metformin/sitagliptin (Janumet, Janumet XR)

Dosing and uses of Janumet, Janjumet XR (metformin-sitagliptin)

• Adult
• Pediatric
• Geriatric

 

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