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

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

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 severity of renal impairment because metformin is substantially excreted by the kidney

Vitamin B12 deficiency reported; patients (those with inadequate vitamin B12 or calcium intake or absorption) may be predisposed to developing subnormal vitamin B12 levels; measure hematologic parameters on an annual basis and vitamin B12 measurements at 2- to 3-year intervals in patients receiving therapy; manage any abnormalities

Renal impairment

• Clinical recommendations based upon the patient’s renal function include the following
• Before initiating therapy, obtain an estimated glomerular filtration rate (eGFR)
• Not recommended in patients with an eGFR between 30 and less than 45 mL/min/1.73 m(squared) because these patients require a lower dosage of sitagliptin than what is available in the fixed combination product
• Obtain an eGFR at least annually in all patients receiving therapy at increased risk for development of renal impairment (e.g., the elderly); renal function should be assessed more frequently

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

There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to drug during pregnancy; health care providers are encouraged to report any prenatal exposure to drug by calling the Pregnancy Registry at 1-800-986-8999

Limited available data 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; there are risks to mother and fetus associated with poorly controlled diabetes in pregnancy

Poorly controlled diabetes in pregnancy increases maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, still birth, and delivery complications; poorly controlled diabetes increases fetal risk for major birth defects, still birth, and macrosomia related morbidity

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 in human milk, effects on breastfed infant, or on milk production; limited published studies report that metformin is present in human milk; there are no reports of adverse effects on breastfed infants exposed to metformin; there is no information on effects of metformin on milk production; sitagliptin is present in rat milk and therefore possibly present in human milk; developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for therapy and any potential adverse effects on breastfed infant from drug or from underlying maternal condition

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

Pharmacokinetics

Half-Life

• Sitagliptin: ~12.4 hr
• Metformin: ~6.2 hr

Bioavailability

• Sitagliptin: 87%
• Metformin: 50-60%

Excretion

• Sitagliptin: Urine 79%
• Metformin: Urine 90%

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