Janumet

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT YANUMET (Janumet®)

Composition:

Active substances: sitagliptin, metformin hydrochloride;

One film-coated tablet contains sitagliptin phosphate monohydrate equivalent to 50 mg of sitagliptin and 500 mg, or 850 mg, or 1000 mg of metformin hydrochloride;

Excipients: microcrystalline cellulose, povidone, sodium lauryl sulfate, sodium stearyl fumarate;

Tablet coating: Opadry II 85F94203 pink (tablets 50 mg/500 mg), or Opadry II 85F94182 pink (tablets 50 mg/850 mg), or Opadry II 85F15464 red (tablets 50 mg/1000 mg);

Coating composition: polyvinyl alcohol, titanium dioxide (E 171), polyethylene glycol 3350, talc, black iron oxide (E 172), red iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Tablets 50/500 mg: film-coated tablets, light pink in color, engraved with "575" on one side and smooth on the other side;

Tablets 50/850 mg: film-coated tablets, pink in color, engraved with "515" on one side and smooth on the other side;

Tablets 50/1000 mg: film-coated tablets, red in color, engraved with "577" on one side and smooth on the other side.

Pharmacotherapeutic group.

Combination of oral blood glucose-lowering medicinal products. ATC code A10BD07.

Pharmacological properties.

Pharmacodynamics.

Janumet is a combination of two antihyperglycemic agents with complementary (complementary) mechanisms of action intended to improve glycemic control in patients with type 2 diabetes mellitus: sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and metformin hydrochloride, a member of the biguanide class.

Pharmacokinetics.

Mechanism of action of Janumet. Janumet combination tablets (sitagliptin/metformin hydrochloride) 50 mg/500 mg and 50 mg/1000 mg are bioequivalent to separate administration of corresponding doses of sitagliptin phosphate (Januvia) and metformin hydrochloride.

Pharmacokinetics in specific patient populations.

Patients with type 2 diabetes mellitus.

Sitagliptin. The pharmacokinetics of sitagliptin in patients with type 2 diabetes mellitus are similar to those in healthy volunteers.

Metformin. With preserved renal function, pharmacokinetic parameters after single and repeated doses of metformin in patients with type 2 diabetes mellitus and healthy volunteers are identical; no drug accumulation occurs with therapeutic dosing.

Patients with impaired renal function.

Sitagliptin. In patients with moderate renal impairment (eGFR ≥ 30 to ≤ 45 mL/min), plasma AUC of sitagliptin increased approximately 2-fold, and in patients with severe (eGFR < 30 mL/min) and end-stage renal disease (on hemodialysis), AUC values increased 4-fold. Sitagliptin is only minimally eliminated by hemodialysis (approximately 13.5% of the administered dose of sitagliptin was removed from the body during a 3–4 hour hemodialysis session initiated 4 hours after drug administration).

Metformin. In patients with impaired renal function, the plasma elimination half-life of the drug is prolonged and renal clearance is reduced (see sections "Contraindications", "Special precautions").

Patients with impaired hepatic function.

Sitagliptin. Dose adjustment of sitagliptin is not required in patients with mild to moderate hepatic impairment (≤ 9 on the Child–Pugh scale). There are no clinical data on the use of sitagliptin in patients with severe hepatic impairment (> 9 on the Child–Pugh scale). Since sitagliptin is primarily eliminated via the kidneys, no significant effect on the pharmacokinetics of sitagliptin is expected in patients with severe hepatic impairment.

Metformin. Pharmacokinetic studies of metformin in patients with hepatic impairment have not been conducted.

Elderly patients. Dose adjustment of the drug is not required based on patient age. Age does not have a clinically significant effect on the pharmacokinetics of sitagliptin. In elderly patients (65–80 years), plasma concentrations of sitagliptin are approximately 19% higher than in younger patients.

Pediatric patients.

The pharmacokinetics of sitagliptin (single doses of 50 mg, 100 mg, or 200 mg) were studied in pediatric patients (aged 10 to 17 years inclusive) with type 2 diabetes mellitus. In this population, plasma AUC values of sitagliptin following weight-adjusted dosing were approximately 18% lower compared to those in adult patients with type 2 diabetes mellitus receiving a 100 mg dose. Studies of sitagliptin use in children under 10 years of age have not been conducted.

Clinical characteristics.

Indications.

For the treatment of adult patients with type 2 diabetes mellitus:

• Janumet is indicated as an adjunct to diet and exercise to improve glycemic control in patients who have not achieved adequate glycemic control on the maximum tolerated dose of metformin monotherapy, as well as in patients already receiving treatment with a combination of sitagliptin and metformin.
• Janumet is indicated in combination with sulfonylurea derivatives (triple therapy) as an adjunct to diet and exercise in patients who have not achieved adequate glycemic control on metformin at the maximum tolerated dose and a sulfonylurea.
• Janumet is indicated in combination with peroxisome proliferator-activated receptor (PPAR-γ) agonists (e.g., thiazolidinediones) (triple therapy) as an adjunct to diet and exercise in patients who have not achieved adequate glycemic control on metformin at the maximum tolerated dose and a PPAR-γ agonist.
• Janumet is also indicated for patients receiving insulin (triple therapy), as an adjunct to diet and exercise to improve glycemic control in patients who have not achieved adequate control on a stable dose of insulin and metformin.

Contraindications.

• Known hypersensitivity to sitagliptin phosphate, metformin hydrochloride, or to any other component of the medicinal product.
• Any type of acute metabolic acidosis (e.g., lactic acidosis, diabetic ketoacidosis).
• Diabetic precoma.
• Severe renal impairment (eGFR < 30 mL/min (see section "Special precautions", "Renal impairment")).
• Acute conditions that may affect renal function: dehydration, severe infections, shock, intravascular administration of iodinated contrast agents (see section "Special precautions").
• Acute or chronic conditions that may lead to tissue hypoxia, such as cardiac or pulmonary failure, recent myocardial infarction, shock.
• Hepatic dysfunction.
• Acute alcohol intoxication, alcoholism.
• Breastfeeding period.

Interaction with other medicinal products and other forms of interaction.

Concomitant administration of multiple doses of sitagliptin (50 mg twice daily) and metformin (1000 mg twice daily) did not result in clinically significant changes in the pharmacokinetic parameters of sitagliptin or metformin in patients with type 2 diabetes mellitus.

Pharmacokinetic studies on drug interactions between Janumet and other medicinal products have not been conducted; however, such studies have been performed separately with the active substances—sitagliptin and metformin.

Concomitant use not recommended.

Alcohol. Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases of fasting, inadequate nutrition, or impaired liver function.

Iodinated contrast agents

Administration of Janumet should be discontinued before or during radiological procedures involving iodinated contrast agents and should not be restarted until at least 48 hours after the procedure, provided that renal function has been re-evaluated and deemed acceptable (see sections "Contraindications" and "Special precautions").

Combinations requiring precautions during use

Some medicinal products may adversely affect renal function, thereby increasing the risk of lactic acidosis, e.g., NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, ACE inhibitors, angiotensin II receptor antagonists, and diuretics, particularly loop diuretics. Careful monitoring of renal function is required when initiating such medicinal products in combination with metformin.

Concomitant use of medicinal products that affect renal tubular transport systems involved in the renal elimination of metformin (e.g., inhibitors of organic cation transporter-2 [OCT2]/multidrug and toxin extrusion [MATE] transporters, such as ranolazine, vandetanib, dolutegravir, and cimetidine) may lead to increased systemic exposure to metformin and increase the risk of lactic acidosis. The benefits and risks of concomitant use should be carefully considered. Close glycemic monitoring, dose adjustments within the recommended dosage range, and changes in diabetes treatment should be considered when these medicinal products are used concomitantly.

Glucocorticoids (systemic and local), beta-2 agonists, and diuretics have their own potential for hyperglycemic effects. Patients should be informed of this and monitored more frequently for blood glucose levels, especially at the beginning of treatment with these medicinal products. If necessary, the dose of the antihyperglycemic medicinal product should be adjusted during concomitant use with these agents and after their discontinuation.

ACE inhibitors may lower blood glucose levels. If necessary, the dose of the antihyperglycemic medicinal product should be adjusted during concomitant use with other medicinal products and after their discontinuation.

Effect of other medicinal products on sitagliptin

The data below indicate a low risk of clinically significant interactions.

In vitro studies showed that the main enzymes involved in the partial metabolism of sitagliptin are cytochrome P450 enzymes CYP3A4 and, to a lesser extent, CYP2C8. In patients with normal renal function, metabolism (including CYP3A4) plays only a minor role in the clearance of sitagliptin. Metabolism may play a more significant role in the elimination of sitagliptin in patients with severe or end-stage renal impairment. Therefore, potent inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir, clarithromycin) may alter the pharmacokinetics of sitagliptin in such patients. The effect of potent CYP3A4 inhibitors in patients with renal impairment has not been studied in clinical trials.

In vitro transport studies showed that sitagliptin is a substrate of P-glycoprotein and organic anion transporter type 3 (OAT3). In vitro, OAT3-mediated transport of sitagliptin was inhibited by probenecid, although the risk of clinically significant interactions is considered low. Concomitant use of OAT3 inhibitors and sitagliptin in vivo has not been studied.

Cyclosporine. In a study of concomitant administration of a single 100 mg dose of sitagliptin and a single 600 mg oral dose of cyclosporine, AUC and Cmax of sitagliptin increased by approximately 29% and 68%, respectively. These changes in sitagliptin pharmacokinetics are not considered clinically significant. Similarly, significant interactions are not expected with other P-glycoprotein inhibitors.

Effect of sitagliptin on other medicinal products

In vitro data show that sitagliptin does not inhibit or induce CYP450 isoenzymes. In clinical studies, sitagliptin did not have a significant effect on the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives; sitagliptin has a low potential for interactions with substrates of CYP3A4, CYP2C8, or CYP2C9 and organic cation transporters. Sitagliptin has a weak effect on digoxin plasma concentrations and may be a weak inhibitor of P-glycoprotein in vivo.

Digoxin. Sitagliptin weakly affects digoxin plasma concentrations. After administration of 0.25 mg digoxin concomitantly with 100 mg sitagliptin daily for 10 days, the AUC of digoxin increased on average by 11%, and Cmax by 18%. Dose adjustment of digoxin is not recommended. However, patients at risk of digoxin toxicity should be monitored when digoxin is co-administered with sitagliptin.

Special precautions for use

The medicinal product Janumet is not used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

Acute pancreatitis

DPP-4 inhibitors have been associated with an increased risk of acute pancreatitis. Patients should be informed about the characteristic symptom of acute pancreatitis — persistent, severe abdominal pain. Resolution of pancreatitis symptoms has been observed after discontinuation of sitagliptin (with or without supportive therapy); however, very rare cases of necrotizing or hemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, Janumet and other medications that may induce acute pancreatitis should be discontinued. Janumet should not be restarted if acute pancreatitis is confirmed. Caution should be exercised in patients with a history of pancreatitis.

Lactic acidosis

Lactic acidosis is a rare but serious metabolic complication, most commonly occurring during acute worsening of renal function or in the presence of cardiopulmonary disease or sepsis. Accumulation of metformin occurs during acute worsening of renal function and increases the risk of lactic acidosis. In cases of dehydration (severe diarrhea or vomiting, fever, or reduced fluid intake), metformin should be temporarily discontinued and medical advice sought.

Medicinal products that may rapidly impair renal function (e.g., antihypertensives, diuretics, and NSAIDs) should be initiated with caution in patients taking metformin. Other risk factors for lactic acidosis include alcohol abuse, hepatic insufficiency, poorly controlled diabetes mellitus, ketosis, prolonged fasting, any condition associated with hypoxia, and concomitant use of medicinal products that may cause lactic acidosis (see sections "Contraindications", "Interaction with other medicinal products and other forms of interaction"). Patients and/or caregivers should be informed about the risk of lactic acidosis. Lactic acidosis is characterized by acidotic dyspnea, abdominal pain, muscle cramps, asthenia, and hypothermia progressing to coma. If these symptoms occur, the patient should discontinue metformin immediately and seek medical attention. Diagnostic laboratory findings include decreased blood pH (< 7.35), elevated plasma lactate levels (> 5 mmol/L), and increased anion gap and lactate/pyruvate ratio.

Hypoglycemia

When Janumet is used in combination with insulin or sulfonylureas, there is a risk of hypoglycemia. To reduce this risk, a lower dose of sulfonylurea or insulin should be used.

Renal function

eGFR should be assessed before initiating treatment and regularly during therapy with Janumet (see section "Dosage and administration").

Janumet is contraindicated in patients with severe renal impairment (eGFR < 30 mL/min). The use of the medicinal product should be temporarily discontinued if there is a likelihood of changes in renal function (see section "Contraindications").

Hypersensitivity reactions

Post-marketing reports have described serious hypersensitivity reactions in patients taking sitagliptin, including anaphylaxis, angioedema, and skin exfoliative conditions such as Stevens-Johnson syndrome. These reactions occurred within the first three months of treatment with sitagliptin and sometimes after the first dose. If hypersensitivity reactions are suspected, Janumet should be discontinued, other potential causes evaluated, and alternative diabetes therapy initiated (see section "Adverse reactions").

Bullous pemphigoid

Post-marketing cases of bullous pemphigoid have been reported in patients taking DPP-4 inhibitors, including sitagliptin. If bullous pemphigoid is suspected, Janumet should be discontinued.

Surgery

Janumet should be discontinued prior to surgery under general, spinal, or epidural anesthesia. Therapy may be resumed no earlier than 48 hours after surgery or restoration of oral intake, and only after renal function has been re-evaluated and found to be stable (see section "Dosage and administration").

Use of iodinated contrast agents

Intravascular administration of iodine-containing contrast agents may cause contrast-induced nephropathy, leading to metformin accumulation and an increased risk of lactic acidosis. Janumet should be discontinued before or during radiological procedures involving such agents and may be restarted no earlier than 48 hours after the procedure, and only after renal function has been re-evaluated and found acceptable (see sections "Contraindications", "Interaction with other medicinal products and other forms of interaction").

Change in clinical status of a patient with previously controlled type 2 diabetes

If a patient with previously well-controlled type 2 diabetes mellitus on Janumet develops unexplained laboratory abnormalities or clinical illness (especially undiagnosed or unidentifiable conditions), ketoacidosis or lactic acidosis should be immediately ruled out by measuring serum electrolytes and ketones, glucose levels, blood pH, and concentrations of lactate, pyruvate, and metformin. If acidosis of any etiology develops, further use of Janumet should be discontinued and appropriate corrective measures initiated.

Other warnings

Metformin may decrease serum vitamin B12 levels. The risk of vitamin B12 deficiency increases with higher metformin doses, longer duration of treatment, and/or in patients with known risk factors for vitamin B12 deficiency. If vitamin B12 deficiency is suspected (e.g., anemia or neuropathy), serum vitamin B12 levels should be monitored. Patients with risk factors for vitamin B12 deficiency may require periodic monitoring of vitamin B12 levels. Metformin therapy should be continued as long as it is tolerated and not contraindicated, with appropriate corrective treatment for vitamin B12 deficiency administered according to current clinical guidelines.

Sodium content

Each 50/500 mg tablet contains less than 1 mmol sodium (23 mg), i.e., essentially "sodium-free".

Each 50/850 mg tablet contains less than 1 mmol sodium (23 mg), i.e., essentially "sodium-free".

Each 50/1000 mg tablet contains less than 1 mmol sodium (23 mg), i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding

Pregnancy
There are inadequate data on the use of sitagliptin in pregnant women. Animal studies have shown reproductive toxicity at high doses of sitagliptin.

Limited available data suggest that metformin use during pregnancy is not associated with an increased risk of fetal/infant congenital malformations. Animal studies with metformin have not shown adverse effects on pregnancy, embryonic or fetal development, parturition, or postnatal development.

Janumet should not be used during pregnancy. If a patient intends to become pregnant or becomes pregnant, treatment with Janumet should be discontinued as soon as possible and insulin therapy initiated.

Breastfeeding
No studies have been conducted with the combination of active substances of Janumet in lactating animals. In separate studies with each active substance, both sitagliptin and metformin were excreted in the milk of lactating rats. Metformin is excreted in human breast milk in small amounts. It is unknown whether sitagliptin is excreted in breast milk. Therefore, Janumet must not be used in women who are breastfeeding (see section "Contraindications").

Fertility
Data from animal studies do not indicate any effect of sitagliptin treatment on male or female fertility. Human fertility data are lacking.

Ability to affect reaction speed when driving or operating machinery

Janumet has no effect or a negligible effect on the ability to drive or operate machinery. However, it should be noted that dizziness and somnolence have been reported with sitagliptin use; therefore, caution should be exercised when driving or operating machinery.

In addition, patients should be warned about the risk of hypoglycemia when Janumet is used in combination with sulfonylurea derivatives or insulin.

Dosage and Administration

Route of Administration

Janumet should be administered twice daily with meals to reduce gastrointestinal (GI) side effects associated with metformin.

The dosage regimen for Janumet should be individualized based on the patient's current therapy, efficacy, and tolerability, but must not exceed the maximum recommended daily dose of sitagliptin – 100 mg.

Adults with Normal Renal Function (eGFR > 90 mL/min)

Available Dosage Strengths:

• 50 mg sitagliptin/500 mg metformin hydrochloride
• 50 mg sitagliptin/850 mg metformin hydrochloride
• 50 mg sitagliptin/1000 mg metformin hydrochloride

For patients who have not achieved adequate glycemic control on maximum tolerated dose of metformin monotherapy.

The recommended starting dose of Janumet for patients not achieving adequate control on metformin monotherapy should provide the recommended daily dose of sitagliptin 100 mg (i.e., 50 mg twice daily) plus the current dose of metformin.

For patients switching from concomitant sitagliptin and metformin.

When switching from treatment with sitagliptin and metformin as separate monotherapies, the initial dose of Janumet should be equivalent to the doses of sitagliptin and metformin previously administered individually.

For patients not achieving adequate control on maximum tolerated dose of metformin and a sulfonylurea.

The dose of Janumet should provide the recommended daily dose of sitagliptin 100 mg (i.e., 50 mg twice daily) plus a dose of metformin close to the current one. Patients receiving Janumet in combination with a sulfonylurea may require a lower dose of the sulfonylurea to reduce the risk of hypoglycemia (see section "Special Warnings and Precautions").

For patients not achieving adequate control on combination therapy with maximum tolerated dose of metformin and a PPAR-γ agonist.

The dose of Janumet should provide a daily dose of sitagliptin 100 mg (i.e., 50 mg twice daily) plus a dose of metformin close to the current one.

For patients not achieving adequate control on combination therapy with insulin and maximum tolerated dose of metformin.

The dose of Janumet should provide a daily dose of sitagliptin 100 mg (i.e., 50 mg twice daily) plus a dose of metformin close to the current one. When Janumet is used in combination with insulin, it may be appropriate to reduce the insulin dose to reduce the risk of hypoglycemia (see section "Special Warnings and Precautions").

Patients should continue to follow a diabetic diet with adequate distribution of carbohydrate intake throughout the day. Obese patients should continue to follow a calorie-restricted diet.

Special Patient Populations

Renal Impairment

Patients with moderate renal impairment (estimated glomerular filtration rate [eGFR] ≥ 60 mL/min) do not require dose adjustment. eGFR should be assessed before initiating treatment with metformin-containing products and at least annually thereafter. In patients at increased risk for worsening renal function, including elderly individuals, renal function should be evaluated more frequently, for example every 3–6 months.

The maximum daily dose of metformin should preferably be divided into 2–3 doses. Factors that may increase the risk of lactic acidosis (see section "Special Warnings and Precautions") should be considered before prescribing metformin to patients with eGFR < 60 mL/min.

If Janumet with an appropriate dosage strength is not available, the individual components should be used instead of the fixed-dose combination.

Hepatic impairment. Janumet should not be prescribed to patients with hepatic insufficiency (see section "Pharmacological properties").

Elderly patients. Since metformin and sitagliptin are eliminated by the kidneys, Janumet should be used with caution in elderly patients. Renal function must be monitored to prevent metformin-associated lactic acidosis, especially in elderly patients (see sections "Contraindications", "Special precautions").

Children.

Janumet should not be used in children aged 10 to 17 years inclusive due to insufficient efficacy. Current data are described in sections "Adverse reactions", "Pharmacological properties: Pharmacokinetics". Studies on the use of Janumet in children under 10 years of age have not been conducted.

Overdose.

Sitagliptin. In controlled clinical studies involving healthy volunteers, single doses up to 800 mg were generally well tolerated. A minor QTc prolongation was observed at a dose of 800 mg, which was not considered clinically significant. There is no clinical experience with doses exceeding 800 mg. During studies, no dose-related adverse reactions were observed with doses up to 600 mg daily for 10 days and 400 mg for 28 days.

Significant metformin overdose (or concomitant risk factors for lactic acidosis) may lead to lactic acidosis, requiring emergency medical care and hospitalization. Hemodialysis is the most effective method for removing lactate and metformin from the body.

During clinical studies, approximately 13.5% of the administered dose of the drug was eliminated over a 3–4 hour hemodialysis session. Prolonged hemodialysis should be performed when clinically indicated. It is unknown whether sitagliptin is eliminated by peritoneal dialysis.

In case of Janumet overdose, standard supportive measures should be initiated: removal of unabsorbed drug from the gastrointestinal tract, clinical monitoring (including ECG), and administration of supportive therapy as needed.

Adverse Reactions

Clinical trials with the medicinal product Janumet have not been conducted; however, bioequivalence of Janumet to co-administered sitagliptin and metformin has been demonstrated. Serious adverse reactions have been reported, including pancreatitis and allergic reactions. Hypoglycemia has been reported when the medicinal product was used in combination with sulfonylureas (13.8%) and insulin (10.9%).

Sitagliptin and Metformin

Adverse reactions are listed using MedDRA terminology, categorized by system organ class and absolute frequency. Frequency of occurrence is defined as: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), and very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

Frequency of adverse reactions was determined based on results from placebo-controlled clinical trials and post-marketing surveillance.

Blood and lymphatic system disorders: rare: thrombocytopenia.

Immune system disorders: frequency not known: hypersensitivity reactions, including anaphylactic reactions*†.

Metabolism and nutrition disorders: common: hypoglycemia†.

Nervous system disorders: uncommon: somnolence.

Respiratory, thoracic and mediastinal disorders: frequency not known: interstitial lung disease*.

Gastrointestinal disorders: common: nausea, flatulence, vomiting; uncommon: diarrhea, constipation, upper abdominal pain; frequency not known: acute pancreatitis*†‡, fatal and non-fatal hemorrhagic and necrotizing pancreatitis*†.

Skin and subcutaneous tissue disorders: uncommon: pruritus*; frequency not known: angioedema*†, rash*†, urticaria*†, skin vasculitis*†, exfoliative skin conditions including Stevens-Johnson syndrome*†, bullous pemphigoid*†.

Musculoskeletal and connective tissue disorders: frequency not known: arthralgia*, myalgia*, limb pain*, back pain*, arthropathy*.

Renal and urinary disorders: frequency not known: worsening of renal function*, acute renal failure*.

*Adverse reactions identified during post-marketing surveillance.

† See section "Special Warnings and Precautions for Use".

‡See "TECOS cardiovascular safety study" below.

Description of selected adverse reactions

The following adverse reactions were observed more frequently with combination therapy of sitagliptin and metformin with other antidiabetic medicinal products than with sitagliptin or metformin alone:

• hypoglycemia (very common when used with sulfonylureas or insulin);
• constipation (common when used with sulfonylureas);
• peripheral edema (common when used with pioglitazone);
• headache and dry mouth (uncommon when used with insulin).

Sitagliptin

In clinical trials of sitagliptin 100 mg once daily compared to placebo, headache, hypoglycemia, constipation, and dizziness were reported. Adverse reactions reported in at least 5% of patients, regardless of causal relationship to the medicinal product, included upper respiratory tract infections and nasopharyngitis. Additionally, osteoarthritis and limb pain were reported uncommonly (0.5% more frequently in patients taking sitagliptin compared to the control group).

Metformin

During clinical trials and post-marketing experience with metformin therapy, very common gastrointestinal adverse reactions were reported. Nausea, vomiting, diarrhea, abdominal pain, and loss of appetite occurred very commonly at the start of treatment and resolved spontaneously in most cases. Metallic taste was also reported (common); lactic acidosis, liver function impairment, hepatitis, urticaria, erythema, pruritus (very rare); decreased levels/deficiency of vitamin B12 (common) (see section "Special Warnings and Precautions for Use").

Pediatric population

In clinical trials of Janumet in children aged 10 to 17 years inclusive with type 2 diabetes, the adverse reaction profile was generally comparable to that in adults. In children receiving or not receiving background insulin, sitagliptin was associated with an increased risk of hypoglycemia.

TECOS cardiovascular safety study

The TECOS cardiovascular safety study of sitagliptin included 7,332 patients receiving sitagliptin 100 mg daily (or 50 mg daily if baseline estimated glomerular filtration rate (eGFR) was ≥30 and <50 mL/min/1.73 m²) and 7,339 patients receiving placebo in the initial treatment group. Both medicinal products were added to background therapy according to regional standards and considering HbA1c levels and cardiovascular risk factors. The overall incidence of serious adverse events in patients receiving sitagliptin was similar to that in patients receiving placebo.

In the population of all randomized patients, the rate of severe hypoglycemia episodes was 2.7% in patients receiving insulin and/or sulfonylureas at baseline and 2.5% in the placebo group; among patients not receiving insulin and/or sulfonylureas at baseline, the rate of severe hypoglycemia episodes was 1.0% in the sitagliptin group and 0.7% in the placebo group. The rate of confirmed pancreatitis cases was 0.3% in patients receiving sitagliptin and 0.2% in the placebo group.

Post-marketing experience

During post-marketing use of Janumet, sitagliptin, or metformin, the following adverse reactions have been identified: tubulointerstitial nephritis.

Reporting suspected adverse reactions

It is important to report suspected adverse reactions after medicinal product authorization. This allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions.

Shelf life. 2 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging.

14 tablets in a blister; 4 blisters in a cardboard box with the instruction for medical use.

Prescription status.

Prescription only.

Manufacturer.

Merck Sharp & Dohme B.V., Netherlands.

Manufacturer's address and location of its business operations.

Waarderweg 39, 2031 BN Haarlem, Netherlands.