metformin/sitagliptin (Janumet, Janumet XR)
Classes: Antidiabetics, Biguanides/Dipeptyl Peptidase-IV Inhibitors
Dosing and uses of Janumet, Janjumet XR (metformin-sitagliptin)
Adult dosage forms and strengths
metformin/sitagliptin
tablet
- 500mg/50mg
- 1,000mg/50mg
tablet, extended-release
- 500mg/50mg
- 1,000mg/50mg
- 1,000mg/100mg
Diabetes Mellitus, Type 2
Indicated as adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with sitagliptin or metformin and have inadequate glycemic control on sitagliptin or metformin alone
Adjust dose gradually considering effectiveness and tolerability
Inadequately controlled on metformin alone
- 100 mg/day sitagliptin PO plus current dose of metformin
- Not to exceed daily PO dose of 2,000 mg of metformin or 100 mg or sitagliptin
Inadequately controlled on sitagliptin alone
- 1000 mg/day metformin PO plus 100 mg/day PO sitagliptin
- Not to exceed daily PO dose of 2,000 mg of metformin or 100 mg or sitagliptin
Dosage modifications
Hepatic impairment: Do not administer
Renal impairment
- Obtain eGFR before starting metformin
- eGFR <30 mL/min/1.73 m²: Contraindicated
- eGFR 30-45 mL/min/1.73 m²: Not recommended to initiate treatment
- Monitor eGFR at least annually or more often for those at risk for renal impairment (eg, elderly)
- If eGFR falls below 45mL/min/1.73 m² while taking metformin, risks and benefits of continuing therapy should be evaluated
- If eGFR falls below 30 mL/min/1.73 m²: while taking metformin, discontinue the drug
Pediatric dosage forms and strengths
<18 years: Safety and efficacy not established
Geriatric dosage forms and strengths
Initial and maintenance dosing should be conservative due to possibility of decreased renal function. Adjust dose gradually and conservatively considering effectiveness and tolerability
Inadequately controlled on metformin alone
100 mg/day sitagliptin PO plus current dose of metformin
Not to exceed daily PO dose of 2,000 mg of metformin or 100 mg or sitagliptin
Do not administer to patients >80 years before assessing renal function and determined to be normaL
Inadequately controlled on sitagliptin alone
1000 mg/day metformin PO plus 100 mg/day PO sitagliptin
Not to exceed daily PO dose of 2,000 mg of metformin or 100 mg or sitagliptin
Do not administer to patients >80 years before assessing renal function and determined to be normaL
Janumet, Janjumet XR (metformin-sitagliptin) adverse (side) 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
Stevens-Johnson syndrome
Lactic acidosis (rare )
Anaphylaxis/hypersensitivity reaction
Rhabdomyolysis
Acute renal failure
Angioedema
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
Worsening renal function, including acute renal failure (sometimes requiring dialysis)
Myalgia, pain in extremity, and back pain
Severe disabling arthralgia
Pruritus
Warnings
Black box warnings
Discontinue metformin at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 30-60 mL/minute/1.73 m²; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinate contrast
Lactic acidosis
- Characterized by elevated blood lactate levels (>5 mmol/L)
- Rare but serious complication that can occur because of metformin accumulation; increased risk with sepsis, dehydration, excess alcohol intake, hepatic insufficiency, renal impairment, and acute congestive heart failure
- Subtle onset with nonspecific symptoms (eg, malaise, myalgias, respiratory distress, somnolence, nonspecific abdominal distress)
- Monitor lab for decreased serum pH, increased anion gap, and elevated blood lactate If suspected, discontinue drug and hospitalize patient immediately
- Metformin is highly dialyzable (clearance up to 170 mL/min under good hemodynamic conditions); prompt hemodialysis is recommended to correct the acidosis and to remove accumulated metformin
Contraindications
Hypersensitivity, including anaphylaxis or angioedema
Severe renal disease: eGFR <30 ml/min/1.73 m²
Acute/chronic metabolic acidosis, including diabetic ketoacidosis; treat with insulin
Cautions
Risk of lactic acidosis with metformin accumulation
Initiate in patients >80 years only if CrCl indicates no reduction in renal function
Avoid excessive alcohol use
Withhold in presence of any condition associated with hypoxemia, dehydration, or sepsis
Discontinue temporarily prior to any intravascular radiocontrast study with iodine containing materials and for any surgical procedure
Risk of hypoglycemia esp in elderly, debilitated or malnourished, adrenal/pituitary insufficiency, strenuous exercise not compensated by caloric intake, heavy alcohol use, hepatic/renal impairment, beta blockers
May cause acute pancreatitis, including hemorrhagic and necrotizing pancreatitis
Unknown if patients with history of pancreatitis are at increased risk
Angioedema reported with other DPP-4 inhibitors; caution with history of angioedema
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
Cases of lactic acidosis reported primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications; monitor renal function of the elderly closely; withhold metformin promptly in presence of any condition associated with hypoxemia, dehydration, or sepsis
Iodinated contrast imaging procedures
- Discontinue metformin at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 30-60 mL/minute/1.73 m²; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinate contrast
- Reevaluate eGFR 48 hr after the imaging procedure; restart metformin if renal function is stable
Pregnancy and lactation
Pregnancy category: B
Lactation: not known if crosses into breast milk, use caution
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.
Pharmacology of Janumet, Janjumet XR (metformin-sitagliptin)
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
Pharmacokinetics
Half-Life
- Sitagliptin: ~12.4 hr
- Metformin: ~6.2 hr
Bioavailability
- Sitagliptin: 87%
- Metformin: 50-60%
Excretion
- Sitagliptin: Urine 79%
- Metformin: Urine 90%
Administration
Instructions
Gradually escalate the dose to reduce the gastrointestinal side effects due to metformin
Immediate-release: Administer q12hr with meals
Extended-release: Administer once daily, 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; do not split, crush, or chew