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Cisplatin is indicated as first line therapy for lung cancer, head & neck cancer and for the treatment of advanced and metastatic ovarian carcinoma, bladder carcinoma and testis carcinoma.

Cytotoxic Chemotherapy

Cisplatin modifies cell cycle by interfering with DNA structure and function. Effects are most prominent during the S phase but cells are killed at all stages. Cisplatin synergises with other anticancer drugs e.g. fluorouracil. It has a narrow therapeutic margin and is highly toxic.

Metastatic ovarian cancer: As monotherapy: 100 mg/m² per cycle, given as a single dose infused in 0.9% sodium chloride or glucose once every 4 wk. For combination therapy with cyclophosphamide: 75-100 mg/m² on day 1 of every 4-wk cycle.

Metastatic testicular tumours: 20 mg/m² BSA daily for 5 days per cycle.

Advanced bladder cancer: 50-70 mg/m² per cycle once every 3-4 wk, depending on the extent of prior exposure to radiation and/or chemotherapy treatment. An initial dose of 50 mg/m² every 4 wk may be used in heavily pre-treated patients.

Usual dosage and schedule: 40 to 120 mg/m² I.V. on day 1 as infusion every 3 weeks. 15 to 20 mg/m² I.V. on days 1 to 5 as infusion every 3 to 4 weeks. The usual dose in adults and children when used as single agent therapy is 50-100 mg/m².

Severe nausea and vomiting. Serious toxic effects on the kidneys, bone marrows and ears. Hypomagnesaemia, hypocalcaemia, hyperuricaemia. Peripheral neuropathies, papilloedema, optic neuritis, seizures. Ototoxicity (children) manifested as tinnitus, loss of hearing, deafness or vestibular toxicity.

Cisplatin is contraindicated in patients with pre-existing renal impairment. Cisplatin should not be employed in myelosuppressed patients, or patients with hearing impairment. It is also contraindicated in patients with a history of allergic reactions to cisplatin or other platinum-containing compounds.

Patients with renal or hepatic disorder, myelosuppression. Monitor renal, neurological and auditory function. Perform blood counts regularly. Maintain adequate hydration before and 24 hr after admin to minimise nephrotoxicity.

Synergistic with 5-fluorouracil and etoposide. Efficacy increased and toxicity reduced when combined with radioprotecting agent WR 2721. At doses ≤100 mg, cisplatin is an ideal drug to combine with other cytotoxic drugs; unlike other antineoplastic drugs, it causes little myelosuppression.

Pregnancy Category D. There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Acute overdosage may result in kidney failure, liver failure, deafness, ocular toxicity, significant myelosuppression, intractable nausea and vomiting and/or neuritis. Death may also occur following overdosage. Treatment should include general supportive measures.

Cisplatin lyophilized powder for injection 10 mg and 50 mg should be reconstituted with 10 ml and 50 ml of water for inj. respectively.

Cisplatin solution after reconstitution should be added to 2 liters of 5% glucose or 0.9% saline and intravenously administered in 6-8 hours; after administration an adequate hydration and diuresis should be maintained during 24 hours.

Stability: The cisplatin remaining in vial following initial entry is stable for 28 days protected from light or for 7 days under fluorescent room light.

Storage: Product should be stored at controlled room temperature 25° C and protected from light.

Albendazole is indicated in single and mixed infestations of-

• Hookworm (Ancylostoma, Necator)
• Roundworm (Ascaris)
• Threadworm (Enterobius)
• Whipworm (Trichuris)
• Strongyloides
• Tapeworm
• Opisthorchi
• Hydatid.

Anthelmintic

Albendazole is a broad spectrum anthelmintic. Albendazole exhibits vermicidal, ovicidal and larvicidal activities. The drug is thought to exert its anthelmintic effect by blocking glucose uptake in the susceptible helminths, thereby depleting the energy level until it becomes inadequate for survival. Immobilization is followed by the parasite. These events may be a consequence of the binding and subsequent inhibition of parasite tubulin polymerization by Albendazole and its metabolites, although the drug also binds to human tubulin. Albendazole is extensively metabolized, probably in the liver. Albendazole is poorly absorbed from the gastrointestinal tract but rapidly undergoes extensive first-pass metabolism. The principal metabolite albendazole sulphoxide has anthelmintic activity and a plasma half-life of about 8.5 hrs. It is excreted in the urine together with other metabolites.

Adults & children over 2 years:

• 400 mg (1 tablet or 10 ml suspension) as a single dose in cases of Enterobius vermicularis, Trichuris trichiura, Ascaris lumbricoides, Ancylostoma duodenale and Necator americanus.
• In cases of strongyloidiasis or taeniasis, 400 mg (1 tablet or 10 ml suspension) daily should be given for 3 consecutive days. If the patient is not cured on follow-up after three weeks, a second course of treatment is indicated. 

Children of 1-2 years: Recommended dose is a single dose of 200 mg (5 ml suspension).

Children under 1 year: Not recommended.

In Hydatid disease (Echinococcosis):

• Albendazole is given by mouth with meals in a dose of 400 mg twice daily for 28 days for patients weighing over 60 kg.
• A dose of 15 mg/kg body weight daily in two divided doses (to a maximum total daily dose of 800 mg) is used for patients weighing less than 60 kg.
• For cystic echinococcosis, the 28 days course may be repeated after 14 days without treatment, to a total of 3 treatment cycles.
• For alveolar echinococcosis, cycles of 28 days of treatment followed by 14 days without treatment, may need to continue for months or years.
• In giardiasis, 400 mg (1 tablet or 10 ml suspension) once daily for five days is used.

Gastrointestinal disturbances, headache, dizziness, changes in liver enzymes, rarely reversible alopecia; rash, fever, blood disorders including leucopenia and pancytopenia reported; allergic shock if cyst leakage; convulsion and meningism in cerebral disease.

Neonates: Albendazole is not normally used in neonates.

Children: Reduction of the dose from 400 mg to 200 mg may be indicated in children weighing less than 10 kg but there are no grounds for a general reduction in dosage to children.

Pregnant woman: Albendazole should not be given during pregnancy or women thought to be pregnant. No information is available on placental transfer.

Concurrent disease: There is no evidence to suggest that dose should be altered in renal, hepatic or cardiac failure.

Blood counts and liver function tests before treatment and twice during each cycle; breastfeeding; exclude pregnancy before starting treatment. Albendazole should only be used in the treatment of Echinococcosis if there is constant medical supervision with regular monitoring of serum-transaminase concentrations and of leucocyte and platelet counts

No interaction involving Albendazole, either pharmacodynamic or pharmacokinetic, has been reported.

US FDA Pregnancy category of Albendazole is C. So, Albendazole should be avoided in pregnancy and lactation unless the potential benefits to the other outweigh the possible risks to the fetus.

Keep in a dry place, away from light and heat. Keep out of the reach of children.

Albendazole is indicated in single and mixed infestations of-

• Hookworm (Ancylostoma, Necator)
• Roundworm (Ascaris)
• Threadworm (Enterobius)
• Whipworm (Trichuris)
• Strongyloides
• Tapeworm
• Opisthorchi
• Hydatid.

Anthelmintic

Albendazole is a broad spectrum anthelmintic. Albendazole exhibits vermicidal, ovicidal and larvicidal activities. The drug is thought to exert its anthelmintic effect by blocking glucose uptake in the susceptible helminths, thereby depleting the energy level until it becomes inadequate for survival. Immobilization is followed by the parasite. These events may be a consequence of the binding and subsequent inhibition of parasite tubulin polymerization by Albendazole and its metabolites, although the drug also binds to human tubulin. Albendazole is extensively metabolized, probably in the liver. Albendazole is poorly absorbed from the gastrointestinal tract but rapidly undergoes extensive first-pass metabolism. The principal metabolite albendazole sulphoxide has anthelmintic activity and a plasma half-life of about 8.5 hrs. It is excreted in the urine together with other metabolites.

Adults & children over 2 years:

• 400 mg (1 tablet or 10 ml suspension) as a single dose in cases of Enterobius vermicularis, Trichuris trichiura, Ascaris lumbricoides, Ancylostoma duodenale and Necator americanus.
• In cases of strongyloidiasis or taeniasis, 400 mg (1 tablet or 10 ml suspension) daily should be given for 3 consecutive days. If the patient is not cured on follow-up after three weeks, a second course of treatment is indicated. 

Children of 1-2 years: Recommended dose is a single dose of 200 mg (5 ml suspension).

Children under 1 year: Not recommended.

In Hydatid disease (Echinococcosis):

• Albendazole is given by mouth with meals in a dose of 400 mg twice daily for 28 days for patients weighing over 60 kg.
• A dose of 15 mg/kg body weight daily in two divided doses (to a maximum total daily dose of 800 mg) is used for patients weighing less than 60 kg.
• For cystic echinococcosis, the 28 days course may be repeated after 14 days without treatment, to a total of 3 treatment cycles.
• For alveolar echinococcosis, cycles of 28 days of treatment followed by 14 days without treatment, may need to continue for months or years.
• In giardiasis, 400 mg (1 tablet or 10 ml suspension) once daily for five days is used.

Gastrointestinal disturbances, headache, dizziness, changes in liver enzymes, rarely reversible alopecia; rash, fever, blood disorders including leucopenia and pancytopenia reported; allergic shock if cyst leakage; convulsion and meningism in cerebral disease.

Neonates: Albendazole is not normally used in neonates.

Children: Reduction of the dose from 400 mg to 200 mg may be indicated in children weighing less than 10 kg but there are no grounds for a general reduction in dosage to children.

Pregnant woman: Albendazole should not be given during pregnancy or women thought to be pregnant. No information is available on placental transfer.

Concurrent disease: There is no evidence to suggest that dose should be altered in renal, hepatic or cardiac failure.

Blood counts and liver function tests before treatment and twice during each cycle; breastfeeding; exclude pregnancy before starting treatment. Albendazole should only be used in the treatment of Echinococcosis if there is constant medical supervision with regular monitoring of serum-transaminase concentrations and of leucocyte and platelet counts

No interaction involving Albendazole, either pharmacodynamic or pharmacokinetic, has been reported.

US FDA Pregnancy category of Albendazole is C. So, Albendazole should be avoided in pregnancy and lactation unless the potential benefits to the other outweigh the possible risks to the fetus.

Keep in a dry place, away from light and heat. Keep out of the reach of children.

This syrup is indicated for the relief of cough, associated congestive symptoms and aiding restful sleep

Combined cough expectorants

Guaifenesin is reported to reduce the viscosity of tenacious sputum end is used as an expectorant. Levomenthol has mild local anesthetic and decongestant properties. Diphenhydramine Hydrochloride possesses antitussive, antihistaminic, and anticholinergic properties.

For adults and children over 12 years: 2 teaspoonfuls syrup 4 times a day or as directed by the physicians. Do not take more than 8 teaspoonful syrup in 24 hours.

Use in Children & Adolescents: The efficacy and safety of Guaifenesin have not been established in pediatric patients and adolescents.

This syrup may cause drowsiness, dizziness, nausea and vomiting, gastro-intestinal disturbance, dry mouth, nose and throat difficulty in urination or blurred vision.

This syrup is contraindicated in individuals with known hypersensitivity to the product or any of its components. This medicine should not be administered to patients who have received treatment with MAOIs within last two weeks.

This syrup may cause drowsiness; if affected, individuals should not drive or operate machinery. Diphenhydramine Hydrochloride should not be taken by individuals with narrow-angle glaucoma or symptomatic prostatic hypertrophy. This product should not be used for persistent or chronic cough, such as occurs with asthma, or where cough is accompanied by excessive secretions unless directed by a physician.

This syrup contains Diphenhydramine Hydrochloride and therefore may potentiate the effects of alcohol, and other CNS depressants. As Diphenhydramine Hydrochloride possess some anticholinergic activity, the effects of anticholinergics (e.g. some psychotrophic drugs and atropine) may be potentiated by this product. This may result in tachycardia, mouth dryness, gastrointestinal disturbances (e.g. colic), urinary retention and headache.

As with any other medicine, care should be taken In administration during pregnancy. This product has not been associated with adverse effects in the human fetus or suckling infant.

When taken in excess, Guaifenesin may cause renal calculi. Treatment of overdose should be symptomatic and supportive.

Store at a temperature not exceeding 30° C in a dry place. Protect from light & moisture. Keep out of the reach of children.

Centrally acting Skeletal Muscle Relaxants

Tizanidine is a centrally acting skeletal muscle relaxant. Its principal site of action is the spinal cord, where the evidence suggests that, by stimulating presynaptic alpha2 receptors, it inhibits the release of excitatory amino acids that stimulate N-methyl-D aspartate (NMDA) receptors.

Polysynaptic signal transmission at spinal interneuron level, which is responsible for excessive muscle tone, is thus inhibited and muscle tone reduced. In addition to its muscle-relaxant properties, tizanidine also exerts a moderate central analgesic effect.

Pharmacodynamic: Tizanidine is effective in both acute painful muscle spasms and chronic spasticity of spinal and cerebral origin. It reduces resistance to passive movements, alleviates spasms and clonus, and may improve voluntary strength. The antispastic activity (measured by the Ashworth score and pendulum test) and adverse effects (heart rate and blood pressure) of Tizanidine are related to plasma tizanidine concentrations.

Tizanidine has a narrow therapeutic index and high inter-patient variability in tizanidine plasma concentrations which requires individualized dose adjustment. A low starting dose of 2 mg three times daily can minimize the risk for adverse effects. The dose should be carefully adjusted upward according to the needs of the individual patient.

Relief of painful muscle spasms: The usual dose is 2 to 4 mg three times daily in tablet form. In severe cases, an extra dose of 2 or 4 mg may be taken, preferably at night to minimize sedation.

Spasticity due to neurological disorders: The initial daily dose should not exceed 6 mg given in 3 divided doses. It may be increased stepwise at half-weekly or weekly intervals by 2 to 4 mg. The optimum therapeutic response is generally achieved with a daily dose of between 12 and 24 mg, administered in 3 or 4 equally spaced doses. The daily dose of 36 mg should not be exceeded.

Pediatrics patients: Experience in patients below 18 years of age is limited and the use of Tizanidine in this population is not recommended.

Geriatric patients (65 years of age or older): Experience with the use of Tizanidine in the elderly is limited. Therefore, it is recommended to start treatment at the lowest dose and increases should be done in small steps according to tolerability and efficacy.

Renal impairment: In patients with renal impairment (creatinine clearance <25 mL/min), it is recommended to start treatment at 2 mg once daily. An increase in dosage should be done in small steps according to tolerability and efficacy. If efficacy has to be improved, it is advisable to first increase the strength of the daily dose before increasing the frequency of administration.

Hepatic impairment: Use of Tizanidine in patients with severe hepatic impairment is contraindicated. While Tizanidine is extensively metabolized in the liver, limited data are available in this population. Its use has been associated with a reversible abnormality in liver function tests. Tizanidine should be used with caution in patients with moderate hepatic impairment and treatment should be started with the lowest dose. Afterward, an increase in dosage should be done carefully and according to patient tolerability.

Discontinuation of treatment: If Tizanidine has to be discontinued, the dosage should be slowly down titrated, particularly in patients who have received high doses for a longer period of time to avoid or minimize the risk of rebound hypertension and tachycardia.

With low doses, such as those recommended for the relief of painful muscle spasms, somnolence, fatigue, dizziness, dry mouth, blood pressure decrease, nausea, gastrointestinal disorder and transaminase increase have been reported, usually as mild and transient adverse reactions.

With the higher doses recommended for the treatment of spasticity, the adverse reactions reported with low doses are more frequent and more pronounced, but seldom severe enough to require discontinuation of treatment. In addition, the following adverse reactions may occur: hypotension, bradycardia, muscular weakness, insomnia, sleep disorder, hallucination & hepatitis.

• Psychiatric disorders: Common- Insomnia, sleep disorder.
• Nervous system disorders: Very common- Somnolence, dizziness
• Cardiac disorders: Uncommon- Bradycardia
• Vascular disorders: Common- Hypotension
• Gastrointestinal disorders: Very common- Gastrointestinal disorder, dry mouth; Common- Nausea.
• Musculoskeletal and connective tissue disorders: Very common- Muscular weakness
• General disorders and administration site conditions: Very common- Fatigue
• Investigations: Common- Blood pressure decreased, transaminases increased.

CYP inhibitors: The concomitant use of Tizanidine with moderate CYP1A2 inhibitors is not recommended. Caution should be exercised when Tizanidine is given with drugs known to increase the QT interval.

Hypotension: Hypotension may occur during treatment with Tizanidine and also as a result of drug interactions with CYP1A2 inhibitors and/or antihypertensive drugs. Severe manifestations of hypotension such as loss of consciousness and circulatory collapse have also been observed.

Withdrawal syndrome: Rebound hypertension and tachycardia have been observed after sudden withdrawal of Tizanidine, when it had been used chronically, and/or in high daily dosages, and/or concomitantly with antihypertensive drugs. In extreme cases, rebound hypertension might lead to cerebrovascular accident. Tizanidine should not be stopped abruptly, but rather gradually down titrated.

Hepatic dysfunction: Since hepatic dysfunction has been reported in association with tizanidine, but rarely at daily doses up to 12 mg, it is recommended that liver function tests should be monitored monthly for the first four months in patients receiving doses of 12 mg and higher and in patients who develop clinical symptoms suggestive of hepatic dysfunction, such as unexplained nausea, anorexia or tiredness. Treatment with Tizanidine should be discontinued if serum levels of SGPT or SGOT are persistently above three times the upper limit of the normal range.

Patients with renal impairment: In patients with renal impairment (creatinine clearance <25 mL/min) systemic exposure to tizanidine may increase up to 6 times compared to patient with normal renal function. Therefore, it is recommended to start treatment at 2 mg once daily.

Hypersensitivity reactions: Hypersensitivity reactions including anaphylaxis, angioedema, dermatitis, rash, urticarial, pruritis and erythema have been reported in association with tizanidine. Careful observation of the patient is recommended for one to two days after the first dose is administered. If anaphylaxis or angioedema with anaphylactic shock or difficulty of breathing is observed treatment with Tizanidine should be discontinued immediately and appropriate medical treatment should be instituted.

Driving and using machines: Patients experiencing somnolence, dizziness or any signs or symptoms of hypotension should refrain from activities requiring a high degree of alertness, e.g. driving a vehicle or operating machines.

Concomitant administration of drugs known to inhibit the activity of CYP1A2 may increase the plasma levels of tizanidine. The increased plasma levels of tizanidine may result in overdose symptoms such as QT(c) prolongation. Concomitant administration of drugs known to induce the activity of CYP1A2 may decrease the plasma levels of tizanidine. The decreased plasma levels of tizanidine may reduce the therapeutic effect of Tizanidine.

Observed interactions resulting in a contraindication: Concomitant use of Tizanidine with fluvoxamine or ciprofloxacin, both CYP1A2 inhibitors is contraindicated. Concomitant use of Tizanidine with fluvoxamine or ciprofloxacin resulted in a 33-fold and 10-fold increase in tizanldine AUC, respectively. Clinically significant and prolonged hypotension may result along with somnolence, dizziness and decreased psychomotor performance. The increased plasma levels of tizanidine may result in overdose symptoms such as QT(c) prolongation.

Observed interactions resulting in concomitant use not recommended: Co administration of Tizanidine with other inhibitors of CYP1A2 such as antiarrhythmics (amiodarone, mexiletine, propafenone), cimetidine, fluoroquinolones (enoxacin, pefloxacin, norfloxacin), rofecoxib, oral contraceptives, and ticlopidine is not recommended.

Observed interactions to be considered: Caution should be exercised when Tizanidine is given with drugs known to prolong the QT interval (including but not limited to cisapride, amytriptyline and azithromycin).

Antihypertensives: Concomitant use of Tizanidine with antihypertensives, including diuretics, may occasionally cause hypotension and bradycardia. In some patients rebound hypertension and tachycardia have been observed upon abrupt discontinuation of Tizanidine when concomitantly used with antihypertensive drugs. In extreme cases, rebound hypertension might lead to cerebrovascular accident.

Rifampicin: Concomitant administration of Tizanidine with rifampicin results in 50% decrease in tizanidine concentrations. Therefore, the therapeutic effects of Tizanidine may be reduced during treatment with rifampicin, which may be of clinical significance in some patients. Long term coadministration should be avoided and if co- administration is considered a careful dose adjustment (increase) may be required. 

Cigarette smoke: Administration of Tizanidine in smokers (>10 cigarettes per day) results in about 30% decrease in tizanidine systemic exposure. Long-term therapy with Tizanidine in heavy smokers may require higher doses than the average doses.

Alcohol: While on Tizanidine therapy, alcohol consumption should be minimized or avoided as it may increase the potential for adverse events (e.g. sedation and hypotension). The central nervous system depressant effects of alcohol may be enhanced by Tizanidine.

Anticipated interactions to be considered: Sedatives, hypnotics (e.g. benzodiazepine or baclofen), and another drug such as antihistamines may enhance the sedative action of tizanidine. Tizanidine should be avoided when using with other alpha-2 adrenergic agonists (such as clonidine) because of their potential additive hypotensive effect.

As there is limited experience with the use of Tizanidine in pregnant women, it should not be used during pregnancy unless the benefit clearly outweighs the risk.

Animal data: Reproduction studies performed in rats and rabbits did not show evidence of teratogenicity. In rats, dose levels of 10 and 30 mg/kg/day increased gestation duration. Prenatal and postnatal pup loss was increased and development retardation occurred. At these doses, dams showed marked signs of muscle relaxation and sedation. Based on body surface area, these doses were 2.2 and 6.7 times the maximum recommended human dose of 0.72 mg/kg/day.

Lactation: Small amounts of tizanidine are excreted in rat milk. Since no human (fata are available Tizanidine should not be given to women who are breast-feeding.

Females and males of reproductive potential: Pregnancy testing:  Sexually-active females of reproductive potential are recommended to have a pregnancy test prior to starting treatment with Tizanidine.

Contraception: Females of reproductive potential should be advised that animal studies have been performed showing Tizanidine to be harmful to the developing fetus. Sexually-active females of reproductive potential are recommended to use effective contraception (methods that result in less than 1 % pregnancy rates) when using Tizanidine during treatment and for 1 day after stopping treatment with Tizanidine.

Fertility: Animal data: No impairment of fertility was observed in male rats at a dose of 10 mg/kg/day, and in female rats at a dose of 3 mg/kg/day. Fertility was reduced in male rats receiving 30 mg/kg/day and in female rats receiving 10 mg/kg/day. Based on body surface area, these doses were 6.7 and 2.2 times the maximum recommended human dose of 0.72 mg/kg. At these doses, maternal behavioral effects and clinical signs were observed including marked sedation, weight loss and ataxia.

Renal impairment (creatinine clearance <25 mL/min): Maximal mean plasma levels were found to be twice as high as in normal volunteers, and the terminal half-life was prolonged to approximately 14 hours, resulting in much higher (approximately 6-fold on average) AUC values.

Hepatic impairment: No specific studies were conducted in this population. As tizanidine is extensively metabolized in the liver by the CYP1A2 enzyme, hepatic impairment may increase its systemic exposure. Tizanidine is contraindicated in patients with severe hepatic impairment.

Geriatrics (65 years of age and older): Pharmacokinetic data in this population are limited.

Gender: Gender has no clinically significant effect on the pharmacokinetics of tizanidine.

Ethnicity: The impact of ethnic sensitivity and race on the pharmacokinetics of tizanidine has not been studied.

In the few reports of Tizanidine overdosage received, recovery was uneventful, including by a patient who ingested 400 mg Tizanidine. Nausea, vomiting, hypotension, QT(c) prolongation, dizziness, somnolence, miosis, restlessness, respiratory distress, coma. It is recommended to eliminate the ingested drug by repeated administration of high doses of activated charcoal. Forced diuresis is expected to accelerate the elimination of Tizanidine. Further treatment should be symptomatic.

Store in a dry place below 30°C. Tizanidine must be kept out of the reach and sight of children.

It is indicated for the relief of symptoms associated with seasonal & perennial allergic rhinitis. It is also indicated for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria and allergen induced asthma.

Sedating Anti-histamine

Cetirizine Hydrochloride is a potent H1 receptor antagonist without any significant anticholinergic and antiserotonic effects. At pharmacologically active dose levels, it has almost no drowsiness effect and does not cause behavioral changes. It inhibits the histamine-mediated early phase of the allergic reaction and also reduces the migration of inflammatory cells and the release of mediators associated with the late phase of the allergic reaction.

Pharmacokinetics: Cetirizine 10 mg achieves peak plasma concentrations of 257 mcg/L within one hour of administration (980 mcg/L in children). Food does not affect the extent of absorption, but it may slightly reduce the rate. Peak blood levels 0.3 micrograms/ml are reached between thirty & sixty minutes after administration of 10 mg dose of Cetirizine. Its plasma half-life is approximately 11 hours. Absorption is very consistent from one subject to the next. Its renal clearance is 30 ml/minute and the excretion half-life is approximately nine hours.

Adults and Children 6 years and older: 1 tablet or 2 teaspoonfuls daily (or 1 teaspoonful twice daily).

Children 2-6 years: 1 teaspoonful once daily or 1/2 teaspoonful twice daily.

Children 6 months to 2 years : 1/2 teaspoonful once daily. The dose in children 12-23 months of age can be increased to a maximum dose as 1/2 teaspoonful every 12 hours.

The most common side effects that occurred more frequently on Cetirizine is somnolence.

It is contraindicated in patients with a history of hypersensitivity to Cetirizine or hydroxyzine.

Caution should be exercised when driving a car or operating a heavy machinery.

No clinically significant drug interactions have been found with Theophylline, Azithromycin, Pseudoephedrine, Ketoconazole or Erythromycin and with other drugs.

US FDA Pregnancy Category of Cetirizine Hydrochloride is B. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Cetirizine Hydrochloride has been shown to be excreted in human milk. So, caution should be exercised when Cetirizine Hydrochloride is administered to a nursing woman.

Keep in a dry place away from light and heat. Keep out of the reach of children.

It is indicated for the relief of symptoms associated with seasonal & perennial allergic rhinitis. It is also indicated for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria and allergen induced asthma.

Sedating Anti-histamine

Cetirizine Hydrochloride is a potent H1 receptor antagonist without any significant anticholinergic and antiserotonic effects. At pharmacologically active dose levels, it has almost no drowsiness effect and does not cause behavioral changes. It inhibits the histamine-mediated early phase of the allergic reaction and also reduces the migration of inflammatory cells and the release of mediators associated with the late phase of the allergic reaction.

Pharmacokinetics: Cetirizine 10 mg achieves peak plasma concentrations of 257 mcg/L within one hour of administration (980 mcg/L in children). Food does not affect the extent of absorption, but it may slightly reduce the rate. Peak blood levels 0.3 micrograms/ml are reached between thirty & sixty minutes after administration of 10 mg dose of Cetirizine. Its plasma half-life is approximately 11 hours. Absorption is very consistent from one subject to the next. Its renal clearance is 30 ml/minute and the excretion half-life is approximately nine hours.

Adults and Children 6 years and older: 1 tablet or 2 teaspoonfuls daily (or 1 teaspoonful twice daily).

Children 2-6 years: 1 teaspoonful once daily or 1/2 teaspoonful twice daily.

Children 6 months to 2 years : 1/2 teaspoonful once daily. The dose in children 12-23 months of age can be increased to a maximum dose as 1/2 teaspoonful every 12 hours.

The most common side effects that occurred more frequently on Cetirizine is somnolence.

It is contraindicated in patients with a history of hypersensitivity to Cetirizine or hydroxyzine.

Caution should be exercised when driving a car or operating a heavy machinery.

No clinically significant drug interactions have been found with Theophylline, Azithromycin, Pseudoephedrine, Ketoconazole or Erythromycin and with other drugs.

US FDA Pregnancy Category of Cetirizine Hydrochloride is B. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Cetirizine Hydrochloride has been shown to be excreted in human milk. So, caution should be exercised when Cetirizine Hydrochloride is administered to a nursing woman.

Keep in a dry place away from light and heat. Keep out of the reach of children.

Dipeptidyl Peptidase-4 (DPP-4) inhibitor

Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by Sitagliptin, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. 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 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, Sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.

The recommended dose of sitagliptin is 50 mg twice a day and 100 mg once daily. Sitagliptin can be taken with or without food.

The most common adverse reactions include headache, upper respiratory tract infection and nasopharyngitis. Hypoglycemia may occur in patients treated with the combination to Sitagliptin and sulfonylurea and add on to insulin.

History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema.

If pancreatitis is suspected, sitagliptin should promptly be discontinued and appropriate management should be initiated.

Use in Patients with Renal Insufficiency: Dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD requiring hemodialysis or peritoneal dialysis.

Use with medications known to cause Hypoglycemia: When sitagliptin is used in combination therapy dosage adjustment of sulfonylurea or insulin may be required to reduce the risk of hypoglycemia.

Hypersensitivity Reactions: There have been post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. If a hypersensitivity reaction is suspected, discontinue sitagliptin, assess for other potential causes for the event, and institute alternative treatment for diabetes.

Effects of sitagliptin on other Drugs: Sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptive.

Digoxin: Sitagliptin slightly increases the mean of Digoxin concentration. However, no dose adjustment of either drug is required.

Pregnancy Category B. Reproduction studies have been performed in rats and rabbits. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Sitagliptin is secreted in the milk of lactating rats at milk to plasma ratio of 4:1. It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sitagliptin is administered to a nursing woman.

Pediatric Use: Safety and effectiveness of sitagliptin in pediatric patients under 18 years of age have not been established.

Geriatric Use: This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly, and it may be useful to assess renal function in these patients prior to initiating dosing and periodically thereafter.

For patients with mild renal insufciency: (CrCl <50 ml/min or serum creatinine levels of <1.7 mg/DL in men and <1.5 mg/DL in women), no dosage adjustment for sitagliptin is required.

For patients with moderate renal insufciency: (CrCl <30 to <50 mL/min, or serum creatinine levels of >1.7 to <3.0 mg/dL in men and >1.5 to <2.5 mg/dL in women), the dose of sitagliptin is 50 mg once daily.

For patients with severe renal insufficiency: (CrCl <30 mL/min or serum creatinine levels of >3.0 mg/dL in men and 2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of sitagliptin is 25 mg once daily. Sitagliptin may be administered without regard to the limiting of hemodialysis.

During controlled clinical trials in healthy subjects, single doses of up to 800 mg Sitagliptin were administered. Maximal mean increases in QTc of 8.0 msec were observed in one study at a dose of 800 mg Sitagliptin, a mean effect that is not considered clinically important. 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 and 400 mg per day for 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), and institute supportive therapy as dictated by the patient's clinical status. Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

Store below 25°C in a dry place away from light. Keep the medicines in a safe place, out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician

Combination Oral hypoglycemic preparations

This tablet combines two antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes. Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and Metformin HCl, a member of the biguanide class. Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated then GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, Sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. The pharmacologic mechanism of action of Metformin HCl is different from other classes of oral antihyperglycemic agents. Metformin HCl decreases hepatic glucose production, decreases intestinal absorption of glucose and increases peripheral glucose uptake and utilization.

Dose of film-coated tablet: The dosage of this tablet should be individualized on the basis of the patient's current regimen, efectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin. Initial combination therapy or maintenance of combination therapy should be individualized and left to the discretion of the health care provider.

This tablet should generally be given twice daily with meals, with gradual dose escalation, to reduce the gastrointestinal (GI) side efects due to metformin.

The starting dose of this tablet should be based on the patient’s current regimen. This tablet should be given twice daily with meals.

The recommended starting dose in patients not currently treated with metformin is 50 mg sitagliptin/500 mg metformin hydrochloride twice daily, with gradual dose escalation recommended to reduce gastrointestinal side efects associated with metformin.

The starting dose in patients already treated with metformin should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and the dose of metformin already being taken. For patients taking metformin 850 mg twice daily, the recommended starting dose of this tablet is 50 mg sitagliptin/1000 mg metformin hydrochloride twice daily.

No studies have been performed specifcally examining the safety and efcacy of Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP in patients previously treated with other oral antihyperglycemic agents and switched to Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

Dose of extended-release tablet: Administer once daily with a meal preferably in the evening. Gradually escalate the dose to reduce the gastrointestinal side effects due to Metformin. May adjust the dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 100 mg Sitagliptin and 2000 mg Metformin extended-release. Maintain the same total daily dose of Sitagliptin and Metformin when changing between film-coated tablet and extended-release tablet, without exceeding the maximum recommended daily dose of 2000 mg Metformin extended-release.

Patients using two extended-release tablets (such as two 50/500 or two 50/1000 tablets) should take the two tablets together once daily. The 100 mg Sitagliptin/1000 mg Metformin HCI extended-release tablet should be taken as a single tablet once daily.

Patients treated with an insulin secretagogue or insulin: Co-administration of the combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.

The most common adverse reactions reported in ≥5% of patients simultaneously started on sitagliptin and metformin and more commonly than in patients treated with placebo were diarrhea, upper respiratory tract infection, and headache.

Adverse reactions reported in ≥5% of patients treated with sitagliptin in combination with sulfonylurea and metformin and more commonly than in patients treated with placebo in combination with sulfonylurea and metformin were hypoglycemia and headache.

Hypoglycemia was the only adverse reaction reported in ≥5% of patients treated with sitagliptin in combination with insulin and metformin and more commonly than in patients treated with placebo in combination with insulin and metformin.

Nasopharyngitis was the only adverse reaction reported in ≥5% of patients treated with sitagliptin monotherapy and more commonly than in patients given placebo.

The most common (>5%) adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, fatulence, abdominal discomfort, indigestion, asthenia, and headache.

This tablet is contraindicated in patients with:

• Renal disease or renal dysfunction, e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females] or abnormal creatinine clearance which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
• History of a serious hypersensitivity reaction to this tablet or sitagliptin, such as anaphylaxis or angioedema.

This tablet should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function.

Lactic Acidosis-

• Lactic acidosis can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic insufciency, renal impairment, and acute congestive heart failure.
• Symptoms include malaise, myalgias, respiratory distress, increasing somnolence, and nonspecifc abdominal distress. Laboratory abnormalities include low pH, increased anion gap and elevated blood lactate.
• If acidosis is suspected, discontinue this tablet and hospitalize the patient immediately.
• Regular monitoring of thyroid-stimulating hormone (TSH) levels is recommended in patients with hypothyroidism.
• Long-term treatment with metformin has been associated with a decrease in vitamin B12 serum levels which may cause peripheral neuropathy. Monitoring of the vitamin B12 level is recommended.

Others-

• Do not use this tablet in patients with hepatic disease.
• There have been postmarketing reports of acute renal failure, sometimes requiring dialysis. Before initiating this tablet and at least annually thereafter, assess renal function and verify as normal.
• There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected, promptly discontinue this tablet.
• Measure hematologic parameters annually.
• Warn patients against excessive alcohol intake.
• May need to discontinue this tablet and temporarily use insulin during periods of stress and decreased intake of fluids and food as may occur with fever, trauma, infection or surgery.
• Promptly evaluate patients previously controlled on this tablet who develop laboratory abnormalities or clinical illness for evidence of ketoacidosis or lactic acidosis.
• When used with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia.
• There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with sitagliptin (one of the components of this tablet ), such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. In such cases, promptly stop this tablet, assess for other potential causes, and institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes.
• There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP or any other anti-diabetic drug.

Cationic Drugs: Cationic drugs eliminated by renal tubular secretion: Use with caution.

Phenprocoumon: Metformin may decrease the anticoagulant effect of phenprocoumon. Therefore, close monitoring of the INR is recommended.

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

Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women with Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP or its individual components; therefore, the safety of Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP in pregnant women is not known. This tablet should be used during pregnancy only if clearly needed.

It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when this tablet is administered to a nursing woman.

Sitagliptin: 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), and institute supportive therapy as indicated by the patient's clinical status. Sitagliptin is modestly dialyzable. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

Metformin hydrochloride: Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Metformin 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 overdosage is suspected. Pancreatitis may occur in the context of a metformin overdose.

Store below 25°C in a dry place away from light. Keep the medicines in a safe place, out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician.

Dipeptidyl Peptidase-4 (DPP-4) inhibitor

Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by Sitagliptin, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. 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 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, Sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.

The recommended dose of sitagliptin is 50 mg twice a day and 100 mg once daily. Sitagliptin can be taken with or without food.

The most common adverse reactions include headache, upper respiratory tract infection and nasopharyngitis. Hypoglycemia may occur in patients treated with the combination to Sitagliptin and sulfonylurea and add on to insulin.

History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema.

If pancreatitis is suspected, sitagliptin should promptly be discontinued and appropriate management should be initiated.

Use in Patients with Renal Insufficiency: Dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD requiring hemodialysis or peritoneal dialysis.

Use with medications known to cause Hypoglycemia: When sitagliptin is used in combination therapy dosage adjustment of sulfonylurea or insulin may be required to reduce the risk of hypoglycemia.

Hypersensitivity Reactions: There have been post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. If a hypersensitivity reaction is suspected, discontinue sitagliptin, assess for other potential causes for the event, and institute alternative treatment for diabetes.

Effects of sitagliptin on other Drugs: Sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptive.

Digoxin: Sitagliptin slightly increases the mean of Digoxin concentration. However, no dose adjustment of either drug is required.

Pregnancy Category B. Reproduction studies have been performed in rats and rabbits. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Sitagliptin is secreted in the milk of lactating rats at milk to plasma ratio of 4:1. It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sitagliptin is administered to a nursing woman.

Pediatric Use: Safety and effectiveness of sitagliptin in pediatric patients under 18 years of age have not been established.

Geriatric Use: This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly, and it may be useful to assess renal function in these patients prior to initiating dosing and periodically thereafter.

For patients with mild renal insufciency: (CrCl <50 ml/min or serum creatinine levels of <1.7 mg/DL in men and <1.5 mg/DL in women), no dosage adjustment for sitagliptin is required.

For patients with moderate renal insufciency: (CrCl <30 to <50 mL/min, or serum creatinine levels of >1.7 to <3.0 mg/dL in men and >1.5 to <2.5 mg/dL in women), the dose of sitagliptin is 50 mg once daily.

For patients with severe renal insufficiency: (CrCl <30 mL/min or serum creatinine levels of >3.0 mg/dL in men and 2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of sitagliptin is 25 mg once daily. Sitagliptin may be administered without regard to the limiting of hemodialysis.

During controlled clinical trials in healthy subjects, single doses of up to 800 mg Sitagliptin were administered. Maximal mean increases in QTc of 8.0 msec were observed in one study at a dose of 800 mg Sitagliptin, a mean effect that is not considered clinically important. 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 and 400 mg per day for 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), and institute supportive therapy as dictated by the patient's clinical status. Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

Store below 25°C in a dry place away from light. Keep the medicines in a safe place, out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician

Dipeptidyl Peptidase-4 (DPP-4) inhibitor

Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by Sitagliptin, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. 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 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, Sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.

The recommended dose of sitagliptin is 50 mg twice a day and 100 mg once daily. Sitagliptin can be taken with or without food.

The most common adverse reactions include headache, upper respiratory tract infection and nasopharyngitis. Hypoglycemia may occur in patients treated with the combination to Sitagliptin and sulfonylurea and add on to insulin.

History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema.

If pancreatitis is suspected, sitagliptin should promptly be discontinued and appropriate management should be initiated.

Use in Patients with Renal Insufficiency: Dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD requiring hemodialysis or peritoneal dialysis.

Use with medications known to cause Hypoglycemia: When sitagliptin is used in combination therapy dosage adjustment of sulfonylurea or insulin may be required to reduce the risk of hypoglycemia.

Hypersensitivity Reactions: There have been post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. If a hypersensitivity reaction is suspected, discontinue sitagliptin, assess for other potential causes for the event, and institute alternative treatment for diabetes.

Effects of sitagliptin on other Drugs: Sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptive.

Digoxin: Sitagliptin slightly increases the mean of Digoxin concentration. However, no dose adjustment of either drug is required.

Pregnancy Category B. Reproduction studies have been performed in rats and rabbits. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Sitagliptin is secreted in the milk of lactating rats at milk to plasma ratio of 4:1. It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sitagliptin is administered to a nursing woman.

Pediatric Use: Safety and effectiveness of sitagliptin in pediatric patients under 18 years of age have not been established.

Geriatric Use: This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly, and it may be useful to assess renal function in these patients prior to initiating dosing and periodically thereafter.

For patients with mild renal insufciency: (CrCl <50 ml/min or serum creatinine levels of <1.7 mg/DL in men and <1.5 mg/DL in women), no dosage adjustment for sitagliptin is required.

For patients with moderate renal insufciency: (CrCl <30 to <50 mL/min, or serum creatinine levels of >1.7 to <3.0 mg/dL in men and >1.5 to <2.5 mg/dL in women), the dose of sitagliptin is 50 mg once daily.

For patients with severe renal insufficiency: (CrCl <30 mL/min or serum creatinine levels of >3.0 mg/dL in men and 2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of sitagliptin is 25 mg once daily. Sitagliptin may be administered without regard to the limiting of hemodialysis.

During controlled clinical trials in healthy subjects, single doses of up to 800 mg Sitagliptin were administered. Maximal mean increases in QTc of 8.0 msec were observed in one study at a dose of 800 mg Sitagliptin, a mean effect that is not considered clinically important. 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 and 400 mg per day for 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), and institute supportive therapy as dictated by the patient's clinical status. Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

Store below 25°C in a dry place away from light. Keep the medicines in a safe place, out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician

Dipeptidyl Peptidase-4 (DPP-4) inhibitor

Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by Sitagliptin, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. 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 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, Sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.

The recommended dose of sitagliptin is 50 mg twice a day and 100 mg once daily. Sitagliptin can be taken with or without food.

The most common adverse reactions include headache, upper respiratory tract infection and nasopharyngitis. Hypoglycemia may occur in patients treated with the combination to Sitagliptin and sulfonylurea and add on to insulin.

History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema.

If pancreatitis is suspected, sitagliptin should promptly be discontinued and appropriate management should be initiated.

Use in Patients with Renal Insufficiency: Dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD requiring hemodialysis or peritoneal dialysis.

Use with medications known to cause Hypoglycemia: When sitagliptin is used in combination therapy dosage adjustment of sulfonylurea or insulin may be required to reduce the risk of hypoglycemia.

Hypersensitivity Reactions: There have been post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. If a hypersensitivity reaction is suspected, discontinue sitagliptin, assess for other potential causes for the event, and institute alternative treatment for diabetes.

Effects of sitagliptin on other Drugs: Sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptive.

Digoxin: Sitagliptin slightly increases the mean of Digoxin concentration. However, no dose adjustment of either drug is required.

Pregnancy Category B. Reproduction studies have been performed in rats and rabbits. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Sitagliptin is secreted in the milk of lactating rats at milk to plasma ratio of 4:1. It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sitagliptin is administered to a nursing woman.

Pediatric Use: Safety and effectiveness of sitagliptin in pediatric patients under 18 years of age have not been established.

Geriatric Use: This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly, and it may be useful to assess renal function in these patients prior to initiating dosing and periodically thereafter.

For patients with mild renal insufciency: (CrCl <50 ml/min or serum creatinine levels of <1.7 mg/DL in men and <1.5 mg/DL in women), no dosage adjustment for sitagliptin is required.

For patients with moderate renal insufciency: (CrCl <30 to <50 mL/min, or serum creatinine levels of >1.7 to <3.0 mg/dL in men and >1.5 to <2.5 mg/dL in women), the dose of sitagliptin is 50 mg once daily.

For patients with severe renal insufficiency: (CrCl <30 mL/min or serum creatinine levels of >3.0 mg/dL in men and 2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of sitagliptin is 25 mg once daily. Sitagliptin may be administered without regard to the limiting of hemodialysis.

During controlled clinical trials in healthy subjects, single doses of up to 800 mg Sitagliptin were administered. Maximal mean increases in QTc of 8.0 msec were observed in one study at a dose of 800 mg Sitagliptin, a mean effect that is not considered clinically important. 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 and 400 mg per day for 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), and institute supportive therapy as dictated by the patient's clinical status. Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

Store below 25°C in a dry place away from light. Keep the medicines in a safe place, out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician

Combination Oral hypoglycemic preparations

This tablet combines two antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes. Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and Metformin HCl, a member of the biguanide class. Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated then GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, Sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. The pharmacologic mechanism of action of Metformin HCl is different from other classes of oral antihyperglycemic agents. Metformin HCl decreases hepatic glucose production, decreases intestinal absorption of glucose and increases peripheral glucose uptake and utilization.

Dose of film-coated tablet: The dosage of this tablet should be individualized on the basis of the patient's current regimen, efectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin. Initial combination therapy or maintenance of combination therapy should be individualized and left to the discretion of the health care provider.

This tablet should generally be given twice daily with meals, with gradual dose escalation, to reduce the gastrointestinal (GI) side efects due to metformin.

The starting dose of this tablet should be based on the patient’s current regimen. This tablet should be given twice daily with meals.

The recommended starting dose in patients not currently treated with metformin is 50 mg sitagliptin/500 mg metformin hydrochloride twice daily, with gradual dose escalation recommended to reduce gastrointestinal side efects associated with metformin.

The starting dose in patients already treated with metformin should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and the dose of metformin already being taken. For patients taking metformin 850 mg twice daily, the recommended starting dose of this tablet is 50 mg sitagliptin/1000 mg metformin hydrochloride twice daily.

No studies have been performed specifcally examining the safety and efcacy of Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP in patients previously treated with other oral antihyperglycemic agents and switched to Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

Dose of extended-release tablet: Administer once daily with a meal preferably in the evening. Gradually escalate the dose to reduce the gastrointestinal side effects due to Metformin. May adjust the dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 100 mg Sitagliptin and 2000 mg Metformin extended-release. Maintain the same total daily dose of Sitagliptin and Metformin when changing between film-coated tablet and extended-release tablet, without exceeding the maximum recommended daily dose of 2000 mg Metformin extended-release.

Patients using two extended-release tablets (such as two 50/500 or two 50/1000 tablets) should take the two tablets together once daily. The 100 mg Sitagliptin/1000 mg Metformin HCI extended-release tablet should be taken as a single tablet once daily.

Patients treated with an insulin secretagogue or insulin: Co-administration of the combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.

The most common adverse reactions reported in ≥5% of patients simultaneously started on sitagliptin and metformin and more commonly than in patients treated with placebo were diarrhea, upper respiratory tract infection, and headache.

Adverse reactions reported in ≥5% of patients treated with sitagliptin in combination with sulfonylurea and metformin and more commonly than in patients treated with placebo in combination with sulfonylurea and metformin were hypoglycemia and headache.

Hypoglycemia was the only adverse reaction reported in ≥5% of patients treated with sitagliptin in combination with insulin and metformin and more commonly than in patients treated with placebo in combination with insulin and metformin.

Nasopharyngitis was the only adverse reaction reported in ≥5% of patients treated with sitagliptin monotherapy and more commonly than in patients given placebo.

The most common (>5%) adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, fatulence, abdominal discomfort, indigestion, asthenia, and headache.

This tablet is contraindicated in patients with:

• Renal disease or renal dysfunction, e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females] or abnormal creatinine clearance which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
• History of a serious hypersensitivity reaction to this tablet or sitagliptin, such as anaphylaxis or angioedema.

This tablet should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function.

Lactic Acidosis-

• Lactic acidosis can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic insufciency, renal impairment, and acute congestive heart failure.
• Symptoms include malaise, myalgias, respiratory distress, increasing somnolence, and nonspecifc abdominal distress. Laboratory abnormalities include low pH, increased anion gap and elevated blood lactate.
• If acidosis is suspected, discontinue this tablet and hospitalize the patient immediately.
• Regular monitoring of thyroid-stimulating hormone (TSH) levels is recommended in patients with hypothyroidism.
• Long-term treatment with metformin has been associated with a decrease in vitamin B12 serum levels which may cause peripheral neuropathy. Monitoring of the vitamin B12 level is recommended.

Others-

• Do not use this tablet in patients with hepatic disease.
• There have been postmarketing reports of acute renal failure, sometimes requiring dialysis. Before initiating this tablet and at least annually thereafter, assess renal function and verify as normal.
• There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected, promptly discontinue this tablet.
• Measure hematologic parameters annually.
• Warn patients against excessive alcohol intake.
• May need to discontinue this tablet and temporarily use insulin during periods of stress and decreased intake of fluids and food as may occur with fever, trauma, infection or surgery.
• Promptly evaluate patients previously controlled on this tablet who develop laboratory abnormalities or clinical illness for evidence of ketoacidosis or lactic acidosis.
• When used with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia.
• There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with sitagliptin (one of the components of this tablet ), such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. In such cases, promptly stop this tablet, assess for other potential causes, and institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes.
• There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP or any other anti-diabetic drug.

Cationic Drugs: Cationic drugs eliminated by renal tubular secretion: Use with caution.

Phenprocoumon: Metformin may decrease the anticoagulant effect of phenprocoumon. Therefore, close monitoring of the INR is recommended.

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

Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women with Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP or its individual components; therefore, the safety of Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP in pregnant women is not known. This tablet should be used during pregnancy only if clearly needed.

It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when this tablet is administered to a nursing woman.

Sitagliptin: 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), and institute supportive therapy as indicated by the patient's clinical status. Sitagliptin is modestly dialyzable. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

Metformin hydrochloride: Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Metformin 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 overdosage is suspected. Pancreatitis may occur in the context of a metformin overdose.

Store below 25°C in a dry place away from light. Keep the medicines in a safe place, out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician.

Combination Oral hypoglycemic preparations

This tablet combines two antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes. Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and Metformin HCl, a member of the biguanide class. Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated then GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, Sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. The pharmacologic mechanism of action of Metformin HCl is different from other classes of oral antihyperglycemic agents. Metformin HCl decreases hepatic glucose production, decreases intestinal absorption of glucose and increases peripheral glucose uptake and utilization.

Dose of film-coated tablet: The dosage of this tablet should be individualized on the basis of the patient's current regimen, efectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin. Initial combination therapy or maintenance of combination therapy should be individualized and left to the discretion of the health care provider.

This tablet should generally be given twice daily with meals, with gradual dose escalation, to reduce the gastrointestinal (GI) side efects due to metformin.

The starting dose of this tablet should be based on the patient’s current regimen. This tablet should be given twice daily with meals.

The recommended starting dose in patients not currently treated with metformin is 50 mg sitagliptin/500 mg metformin hydrochloride twice daily, with gradual dose escalation recommended to reduce gastrointestinal side efects associated with metformin.

The starting dose in patients already treated with metformin should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and the dose of metformin already being taken. For patients taking metformin 850 mg twice daily, the recommended starting dose of this tablet is 50 mg sitagliptin/1000 mg metformin hydrochloride twice daily.

No studies have been performed specifcally examining the safety and efcacy of Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP in patients previously treated with other oral antihyperglycemic agents and switched to Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

Dose of extended-release tablet: Administer once daily with a meal preferably in the evening. Gradually escalate the dose to reduce the gastrointestinal side effects due to Metformin. May adjust the dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 100 mg Sitagliptin and 2000 mg Metformin extended-release. Maintain the same total daily dose of Sitagliptin and Metformin when changing between film-coated tablet and extended-release tablet, without exceeding the maximum recommended daily dose of 2000 mg Metformin extended-release.

Patients using two extended-release tablets (such as two 50/500 or two 50/1000 tablets) should take the two tablets together once daily. The 100 mg Sitagliptin/1000 mg Metformin HCI extended-release tablet should be taken as a single tablet once daily.

Patients treated with an insulin secretagogue or insulin: Co-administration of the combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.

The most common adverse reactions reported in ≥5% of patients simultaneously started on sitagliptin and metformin and more commonly than in patients treated with placebo were diarrhea, upper respiratory tract infection, and headache.

Adverse reactions reported in ≥5% of patients treated with sitagliptin in combination with sulfonylurea and metformin and more commonly than in patients treated with placebo in combination with sulfonylurea and metformin were hypoglycemia and headache.

Hypoglycemia was the only adverse reaction reported in ≥5% of patients treated with sitagliptin in combination with insulin and metformin and more commonly than in patients treated with placebo in combination with insulin and metformin.

Nasopharyngitis was the only adverse reaction reported in ≥5% of patients treated with sitagliptin monotherapy and more commonly than in patients given placebo.

The most common (>5%) adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, fatulence, abdominal discomfort, indigestion, asthenia, and headache.

This tablet is contraindicated in patients with:

• Renal disease or renal dysfunction, e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females] or abnormal creatinine clearance which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
• History of a serious hypersensitivity reaction to this tablet or sitagliptin, such as anaphylaxis or angioedema.

This tablet should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function.

Lactic Acidosis-

• Lactic acidosis can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic insufciency, renal impairment, and acute congestive heart failure.
• Symptoms include malaise, myalgias, respiratory distress, increasing somnolence, and nonspecifc abdominal distress. Laboratory abnormalities include low pH, increased anion gap and elevated blood lactate.
• If acidosis is suspected, discontinue this tablet and hospitalize the patient immediately.
• Regular monitoring of thyroid-stimulating hormone (TSH) levels is recommended in patients with hypothyroidism.
• Long-term treatment with metformin has been associated with a decrease in vitamin B12 serum levels which may cause peripheral neuropathy. Monitoring of the vitamin B12 level is recommended.

Others-

• Do not use this tablet in patients with hepatic disease.
• There have been postmarketing reports of acute renal failure, sometimes requiring dialysis. Before initiating this tablet and at least annually thereafter, assess renal function and verify as normal.
• There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected, promptly discontinue this tablet.
• Measure hematologic parameters annually.
• Warn patients against excessive alcohol intake.
• May need to discontinue this tablet and temporarily use insulin during periods of stress and decreased intake of fluids and food as may occur with fever, trauma, infection or surgery.
• Promptly evaluate patients previously controlled on this tablet who develop laboratory abnormalities or clinical illness for evidence of ketoacidosis or lactic acidosis.
• When used with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia.
• There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with sitagliptin (one of the components of this tablet ), such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. In such cases, promptly stop this tablet, assess for other potential causes, and institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes.
• There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP or any other anti-diabetic drug.

Cationic Drugs: Cationic drugs eliminated by renal tubular secretion: Use with caution.

Phenprocoumon: Metformin may decrease the anticoagulant effect of phenprocoumon. Therefore, close monitoring of the INR is recommended.

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

Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women with Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP or its individual components; therefore, the safety of Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP in pregnant women is not known. This tablet should be used during pregnancy only if clearly needed.

It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when this tablet is administered to a nursing woman.

Sitagliptin: 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), and institute supportive therapy as indicated by the patient's clinical status. Sitagliptin is modestly dialyzable. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

Metformin hydrochloride: Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Metformin 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 overdosage is suspected. Pancreatitis may occur in the context of a metformin overdose.

Store below 25°C in a dry place away from light. Keep the medicines in a safe place, out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician.

Dipeptidyl Peptidase-4 (DPP-4) inhibitor

Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by Sitagliptin, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. 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 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, Sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.

The recommended dose of sitagliptin is 50 mg twice a day and 100 mg once daily. Sitagliptin can be taken with or without food.

The most common adverse reactions include headache, upper respiratory tract infection and nasopharyngitis. Hypoglycemia may occur in patients treated with the combination to Sitagliptin and sulfonylurea and add on to insulin.

History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema.

If pancreatitis is suspected, sitagliptin should promptly be discontinued and appropriate management should be initiated.

Use in Patients with Renal Insufficiency: Dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD requiring hemodialysis or peritoneal dialysis.

Use with medications known to cause Hypoglycemia: When sitagliptin is used in combination therapy dosage adjustment of sulfonylurea or insulin may be required to reduce the risk of hypoglycemia.

Hypersensitivity Reactions: There have been post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. If a hypersensitivity reaction is suspected, discontinue sitagliptin, assess for other potential causes for the event, and institute alternative treatment for diabetes.

Effects of sitagliptin on other Drugs: Sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptive.

Digoxin: Sitagliptin slightly increases the mean of Digoxin concentration. However, no dose adjustment of either drug is required.

Pregnancy Category B. Reproduction studies have been performed in rats and rabbits. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Sitagliptin is secreted in the milk of lactating rats at milk to plasma ratio of 4:1. It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sitagliptin is administered to a nursing woman.

Pediatric Use: Safety and effectiveness of sitagliptin in pediatric patients under 18 years of age have not been established.

Geriatric Use: This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly, and it may be useful to assess renal function in these patients prior to initiating dosing and periodically thereafter.

For patients with mild renal insufciency: (CrCl <50 ml/min or serum creatinine levels of <1.7 mg/DL in men and <1.5 mg/DL in women), no dosage adjustment for sitagliptin is required.

For patients with moderate renal insufciency: (CrCl <30 to <50 mL/min, or serum creatinine levels of >1.7 to <3.0 mg/dL in men and >1.5 to <2.5 mg/dL in women), the dose of sitagliptin is 50 mg once daily.

For patients with severe renal insufficiency: (CrCl <30 mL/min or serum creatinine levels of >3.0 mg/dL in men and 2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of sitagliptin is 25 mg once daily. Sitagliptin may be administered without regard to the limiting of hemodialysis.

During controlled clinical trials in healthy subjects, single doses of up to 800 mg Sitagliptin were administered. Maximal mean increases in QTc of 8.0 msec were observed in one study at a dose of 800 mg Sitagliptin, a mean effect that is not considered clinically important. 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 and 400 mg per day for 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), and institute supportive therapy as dictated by the patient's clinical status. Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

Store below 25°C in a dry place away from light. Keep the medicines in a safe place, out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician

Dipeptidyl Peptidase-4 (DPP-4) inhibitor

Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by Sitagliptin, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. 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 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, Sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.

The recommended dose of sitagliptin is 50 mg twice a day and 100 mg once daily. Sitagliptin can be taken with or without food.

The most common adverse reactions include headache, upper respiratory tract infection and nasopharyngitis. Hypoglycemia may occur in patients treated with the combination to Sitagliptin and sulfonylurea and add on to insulin.

History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema.

If pancreatitis is suspected, sitagliptin should promptly be discontinued and appropriate management should be initiated.

Use in Patients with Renal Insufficiency: Dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD requiring hemodialysis or peritoneal dialysis.

Use with medications known to cause Hypoglycemia: When sitagliptin is used in combination therapy dosage adjustment of sulfonylurea or insulin may be required to reduce the risk of hypoglycemia.

Hypersensitivity Reactions: There have been post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. If a hypersensitivity reaction is suspected, discontinue sitagliptin, assess for other potential causes for the event, and institute alternative treatment for diabetes.

Effects of sitagliptin on other Drugs: Sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptive.

Digoxin: Sitagliptin slightly increases the mean of Digoxin concentration. However, no dose adjustment of either drug is required.

Pregnancy Category B. Reproduction studies have been performed in rats and rabbits. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Sitagliptin is secreted in the milk of lactating rats at milk to plasma ratio of 4:1. It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sitagliptin is administered to a nursing woman.

Pediatric Use: Safety and effectiveness of sitagliptin in pediatric patients under 18 years of age have not been established.

Geriatric Use: This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly, and it may be useful to assess renal function in these patients prior to initiating dosing and periodically thereafter.

For patients with mild renal insufciency: (CrCl <50 ml/min or serum creatinine levels of <1.7 mg/DL in men and <1.5 mg/DL in women), no dosage adjustment for sitagliptin is required.

For patients with moderate renal insufciency: (CrCl <30 to <50 mL/min, or serum creatinine levels of >1.7 to <3.0 mg/dL in men and >1.5 to <2.5 mg/dL in women), the dose of sitagliptin is 50 mg once daily.

For patients with severe renal insufficiency: (CrCl <30 mL/min or serum creatinine levels of >3.0 mg/dL in men and 2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of sitagliptin is 25 mg once daily. Sitagliptin may be administered without regard to the limiting of hemodialysis.

During controlled clinical trials in healthy subjects, single doses of up to 800 mg Sitagliptin were administered. Maximal mean increases in QTc of 8.0 msec were observed in one study at a dose of 800 mg Sitagliptin, a mean effect that is not considered clinically important. 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 and 400 mg per day for 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), and institute supportive therapy as dictated by the patient's clinical status. Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

Store below 25°C in a dry place away from light. Keep the medicines in a safe place, out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician

Dipeptidyl Peptidase-4 (DPP-4) inhibitor

Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by Sitagliptin, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. 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 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, Sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.

The recommended dose of sitagliptin is 50 mg twice a day and 100 mg once daily. Sitagliptin can be taken with or without food.

The most common adverse reactions include headache, upper respiratory tract infection and nasopharyngitis. Hypoglycemia may occur in patients treated with the combination to Sitagliptin and sulfonylurea and add on to insulin.

History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema.

If pancreatitis is suspected, sitagliptin should promptly be discontinued and appropriate management should be initiated.

Use in Patients with Renal Insufficiency: Dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD requiring hemodialysis or peritoneal dialysis.

Use with medications known to cause Hypoglycemia: When sitagliptin is used in combination therapy dosage adjustment of sulfonylurea or insulin may be required to reduce the risk of hypoglycemia.

Hypersensitivity Reactions: There have been post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. If a hypersensitivity reaction is suspected, discontinue sitagliptin, assess for other potential causes for the event, and institute alternative treatment for diabetes.

Effects of sitagliptin on other Drugs: Sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptive.

Digoxin: Sitagliptin slightly increases the mean of Digoxin concentration. However, no dose adjustment of either drug is required.

Pregnancy Category B. Reproduction studies have been performed in rats and rabbits. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Sitagliptin is secreted in the milk of lactating rats at milk to plasma ratio of 4:1. It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sitagliptin is administered to a nursing woman.

Pediatric Use: Safety and effectiveness of sitagliptin in pediatric patients under 18 years of age have not been established.

Geriatric Use: This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly, and it may be useful to assess renal function in these patients prior to initiating dosing and periodically thereafter.

For patients with mild renal insufciency: (CrCl <50 ml/min or serum creatinine levels of <1.7 mg/DL in men and <1.5 mg/DL in women), no dosage adjustment for sitagliptin is required.

For patients with moderate renal insufciency: (CrCl <30 to <50 mL/min, or serum creatinine levels of >1.7 to <3.0 mg/dL in men and >1.5 to <2.5 mg/dL in women), the dose of sitagliptin is 50 mg once daily.

For patients with severe renal insufficiency: (CrCl <30 mL/min or serum creatinine levels of >3.0 mg/dL in men and 2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of sitagliptin is 25 mg once daily. Sitagliptin may be administered without regard to the limiting of hemodialysis.

During controlled clinical trials in healthy subjects, single doses of up to 800 mg Sitagliptin were administered. Maximal mean increases in QTc of 8.0 msec were observed in one study at a dose of 800 mg Sitagliptin, a mean effect that is not considered clinically important. 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 and 400 mg per day for 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), and institute supportive therapy as dictated by the patient's clinical status. Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

Store below 25°C in a dry place away from light. Keep the medicines in a safe place, out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician

Combination Oral hypoglycemic preparations

This tablet combines two antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes. Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and Metformin HCl, a member of the biguanide class. Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated then GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, Sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. The pharmacologic mechanism of action of Metformin HCl is different from other classes of oral antihyperglycemic agents. Metformin HCl decreases hepatic glucose production, decreases intestinal absorption of glucose and increases peripheral glucose uptake and utilization.

Dose of film-coated tablet: The dosage of this tablet should be individualized on the basis of the patient's current regimen, efectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin. Initial combination therapy or maintenance of combination therapy should be individualized and left to the discretion of the health care provider.

This tablet should generally be given twice daily with meals, with gradual dose escalation, to reduce the gastrointestinal (GI) side efects due to metformin.

The starting dose of this tablet should be based on the patient’s current regimen. This tablet should be given twice daily with meals.

The recommended starting dose in patients not currently treated with metformin is 50 mg sitagliptin/500 mg metformin hydrochloride twice daily, with gradual dose escalation recommended to reduce gastrointestinal side efects associated with metformin.

The starting dose in patients already treated with metformin should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and the dose of metformin already being taken. For patients taking metformin 850 mg twice daily, the recommended starting dose of this tablet is 50 mg sitagliptin/1000 mg metformin hydrochloride twice daily.

No studies have been performed specifcally examining the safety and efcacy of Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP in patients previously treated with other oral antihyperglycemic agents and switched to Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

Dose of extended-release tablet: Administer once daily with a meal preferably in the evening. Gradually escalate the dose to reduce the gastrointestinal side effects due to Metformin. May adjust the dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 100 mg Sitagliptin and 2000 mg Metformin extended-release. Maintain the same total daily dose of Sitagliptin and Metformin when changing between film-coated tablet and extended-release tablet, without exceeding the maximum recommended daily dose of 2000 mg Metformin extended-release.

Patients using two extended-release tablets (such as two 50/500 or two 50/1000 tablets) should take the two tablets together once daily. The 100 mg Sitagliptin/1000 mg Metformin HCI extended-release tablet should be taken as a single tablet once daily.

Patients treated with an insulin secretagogue or insulin: Co-administration of the combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.

The most common adverse reactions reported in ≥5% of patients simultaneously started on sitagliptin and metformin and more commonly than in patients treated with placebo were diarrhea, upper respiratory tract infection, and headache.

Adverse reactions reported in ≥5% of patients treated with sitagliptin in combination with sulfonylurea and metformin and more commonly than in patients treated with placebo in combination with sulfonylurea and metformin were hypoglycemia and headache.

Hypoglycemia was the only adverse reaction reported in ≥5% of patients treated with sitagliptin in combination with insulin and metformin and more commonly than in patients treated with placebo in combination with insulin and metformin.

Nasopharyngitis was the only adverse reaction reported in ≥5% of patients treated with sitagliptin monotherapy and more commonly than in patients given placebo.

The most common (>5%) adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, fatulence, abdominal discomfort, indigestion, asthenia, and headache.

This tablet is contraindicated in patients with:

• Renal disease or renal dysfunction, e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females] or abnormal creatinine clearance which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
• History of a serious hypersensitivity reaction to this tablet or sitagliptin, such as anaphylaxis or angioedema.

This tablet should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function.

Lactic Acidosis-

• Lactic acidosis can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic insufciency, renal impairment, and acute congestive heart failure.
• Symptoms include malaise, myalgias, respiratory distress, increasing somnolence, and nonspecifc abdominal distress. Laboratory abnormalities include low pH, increased anion gap and elevated blood lactate.
• If acidosis is suspected, discontinue this tablet and hospitalize the patient immediately.
• Regular monitoring of thyroid-stimulating hormone (TSH) levels is recommended in patients with hypothyroidism.
• Long-term treatment with metformin has been associated with a decrease in vitamin B12 serum levels which may cause peripheral neuropathy. Monitoring of the vitamin B12 level is recommended.

Others-

• Do not use this tablet in patients with hepatic disease.
• There have been postmarketing reports of acute renal failure, sometimes requiring dialysis. Before initiating this tablet and at least annually thereafter, assess renal function and verify as normal.
• There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected, promptly discontinue this tablet.
• Measure hematologic parameters annually.
• Warn patients against excessive alcohol intake.
• May need to discontinue this tablet and temporarily use insulin during periods of stress and decreased intake of fluids and food as may occur with fever, trauma, infection or surgery.
• Promptly evaluate patients previously controlled on this tablet who develop laboratory abnormalities or clinical illness for evidence of ketoacidosis or lactic acidosis.
• When used with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia.
• There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with sitagliptin (one of the components of this tablet ), such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. In such cases, promptly stop this tablet, assess for other potential causes, and institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes.
• There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP or any other anti-diabetic drug.

Cationic Drugs: Cationic drugs eliminated by renal tubular secretion: Use with caution.

Phenprocoumon: Metformin may decrease the anticoagulant effect of phenprocoumon. Therefore, close monitoring of the INR is recommended.

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

Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women with Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP or its individual components; therefore, the safety of Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP in pregnant women is not known. This tablet should be used during pregnancy only if clearly needed.

It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when this tablet is administered to a nursing woman.

Sitagliptin: 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), and institute supportive therapy as indicated by the patient's clinical status. Sitagliptin is modestly dialyzable. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

Metformin hydrochloride: Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Metformin 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 overdosage is suspected. Pancreatitis may occur in the context of a metformin overdose.

Store below 25°C in a dry place away from light. Keep the medicines in a safe place, out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician.

Combination Oral hypoglycemic preparations

This tablet combines two antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes. Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and Metformin HCl, a member of the biguanide class. Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated then GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, Sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. The pharmacologic mechanism of action of Metformin HCl is different from other classes of oral antihyperglycemic agents. Metformin HCl decreases hepatic glucose production, decreases intestinal absorption of glucose and increases peripheral glucose uptake and utilization.

Dose of film-coated tablet: The dosage of this tablet should be individualized on the basis of the patient's current regimen, efectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin. Initial combination therapy or maintenance of combination therapy should be individualized and left to the discretion of the health care provider.

This tablet should generally be given twice daily with meals, with gradual dose escalation, to reduce the gastrointestinal (GI) side efects due to metformin.

The starting dose of this tablet should be based on the patient’s current regimen. This tablet should be given twice daily with meals.

The recommended starting dose in patients not currently treated with metformin is 50 mg sitagliptin/500 mg metformin hydrochloride twice daily, with gradual dose escalation recommended to reduce gastrointestinal side efects associated with metformin.

The starting dose in patients already treated with metformin should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and the dose of metformin already being taken. For patients taking metformin 850 mg twice daily, the recommended starting dose of this tablet is 50 mg sitagliptin/1000 mg metformin hydrochloride twice daily.

No studies have been performed specifcally examining the safety and efcacy of Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP in patients previously treated with other oral antihyperglycemic agents and switched to Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

Dose of extended-release tablet: Administer once daily with a meal preferably in the evening. Gradually escalate the dose to reduce the gastrointestinal side effects due to Metformin. May adjust the dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 100 mg Sitagliptin and 2000 mg Metformin extended-release. Maintain the same total daily dose of Sitagliptin and Metformin when changing between film-coated tablet and extended-release tablet, without exceeding the maximum recommended daily dose of 2000 mg Metformin extended-release.

Patients using two extended-release tablets (such as two 50/500 or two 50/1000 tablets) should take the two tablets together once daily. The 100 mg Sitagliptin/1000 mg Metformin HCI extended-release tablet should be taken as a single tablet once daily.

Patients treated with an insulin secretagogue or insulin: Co-administration of the combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.

The most common adverse reactions reported in ≥5% of patients simultaneously started on sitagliptin and metformin and more commonly than in patients treated with placebo were diarrhea, upper respiratory tract infection, and headache.

Adverse reactions reported in ≥5% of patients treated with sitagliptin in combination with sulfonylurea and metformin and more commonly than in patients treated with placebo in combination with sulfonylurea and metformin were hypoglycemia and headache.

Hypoglycemia was the only adverse reaction reported in ≥5% of patients treated with sitagliptin in combination with insulin and metformin and more commonly than in patients treated with placebo in combination with insulin and metformin.

Nasopharyngitis was the only adverse reaction reported in ≥5% of patients treated with sitagliptin monotherapy and more commonly than in patients given placebo.

The most common (>5%) adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, fatulence, abdominal discomfort, indigestion, asthenia, and headache.

This tablet is contraindicated in patients with:

• Renal disease or renal dysfunction, e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females] or abnormal creatinine clearance which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
• History of a serious hypersensitivity reaction to this tablet or sitagliptin, such as anaphylaxis or angioedema.

This tablet should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function.

Lactic Acidosis-

• Lactic acidosis can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic insufciency, renal impairment, and acute congestive heart failure.
• Symptoms include malaise, myalgias, respiratory distress, increasing somnolence, and nonspecifc abdominal distress. Laboratory abnormalities include low pH, increased anion gap and elevated blood lactate.
• If acidosis is suspected, discontinue this tablet and hospitalize the patient immediately.
• Regular monitoring of thyroid-stimulating hormone (TSH) levels is recommended in patients with hypothyroidism.
• Long-term treatment with metformin has been associated with a decrease in vitamin B12 serum levels which may cause peripheral neuropathy. Monitoring of the vitamin B12 level is recommended.

Others-

• Do not use this tablet in patients with hepatic disease.
• There have been postmarketing reports of acute renal failure, sometimes requiring dialysis. Before initiating this tablet and at least annually thereafter, assess renal function and verify as normal.
• There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected, promptly discontinue this tablet.
• Measure hematologic parameters annually.
• Warn patients against excessive alcohol intake.
• May need to discontinue this tablet and temporarily use insulin during periods of stress and decreased intake of fluids and food as may occur with fever, trauma, infection or surgery.
• Promptly evaluate patients previously controlled on this tablet who develop laboratory abnormalities or clinical illness for evidence of ketoacidosis or lactic acidosis.
• When used with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia.
• There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with sitagliptin (one of the components of this tablet ), such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. In such cases, promptly stop this tablet, assess for other potential causes, and institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes.
• There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP or any other anti-diabetic drug.

Cationic Drugs: Cationic drugs eliminated by renal tubular secretion: Use with caution.

Phenprocoumon: Metformin may decrease the anticoagulant effect of phenprocoumon. Therefore, close monitoring of the INR is recommended.

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

Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women with Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP or its individual components; therefore, the safety of Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP in pregnant women is not known. This tablet should be used during pregnancy only if clearly needed.

It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when this tablet is administered to a nursing woman.

Sitagliptin: 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), and institute supportive therapy as indicated by the patient's clinical status. Sitagliptin is modestly dialyzable. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

Metformin hydrochloride: Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Metformin 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 overdosage is suspected. Pancreatitis may occur in the context of a metformin overdose.

Store below 25°C in a dry place away from light. Keep the medicines in a safe place, out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician.

Combination Oral hypoglycemic preparations

This tablet combines two antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes. Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and Metformin HCl, a member of the biguanide class. Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated then GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, Sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. The pharmacologic mechanism of action of Metformin HCl is different from other classes of oral antihyperglycemic agents. Metformin HCl decreases hepatic glucose production, decreases intestinal absorption of glucose and increases peripheral glucose uptake and utilization.

Dose of film-coated tablet: The dosage of this tablet should be individualized on the basis of the patient's current regimen, efectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin. Initial combination therapy or maintenance of combination therapy should be individualized and left to the discretion of the health care provider.

This tablet should generally be given twice daily with meals, with gradual dose escalation, to reduce the gastrointestinal (GI) side efects due to metformin.

The starting dose of this tablet should be based on the patient’s current regimen. This tablet should be given twice daily with meals.

The recommended starting dose in patients not currently treated with metformin is 50 mg sitagliptin/500 mg metformin hydrochloride twice daily, with gradual dose escalation recommended to reduce gastrointestinal side efects associated with metformin.

The starting dose in patients already treated with metformin should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and the dose of metformin already being taken. For patients taking metformin 850 mg twice daily, the recommended starting dose of this tablet is 50 mg sitagliptin/1000 mg metformin hydrochloride twice daily.

No studies have been performed specifcally examining the safety and efcacy of Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP in patients previously treated with other oral antihyperglycemic agents and switched to Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

Dose of extended-release tablet: Administer once daily with a meal preferably in the evening. Gradually escalate the dose to reduce the gastrointestinal side effects due to Metformin. May adjust the dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 100 mg Sitagliptin and 2000 mg Metformin extended-release. Maintain the same total daily dose of Sitagliptin and Metformin when changing between film-coated tablet and extended-release tablet, without exceeding the maximum recommended daily dose of 2000 mg Metformin extended-release.

Patients using two extended-release tablets (such as two 50/500 or two 50/1000 tablets) should take the two tablets together once daily. The 100 mg Sitagliptin/1000 mg Metformin HCI extended-release tablet should be taken as a single tablet once daily.

Patients treated with an insulin secretagogue or insulin: Co-administration of the combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.

The most common adverse reactions reported in ≥5% of patients simultaneously started on sitagliptin and metformin and more commonly than in patients treated with placebo were diarrhea, upper respiratory tract infection, and headache.

Adverse reactions reported in ≥5% of patients treated with sitagliptin in combination with sulfonylurea and metformin and more commonly than in patients treated with placebo in combination with sulfonylurea and metformin were hypoglycemia and headache.

Hypoglycemia was the only adverse reaction reported in ≥5% of patients treated with sitagliptin in combination with insulin and metformin and more commonly than in patients treated with placebo in combination with insulin and metformin.

Nasopharyngitis was the only adverse reaction reported in ≥5% of patients treated with sitagliptin monotherapy and more commonly than in patients given placebo.

The most common (>5%) adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, fatulence, abdominal discomfort, indigestion, asthenia, and headache.

This tablet is contraindicated in patients with:

• Renal disease or renal dysfunction, e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females] or abnormal creatinine clearance which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
• History of a serious hypersensitivity reaction to this tablet or sitagliptin, such as anaphylaxis or angioedema.

This tablet should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function.

Lactic Acidosis-

• Lactic acidosis can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic insufciency, renal impairment, and acute congestive heart failure.
• Symptoms include malaise, myalgias, respiratory distress, increasing somnolence, and nonspecifc abdominal distress. Laboratory abnormalities include low pH, increased anion gap and elevated blood lactate.
• If acidosis is suspected, discontinue this tablet and hospitalize the patient immediately.
• Regular monitoring of thyroid-stimulating hormone (TSH) levels is recommended in patients with hypothyroidism.
• Long-term treatment with metformin has been associated with a decrease in vitamin B12 serum levels which may cause peripheral neuropathy. Monitoring of the vitamin B12 level is recommended.

Others-

• Do not use this tablet in patients with hepatic disease.
• There have been postmarketing reports of acute renal failure, sometimes requiring dialysis. Before initiating this tablet and at least annually thereafter, assess renal function and verify as normal.
• There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected, promptly discontinue this tablet.
• Measure hematologic parameters annually.
• Warn patients against excessive alcohol intake.
• May need to discontinue this tablet and temporarily use insulin during periods of stress and decreased intake of fluids and food as may occur with fever, trauma, infection or surgery.
• Promptly evaluate patients previously controlled on this tablet who develop laboratory abnormalities or clinical illness for evidence of ketoacidosis or lactic acidosis.
• When used with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia.
• There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with sitagliptin (one of the components of this tablet ), such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. In such cases, promptly stop this tablet, assess for other potential causes, and institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes.
• There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP or any other anti-diabetic drug.

Cationic Drugs: Cationic drugs eliminated by renal tubular secretion: Use with caution.

Phenprocoumon: Metformin may decrease the anticoagulant effect of phenprocoumon. Therefore, close monitoring of the INR is recommended.

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

Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women with Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP or its individual components; therefore, the safety of Sitagliptin Phosphate Monohydrate INN/Metformin Hydrochloride BP in pregnant women is not known. This tablet should be used during pregnancy only if clearly needed.

It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when this tablet is administered to a nursing woman.

Sitagliptin: 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), and institute supportive therapy as indicated by the patient's clinical status. Sitagliptin is modestly dialyzable. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

Metformin hydrochloride: Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Metformin 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 overdosage is suspected. Pancreatitis may occur in the context of a metformin overdose.

Store below 25°C in a dry place away from light. Keep the medicines in a safe place, out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician.