Medicine guide

Sitagliptin and Metformin Hydrochloride

100 mg + 1000 mg · Tablet, Film Coated, Extended Release

Prescription only
Biguanide

Active substance: Sitagliptin and Metformin Hydrochloride
Used in: Digestion, stomach, diabetes and nutrition
Made by: Zydus Pharmaceuticals USA Inc.
Source: Official label

Quoted from the official source. Not yet reviewed by Mediclarum — the leaflet in your pack is authoritative.

At a glance

Quoted from the official label · 2024-08-31

What it is

Biguanide

Used for

Sitagliptin and metformin hydrochloride extended-release tablets are indicated as an adjunct to diet and exercise to improve glycemic control in

The label’s usual adult dose

( 2.1 ) The starting dose in patients already treated with metformin should provide sitagliptin dosed as 100 mg and the dose of metformin already being taken once daily.

( 2.1 ) The maximum recommended daily dose is 100 mg of sitagliptin and 2,000 mg of metformin hydrochloride extended-release.

Full directions ↓

Serious warning

LACTIC ACIDOSIS Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias.

All warnings ↓

Good to know

Prescription only
FDA enforcement reports list no ongoing recall, and none from the last two years, for this product code · checked 2026-10-02

36other products contain Sitagliptin and Metformin Hydrochloride — compare makers, forms and strengths

Every line above is selected, not written, from the official label. Nothing is reworded. DailyMed

What it is for

Sitagliptin and metformin hydrochloride extended-release tablets are indicated as an adjunct to diet and exercise to improve glycemic control in
adults with type 2 diabetes mellitus.
Limitations of Use Sitagliptin and metformin hydrochloride extended-release tablets are not recommended in patients with type 1 diabetes mellitus.
Sitagliptin and metformin hydrochloride extended-release tablets have not been studied in patients with a history of pancreatitis.
It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using sitagliptin and metformin hydrochloride extended-release tablets [see Warnings and Precautions ( 5.2 )].
Sitagliptin and metformin hydrochloride extended-release tablets are combination of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and metformin hydrochloride (HCl), a biguanide indicated as an adjunct to diet and exercise to improve glycemic control in
adults with type 2 diabetes mellitus.
( 1 ) Limitations of Use: Not for the treatment of type 1 diabetes mellitus.
( 1 ) Has not been studied in patients with a history of pancreatitis.
( 1 )

From the official label · 2024-08-31 · DailyMed

How it works

From this product’s own US prescribing label.

Sitagliptin and metformin hydrochloride extended-release tablets Sitagliptin and metformin hydrochloride extended-release tablets combine two antihyperglycemic agents: sitagliptin and metformin extended-release.
Sitagliptin Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes mellitus by slowing the inactivation of incretin hormones.

Half-life12.4 h

Mostly cleared after≈ 3 daysfive half-lives — our arithmetic

How the body breaks it down

In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

How it leaves the body

Sitagliptin Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.

With food

Effect of Food After administration of sitagliptin and metformin hydrochloride extended-release tablets with a high-fat breakfast, the AUC for sitagliptin was not altered.

Quoted from the prescribing label, sections “Mechanism of Action” and “Pharmacokinetics”. DailyMed · 2024-08-31

Serious warning

The strongest warning the FDA requires. It is printed in a box at the top of the label.

WARNING:
LACTIC ACIDOSIS Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias.
The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain.
Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio, and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions ( 5.1 )] .
Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information [see Dosage and Administration (2.2), Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), Drug Interactions ( 7 ), and Use in Specific Populations ( 8.6 , 8.7 )] .
If metformin-associated lactic acidosis is suspected, immediately discontinue sitagliptin and metformin hydrochloride extended-release tablets and institute general supportive measures in a hospital setting.
Prompt hemodialysis is recommended [see Warnings and Precautions ( 5.1 )] .
WARNING: LACTIC ACIDOSIS See full prescribing information for complete boxed warning.
Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias.
Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain.
Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio, and metformin plasma levels generally >5 mcg/mL.
( 5.1 ) Risk factors include renal impairment, concomitant use of certain drugs, age ≥65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment.
Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the Full Prescribing Information.
( 5.1 ) If lactic acidosis is suspected, discontinue sitagliptin and metformin hydrochloride extended-release tablets and institute general supportive measures in a hospital setting.
Prompt hemodialysis is recommended.
( 5.1 )

Quoted from the official label, section “Boxed Warning”.

Do not take it if

Sitagliptin and metformin hydrochloride extended-release tablets are contraindicated in patients with:
Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) [see Warnings and Precautions ( 5.1 )] .
Acute or chronic metabolic acidosis, including diabetic ketoacidosis.
A history of a serious hypersensitivity reaction to sitagliptin, metformin, or any of the excipients in sitagliptin and metformin hydrochloride extended-release tablets.
Serious hypersensitivity reactions including anaphylaxis or angioedema have been reported [see Warnings and Precautions ( 5.7 ) and Adverse Reactions ( 6.2 )].
Severe renal impairment: eGFR below 30 mL/min/1.73 m 2 .
( 4 ) Metabolic acidosis, including diabetic ketoacidosis.
( 4 ) History of a serious hypersensitivity reaction to sitagliptin and metformin hydrochloride extended-release tablets, sitagliptin, or metformin, such as anaphylaxis or angioedema) ( 4 )

Quoted from the official label, section “Contraindications”.

How to take it

These directions are for this exact strength and form. Another one is different.

Take sitagliptin and metformin hydrochloride extended-release tablets orally once daily with a meal.
Patients taking two sitagliptin and metformin hydrochloride extended-release tablets should take the tablets together.
( 2.1 ) Individualize the dosage of sitagliptin and metformin hydrochloride extended-release tablets on the basis of the patient's current regimen, effectiveness, and tolerability.
( 2.1 ) The maximum recommended daily dose is 100 mg of sitagliptin and 2,000 mg of metformin hydrochloride extended-release.
( 2.1 ) The recommended starting dose in patients not currently treated with metformin is 100 mg sitagliptin and 1,000 mg metformin hydrochloride once daily, with gradual dose escalation recommended to reduce gastrointestinal side effects associated with metformin.
( 2.1 ) The starting dose in patients already treated with metformin should provide sitagliptin dosed as 100 mg and the dose of metformin already being taken once daily.
For patients taking metformin hydrochloride 850 mg twice daily or 1,000 mg twice daily, the recommended starting dose of sitagliptin and metformin hydrochloride extended-release tablets are two 50 mg sitagliptin and 1,000 mg metformin hydrochloride extended-release tablets once daily.
( 2.1 ) Maintain the same total daily dose of sitagliptin and metformin when changing between sitagliptin and metformin immediate-release or sitagliptin and metformin extended-release and sitagliptin and metformin hydrochloride extended-release tablets.
( 2.1 ) Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) ( 2.2 )
Do not use in patients with eGFR below 30 mL/min/1.73 m 2 .
Sitagliptin and metformin hydrochloride extended-release tablets are not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m 2 .
Limit dose of sitagliptin to 50 mg once daily if eGFR falls below 45 mL/min/1.73 m 2 .
Sitagliptin and metformin hydrochloride extended-release tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures.
( 2.3 )
2.1 Recommended Dosage and Administration Take sitagliptin and metformin hydrochloride extended-release tablets orally once daily with a meal.
Patients taking two sitagliptin and metformin hydrochloride extended-release tablets should take the two tablets together once daily.
Individualize the dosage of sitagliptin and metformin hydrochloride extended-release tablets on the basis of the patient's current regimen, effectiveness, and tolerability.
The maximum recommended daily dose is 100 mg of sitagliptin and 2,000 mg of metformin hydrochloride (HCl) extended-release.
The recommended starting dose in patients not currently treated with metformin is 100 mg sitagliptin and 1,000 mg metformin hydrochloride extended-release once daily, with gradual dose escalation recommended to reduce gastrointestinal side effects associated with metformin.
The starting dose in patients already treated with metformin should provide 100 mg sitagliptin and the previously prescribed dose of metformin.
For patients taking metformin hydrochloride immediate-release 850 mg twice daily or 1,000 mg twice daily, the recommended starting dose of sitagliptin and metformin hydrochloride extended-release tablets are two 50 mg sitagliptin and 1,000 mg metformin hydrochloride extended-release tablets taken together once daily.
Maintain the same total daily dose of sitagliptin and metformin when changing between sitagliptin and metformin hydrochloride immediate-release or sitagliptin and metformin extended-release and sitagliptin and metformin hydrochloride extended-release tablets.
Do not split, crush or chew sitagliptin and metformin hydrochloride extended-release tablets .
2.2 Recommendations for Use in Renal Impairment Assess renal function prior to initiation of sitagliptin and metformin hydrochloride extended-release tablets and periodically thereafter.
Sitagliptin and metformin hydrochloride extended-release tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m 2 [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] .
Initiation of sitagliptin and metformin hydrochloride extended-release tablets in patients with an eGFR between 30 and 45 mL/min/1.73 m 2 is not recommended.
In patients taking sitagliptin and metformin hydrochloride extended-release tablets whose eGFR later falls below 45 mL/min/1.73 m 2 , assess the benefit risk of continuing therapy and limit dose of the sitagliptin component to 50 mg once daily.
2.3 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue sitagliptin and metformin hydrochloride extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m 2 ; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast.
Re-evaluate eGFR 48 hours after the imaging procedure; restart sitagliptin and metformin hydrochloride extended-release tablets if renal function is stable [see Warnings and Precautions ( 5.1 )] .

Quoted from the official label, section “Dosage & Administration”.

Other warnings

Lactic Acidosis: See boxed warning.
( 5.1 ) Pancreatitis:
There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis.
If pancreatitis is suspected, promptly discontinue sitagliptin and metformin hydrochloride extended-release tablets.
( 5.2 ) Heart Failure:
Has been observed with two other members of the DPP-4 inhibitor class.
Consider risks and benefits of sitagliptin and metformin hydrochloride extended-release tablets in patients who have known risk factors for heart failure.
Monitor patients for signs and symptoms.
( 5.3 ) Acute Renal Failure:
Has been reported postmarketing sometimes requiring dialysis.
Before initiating sitagliptin and metformin hydrochloride extended-release tablets and at least annually thereafter, assess renal function.
( 5.4 ) Vitamin B 12 Deficiency: Metformin may lower vitamin B 12 levels.
Measure hematologic parameters annually and vitamin B 12 at 2 to 3 year intervals and manage any abnormalities.
Increased risk of hypoglycemia when used in combination with insulin and/or an insulin secretagogue.
A lower dose of insulin or insulin secretagogue may be required.
( 5.6 ) Hypersensitivity Reactions:
There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with sitagliptin, such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome.
Promptly stop sitagliptin and metformin hydrochloride extended-release tablets, assess for other potential causes, institute appropriate monitoring and treatment.
Has been reported in patients taking DPP-4 inhibitors.
Consider as a possible cause for severe joint pain and discontinue drug if appropriate.
( 5.8 ) Bullous Pemphigoid:
There have been postmarketing reports requiring hospitalization in patients taking DPP-4 inhibitors.
Tell patients to report development of blisters or erosions.
If bullous pemphigoid is suspected, discontinue sitagliptin and metformin hydrochloride extended-release tablets.
( 5.9 )
5.1 Lactic Acidosis There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases.
These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis.
Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate/pyruvate ratio; metformin plasma levels were generally >5 mcg/mL Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.
If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of sitagliptin and metformin hydrochloride extended-release tablets.
In sitagliptin and metformin hydrochloride extended-release tablet-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions).
Hemodialysis has often resulted in reversal of symptoms and recovery.
Educate patients and their families about the symptoms of lactic acidosis, and if these symptoms occur instruct them to discontinue sitagliptin and metformin hydrochloride extended-release tablets and report these symptoms to their health care provider.
For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:
Renal Impairment The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment.
The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney.
Clinical recommendations based upon the patient's renal function include [see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 )] :
Before initiating sitagliptin and metformin hydrochloride extended-release tablets, obtain an estimated glomerular filtration rate (eGFR).
Sitagliptin and metformin hydrochloride extended-release tablets are contraindicated in patients with an eGFR below 30 mL/min/1.73 m 2 [see Contraindications ( 4 )] .
Initiation of sitagliptin and metformin hydrochloride extended-release tablets are not recommended in patients with an eGFR between 30 and less than 45 mL/min/1.73 m 2 In patients taking sitagliptin and metformin hydrochloride extended-release tablets whose eGFR later falls below 45 mL/min/1.73 m 2 , assess the benefit and risk of continuing therapy.
Obtain an eGFR at least annually in all patients taking sitagliptin and metformin hydrochloride extended-release tablets.
In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
Drug Interactions The concomitant use of sitagliptin and metformin hydrochloride extended-release tablets with specific drugs may increase the risk of metformin-associated lactic acidosis:
those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see Drug Interactions ( 7 )].
Therefore, consider more frequent monitoring of patients.
Age 65 or Greater The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients.
Assess renal function more frequently in elderly patients [see Use in Specific Populations ( 8.5 )].
Radiological Studies with Contrast Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis.
Stop sitagliptin and metformin hydrochloride extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m 2 ; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast.
Re-evaluate eGFR 48 hours after the imaging procedure, and restart sitagliptin and metformin hydrochloride extended-release tablets if renal function is stable.
Surgery and Other Procedures Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment.
Sitagliptin and metformin hydrochloride extended-release tablets should be temporarily discontinued while patients have restricted food and fluid intake.
Hypoxic States Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia).
Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia.
When such events occur, discontinue sitagliptin and metformin hydrochloride extended-release tablets.
Excessive Alcohol Intake Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis.
Warn patients against excessive alcohol intake while receiving sitagliptin and metformin hydrochloride extended-release tablets.
Hepatic Impairment Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis.
This may be due to impaired lactate clearance resulting in higher lactate blood levels.
Therefore,
avoid use of sitagliptin and metformin hydrochloride extended-release tablets in patients with clinical or laboratory evidence of hepatic disease.
5.2 Pancreatitis There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking sitagliptin with or without metformin.
After initiation of sitagliptin and metformin hydrochloride extended-release tablets, patients should be observed carefully for signs and symptoms of pancreatitis.
If pancreatitis is suspected, sitagliptin and metformin hydrochloride extended-release tablets should promptly be discontinued and appropriate management should be initiated.
5.3 Heart Failure An association between dipeptidyl peptidase-4 (DPP-4) inhibitor treatment and heart failure has been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class.
These trials evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease.
Consider the risks and benefits of sitagliptin and metformin hydrochloride extended-release tablets prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment, and observe these patients for signs and symptoms of heart failure during therapy.
Advise patients of the characteristic symptoms of heart failure and to immediately report such symptoms.
If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of sitagliptin and metformin hydrochloride extended-release tablets.
5.4 Acute Renal Failure There have been postmarketing reports of worsening renal function in patients taking sitagliptin with or without metformin, including acute renal failure, sometimes requiring dialysis.
Before initiation of therapy with sitagliptin and metformin hydrochloride extended-release tablets and at least annually thereafter, renal function should be assessed.
In patients in whom development of renal dysfunction is anticipated, particularly in elderly patients, renal function should be assessed more frequently and sitagliptin and metformin hydrochloride extended-release tablets discontinued if evidence of renal impairment is present.
Sitagliptin and metformin hydrochloride extended-release tablets is contraindicated in patients with severe renal impairment [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] .
5.5 Vitamin B 12 Deficiency In controlled clinical trials of metformin of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients.
Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation.
Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels.
Measure hematologic parameters on an annual basis and vitamin B 12 measurements at 2- to 3-year intervals in patients on sitagliptin and metformin hydrochloride extended-release tablets and manage any abnormalities [see Adverse Reactions ( 6.1 )] .
5.6 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues Sitagliptin and metformin hydrochloride extended-release tablets may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue (e.g., sulfonylurea) [see Adverse Reactions ( 6 )] .
A lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with sitagliptin and metformin hydrochloride extended-release tablets [see Drug Interactions ( 7 )] .
5.7 Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin, one of the components of sitagliptin and metformin hydrochloride extended-release tablets.
These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome.
Onset of these reactions occurred within the first 3 months after initiation of treatment with sitagliptin, with some reports occurring after the first dose.
If a hypersensitivity reaction is suspected, discontinue sitagliptin and metformin hydrochloride extended-release tablets, assess for other potential causes for the event, and institute alternative treatment for diabetes [see Adverse Reactions ( 6.2 )].
Angioedema has also been reported with other DPP-4 inhibitors Use caution in a patient with a history of angioedema to another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with sitagliptin and metformin hydrochloride extended-release tablets.
5.8 Severe and Disabling Arthralgia There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors.
The time to onset of symptoms following initiation of drug therapy varied from one day to years.
Patients experienced relief of symptoms upon discontinuation of the medication.
A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor.
Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.
5.9 Bullous Pemphigoid Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use.
In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor.
Tell patients to report development of blisters or erosions while receiving sitagliptin and metformin hydrochloride extended-release tablets.
If bullous pemphigoid is suspected, sitagliptin and metformin hydrochloride extended-release tablets should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

Quoted from the official label, section “Warnings”.

Pregnancy and breastfeeding

Risk Summary The limited available data with sitagliptin and metformin hydrochloride extended-release tablets in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage.
Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see Data] .
There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations] .
No adverse developmental effects were observed when sitagliptin was administered to pregnant rats and rabbits during organogenesis at oral doses up to 30-times and 20-times, respectively, the 100 mg clinical dose, based on AUC.
No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during organogenesis at doses up to 2- and 6-times, respectively, a 2,000 mg clinical dose, based on body surface area [see Data] .
The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a hemoglobin A1c (A1c) >7% and has been reported to be as high as 20 to 25% in women with a A1C >10%.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications.
Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity.
Data Human Data Published data from post-marketing studies do not report a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin is used during pregnancy.
However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and inconsistent comparator groups.
Animal Data Sitagliptin and Metformin No animal reproduction studies were conducted with the coadministration of sitagliptin and metformin.
Sitagliptin In embryo-fetal development studies, sitagliptin administered to pregnant rats and rabbits during organogenesis (gestation day 6 to 20) did not adversely affect developmental outcomes at oral doses up to 250 mg/kg (30-times the 100 mg clinical dose) and 125 mg/kg (20-times the 100 mg clinical dose), respectively, based on AUC.
Higher doses in rats associated with maternal toxicity increased the incidence of rib malformations in offspring at 1,000 mg/kg, or approximately 100-times the clinical dose, based on AUC.
Placental transfer of sitagliptin was observed in pregnant rats and rabbits.
Sitagliptin administered to female rats from gestation day 6 to lactation day 21 caused no functional or behavioral toxicity in offspring of rats at doses up to 1,000 mg/kg.
Metformin Metformin did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis.
This represents an exposure of about 2- and 6-times a 2,000 mg clinical dose based on body surface area (mg/m 2 ) for rats and rabbits, respectively.
IN SPECIFIC POPULATIONS Females and Males of Reproductive Potential:
Advise premenopausal females of the potential for an unintended pregnancy.
( 8.3 ) Geriatric Use: Assess renal function more frequently.
( 8.5 ) Hepatic Impairment: Avoid use in patients with hepatic impairment.
( 8.7 )
8.1 Pregnancy Risk Summary The limited available data with sitagliptin and metformin hydrochloride extended-release tablets in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage.
Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see Data] .
There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations] .
No adverse developmental effects were observed when sitagliptin was administered to pregnant rats and rabbits during organogenesis at oral doses up to 30-times and 20-times, respectively, the 100 mg clinical dose, based on AUC.
No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during organogenesis at doses up to 2- and 6-times, respectively, a 2,000 mg clinical dose, based on body surface area [see Data] .
The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a hemoglobin A1c (A1c) >7% and has been reported to be as high as 20 to 25% in women with a A1C >10%.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications.
Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity.
Data Human Data Published data from post-marketing studies do not report a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin is used during pregnancy.
However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and inconsistent comparator groups.
Animal Data Sitagliptin and Metformin No animal reproduction studies were conducted with the coadministration of sitagliptin and metformin.
Sitagliptin In embryo-fetal development studies, sitagliptin administered to pregnant rats and rabbits during organogenesis (gestation day 6 to 20) did not adversely affect developmental outcomes at oral doses up to 250 mg/kg (30-times the 100 mg clinical dose) and 125 mg/kg (20-times the 100 mg clinical dose), respectively, based on AUC.
Higher doses in rats associated with maternal toxicity increased the incidence of rib malformations in offspring at 1,000 mg/kg, or approximately 100-times the clinical dose, based on AUC.
Placental transfer of sitagliptin was observed in pregnant rats and rabbits.
Sitagliptin administered to female rats from gestation day 6 to lactation day 21 caused no functional or behavioral toxicity in offspring of rats at doses up to 1,000 mg/kg.
Metformin Metformin did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis.
This represents an exposure of about 2- and 6-times a 2,000 mg clinical dose based on body surface area (mg/m 2 ) for rats and rabbits, respectively.
8.2 Lactation Risk Summary There is no information regarding the presence of sitagliptin and metformin hydrochloride in human milk, the effects on the breastfed infant, or the effects on milk production.
Limited published studies report that metformin is present in human milk [see Data] .
There are no reports of adverse effects on breastfed infants exposed to metformin.
There is no information on the effects of metformin on milk production.
Sitagliptin is present in rat milk and therefore possibly present in human milk [see Data] .
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for sitagliptin and metformin hydrochloride and any potential adverse effects on the breastfed infant from sitagliptin and metformin hydrochloride or from the underlying maternal condition.
Data Sitagliptin Sitagliptin is secreted in the milk of lactating rats at a milk to plasma ratio of 4:1.
Metformin Published clinical lactation studies report that metformin is present in human milk, which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1.
However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants.
8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women.
8.4 Pediatric Use The safety and effectiveness of sitagliptin and metformin hydrochloride extended-release tablets have not been established in pediatric patients.
Three 20-week double-blind, placebo-controlled studies each with 34-week extensions were conducted to evaluate the efficacy and safety of sitagliptin in 410 pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes mellitus, with or without insulin therapy (HbA1c 6.5 to 10% for patients not on insulin, HbA1c 7 to 10% for patients on insulin).
At study entry, patients in study 1 were not treated with oral antihyperglycemic agents; patients in studies 2 and 3 were on maximally tolerated metformin therapy.
The primary efficacy endpoint was the change from baseline in HbA1c after 20 weeks of therapy.
The pre-specified primary efficacy analyses included data from study 1 and pooled data from studies 2 and 3, regardless of glycemic rescue or treatment discontinuation.
In both efficacy analyses, the effect of treatment with sitagliptin was not significantly different from placebo.
In study 1, the mean baseline HbA1c was 7.5%, and 12% of patients were on insulin therapy.
At week 20, the change from baseline in HbA1c in patients treated with sitagliptin (N=95) was 0.06% compared to 0.23% in patients treated with placebo (N=95), a difference of -0.17% (95% CI:
-0.62, 0.28).
In studies 2 and 3, the mean baseline HbA1c was 8%, 15% of patients were on insulin and 72% were on metformin hydrochloride doses of greater than 1,500 mg daily.
At week 20, the change from baseline in HbA1c in patients treated with sitagliptin (N=107) was -0.23% compared to 0.09% in patients treated with placebo (N=113), a difference of -0.33% (95% CI:
-0.70, 0.05).
8.5 Geriatric Use Sitagliptin and metformin hydrochloride extended-release tablets In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy and the higher risk of lactic acidosis.
Renal function should be assessed more frequently in elderly patients [see Contraindications (4), Warnings and Precautions (5.1, 5.4) and;
Clinical Pharmacology (12.3)].
Sitagliptin Of the total number of subjects (N=3,884) in clinical studies of sitagliptin, 725 patients were 65 years and over, while 61 patients were 75 years and over.
No overall differences in safety or effectiveness of sitagliptin have been observed between subjects 65 years and over and younger.
Metformin Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients.
8.6 Renal Impairment Sitagliptin and metformin hydrochloride extended-release tablets The dose of the sitagliptin component should be limited to 50 mg once daily if eGFR falls below 45 mL/min/1.73 m 2 .
Sitagliptin and metformin hydrochloride extended-release tablets is contraindicated in severe renal impairment, patients with an eGFR below 30 mL/min/1.73 m 2 [see Dosage and Administration ( 2.2 ), Contraindications ( 4 ), Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 )].
Sitagliptin Sitagliptin is excreted by the kidney, and sitagliptin exposure is increased in patients with renal impairment [see Clinical Pharmacology ( 12.3 )].
Metformin Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment.
8.7 Hepatic Impairment Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis.
Sitagliptin and metformin hydrochloride extended-release tablets are not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1)].

Quoted from the official label, section “OTC — Pregnancy or Breast Feeding”.

Other medicines

Table 4 presents clinically significant drug interactions with sitagliptin and metformin hydrochloride extended-release tablets:
Table 4 Clinically Significant Drug Interactions with Sitagliptin and Metformin Hydrochloride Extended-Release Tablets Carbonic Anhydrase Inhibitors Clinical Impact:
Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis.
Concomitant use of these drugs with sitagliptin and metformin hydrochloride extended-release tablets may increase the risk for lactic acidosis.
Intervention: Consider more frequent monitoring of these patients.
Examples: Topiramate, zonisamide, acetazolamide or dichlorphenamide.
Drugs that Reduce Metformin Clearance Clinical Impact:
Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT 2 ] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology ( 12.3 )] .
Intervention:
Consider the benefits and risks of concomitant use with sitagliptin and metformin hydrochloride extended-release tablets.
Examples: Ranolazine, vandetanib, dolutegravir, and cimetidine.
Alcohol Clinical Impact:
Alcohol is known to potentiate the effect of metformin on lactate metabolism.
Intervention:
Warn patients against alcohol intake while receiving sitagliptin and metformin hydrochloride extended-release tablets.
Insulin Secretagogues or Insulin Clinical Impact:
Coadministration of sitagliptin and metformin hydrochloride extended-release tablets with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia.
Intervention:
Patients receiving an insulin secretagogue or insulin may require lower doses of the insulin secretagogue or insulin.
Drugs Affecting Glycemic Control Clinical Impact:
Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control.
Intervention:
When such drugs are administered to a patient receiving sitagliptin and metformin hydrochloride extended-release tablets, observe the patient closely for loss of blood glucose control.
When such drugs are withdrawn from a patient receiving sitagliptin and metformin hydrochloride extended-release tablets, observe the patient closely for hypoglycemia.
Examples:
Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid.
Carbonic anhydrase inhibitors may increase risk of lactic acidosis.
Consider more frequent monitoring.
( 7 ) Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the accumulation of metformin.
Consider the benefits and risks of concomitant use.
( 7 ) Alcohol can potentiate the effect of metformin on lactate metabolism.
Warn patients against excessive alcohol intake.
( 7 )

Quoted from the official label, section “Drug Interactions”.

If you take too much

In an emergency, call your local emergency number or a poison control centre.

In the event of overdose with sitagliptin and metformin hydrochloride extended-release tablets, consider contacting the Poison Help Line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.
Employ supportive measures dictated by the patient's clinical status.
Per clinical judgement, consider removal of unabsorbed material from the gastrointestinal tract, and clinical monitoring (including obtaining an ECG).
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.
Overdose of metformin has occurred, including ingestion of amounts greater than 50 grams.
Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established.
Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.1)] .
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.

Quoted from the official label, section “Overdosage”.

Use in children

The safety and effectiveness of sitagliptin and metformin hydrochloride extended-release tablets have not been established in pediatric patients.
Three 20-week double-blind, placebo-controlled studies each with 34-week extensions were conducted to evaluate the efficacy and safety of sitagliptin in 410 pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes mellitus, with or without insulin therapy (HbA1c 6.5 to 10% for patients not on insulin, HbA1c 7 to 10% for patients on insulin).
At study entry, patients in study 1 were not treated with oral antihyperglycemic agents; patients in studies 2 and 3 were on maximally tolerated metformin therapy.
The primary efficacy endpoint was the change from baseline in HbA1c after 20 weeks of therapy.
The pre-specified primary efficacy analyses included data from study 1 and pooled data from studies 2 and 3, regardless of glycemic rescue or treatment discontinuation.
In both efficacy analyses, the effect of treatment with sitagliptin was not significantly different from placebo.
In study 1, the mean baseline HbA1c was 7.5%, and 12% of patients were on insulin therapy.
At week 20, the change from baseline in HbA1c in patients treated with sitagliptin (N=95) was 0.06% compared to 0.23% in patients treated with placebo (N=95), a difference of -0.17% (95% CI:
-0.62, 0.28).
In studies 2 and 3, the mean baseline HbA1c was 8%, 15% of patients were on insulin and 72% were on metformin hydrochloride doses of greater than 1,500 mg daily.
At week 20, the change from baseline in HbA1c in patients treated with sitagliptin (N=107) was -0.23% compared to 0.09% in patients treated with placebo (N=113), a difference of -0.33% (95% CI:
-0.70, 0.05).

Quoted from the official label, section “Pediatric Use”.

Use in older people

Sitagliptin and metformin hydrochloride extended-release tablets In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy and the higher risk of lactic acidosis.
Renal function should be assessed more frequently in elderly patients [see Contraindications (4), Warnings and Precautions (5.1, 5.4) and;
Clinical Pharmacology (12.3)].
Sitagliptin Of the total number of subjects (N=3,884) in clinical studies of sitagliptin, 725 patients were 65 years and over, while 61 patients were 75 years and over.
No overall differences in safety or effectiveness of sitagliptin have been observed between subjects 65 years and over and younger.
Metformin Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients.

Quoted from the official label, section “Geriatric Use”.

Side effects

The following adverse reactions are also discussed elsewhere in the prescribing information:
Lactic Acidosis [see Warnings and Precautions ( 5.1 )] Pancreatitis [see Warnings and Precautions ( 5.2 )] Heart Failure [see Warnings and Precautions ( 5.3 )] Acute Renal Failure [see Warnings and Precautions ( 5.4 )] Vitamin B 12 Deficiency [see Warnings and Precautions ( 5.5 )] Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions ( 5.6 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.7 )] Severe and Disabling Arthralgia [see Warnings and Precautions ( 5.8 )] Bullous Pemphigoid [see Warnings and Precautions ( 5.9 )] Most common adverse reactions (incidence ≥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.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Common Adverse Reactions Sitagliptin and Metformin Immediate-Release Coadministration in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Diet and Exercise Table 1 summarizes the most common (≥5% of patients) adverse reactions reported in a 24-week placebo-controlled factorial trial in which sitagliptin and metformin immediate-release were coadministered to patients with type 2 diabetes mellitus inadequately controlled on diet and exercise.
Table 1 Sitagliptin and Metformin Immediate-Release Coadministered to Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Diet and Exercise:
Adverse Reactions Reported in ≥5% of Patients Receiving Combination Therapy (and Greater than in Patients Receiving Placebo) * * Intent-to-treat population. † Data pooled for the patients given the lower and higher doses of metformin.
Number of Patients (%) Placebo Sitagliptin 100 mg once daily Metformin hydrochloride Immediate-Release 500 mg or 1,000 mg twice daily † Sitagliptin 50 mg twice daily + Metformin hydrochloride Immediate-Release 500 mg or 1,000 mg twice daily † N = 176 N = 179 N = 364 † N = 372 † Diarrhea 7 (4) 5 (2.8) 28 (7.7) 28 (7.5) Upper Respiratory Tract Infection 9 (5.1) 8 (4.5) 19 (5.2) 23 (6.2) Headache 5 (2.8) 2 (1.1) 14 (3.8) 22 (5.9) Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin Immediate-Release Alone In a 24-week placebo-controlled trial of sitagliptin 100 mg administered once daily added to a twice daily metformin immediate-release regimen, there were no adverse reactions reported in ≥5% of patients and more commonly than in patients given placebo.
Discontinuation of therapy due to clinical adverse reactions was similar to the placebo treatment group (sitagliptin and metformin immediate-release, 1.9%; placebo and metformin immediate-release, 2.5%).
Gastrointestinal Adverse Reactions The incidences of pre-selected gastrointestinal adverse experiences in patients treated with sitagliptin and metformin immediate-release were similar to those reported for patients treated with metformin immediate-release alone.
See Table 2.
Table 2 Pre-selected Gastrointestinal Adverse Reactions Reported in Patients with Type 2 Diabetes Mellitus Receiving Sitagliptin and Metformin Immediate-Release * Data pooled for the patients given the lower and higher doses of metformin. † Abdominal discomfort was included in the analysis of abdominal pain in the trial of initial therapy.
Number of Patients (%) Trial of Sitagliptin and Metformin Immediate-Release in Patients Inadequately Controlled on Diet and Exercise Trial of Sitagliptin Add-on in Patients Inadequately Controlled on Metformin Immediate-Release Alone Placebo Sitagliptin 100 mg once daily Metformin hydrochloride Immediate-Release 500 mg or 1,000 mg twice daily * Sitagliptin 50 mg twice daily + Metformin hydrochloride Immediate-Release 500 mg or 1,000 mg twice daily * Placebo and Metformin hydrochloride Immediate- Release ≥1,500 mg daily Sitagliptin 100 mg once daily and Metformin hydrochloride Immediate- Release ≥1,500 mg daily N = 176 N = 179 N = 364 N = 372 N = 237 N = 464 Diarrhea 7 (4) 5 (2.8) 28 (7.7) 28 (7.5) 6 (2.5) 11 (2.4) Nausea 2 (1.1) 2 (1.1) 20 (5.5) 18 (4.8) 2 (0.8) 6 (1.3) Vomiting 1 (0.6) 0 (0) 2 (0.5) 8 (2.2) 2 (0.8) 5 (1.1) Abdominal Pain † 4 (2.3) 6 (3.4) 14 (3.8) 11 (3) 9 (3.8) 10 (2.2) Sitagliptin in Combination with Metformin Immediate-Release and Glimepiride In a 24-week placebo-controlled trial of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes mellitus inadequately controlled on metformin immediate-release and glimepiride (sitagliptin, N=116; placebo, N=113), the adverse reactions reported in ≥ 5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were:
hypoglycemia (Table 3) and headache (6.9%, 2.7%).
Sitagliptin in Combination with Metformin Immediate-Release and Rosiglitazone In a placebo-controlled trial of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes mellitus inadequately controlled on metformin immediate-release and rosiglitazone (sitagliptin, N=181; placebo, N=97), the adverse reactions reported through Week 18 in ≥ 5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were:
upper respiratory tract infection (sitagliptin, 5.5%; placebo, 5.2%) and nasopharyngitis (6.1%, 4.1%).
Through Week 54, the adverse reactions reported in ≥ 5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were:
upper respiratory tract infection (sitagliptin, 15.5%; placebo, 6.2%), nasopharyngitis (11%, 9.3%), peripheral edema (8.3%, 5.2%), and headache (5.5%, 4.1%).
Sitagliptin in Combination with Metformin Immediate-Release and Insulin In a 24-week placebo-controlled trial of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes mellitus inadequately controlled on metformin immediate-release and insulin (sitagliptin, N=229; placebo, N=233), the only adverse reaction reported regardless of investigator assessment of causality in ≥ 5% of patients treated with sitagliptin and more commonly than in patients treated with placebo was hypoglycemia (Table 3).
Hypoglycemia In the above trials (N=5), adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required although most (77%) reports of hypoglycemia were accompanied by a blood glucose measurement ≤70 mg/dL.
When the combination of sitagliptin and metformin immediate-release was coadministered with a sulfonylurea or with insulin, the percentage of patients reporting at least one adverse reaction of hypoglycemia was higher than that observed with placebo and metformin immediate-release coadministered with a sulfonylurea or with insulin (Table 3).
Table 3 Incidence and Rate of Hypoglycemia * in Placebo-Controlled Clinical Trials of Sitagliptin in Combination with Metformin Immediate-Release Coadministered with Glimepiride or Insulin * Adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required:
Intent-to-treat population. † Based on total number of events (i.e., a single patient may have had multiple events). ‡ Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level/loss of consciousness or seizure.
Add-On to Glimepiride + Metformin Immediate-Release (24 weeks) Sitagliptin 100 mg + Metformin Immediate-Release + Glimepiride Placebo + Metformin Immediate-Release + Glimepiride N = 116 N = 113 Overall (%) 19 (16.4) 1 (0.9) Rate (episodes/patient-year) † 0.82
0.02 Severe (%) ‡ 0 (0) 0 (0) Add-On to Insulin + Metformin Immediate-Release (24 weeks) Sitagliptin 100 mg + Metformin Immediate-Release + Insulin Placebo + Metformin Immediate-Release + Insulin N = 229 N = 233 Overall (%) 35 (15.3) 19 (8.2) Rate (episodes/patient-year) † 0.98
0.61 Severe (%) ‡ 1 (0.4) 1 (0.4) The overall incidence of reported adverse reactions of hypoglycemia in patients with type 2 diabetes mellitus inadequately controlled on diet and exercise was 0.6% in patients given placebo, 0.6% in patients given sitagliptin alone, 0.8% in patients given metformin immediate-release alone, and 1.6% in patients given sitagliptin in combination with metformin immediate-release.
In patients with type 2 diabetes mellitus inadequately controlled on metformin immediate-release alone, the overall incidence of adverse reactions of hypoglycemia was 1.3% in patients given add-on sitagliptin and 2.1% in patients given add-on placebo.
In the trial of sitagliptin and add-on combination therapy with metformin immediate-release and rosiglitazone, the overall incidence of hypoglycemia was 2.2% in patients given add-on sitagliptin and 0% in patients given add-on placebo through Week 18.
Through Week 54, the overall incidence of hypoglycemia was 3.9% in patients given add-on sitagliptin and 1% in patients given add-on placebo.
In an additional 30-week placebo-controlled trial of patients with type 2 diabetes mellitus inadequately controlled with metformin comparing the maintenance of sitagliptin 100 mg versus withdrawal of sitagliptin when initiating basal insulin therapy, the event rate and incidence of documented symptomatic hypoglycemia (blood glucose measurement ≤70 mg/dL) did not differ between the sitagliptin and placebo groups.
Vital Signs and Electrocardiograms With the combination of sitagliptin and metformin immediate-release, no clinically meaningful changes in vital signs or in electrocardiogram parameters (ECG) (including the QTc interval) were observed.
Pancreatitis In a pooled analysis of 19 double-blind clinical trials that included data from 10,246 patients randomized to receive sitagliptin 100 mg/day (N=5,429) or corresponding (active or placebo) control (N=4,817), the incidence of acute pancreatitis was 0.1 per 100 patient-years in each group (4 patients with an event in 4,708 patient-years for sitagliptin and 4 patients with an event in 3,942 patient-years for control).
Sitagliptin The most common adverse experience in sitagliptin monotherapy reported in ≥5% of patients and more commonly than in patients given placebo was nasopharyngitis.
Metformin Extended-Release In a 24-week clinical trial in which extended-release metformin or placebo was added to glyburide therapy, the most common (>5% and greater than placebo) adverse reactions in the combined treatment group were hypoglycemia (13.7% vs. 4.9%), diarrhea (12.5% vs. 5.6%), and nausea (6.7% vs. 4.2%).
Laboratory Tests Sitagliptin The incidence of laboratory adverse reactions was similar in patients treated with sitagliptin and metformin immediate-release (7.6%) compared to patients treated with placebo and metformin (8.7%).
In most but not all trials, a small increase in white blood cell count (approximately 200 cells/microL difference in WBC vs. placebo; mean baseline WBC approximately 6,600 cells/microL) was observed due to a small increase in neutrophils.
This change in laboratory parameters is not considered to be clinically relevant.
Metformin In controlled clinical trials of metformin of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels, without clinical manifestations, was observed in approximately 7% of patients.
6.2 Postmarketing Experience Additional adverse reactions have been identified during postapproval use of sitagliptin with metformin, sitagliptin, or metformin.
Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Skin and subcutaneous tissue disorders:
hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, bullous pemphigoid, and exfoliative skin conditions including Stevens-Johnson syndrome Respiratory, thoracic and mediastinal disorders:
upper respiratory tract infection Hepatobiliary disorders:
hepatic enzyme elevations; cholestatic, hepatocellular, and mixed hepatocellular liver injury Gastrointestinal disorders:
acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis, constipation, vomiting, mouth ulceration, stomatitis Renal and urinary disorders :
worsening renal function, including acute renal failure (sometimes requiring dialysis) and tubulointerstitial nephritis Musculoskeletal and connective tissue disorders:
severe and disabling arthralgia, myalgia, pain in extremity, back pain, pruritus, rhabdomyolysis Nervous system disorders:
headache.

Quoted from the official label, section “Adverse Reactions”.

What to discuss with your doctor

Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Lactic Acidosis Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its development.
Advise patients to discontinue sitagliptin and metformin hydrochloride extended-release tablets immediately and to promptly notify their healthcare provider if unexplained hyperventilation, myalgias, malaise, unusual somnolence or other nonspecific symptoms occur.
Counsel patients against excessive alcohol intake and inform patients about the importance of regular testing of renal function while receiving sitagliptin and metformin hydrochloride extended-release tablets.
Instruct patients to inform their doctor that they are taking sitagliptin and metformin hydrochloride extended-release tablets prior to any surgical or radiological procedure, as temporary discontinuation may be required [see Warnings and Precautions ( 5.1 )].
Pancreatitis Inform patients that acute pancreatitis has been reported during postmarketing use of sitagliptin and metformin hydrochloride extended-release tablets.
Inform patients that persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis.
Instruct patients to promptly discontinue sitagliptin and metformin hydrochloride extended-release tablets and contact their physician if persistent severe abdominal pain occurs [see Warnings and Precautions ( 5.2 )].
Heart Failure Inform patients of the signs and symptoms of heart failure.
Before initiating sitagliptin and metformin hydrochloride extended-release tablets, ask patients about a history of heart failure or other risk factors for heart failure including moderate to severe renal impairment.
Instruct patients to contact their health care provider as soon as possible if they experience symptoms of heart failure, including increasing shortness of breath, rapid increase in weight or swelling of the feet [see Warnings and Precautions ( 5.3 )].
Vitamin B 12 Deficiency Inform patients about the importance of regular monitoring of hematological parameters while receiving sitagliptin and metformin hydrochloride extended-release tablets [see Warnings and Precautions ( 5.5 )].
Hypoglycemia Inform patients that the incidence of hypoglycemia is increased when sitagliptin and metformin hydrochloride extended-release tablets is added to an insulin secretagogue (e.g., sulfonylurea) or insulin therapy.
Explain to patients receiving sitagliptin and metformin hydrochloride extended-release tablets in combination with these medications the risks of hypoglycemia, its symptoms and treatment and conditions that predispose to its development [see Warnings and Precautions ( 5.6 )].
Hypersensitivity Reactions Inform patients that allergic reactions have been reported during postmarketing use of sitagliptin, one of the components of sitagliptin and metformin hydrochloride extended-release tablets.
If symptoms of allergic reactions (including rash, hives, and swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing) occur, patients must stop taking sitagliptin and metformin hydrochloride extended-release tablets and seek medical advice promptly.
Severe and Disabling Arthralgia Inform patients that severe and disabling joint pain may occur with this class of drugs.
The time to onset of symptoms can range from one day to years.
Instruct patients to seek medical advice if severe joint pain occurs [see Warnings and Precautions ( 5.8 )] .
Bullous Pemphigoid Inform patients that bullous pemphigoid may occur with this class of drugs.
Instruct patients to seek medical advice if blisters or erosions occur [see Warnings and Precautions ( 5.9 )].
Administration Instructions Inform patients that the tablets must be swallowed whole and never split, crushed or chewed.
Incompletely Dissolved Tablets in Feces Inform patients that incompletely dissolved sitagliptin and metformin hydrochloride extended-release tablets may be eliminated in the feces.
Tell patients that, if they repeatedly see tablets in feces, they should report this finding to their health care provider.
Assess adequacy of glycemic control if a patient reports repeatedly observing tablets in feces.
Females of Reproductive Age:
Inform females that treatment with sitagliptin and metformin hydrochloride extended-release tablets may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy [see Use in Specific Populations ( 8.3 )] .
Medication Guide available at www.zydususa.com/medguides or call 1-877-993-8779.
The trademarks depicted herein are owned by their respective companies.

Quoted from the official label, section “Patient Counseling Information”.

Strengths and forms

FORMS AND STRENGTHS Tablets:
Sitagliptin 100 mg and metformin hydrochloride 1,000 mg extended-release tablets are reddish brown to brown colored, oval shaped, film-coated tablets debossed with "1806" on one side and plain on the other side.
Sitagliptin 50 mg and metformin hydrochloride 500 mg extended-release tablets are light orange to beige colored, oval shaped, film-coated tablets debossed with "1804" on one side and plain on the other side.
Sitagliptin 50 mg and metformin hydrochloride 1,000 mg extended-release tablets are yellow to beige colored, oval shaped, film-coated tablets debossed with "1805" on one side and plain on the other side.
Sitagliptin and metformin hydrochloride extended-release Tablets:
sitagliptin 100 mg and metformin hydrochloride 1,000 mg extended-release sitagliptin 50 mg and metformin hydrochloride 500 mg extended-release sitagliptin 50 mg and metformin hydrochloride 1,000 mg extended-release ( 3 )

Quoted from the official label, section “Dosage Forms & Strengths”.

What it looks like and how it is packed

Tablets supplied as follows:
Contents Description How Supplied NDC 50 mg sitagliptin and 500 mg metformin hydrochloride extended-release tablets Light orange to beige colored, oval shaped, film-coated tablets debossed with "1804" on one side and plain on the other side.
Bottles of 60 tablets with child-resistant closure NDC 70710-2036-6 50 mg sitagliptin and 1,000 mg metformin hydrochloride extended-release tablets Yellow to beige colored, oval shaped, film-coated tablets debossed with "1805" on one side and plain on the other side.
Bottles of 60 tablets with child-resistant closure NDC 70710-2037-6 100 mg sitagliptin and 1,000 mg metformin hydrochloride extended-release tablets Reddish brown to brown colored, oval shaped, film-coated tablets debossed with "1806" on one side and plain on the other side.
Bottles of 30 tablets with child-resistant closure NDC 70710-2038-3
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Store in a dry place with cap tightly closed.
Keep sitagliptin and metformin hydrochloride extended-release tablets in the original container to protect it from moisture.
Use sitagliptin and metformin hydrochloride extended-release tablets within 1 month of opening the bottle.

Quoted from the official label, section “How Supplied”.

What is in it

Sitagliptin and metformin hydrochloride extended-release tablets for oral use contain two antihyperglycemic medications:
sitagliptin and metformin hydrochloride. Sitagliptin Sitagliptin is an orally-active inhibitor of the DPP-4 enzyme. Sitagliptin free base drug substance is used to manufacture sitagliptin and metformin hydrochloride extended-release tablets. Sitagliptin free base is described chemically as 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-α]pyrazine with an empirical formula of C 16 H 15 F 6 N 5 O and a molecular weight of 407.31. The structural formula is:
Sitagliptin free base is a white to off-white, non-hygroscopic powder. It is soluble in methanol and slightly soluble in water. Metformin hydrochloride Metformin hydrochloride ( N , N -dimethylimidodicarbonimidic diamide hydrochloride) is a white crystalline powder with a molecular formula of C 4 H 11 N 5
HCl and a molecular weight of 165.62. Metformin hydrochloride is freely soluble in water, slightly soluble in ethanol (95%), practically insoluble in acetone and in methylene chloride. The pK a of metformin hydrochloride is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula is as shown:
Sitagliptin and metformin hydrochloride extended-release tablets Sitagliptin and metformin hydrochloride extended-release tablets are available as film-coated tablets containing:
50 mg sitagliptin and 389.93 mg of metformin equivalent to 500 mg metformin hydrochloride (sitagliptin and metformin hydrochloride extended-release tablets 50/500). 50 mg sitagliptin and 779.86 mg of metformin equivalent to 1,000 mg metformin hydrochloride (sitagliptin and metformin hydrochloride extended-release tablets 50/1,000). 100 mg sitagliptin and 779.86 mg of metformin equivalent to 1,000 mg metformin hydrochloride (sitagliptin and metformin hydrochloride extended-release tablets 100/1,000). All doses of sitagliptin and metformin hydrochloride extended-release tablets contain the following inactive ingredients:
colloidal silicon dioxide, croscarmellose sodium, dibasic calcium phosphate anhydrous, ferric oxide yellow, hypromellose, magnesium stearate, malic acid, microcrystalline cellulose, povidone, pregelatinized starch (maize) and sodium stearyl fumarate. In addition, the film-coating for all doses contains the following inactive ingredients:
polyethylene glycol, polyvinyl alcohol-partially hydrolyzed, iron oxide yellow, talc and titanium dioxide. Additionally, sitagliptin and metformin hydrochloride extended-release tablets 50 mg/500 mg and 100 mg/1,000 mg tablets film-coating contain the inactive ingredient red iron oxide and 50 mg/1,000 mg and 100 mg/1,000 mg tablets film-coating contain the FD&C yellow#6 Aluminum Lake. Image Image

Quoted from the official label, section “Description”.

Ingredients people check for

Lactose, gluten, dyes, sugars and other ingredients that matter with an allergy, intolerance or diet — as this product’s FDA label lists them.

This label’s list of inactive ingredients names none of: lactose, wheat or gluten, colour dyes, sugars, sugar alcohols, alcohol (ethanol), aspartame (phenylalanine), gelatin, peanut oil, soy, parabens, sulfites, titanium dioxide.

Quoted from the FDA label. A label that does not name an ingredient is not a guarantee that the product is free of it, and formulations change. With an allergy, check the pack and ask a pharmacist.

Every version of this medicine (6)

The same active substance, strength and kind of form, from every company that sells it — with what each label lists.

Showing 6 of 6

Same active substance, strength and form in other countries

Matched on active substance, strength and kind of form only. This is not a statement that the products are equivalent or interchangeable: other ingredients, release and approved uses can differ — ask a pharmacist before swapping.

Medicine passport: one printable page to show a pharmacist abroad

European UnionNo exact match for this strength and form

Every strength and form (7)

Details

Made by	Zydus Pharmaceuticals USA Inc.
Active substance	Sitagliptin and Metformin Hydrochloride
Used in	Digestion, stomach, diabetes and nutrition
Strength	100 mg + 1000 mg
Form	Tablet, Film Coated, Extended Release
Route	Oral
Packs	30 TABLET, FILM COATED, EXTENDED RELEASE in 1 BOTTLE
NDC	70710-2038

Source: NDC Directory · 2026-09-13 · not reviewed by a clinician

Source: US Food and Drug Administration, NDC Directory. Reuse terms: US government work (FDA).

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Other strengths and forms

19 products are sold under this name. Grouped by form; a number on a strength means several companies make it.

Tablet, Film Coated10 products
- 50 mg + 500 mg5
  50 mg + 500 mg · 5 companies
- 50 mg + 1000 mg5
  50 mg + 1000 mg · 5 companies
Tablet, Film Coated, Extended Release9 products
- 50 mg + 500 mg3
  50 mg + 500 mg · 3 companies
- 50 mg + 1000 mg3
  50 mg + 1000 mg · 3 companies
- 100 mg + 1000 mg3
  100 mg + 1000 mg · 3 companies
  - Par Health USA, LLC
  - Zydus Lifesciences Limited
  - Zydus Pharmaceuticals USA Inc. · this page

Same active substance

These contain the same substance. That does not mean one can replace another — ask a pharmacist.

Janumet50 mg + 500 mgPrescription onlyTablet, Film Coated Merck Sharp & Dohme LLC · Sitagliptin and Metformin Hydrochloride Janumet50 mg + 1000 mgPrescription onlyTablet, Film Coated Merck Sharp & Dohme LLC · Sitagliptin and Metformin Hydrochloride Janumet50 mg + 1000 mgPrescription onlyTablet, Film Coated A-S Medication Solutions · Sitagliptin and Metformin Hydrochloride Janumet50 mg + 500 mgPrescription onlyTablet, Film Coated A-S Medication Solutions · Sitagliptin and Metformin Hydrochloride Janumet Xr50 mg + 500 mgPrescription onlyTablet, Film Coated, Extended Release Merck Sharp & Dohme LLC · Sitagliptin and Metformin Hydrochloride Janumet Xr50 mg + 1000 mgPrescription onlyTablet, Film Coated, Extended Release Merck Sharp & Dohme LLC · Sitagliptin and Metformin Hydrochloride

See every product with Sitagliptin and Metformin Hydrochloride