metformin/sitagliptin (Rx)

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

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

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.

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)

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)