂H₂O)nH in which n represents the average number of oxyethylene groups.

Below 55°C it is a free flowing white powder freely soluble in water.

8.1 Incompatibilities

None applicable

8.2 Shelf-life

Refer on pack.

8.3 Packaging information

Pegclear^TM Jar contains 119 g of PEG 3350 Powder for Oral Solution

8.4 Storage and handing instructions

Store in a dry place below 25°C.

Protect from light and moisture.

Keep out of reach of children.

• PEG 3350 softens the stool and Increases the frequency of bowel movements by retaining water in the stool.
• It should always be taken by mouth after being dissolved in Water/milk/fresh Juice. Should unusual cramps, bloating, or diarrhea occur, consult your physician.
• 1 to 3 days may be required to produce a bowel movement.
• This product should be used for 2 weeks or less or as directed by a physician.
• Prolonged, frequent or excessive use of PEG 3350 may result in electrolyte Imbalance and dependence on laxatives.

28th June 2024