metformin/sitagliptin (Rx)

Brand and Other Names:Janumet, Janumet XR
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

metformin/sitagliptin

tablet

  • 500mg/50mg
  • 1,000mg/50mg

tablet, extended-release

  • 500mg/50mg
  • 1,000mg/50mg
  • 1,000mg/100mg

Type 2 Diabetes Mellitus

Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM)

Adjust dose gradually considering effectiveness and tolerability

Not currently treated with metformin

  • Immediate-release: 50 mg sitagliptin/500 mg metformin PO BID
  • Extended-release: 100 mg sitagliptin/1000 mg metformin PO qDay
  • Gradually escalate dose to reduce gastrointestinal side effects associated with metformin
  • Not to exceed daily dose of 2,000 mg of metformin or 100 mg of sitagliptin

Currently treated with metformin

  • Immediate-release
    • Sitagliptin 50 mg PO BID (100 mg/day) and current daily dose of metformin
    • For patients taking metformin HCl 850 mg BID, recommended starting dose is 50 mg sitagliptin/1000 mg metformin HCl PO BID
  • Extended-release
    • Sitagliptin 100 mg and current daily dose of metformin
    • For patients taking metformin HCl immediate-release 850 mg or 1000 mg PO BID, recommended starting dose 100 mg sitagliptin/1000 mg metformin
    • Not to exceed daily dose of 2,000 mg of metformin or 100 mg of sitagliptin

Dosage Modifications

Hepatic impairment: Not recommended

Renal impairment

  • eGFR 30-45 mL/min/1.73 m2: Not recommended
  • eGFR <30 mL/min/1.73 m2: Contraindicated
  • Extended-release only
    • If eGFR falls 30-45 mL/min/1.73 m2 during treatment, evaluate risks and benefits of continuing therapy, limit dose of sitagliptin component to 50 mg/day
    • If eGFR falls <30 mL/min/1.73 m2 during treatment, discontinue drug

Iodinated contrast imaging procedures

  • Discontinue at time of, or before, an iodinated contrast imaging procedure in patients with an eGFR 30-60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast
  • Reevaluate eGFR 48 hr after imaging procedure; restart if renal function is stable

<18 years: Safety and efficacy not established

Three double-blind, placebo-controlled studies evaluated the efficacy and safety of sitagliptin in patients (n=410) aged 10-17 years with uncontrolled T2DM, with or without insulin therapy; results showed effects of patients treated with sitagliptin were not significantly different from placebo

Type 2 Diabetes Mellitus

Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM)

Initial and maintenance dosing should be conservative due to possibility of decreased renal function

Adjust dose gradually and conservatively considering effectiveness and tolerability

Not currently treated with metformin

  • Immediate-release: 50 mg sitagliptin/500 mg metformin PO BID
  • Extended-release: 100 mg sitagliptin/1000 mg metformin PO qDay
  • Gradually escalate dose to reduce gastrointestinal side effects associated with metformin
  • Not to exceed daily dose of 2,000 mg of metformin or 100 mg of sitagliptin

Currently treated with metformin

  • Immediate-release
    • Sitagliptin 50 mg PO BID (100 mg/day) and current daily dose of metformin
    • For patients taking metformin HCl 850 mg BID, recommended starting dose is 50 mg sitagliptin/1000 mg metformin HCl PO BID
  • Extended-release
    • Sitagliptin 100 mg and current daily dose of metformin
    • For patients taking metformin HCl immediate-release 850 mg or 1000 mg PO BID, recommended starting dose 100 mg sitagliptin/1000 mg metformin
    • Not to exceed daily dose of 2,000 mg of metformin or 100 mg of sitagliptin

Dosage Modifications

Hepatic impairment: Not recommended

Renal impairment

  • eGFR 30-45 mL/min/1.73 m2: Not recommended
  • eGFR <30 mL/min/1.73 m2: Contraindicated
  • Extended-release only
    • If eGFR falls 30-45 mL/min/1.73 m2 during treatment, evaluate risks and benefits of continuing therapy, limit dose of sitagliptin component to 50 mg/day
    • If eGFR falls <30 mL/min/1.73 m2 during treatment, discontinue drug

Iodinated contrast imaging procedures

  • Discontinue at time of, or before, an iodinated contrast imaging procedure in patients with an eGFR 30-60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast
  • Reevaluate eGFR 48 hr after imaging procedure; restart if renal function is stable
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Interactions

Interaction Checker

and metformin/sitagliptin

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    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Adverse Effects

            1-10%

            Abdominal pain (2.2%)

            Diarrhea (2.4%)

            Hypoglycemia (2.1%)

            Nausea (1.3%)

            Vomiting (1.1%)

            Frequency Not Defined

            Exfoliative disorder of skin of scalp

            Lactic acidosis (rare)

            Postmarketing Reports

            Hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin conditions including Stevens-Johnson syndrome

            Upper respiratory tract infection

            Hepatic enzyme elevations

            Acute pancreatitis including fatal and nonfatal hemorrhagic and necrotizing pancreatitis

            Gastrointestinal: Constipation, vomiting

            Neurologic: Headache

            Rhabdomyolysis

            Worsening renal function, including acute renal failure (sometimes requiring dialysis)

            Myalgia, pain in extremity, and back pain

            Severe disabling arthralgia

            Pruritus

            Bullous pemphigoid

            Mouth ulceration; stomatitis

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            Warnings

            Black Box Warnings

            Lactic acidosis

            • Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias
            • Onset is often subtle, accompanied only by nonspecific symptoms (eg, malaise, myalgias, respiratory distress, somnolence, abdominal pain)
            • Characterized by elevated blood lactate levels (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio, and metformin plasma levels generally >5 mcg/mL
            • Risk factors include renal impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), age ≥65 years old, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment
            • Steps to reduce risk and manage in these high risk groups are provided in the full prescribing information
            • If metformin-associated lactic acidosis is suspected, immediately discontinue treatment and institute general supportive measures in a hospital setting; prompt hemodialysis is recommended

            Contraindications

            Serious hypersensitivity reaction (eg, anaphylaxis, angioedema) to sitagliptin/metformin, sitagliptin, or metformin

            Severe renal impairment (eGFR <30 ml/min/1.73 m2)

            Acute/chronic metabolic acidosis, including diabetic ketoacidosis

            Cautions

            Metformin-associated lactic acidosis have been reported; cases primarily occurred in patients with significant renal impairment; assess renal function before initiating, at least annually during treatment, and more frequently in high-risk patients (eg, elderly)

            Acute pancreatitis reported, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis; if pancreatitis suspected, discontinue promptly

            Heart failure observed with other DPP-4 inhibitors; consider risks and benefits in patients with risk factors for heart failure; monitor for signs and symptoms; if heart failure develops, manage accordingly to standard of care and consider interrupting treatment

            Acute renal failure reported, sometimes requiring dialysis; assess renal function before initiation and periodically thereafter

            Metformin may lower vitamin B12 levels; monitor hematologic parameters annually and Serious allergic and hypersensitivity reactions (eg, anaphylaxis, angioedema, exfoliative skin conditions including Stevens-Johnson syndrome) reported; promptly stop treatment and assess for other potential causes; appropriately monitor and treat

            Severe and disabling arthralgia reported in patients taking DPP-4 inhibitors; consider as a possible cause for severe joint pain and discontinue drug if appropriate

            Bullous pemphigoid reported with DPP-4 inhibitor use, which required hospitalization; in reported cases, patients recovered with topical or systemic immunosuppressive treatment and discontinuation of DPP-4 inhibitor; advise to report any developing blisters/erosions; discontinue DPP-4 therapy and consult a dermatologist if bullous pemphigoid suspected

            Drug interaction overview

            • Sitagliptin is a P-gp and organic anion transporter-3 substrate; weak CYP3A4 and CYP2C8 substrates
            • Insulin or insulin secretagogues
              • Increased risk of hypoglycemia when concomitantly used with insulin and/or an insulin secretagogue; consider lowering dose of insulin or insulin secretagogue
            • Carbonic anhydrase inhibitors
              • Consider more frequent monitoring
              • Coadministration of these drugs may increase the risk for lactic acidosis
            • Drugs that reduce metformin clearance
              • Consider benefits and risks of coadministration
              • Drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (eg, organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis
            • Alcohol
              • Warn against alcohol intake during treatment
              • Alcohol potentiates the effect of metformin on lactate metabolism
            • Drugs affecting glycemic control
              • Closely monitor for loss of blood glucose control
              • When such drugs are discontinued, observe closely for hypoglycemia
              • Certain drugs (eg, thiazides, corticosteroids) tend to produce hyperglycemia and may lead to loss of glycemic control
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            Pregnancy & Lactation

            Pregnancy

            Limited available data in pregnant females are not sufficient to inform a drug-associated risk for major birth defects and miscarriage

            Metformin

            • Published studies with use during pregnancy have not reported a clear association with drug and major birth defects or miscarriage risks

            Pregnancy registry

            • Monitors pregnancy outcomes in females exposed to drug during pregnancy
            • Encourage patients to report any prenatal exposure to drug by calling 1-800-986-8999

            Animal data

            • Sitagliptin: No adverse developmental effects were observed when administered to pregnant rats and rabbits during organogenesis at oral doses up to 30x and 20x, respectively, the 100-mg clinical dose, based on AUC
            • Metformin: No adverse developmental effects were observed when administered to pregnant Sprague Dawley rats and rabbits during organogenesis at doses up to 2x and 6x, respectively, a 2000-mg clinical dose, based on BSA

            Clinical considerations

            • Poorly controlled diabetes in pregnancy increases maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, still birth, and delivery complications
            • Poorly controlled diabetes increases fetal risk for major birth defects, stillbirth, and macrosomia related morbidity

            Females and males of reproductive potential

            • Discuss potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women

            Lactation

            There is no information regarding presence of drug in human milk, its effects on breastfed infants, or on milk production

            Sitagliptin

            • Present in rat milk and therefore possibly present in human

            Metformin

            • Limited published studies report of drug presence in human milk
            • No adverse effects reported on breastfed infants exposed to metformin
            • No information available on effects of drug on milk production

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Sitagliptin: Dipeptidyl peptidase 4 (DPP-4) inhibitor, thereby increasing and prolonging incretin hormone activity which are inactivated by DPP-4 enzyme. Incretins increase insulin release and synthesis from pancreatic beta cells and reduce glucagon secretion pancreatic alpha cells

            Metformin: Biguanide; acts by decreasing endogenous hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization; improves glucose tolerance and lowers both basal and postprandial plasma glucose

            Absorption

            Sitagliptin

            • Mean AUC: 8.52 microM⋅hr (single oral 100-mg dose)
            • Peak plasma concentration: 950 nM (single oral 100-mg dose)
            • Peak plasma time: 1-4 hr
            • Bioavailability: ~87%

            Metformin

            • Bioavailability: ~50-60%
            • Steady-state is reached within 24-48 hr
            • Food decreases extent of and slightly delays absorption of metformin (~40% lower mean peak plasma concentration, a 25% lower AUC, and a 35-min delay in peak plasma time following a single 850-mg dose with food, compared to fasting; clinical relevance is unknown

            Distribution

            Sitagliptin

            • Vd= ~198L
            • Protein bound: 38%

            Metformin

            • Vd= ~654L
            • Protein bound: >90%

            Metabolism

            • Sitagliptin: Limited metabolism with CYP3A4 and CYP2C8
            • Metformin: No hepatic metabolism

            Elimination

            Sitagliptin

            • Renal clearance: 350 mL/min
            • Half-life, terminal: 12.4 hr
            • Excretion: Urine (87% [79% unchanged]), feces (13%)

            Metformin

            • Renal clearance: 350 mL/min
            • Half-life: ~6.2 hr (plasma); ~17.6 hr (blood)
            • Excretion: Urine (90%, by tubular secretion)
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            Administration

            Oral Administration

            Gradually escalate the dose to reduce the gastrointestinal side effects due to metformin

            Immediate-release: Administer with meals

            Extended-release: Administer with a meal preferably in the evening

            Maintain the same total daily dose of sitagliptin and metformin when changing between immediate-release and extended-release, without exceeding the maximum recommended daily dose

            Swallow whole tablet; do not split, crush, or chew

            Storage

            All formulations: Store at 20-25ºC (68-77ºF), excursions permitted to 15-30ºC (59-86ºF)

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            Formulary

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
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            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            Code Definition
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.