Reditn M Special Precautions

Exfoliative dermatitis, history of angioedema, serious rash: Metformin; sitagliptin is contraindicated in patients with a known metformin hypersensitivity or sitagliptin hypersensitivity such as anaphylaxis, urticaria, angioedema, exfoliative dermatitis or other serious skin conditions (serious rash), including Stevens-Johnson syndrome. A risk of serious hypersensitivity reactions or anaphylaxis has been reported in patients during the first 3 months of therapy with sitagliptin; some reports occurred after the first dose. Use caution in patients with a history of angioedema or anaphylaxis to another dipeptidyl peptidase-4 (DPP-4) inhibitor because it is unknown whether such patients will be predisposed to serious reactions with sitagliptin. Postmarketing cases of serious rash, specifically bullous pemphigoid, requiring hospitalization have been reported with DPP-4 inhibitor use. Treatment with topical or systemic immunosuppressives and discontinuation of the DPP-4 inhibitor has typically resulted in resolution of the rash. Inform patients of the risk of serious rash and tell them to report development of blisters or erosions while receiving metformin; sitagliptin. If a serious reaction is suspected, discontinue metformin; sitagliptin and refer the patient to a dermatologist for diagnosis and appropriate treatment.
Diabetic ketoacidosis, type 1 diabetes mellitus: Metformin; sitagliptin use is contraindicated in patients with diabetic ketoacidosis (DKA), with or without coma. This combination is not intended for the treatment of type 1 diabetes mellitus.
Acidemia, hypoxemia, lactic acidosis, metabolic acidosis: Metformin; sitagliptin is contraindicated in patients with metabolic acidosis. Metformin is associated with a risk for lactic acidosis. Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia). Lactic acidosis is a rare but serious complication that can occur due to metformin accumulation; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia or significant renal dysfunction. Certain medications used concomitantly with metformin may also increase the risk of lactic acidosis. Lactic acidosis is characterized by elevated blood lactate levels, acidemia, electrolyte disturbances, an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels more than 5 mcg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin is very low; in more than 20,000 patient-years exposure to metformin in clinical trials, there have been no reports of lactic acidosis and approximately 0.03 cases/1,000 patient-years have been estimated with post-marketing surveillance. A nested case-control study of 50,048 patients with type 2 diabetes mellitus demonstrated that during concurrent use of oral diabetes drugs, there were 6 identified cases of lactic acidosis. The crude incidence rate was 3.3 cases per 100,000 person years in patients treated with metformin; it should be noted that all of the subjects had relevant comorbidities known to be risk factors for lactic acidosis. The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradycardia with more marked acidemia. The patient and the prescriber must be aware of such symptoms and the patient should be instructed to notify the physician immediately if they occur. Metformin; sitagliptin should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood metformin levels may be useful.
Pancreatitis: Use metformin; sitagliptin with caution in patients with a history of pancreatitis; use in these patients has not been studied. It is not known whether these patients are at an increased risk for developing pancreatitis. During postmarketing surveillance between October 2006 and February 2009, acute pancreatitis was reported in 88 patients taking sitagliptin or metformin; sitagliptin. In 19 of the 88 reported cases (21%), pancreatitis occurred within 30 days of starting sitagliptin or metformin; sitagliptin. Upon discontinuation of sitagliptin, 47 of the 88 cases (53%) resolved. At least one other risk factor for developing pancreatitis was evident in 45 cases (51%). In March 2013, the FDA announced that it is evaluating unpublished findings that suggest an increased risk of pancreatitis and pre-cancerous cellular changes called pancreatic duct metaplasia in patients treated with incretin mimetics. These findings were based on examination of a small number of pancreatic tissue specimens taken from patients after they died from unspecified causes. In February 2014, the FDA and EMA stated that after reviewing a number of clinical trials and animal studies, the current data does not support an increased risk of pancreatitis and pancreatic cancer in patients receiving incretin mimetics, including the dipeptidyl peptidase 4 (DPP-4) inhibitors. The agencies have not reached any new conclusions about safety risks of the incretin mimetics, although the totality of the reviewed data provides reassurance. Recommendations will be communicated once the review is complete; continue to consider precautions related to pancreatic risk until more data are available. Monitor patients carefully after initiation or dose increases; if pancreatitis is suspected, sitagliptin; metformin should be discontinued.
Adrenal insufficiency, diarrhea, fever, gastroparesis, GI obstruction, hypercortisolism, hyperglycemia, hyperthyroidism, hypoglycemia, hypothyroidism, ileus, malnutrition, pituitary insufficiency, vomiting: Conditions that predispose patients to developing hypoglycemia or hyperglycemia may alter antidiabetic agent efficacy. Conditions associated with hypoglycemia include debilitated physical condition, drug interactions, malnutrition, uncontrolled adrenal insufficiency, pituitary insufficiency, or hypothyroidism. The risk of hypoglycemia is also increased when metformin; sitagliptin is used in combination with insulin or sulfonylureas. The risk of hypoglycemia when metformin; sitagliptin is used in combination with other drugs known to cause hypoglycemia (e.g., exenatide, nateglinide, repaglinide) is not known. Hyperglycemia related conditions include drug interactions, female hormonal changes, high fever, severe psychological stress, and uncontrolled hypercortisolism or hyperthyroidism. More frequent blood glucose monitoring may be necessary in patients with these conditions. Gastrointestinal (GI) side effects may occur during metformin; sitagliptin initiation; however, later occurrence of GI symptoms may be due to a change in clinical status and may increase the risk of lactic acidosis. Patients stable on metformin; sitagliptin who complain of an increase in GI symptoms should undergo laboratory investigation to determine the etiology of the GI symptoms and rule out serious GI conditions.
Furthermore, withholding metformin; sitagliptin therapy until the cause of the GI symptoms is known may be necessary. Finally, diarrhea and nausea/vomiting may alter gastric emptying and caloric intake, which could all affect blood glucose control, especially increasing the risk of low blood glucose. Patients should be advised to contact their prescriber if an increase in GI symptoms occurs while taking metformin; sitagliptin.
Patients should also be advised to monitor their blood glucose concentrations more frequently. Changes in gastric emptying may alter blood glucose control; monitor patients with diarrhea, gastroparesis, GI obstruction, ileus, or vomiting carefully.
Renal disease, renal failure, renal impairment: Due to the metformin component, sitagliptin; metformin is contraindicated for use in patients with renal failure or severe renal impairment, defined as an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m². Initiating metformin in patients with an eGFR between 30 to 45 mL/minute/1.73 m² is not recommended. Metformin is substantially eliminated by the kidney and the risk of lactic acidosis increases with the degree of intrinsic renal disease or impairment. Certain medications that are eliminated via the kidney when used concomitantly with metformin may also increase the risk of lactic acidosis. Sitagliptin requires dosage adjustment in renal impairment when patients have a CrCl less than 50 mL/min. Before initiation of metformin; sitagliptin and at least annually thereafter, renal function should be assessed in all patients receiving sitagliptin; metformin, using an eGFR to assess renal function. In those patients at increased risk for the development of renal impairment such as the elderly, renal function should be assessed more frequently. In patients taking sitagliptin; metformin whose eGFR later falls below 45 mL/minute/1.73 m², assess the benefits and risks of continuing treatment. Discontinue sitagliptin; metformin if the patient's eGFR later falls below 30 mL/minute/1.73 m². Based on the results of a comprehensive FDA safety review, the FDA concluded that metformin can be used safely in patients with mild renal impairment, and in some patients with moderate renal impairment. The measure of kidney function used to determine whether a patient can receive metformin has been changed from serum creatinine to the eGFR; this is because in addition to serum creatinine concentration, the eGFR takes into account additional parameters that are important, such as the patient's age, gender, race and/or weight.
Acute heart failure, acute myocardial infarction, cardiac disease, cardiogenic shock, heart failure: Use metformin; sitagliptin with caution in patients who have a history of or who have increased risk factors for heart failure, including patients with existing cardiac disease or kidney disease. Observe patients receiving metformin; sitagliptin for signs and symptoms of heart failure, and if heart failure develops, consider discontinuing the drug and monitoring for diabetic control. In patients receiving other DPP-4 inhibitors, including linagliptin and saxagliptin, an increased risk of hospitalization for heart failure has been reported. In the EXAMINE trial, 5,380 patients with type 2 diabetes and established cardiovascular disease who had a recent acute coronary syndrome event were randomized to receive either alogliptin therapy or placebo. More patients randomized to the alogliptin group (3.9%) experienced at least 1 hospitalization for heart failure compared to patients randomized to placebo (3.3%). In the SAVOR trial, 16,492 patients with type 2 diabetes who had either a history of cardiovascular events or a risk for cardiovascular events were randomized to receive either saxagliptin therapy or placebo. Although the SAVOR trial was not specifically designed to assess heart failure risk, results showed that 3.5% of patients in the saxagliptin group were hospitalized for heart failure compared to 2.8% of patients in the placebo group (HR 1.27, 95% CI 1.07 to 1.51; p = 0.007). Metformin; sitagliptin should also be used with caution in patients with congestive heart failure requiring pharmacologic treatment. Acute congestive heart failure characterized by acute hypoxia has been associated with the development of lactic acidosis in patients taking metformin. To reduce the risk of lactic acidosis, metformin; sitagliptin should be promptly withheld in the presence of any condition associated with hypoxemia. Acute hypoxia and acute cardiac disease (e.g., acute heart failure, cardiogenic shock, or acute myocardial infarction) and other conditions characterized by acute hypoxia have been associated with the development of lactic acidosis and may cause prerenal azotemia.
Alcoholism, ethanol intoxication, hepatic disease: The use of metformin has been associated with lactic acidosis in rare instances. Since the liver is important for clearing accumulated lactic acid, metformin; sitagliptin should generally be avoided in patients with hepatic disease as the risk of lactic acidosis may be increased. Hepatic disease also causes altered gluconeogenesis, which may affect glycemic control. Alcohol is known to potentiate the effect of metformin on lactate metabolism and patients should be warned against ethanol intoxication (acute or chronic) while on metformin; sitagliptin. This drug is not recommended for those with alcoholism.
Radiographic contrast administration: Discontinue sitagliptin; metformin at the time of or before radiographic contrast administration in patients with an estimated glomerular filtration rate (eGFR) between 30 and 60 mL/minute/1.73 m²; in patients with a history of hepatic disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Reevaluate the eGFR 48 hours after the imaging procedure; restart sitagliptin; metformin if renal function is stable.
Burns, dehydration, infection, sepsis, surgery, trauma: The use of metformin has been associated with lactic acidosis in rare instances. To reduce the risk of lactic acidosis, metformin; sitagliptin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Metformin; sitagliptin therapy should be temporarily suspended for any surgery, except for minor procedures where intake of fluids and food is not restricted. Do not restart this drug until oral intake is resumed and renal function has been evaluated as normal. Temporary use of insulin in place of oral antidiabetic agents may be necessary during periods of physiologic stress (e.g., burns, systemic infection, trauma, surgery, or fever). Any change in clinical status, including diarrhea or vomiting, may also increase the risk of lactic acidosis and may require laboratory evaluation in patients on metformin; sitagliptin and may require the drug to be withheld.
Anemia, pernicious anemia, vitamin B12 deficiency: As the metformin component of metformin; sitagliptin has been associated with suboptimal vitamin B12 absorption, possibly due to interference with the B12-intrinsic factor complex, use this medication with caution, if at all, in patients with vitamin B12 deficiency or vitamin B12-dependent anemia. The interaction very rarely results in a pernicious anemia that appears reversible with discontinuation of metformin or with cyanocobalamin supplementation. Certain individuals may be predisposed to this type of anemia; a nested case-control study of 465 patients taking metformin (155 with vitamin B12 deficiency and 310 without) demonstrated that dose and duration of metformin use may be associated with an increased odds of vitamin B12 deficiency. Each 1 gram/day increment in dose significantly increased the odds of vitamin B12 deficiency (OR 2.88, 95% CI 2.15 to 3.87) as did taking metformin for 3 or more years (OR 2.39, 95% CI 1.46 to 3.91). Annual measurement of hematologic parameters is recommended in all patients on chronic metformin; sitagliptin treatment.
Arthralgia: Cases of severe, sometimes disabling, arthralgia (joint pain) have been reported with the use of dipeptidyl peptidase-4 (DPP-4) inhibitors, including sitagliptin. Advise patients not to discontinue therapy but to contact their health care professional immediately if they experience severe and persistent joint pain while taking metformin; sitagliptin. Consider metformin; sitagliptin as a possible cause of joint pain and discontinue if appropriate. The FDA has identified 33 cases of severe arthralgia with the use of DPP-4 inhibitors, all of which resulted in substantial reduction of the patient's prior level of activity and, in 10 cases, required hospitalization. In the reported cases, the onset of symptoms occurred from 1 day to several years after the start of therapy with a DPP-4 inhibitor. Symptoms resolved with discontinuation of therapy, usually in less than a month; however, some patients experienced a recurrence of joint pain when restarting the same drug or switching to another DPP-4 inhibitor.
Effects on ability to drive and use machines: Sitagliptin + metformin has no or negligible influence on the ability to drive and use machines. However, when driving or using machines, it should be taken into account that dizziness and somnolence have been reported with sitagliptin.
In addition, patients should be alerted to the risk of hypoglycaemia when Sitagliptin + metformin is used in combination with a sulphonylurea or with insulin.
Use in Pregnancy: Polycystic ovary syndrome, pregnancy: There are no adequate and well-controlled studies with the combination of metformin; sitagliptin in pregnant women; use during pregnancy only if clearly needed. Placental transfer of sitagliptin has been demonstrated in animal studies. Sitagliptin doses of up to 30 times the human exposure at the maximum recommended human dose (MRHD) were not teratogenic when administered to rats and rabbits on gestation days 6 to 20; a dose of 1,000 mg/kg (100 times the human exposure at the MRHD) caused rib malformations in offspring and the dose resulted in a decrease in offspring weight; neither functional nor behavioral toxicity was observed. Metformin does pass through the placenta and the fetus is exposed to therapeutic concentrations of metformin. Epidemiologic data suggest no increase in the rates of expected birth defects in women taking metformin who become pregnant. The American College of Obstetricians and Gynecologists (ACOG) and the American Diabetes Association (ADA) continue to recommend human insulin as the standard of care in women with diabetes mellitus and gestational diabetes mellitus (GDM) requiring medical therapy; insulin does not cross the placenta. Per ACOG, in women who decline insulin therapy or are unable to safely administer insulin, metformin monotherapy is the preferred second-line choice. Per the ADA, metformin monotherapy may be used to treat GDM as a treatment option; however, no long term safety data are available for any oral agent. Metformin may cause a lower risk of neonatal hypoglycemia and less maternal weight gain than insulin; however, some data suggest that metformin may slightly increase the risk of prematurity. The ADA notes that in some clinical studies, nearly 50% of GDM patients initially treated with metformin have needed the addition of insulin in order to achieve acceptable glucose control. Many studies and analyses of metformin in use in pregnancy have been published. Data suggest no increase in the rates of expected birth defects or other adverse outcomes in exposed infants and studies comparing metformin to insulin in the treatment of gestational diabetes have generally found no significant differences in glycemic control or pregnancy outcomes. Premenopausal anovulatory females with insulin resistance, such as those with polycystic ovary syndrome (PCOS), may resume ovulation as a result of metformin therapy; patients may be at risk of conception if adequate contraception is not used.
Use in Lactation: Caution should be used when administering metformin; sitagliptin to women who are breast-feeding. No studies have been conducted with the combined ingredients of metformin; sitagliptin. Sitagliptin is secreted in the milk of lactating rats at a plasma ratio of 4:1. It is not known whether sitagliptin is excreted in human milk. Animal data show that metformin is excreted into breast milk and reaches levels similar to those in plasma. Small studies indicate that metformin is excreted in human breast milk. Infant hypoglycemia or other side effects are a possibility; however, adverse effects on infant plasma glucose have not been reported in human studies. Furthermore, the use of metformin 2,550 mg/day by mothers breastfeeding their infants for 6 months does not affect growth, motor, or social development; the effects beyond 6 months are not known. In all of these studies, the estimated weight-adjusted infant exposure to metformin ranged from 0.11% to 1.08% of the mother's dose. The results of these studies indicate that maternal ingestion of metformin during breast-feeding is probably safe to the infant. However, a risk and benefit analysis should be made for each mother and her infant. If patients elect to continue metformin; sitagliptin while breast-feeding, the mother should be aware of the potential risks to the infant. If metformin; sitagliptin is discontinued and blood glucose is not controlled on diet and exercise alone, insulin therapy should be considered. Metformin monotherapy may be a consideration. Other oral hypoglycemics may also be considered. Because acarbose has limited systemic absorption, which results in minimal maternal plasma concentrations, clinically significant exposure via breast milk is not expected; therefore, this agent may represent a reasonable alternative for some patients.
Use in Children: The safety and effectiveness of metformin; sitagliptin in pediatric patients less than 18 years of age has not been established. Sitagliptin is not indicated for the treatment of children, adolescents, or infants; sitagliptin is not proven to improve blood sugar control in pediatric patients. Three 20-week double-blind, placebo-controlled studies were conducted in 410 pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes, with or without insulin therapy (A1C 6.5% to 10% for patients not on insulin, A1C 7% to 10% for patients on insulin); the effect of treatment with sitagliptin was not significantly different from placebo. In study 1, at week 20, the change from baseline in A1C in patients treated with sitagliptin (n = 95) was 0.06% compared to 0.23% in patients treated with placebo (n = 95), a difference of -0.17% (95% CI -0.62, 0.28). In studies 2 and 3, at week 20, the change from baseline in A1C in patients treated with sitagliptin (n = 107) was -0.23% compared to 0.09% in patients treated with placebo (n = 113), a difference of -0.33% (95% CI -0.70, 0.05).
Use in the Elderly: Use the combination of metformin; sitagliptin with caution in geriatric patients. Metformin is substantially excreted by the kidney and the risk of adverse reactions (including lactic acidosis) is greater in patients with reduced renal function. Because aging is associated with renal function decline, care should be taken with dose selection and titration. Sitagliptin dosing is recommended to be decreased in patients with a CrCl less than 50 mL/min. Obtain an estimated glomerular filtration rate (eGFR) at least annually in all patients taking metformin; sitagliptin. In patients at increased risk for the development of renal impairment such as geriatric patients, renal function should be assessed more frequently. Unless estimated renal function via the eGFR is determined to not be reduced, do not use metformin in geriatric patients 80 years of age and older. Generally, geriatric or debilitated patients should not be titrated up to maximum metformin dosages. Older, debilitated, or malnourished patients are also particularly susceptible to hypoglycemic effects of antidiabetic agents; monitor blood glucose frequently. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, the use of antidiabetic medications should include monitoring (e.g., periodic blood glucose) for effectiveness based on desired goals for that individual and to identify complications of treatment such as hypoglycemia or impaired renal function. Metformin has been associated with lactic acidosis, which is more likely to occur under the following conditions: serum creatinine of 1.5 mg/dL or higher in males or 1.4 mg/dL or higher in females, abnormal creatinine clearance from any cause, age of 80 years or older unless measurement of creatinine clearance verifies normal renal function, radiologic studies in which intravascular iodinated contrast materials are given, congestive heart failure requiring pharmacologic management, or acute/chronic metabolic acidosis with or without coma (including diabetic ketoacidosis).