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Medically reviewed by Kovalenko Svetlana Olegovna, PharmD. Last updated on 19.03.2022
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JANUMET® XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both sitagliptin and metformin extended-release is appropriate.
Important Limitations Of Use
Ristfor (Metformin hydrochloride_Sitagliptin) should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
Ristfor (Metformin hydrochloride_Sitagliptin) has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using Ristfor (Metformin hydrochloride_Sitagliptin).
Recommended Dosing
The dose of Ristfor (Metformin hydrochloride_Sitagliptin) should be individualized on the basis of the patient's current regimen, effectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin. Initial combination therapy or maintenance of combination therapy should be individualized and left to the discretion of the healthcare provider.
- In patients not currently treated with metformin, the recommended total daily starting dose of Ristfor (Metformin hydrochloride_Sitagliptin) is 100 mg sitagliptin and 1000 mg metformin hydrochloride (HCl) extended-release. Patients with inadequate glycemic control on this dose of metformin can be titrated gradually, to reduce gastrointestinal side effects associated with metformin, up to the maximum recommended daily dose.
- In patients already treated with metformin, the recommended total daily starting dose of Ristfor (Metformin hydrochloride_Sitagliptin) is 100 mg sitagliptin and the previously prescribed dose of metformin.
- For patients taking metformin immediate-release 850 mg twice daily or 1000 mg twice daily, the recommended starting dose of Ristfor (Metformin hydrochloride_Sitagliptin) is two 50 mg sitagliptin/1000 mg metformin hydrochloride extended-release tablets taken together once daily.
- Maintain the same total daily dose of sitagliptin and metformin when changing between JANUMET (sitagliptin and metformin HCl immediate-release) and Ristfor (Metformin hydrochloride_Sitagliptin). Patients with inadequate glycemic control on this dose of metformin can be titrated gradually, to reduce gastrointestinal side effects associated with metformin, up to the maximum recommended daily dose.
Ristfor (Metformin hydrochloride_Sitagliptin) should be administered with food to reduce the gastrointestinal side effects associated with the metformin component. Ristfor (Metformin hydrochloride_Sitagliptin) should be given once daily with a meal preferably in the evening. Ristfor (Metformin hydrochloride_Sitagliptin) should be swallowed whole. The tablets must not be split, crushed, or chewed before swallowing. There have been reports of incompletely dissolved Ristfor (Metformin hydrochloride_Sitagliptin) tablets being eliminated in the feces. It is not known whether this material seen in feces contains active drug. If a patient reports repeatedly seeing tablets in feces, the healthcare provider should assess adequacy of glycemic control.
The 100 mg sitagliptin/1000 mg metformin hydrochloride extended-release tablet should be taken as a single tablet once daily. Patients using two Ristfor (Metformin hydrochloride_Sitagliptin) tablets (such as two 50 mg sitagliptin/500 mg metformin hydrochloride extended-release tablets or two 50 mg sitagliptin/1000 mg metformin hydrochloride extended-release tablets) should take the two tablets together once daily.
No studies have been performed specifically examining the safety and efficacy of Ristfor (Metformin hydrochloride_Sitagliptin) in patients previously treated with other oral antihyperglycemic agents and switched to Ristfor (Metformin hydrochloride_Sitagliptin). Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.
Recommendations For Use In Renal Impairment
Assess renal function prior to initiation of Ristfor (Metformin hydrochloride_Sitagliptin) and periodically thereafter.
Ristfor (Metformin hydrochloride_Sitagliptin) is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2. Discontinue Ristfor (Metformin hydrochloride_Sitagliptin) if the patient's eGFR later falls below 30 mL/min/1.73 m2.
Initiation of Ristfor (Metformin hydrochloride_Sitagliptin) in patients with an eGFR between 30 and 45 mL/min/1.73 m2 is not recommended.
In patients taking Ristfor (Metformin hydrochloride_Sitagliptin) whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit risk of continuing therapy and limit dose of the sitagliptin component to 50 mg once daily.
Discontinuation For Iodinated Contrast Imaging Procedures
Discontinue Ristfor (Metformin hydrochloride_Sitagliptin) at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Reevaluate eGFR 48 hours after the imaging procedure; restart Ristfor (Metformin hydrochloride_Sitagliptin) if renal function is stable.
Ristfor (Metformin hydrochloride_Sitagliptin) is contraindicated in patients with:
- Severe renal impairment (eGFR below 30 mL/min/1.73 m2).
- Hypersensitivity to metformin hydrochloride.
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin.
- History of a serious hypersensitivity reaction to Ristfor (Metformin hydrochloride_Sitagliptin) or sitagliptin, such as anaphylaxis or angioedema.
WARNINGS
Included as part of the "PRECAUTIONS" Section
PRECAUTIONS
Lactic Acidosis
Metformin Hydrochloride
There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate/pyruvate ratio; metformin plasma levels were generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.
If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of Ristfor (Metformin hydrochloride_Sitagliptin). In Ristfor (Metformin hydrochloride_Sitagliptin)-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.
Educate patients and their families about the symptoms of lactic acidosis, and if these symptoms occur instruct them to discontinue Ristfor (Metformin hydrochloride_Sitagliptin) and report these symptoms to their healthcare provider.
For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:
Renal Impairment: 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 the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include :
- Before initiating Ristfor (Metformin hydrochloride_Sitagliptin), obtain an estimated glomerular filtration rate (eGFR).
- Ristfor (Metformin hydrochloride_Sitagliptin) is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2. Discontinue Ristfor (Metformin hydrochloride_Sitagliptin) if the patient’s eGFR later falls below 30 mL/min/1.73 m2.
- Initiation of Ristfor (Metformin hydrochloride_Sitagliptin) is not recommended in patients with eGFR between 30 and 45 mL/min/1.73 m2.
- In patients taking Ristfor (Metformin hydrochloride_Sitagliptin) whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy.
- Obtain an eGFR at least annually in all patients taking Ristfor (Metformin hydrochloride_Sitagliptin). In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
Drug Interactions
The concomitant use of Ristfor (Metformin hydrochloride_Sitagliptin) with specific drugs may increase the risk of metforminassociated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation. Therefore, consider more frequent monitoring of patients.
Age 65 Or Greater
The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.
Radiological Studies With Contrast
Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop Ristfor (Metformin hydrochloride_Sitagliptin) at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart Ristfor (Metformin hydrochloride_Sitagliptin) if renal function is stable.
Surgery And Other Procedures
Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. Ristfor (Metformin hydrochloride_Sitagliptin) should be temporarily discontinued while patients have restricted food and fluid intake.
Hypoxic States
Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue Ristfor (Metformin hydrochloride_Sitagliptin).
Excessive Alcohol Intake
Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving Ristfor (Metformin hydrochloride_Sitagliptin).
Hepatic Impairment
Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of Ristfor (Metformin hydrochloride_Sitagliptin) in patients with clinical or laboratory evidence of hepatic disease.
Pancreatitis
There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking sitagliptin with or without metformin. After initiation of Ristfor (Metformin hydrochloride_Sitagliptin), patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, Ristfor (Metformin hydrochloride_Sitagliptin) should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using Ristfor (Metformin hydrochloride_Sitagliptin).
Assessment Of Renal Function
Metformin and sitagliptin are substantially excreted by the kidney.
Metformin Hydrochloride
Ristfor (Metformin hydrochloride_Sitagliptin) is contraindicated in patients with severe renal impairment.
Sitagliptin
There have been postmarketing reports of worsening renal function in patients taking sitagliptin with or without metformin, including acute renal failure, sometimes requiring dialysis. Before initiation of therapy with Ristfor (Metformin hydrochloride_Sitagliptin) and at least annually thereafter, renal function should be assessed. In patients in whom development of renal dysfunction is anticipated, particularly in elderly patients, renal function should be assessed more frequently and Ristfor (Metformin hydrochloride_Sitagliptin) discontinued if evidence of renal impairment is present.
Vitamin B12 Levels
In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum Vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or Vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on Ristfor (Metformin hydrochloride_Sitagliptin) and any apparent abnormalities should be appropriately investigated and managed.
Certain individuals (those with inadequate Vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal Vitamin B12 levels. In these patients, routine serum Vitamin B12 measurements at two-to three-year intervals may be useful.
Change In Clinical Status Of Patients With Previously Controlled Type 2 Diabetes
A patient with type 2 diabetes previously well controlled on Ristfor (Metformin hydrochloride_Sitagliptin) who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, Ristfor (Metformin hydrochloride_Sitagliptin) must be stopped immediately and other appropriate corrective measures initiated.
Use With Medications Known To Cause Hypoglycemia
Sitagliptin
When sitagliptin was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or with insulin. Therefore, patients also receiving an insulin secretagogue (e.g., sulfonylurea) or insulin may require a lower dose of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.
Metformin Hydrochloride
Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking β-adrenergic blocking drugs.
Loss Of Control Of Blood Glucose
When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold Ristfor (Metformin hydrochloride_Sitagliptin) and temporarily administer insulin. Ristfor (Metformin hydrochloride_Sitagliptin) may be reinstituted after the acute episode is resolved.
Hypersensitivity Reactions
There have been postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin, one of the components of Ristfor (Metformin hydrochloride_Sitagliptin). These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment with sitagliptin, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue Ristfor (Metformin hydrochloride_Sitagliptin), assess for other potential causes for the event, and institute alternative treatment for diabetes.
Use caution in a patient with a history of angioedema to another dipeptidyl peptidase-4 (DPP4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with Ristfor (Metformin hydrochloride_Sitagliptin).
Severe And Disabling Arthralgia
There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.
Bullous Pemphigoid
Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving Ristfor (Metformin hydrochloride_Sitagliptin). If bullous pemphigoid is suspected, Ristfor (Metformin hydrochloride_Sitagliptin) should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.
Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Ristfor (Metformin hydrochloride_Sitagliptin) or any other anti-diabetic drug.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Instructions
Patients should be informed of the potential risks and benefits of Ristfor (Metformin hydrochloride_Sitagliptin) and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and A1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be advised to seek medical advice promptly.
The risks of lactic acidosis due to the metformin component, its symptoms, and conditions that predispose to its development, as noted in WARNINGS AND PRECAUTIONS, should be explained to patients. Patients should be advised to discontinue Ristfor (Metformin hydrochloride_Sitagliptin) immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, dizziness, slow or irregular heart beat, sensation of feeling cold (especially in the extremities) or other nonspecific symptoms occur. Gastrointestinal symptoms are common during initiation of metformin treatment and may occur during initiation of Ristfor (Metformin hydrochloride_Sitagliptin) therapy; however, patients should consult their physician if they develop unexplained symptoms. Although gastrointestinal symptoms that occur after stabilization are unlikely to be drug related, such an occurrence of symptoms should be evaluated to determine if it may be due to lactic acidosis or other serious disease. Instruct patients to inform their doctor that they are taking Ristfor (Metformin hydrochloride_Sitagliptin) prior to any surgical or radiological procedure, as temporary discontinuation of Ristfor (Metformin hydrochloride_Sitagliptin) may be required until renal function has been confirmed to have returned to its prior level.
Patients should be advised to notify their health practitioner or call the Poison Control Center immediately in case of Ristfor (Metformin hydrochloride_Sitagliptin) overdose.
Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving Ristfor (Metformin hydrochloride_Sitagliptin).
Patients should be informed about the importance of regular testing of renal function and hematological parameters when receiving treatment with Ristfor (Metformin hydrochloride_Sitagliptin).
Patients should be informed that acute pancreatitis has been reported during postmarketing use of JANUMET. Patients should be informed that persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Patients should be instructed to promptly discontinue Ristfor (Metformin hydrochloride_Sitagliptin) and contact their physician if persistent severe abdominal pain occurs.
Patients should be informed that the incidence of hypoglycemia is increased when sitagliptin with or without metformin is added to an insulin secretagogue (e.g., sulfonylurea) or insulin therapy and that a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia.
Patients should be informed that allergic reactions have been reported during postmarketing use of sitagliptin, one of the components of Ristfor (Metformin hydrochloride_Sitagliptin). If symptoms of allergic reactions (including rash, hives, and swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing) occur, patients must stop taking Ristfor (Metformin hydrochloride_Sitagliptin) and seek medical advice promptly.
Inform patients that severe and disabling joint pain may occur with this class of drugs. The time to onset of symptoms can range from one day to years. Instruct patients to seek medical advice if severe joint pain occurs.
Inform patients that bullous pemphigoid may occur with this class of drugs. Instruct patients to seek medical advice if blisters or erosions occur.
Patients should be informed that the tablets must be swallowed whole and never split, crushed or chewed.
Patients should be informed that incompletely dissolved Ristfor (Metformin hydrochloride_Sitagliptin) tablets may be eliminated in the feces. Tell patients that, if they repeatedly see tablets in feces, they should report this finding to their healthcare provider. If a patient reports repeatedly observing tablets in feces, the healthcare provider should assess adequacy of glycemic control.
Physicians should instruct their patients to read the Medication Guide before starting Ristfor (Metformin hydrochloride_Sitagliptin) therapy and to reread each time the prescription is renewed. Patients should be instructed to inform their doctor if they develop any bothersome or unusual symptom, or if any symptom persists or worsens.
Laboratory Tests
Response to all diabetic therapies should be monitored by periodic measurements of blood glucose and A1C levels, with a goal of decreasing these levels towards the normal range. A1C is especially useful for evaluating long-term glycemic control.
Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with metformin therapy, if this is suspected, Vitamin B12 deficiency should be excluded.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Ristfor (Metformin hydrochloride_Sitagliptin)
No animal studies have been conducted with the combined products in Ristfor (Metformin hydrochloride_Sitagliptin) to evaluate carcinogenesis, mutagenesis or impairment of fertility. The following data are based on the findings in studies with sitagliptin and metformin individually.
Sitagliptin
A two-year carcinogenicity study was conducted in male and female rats given oral doses of sitagliptin of 50, 150, and 500 mg/kg/day. There was an increased incidence of combined liver adenoma/carcinoma in males and females and of liver carcinoma in females at 500 mg/kg. This dose results in exposures approximately 60 times the human exposure at the maximum recommended daily adult human dose (MRHD) of 100 mg/day based on AUC comparisons. Liver tumors were not observed at 150 mg/kg, approximately 20 times the human exposure at the MRHD. A two-year carcinogenicity study was conducted in male and female mice given oral doses of sitagliptin of 50, 125, 250, and 500 mg/kg/day. There was no increase in the incidence of tumors in any organ up to 500 mg/kg, approximately 70 times human exposure at the MRHD. Sitagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, a Chinese hamster ovary (CHO) chromosome aberration assay, an in vitro cytogenetics assay in CHO, an in vitro rat hepatocyte DNA alkaline elution assay, and an in vivo micronucleus assay.
In rat fertility studies with oral gavage doses of 125, 250, and 1000 mg/kg, males were treated for 4 weeks prior to mating, during mating, up to scheduled termination (approximately 8 weeks total), and females were treated 2 weeks prior to mating through gestation day 7. No adverse effect on fertility was observed at 125 mg/kg (approximately 12 times human exposure at the MRHD of 100 mg/day based on AUC comparisons). At higher doses, nondose-related increased resorptions in females were observed (approximately 25 and 100 times human exposure at the MRHD based on AUC comparison).
Metformin Hydrochloride
Long-term carcinogenicity studies have been performed in Sprague Dawley rats at doses of 150, 300, and 450 mg/kg/day in males and 150, 450, 900, and 1200 mg/kg/day in females. These doses are approximately 2, 4, and 8 times in males, and 3, 7, 12, and 16 times in females of the maximum recommended human daily dose of 2000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female rats. A carcinogenicity study was also performed in Tg. AC transgenic mice at doses up to 2000 mg applied dermally. No evidence of carcinogenicity was observed in male or female mice.
Genotoxicity assessments in the Ames test, gene mutation test (mouse lymphoma cells), chromosomal aberrations test (human lymphocytes) and in vivo mouse micronucleus tests were negative. Fertility of male or female rats was not affected by metformin when administered at doses up to 600 mg/kg/day, which is approximately 3 times the maximum recommended human daily dose based on body surface area comparisons.
Use In Specific Populations
Pregnancy
Pregnancy Category B
Ristfor (Metformin hydrochloride_Sitagliptin)
There are no adequate and well-controlled studies in pregnant women with Ristfor (Metformin hydrochloride_Sitagliptin) or its individual components; therefore, the safety of Ristfor (Metformin hydrochloride_Sitagliptin) in pregnant women is not known. Ristfor (Metformin hydrochloride_Sitagliptin) should be used during pregnancy only if clearly needed.
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., maintains a registry to monitor the pregnancy outcomes of women exposed to Ristfor (Metformin hydrochloride_Sitagliptin) while pregnant. Healthcare providers are encouraged to report any prenatal exposure to Ristfor (Metformin hydrochloride_Sitagliptin) by calling the Pregnancy Registry at 1-800986- 8999.
No animal studies have been conducted with the combined products in Ristfor (Metformin hydrochloride_Sitagliptin) to evaluate effects on reproduction. The following data are based on findings in studies performed with sitagliptin or metformin individually.
Sitagliptin
Reproduction studies have been performed in rats and rabbits. Doses of sitagliptin up to 125 mg/kg (approximately 12 times the human exposure at the maximum recommended human dose) did not impair fertility or harm the fetus. There are, however, no adequate and well-controlled studies with sitagliptin in pregnant women.
Sitagliptin administered to pregnant female rats and rabbits from gestation day 6 to 20 (organogenesis) was not teratogenic at oral doses up to 250 mg/kg (rats) and 125 mg/kg (rabbits), or approximately 30 and 20 times human exposure at the maximum recommended human dose (MRHD) of 100 mg/day based on AUC comparisons. Higher doses increased the incidence of rib malformations in offspring at 1000 mg/kg, or approximately 100 times human exposure at the MRHD.
Sitagliptin administered to female rats from gestation day 6 to lactation day 21 decreased body weight in male and female offspring at 1000 mg/kg. No functional or behavioral toxicity was observed in offspring of rats.
Placental transfer of sitagliptin administered to pregnant rats was approximately 45% at 2 hours and 80% at 24 hours postdose. Placental transfer of sitagliptin administered to pregnant rabbits was approximately 66% at 2 hours and 30% at 24 hours.
Metformin hydrochloride
Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day, which represent 3 and 6 times the maximum recommended human daily dose of 2000 mg based on body surface area comparison for rats and rabbits, respectively. However, because animal reproduction studies are not always predictive of human response, metformin hydrochloride should not be used during pregnancy unless clearly needed.
Nursing Mothers
No studies in lactating animals have been conducted with the combined components of Ristfor (Metformin hydrochloride_Sitagliptin). In studies performed with the individual components, both sitagliptin and metformin are secreted in the milk of lactating rats. It is not known whether sitagliptin or metformin are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Ristfor (Metformin hydrochloride_Sitagliptin) is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of Ristfor (Metformin hydrochloride_Sitagliptin) in pediatric patients under 18 years have not been established.
Geriatric Use
Ristfor (Metformin hydrochloride_Sitagliptin)
Because sitagliptin and metformin are substantially excreted by the kidney, and because aging can be associated with reduced renal function, renal function should be assessed more frequently in elderly patients.
Sitagliptin
Of the total number of subjects (N=3884) in premarketing Phase II and III clinical studies of sitagliptin, 725 patients were 65 years and over, while 61 patients were 75 years and over. No overall differences in safety or effectiveness were observed between subjects 65 years and over and younger subjects. While this and other reported clinical experience have not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.
Metformin Hydrochloride
Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients.
Renal Impairment
Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Ristfor (Metformin hydrochloride_Sitagliptin) is contraindicated in severe renal impairment, patients with an eGFR below 30 mL/min/1.73 m2.. The dose of the sitagliptin component should be limited to 50 mg once daily if eGFR falls below 45 mL/min/1.73m2.
Hepatic Impairment
Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Ristfor (Metformin hydrochloride_Sitagliptin) is not recommended in patients with hepatic impairment.
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Sitagliptin And Metformin Immediate-Release Coadministration In Patients With Type 2 Diabetes Inadequately Controlled On Diet And Exercise
Table 1 summarizes the most common (≥5% of patients) adverse reactions reported (regardless of investigator assessment of causality) in a 24-week placebo-controlled factorial study in which sitagliptin and metformin immediate-release were coadministered to patients with type 2 diabetes inadequately controlled on diet and exercise.
Table 1: Sitagliptin and Metformin Immediate-Release Coadministered to Patients with Type 2 Diabetes Inadequately Controlled on Diet and Exercise:
Adverse Reactions Reported (Regardless of Investigator Assessment of Causality) in ≥5% of Patients Receiving Combination Therapy (and Greater than in Patients Receiving Placebo) *
| Number of Patients (%) | ||||
| Placebo | Sitagliptin 100 mg once daily | Metformin Immediate-Release 500 mg or 1000 mg twice daily † | Sitagliptin 50 mg twice daily + Metformin Immediate-Release 500 mg or 1000 mg twice daily† | |
| N = 176 | N = 179 | N = 364† | N = 372† | |
| Diarrhea | 7 (4.0) | 5 (2.8) | 28 (7.7) | 28 (7.5) |
| Upper Respiratory Tract Infection | 9 (5.1) | 8 (4.5) | 19 (5.2) | 23 (6.2) |
| Headache | 5 (2.8) | 2 (1.1) | 14 (3.8) | 22 (5.9) |
| * Intent-to-treat population. †Data pooled for the patients given the lower and higher doses of metformin. |
Sitagliptin Add-On Therapy In Patients With Type 2 Diabetes Inadequately Controlled On Metformin Immediate-Release Alone
In a 24-week placebo-controlled trial of sitagliptin 100 mg administered once daily added to a twice daily metformin immediate-release regimen, there were no adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo. Discontinuation of therapy due to clinical adverse reactions was similar to the placebo treatment group (sitagliptin and metformin immediate-release, 1.9%; placebo and metformin immediate-release, 2.5%).
Gastrointestinal Adverse Reactions
The incidences of pre-selected gastrointestinal adverse experiences in patients treated with sitagliptin and metformin immediate-release were similar to those reported for patients treated with metformin immediate-release alone. See Table 2.
Table 2: Pre-selected Gastrointestinal Adverse Reactions (Regardless of Investigator Assessment of Causality) Reported in Patients with Type 2 Diabetes Receiving Sitagliptin and Metformin Immediate-Release
| Number of Patients (%) | ||||||
| Study of Sitagliptin and Metformin Immediate-Release in Patients Inadequately Controlled on Diet and Exercise | Study of Sitagliptin Add-on in Patients Inadequately Controlled on Metformin Immediate-Release Alone | |||||
| Placebo | Sitagliptin 100 mg once daily | Metformin Immediate-Release 500 mg or 1000 mg twice daily * | Sitagliptin 50 mg bid + Metformin Immediate-Release 500 mg or 1000 mg twice daily * | Placebo and Metformin Immediate-Release ≥1500 mg daily | Sitagliptin 100 mg once daily and Metformin Immediate-Release ≥1500 mg daily | |
| N = 176 | N = 179 | N = 364 | N = 372 | N = 237 | N = 464 | |
| Diarrhea | 7 (4.0) | 5 (2.8) | 28 (7.7) | 28 (7.5) | 6 (2.5) | 11 (2.4) |
| Nausea | 2 (1.1) | 2 (1.1) | 20 (5.5) | 18 (4.8) | 2 (0.8) | 6 (1.3) |
| Vomiting | 1 (0.6) | 0 (0.0) | 2 (0.5) | 8 (2.2) | 2 (0.8) | 5 (1.1) |
| Abdominal Pain† | 4 (2.3) | 6 (3.4) | 14 (3.8) | 11 (3.0) | 9 (3.8) | 10 (2.2) |
| * Data pooled for the patients given the lower and higher doses of metformin. † Abdominal discomfort was included in the analysis of abdominal pain in the study of initial therapy. |
Sitagliptin In Combination With Metformin Immediate-Release And Glimepiride
In a 24-week placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin immediate-release and glimepiride (sitagliptin, N=116; placebo, N=113), the adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were: hypoglycemia (Table 3) and headache (6.9%, 2.7%).
Sitagliptin In Combination With Metformin Immediate-Release And Rosiglitazone
In a placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin immediate-release and rosiglitazone (sitagliptin, N=181; placebo, N=97), the adverse reactions reported regardless of investigator assessment of causality through Week 18 in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were: upper respiratory tract infection (sitagliptin, 5.5%; placebo, 5.2%) and nasopharyngitis (6.1%, 4.1%). Through Week 54, the adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were: upper respiratory tract infection (sitagliptin, 15.5%; placebo, 6.2%), nasopharyngitis (11.0%, 9.3%), peripheral edema (8.3%, 5.2%), and headache (5.5%, 4.1%).
Sitagliptin In Combination With Metformin Immediate-Release And Insulin
In a 24-week placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin immediate-release and insulin (sitagliptin, N=229; placebo, N=233), the only adverse reaction reported regardless of investigator assessment of causality in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo was hypoglycemia (Table 3).
Hypoglycemia
In all (N=5) studies, adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required although most (77%) reports of hypoglycemia were accompanied by a blood glucose measurement ≤70 mg/dL. When the combination of sitagliptin and metformin immediate-release was coadministered with a sulfonylurea or with insulin, the percentage of patients reporting at least one adverse reaction of hypoglycemia was higher than that observed with placebo and metformin immediate-release coadministered with a sulfonylurea or with insulin (Table 3).
Table 3: Incidence and Rate of Hypoglycemia* (Regardless of Investigator Assessment of Causality) in Placebo-Controlled Clinical Studies of Sitagliptin in Combination with Metformin Immediate-Release Coadministered with Glimepiride or Insulin
| Add-On to Glimepiride + Metformin Immediate-Release (24 weeks) | Sitagliptin 100 mg + Metformin Immediate-Release + Glimepiride | Placebo + Metformin Immediate-Release + Glimepiride |
| N = 116 | N = 113 | |
| Overall (%) | 19 (16.4) | 1 (0.9) |
| Rate (episodes/patient-year) † | 0.82 | 0.02 |
| Severe (%)‡ | 0 (0.0) | 0 (0.0) |
| Add-On to Insulin + Metformin Immediate-Release (24 weeks) | Sitagliptin 100 mg + Metformin Immedia | Placebo + Metformin Immediate-Release + Insulin |
| N = 229 | N = 233 | |
| Overall (%) | 35 (15.3) | 19 (8.2) |
| Rate (episodes/patient-year) † | 0.98 | 0.61 |
| Severe (%)‡ | 1 (0.4) | 1 (0.4) |
| * Adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required: Intent-to-treat population. † Based on total number of events (i.e., a single patient may have had multiple events). ‡ Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level/loss of consciousness or seizure. |
The overall incidence of reported adverse reactions of hypoglycemia in patients with type 2 diabetes inadequately controlled on diet and exercise was 0.6% in patients given placebo, 0.6% in patients given sitagliptin alone, 0.8% in patients given metformin immediate-release alone, and 1.6% in patients given sitagliptin in combination with metformin immediate-release. In patients with type 2 diabetes inadequately controlled on metformin immediate-release alone, the overall incidence of adverse reactions of hypoglycemia was 1.3% in patients given add-on sitagliptin and 2.1% in patients given add-on placebo.
In the study of sitagliptin and add-on combination therapy with metformin immediate-release and rosiglitazone, the overall incidence of hypoglycemia was 2.2% in patients given add-on sitagliptin and 0.0% in patients given add-on placebo through Week 18. Through Week 54, the overall incidence of hypoglycemia was 3.9% in patients given add-on sitagliptin and 1.0% in patients given add-on placebo.
Vital Signs And Electrocardiograms
With the combination of sitagliptin and metformin immediate-release, no clinically meaningful changes in vital signs or in electrocardiogram parameters (including the QTc interval) were observed.
Pancreatitis
In a pooled analysis of 19 double-blind clinical trials that included data from 10,246 patients randomized to receive sitagliptin 100 mg/day (N=5429) or corresponding (active or placebo) control (N=4817), the incidence of acute pancreatitis was 0.1 per 100 patient-years in each group (4 patients with an event in 4708 patient-years for sitagliptin and 4 patients with an event in 3942 patient-years for control).
Sitagliptin
The most common adverse experience in sitagliptin monotherapy reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo was nasopharyngitis.
Metformin Extended-Release
In a 24-week clinical trial in which extended-release metformin or placebo was added to glyburide therapy, the most common (>5% and greater than placebo) adverse reactions in the combined treatment group were hypoglycemia (13.7% vs. 4.9%), diarrhea (12.5% vs. 5.6%), and nausea (6.7% vs. 4.2%).
Laboratory Tests
Sitagliptin
The incidence of laboratory adverse reactions was similar in patients treated with sitagliptin and metformin immediate-release (7.6%) compared to patients treated with placebo and metformin (8.7%). In most but not all studies, a small increase in white blood cell count (approximately 200 cells/microL difference in WBC vs. placebo; mean baseline WBC approximately 6600 cells/microL) was observed due to a small increase in neutrophils. This change in laboratory parameters is not considered to be clinically relevant.
Metformin hydrochloride
In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum Vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or Vitamin B12 supplementation.
Postmarketing Experience
Additional adverse reactions have been identified during postapproval use of sitagliptin with metformin, sitagliptin, or metformin. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
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 ; worsening renal function, including acute renal failure (sometimes requiring dialysis) ; severe and disabling arthralgia ; bullous pemphigoid ; constipation; vomiting; headache; myalgia; pain in extremity; back pain; pruritus; cholestatic, hepatocellular, and mixed hepatocellular liver injury.
Sitagliptin
During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were administered. Maximal mean increases in QTc of 8.0 msec were observed in one study at a dose of 800 mg sitagliptin, a mean effect that is not considered clinically important. There is no experience with doses above 800 mg in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse reactions observed with sitagliptin with doses of up to 400 mg per day for periods of up to 28 days.
In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy as indicated by the patient's clinical status.
Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over a 3-to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.
Metformin Hydrochloride
Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.
Sitagliptin
In patients with type 2 diabetes, administration of sitagliptin led to inhibition of DPP-4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP-4 inhibition resulted in a 2-to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased responsiveness of insulin release to glucose, resulting in higher C-peptide and insulin concentrations. The rise in insulin with the decrease in glucagon was associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.
Sitagliptin And Metformin Hydrochloride Coadministration
In a two-day study in healthy subjects, sitagliptin alone increased active GLP-1 concentrations, whereas metformin alone increased active and total GLP-1 concentrations to similar extents. Coadministration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations. Sitagliptin, but not metformin, increased active GIP concentrations. It is unclear what these findings mean for changes in glycemic control in patients with type 2 diabetes.
In studies with healthy subjects, sitagliptin did not lower blood glucose or cause hypoglycemia.
Cardiac Electrophysiology
In a randomized, placebo-controlled crossover study, 79 healthy subjects were administered a single oral dose of sitagliptin 100 mg, sitagliptin 800 mg (8 times the recommended dose), and placebo. At the recommended dose of 100 mg, there was no effect on the QTc interval obtained at the peak plasma concentration, or at any other time during the study. Following the 800-mg dose, the maximum increase in the placebo-corrected mean change in QTc from baseline at 3 hours postdose was 8.0 msec. This increase is not considered to be clinically significant. At the 800-mg dose, peak sitagliptin plasma concentrations were approximately 11 times higher than the peak concentrations following a 100-mg dose.
In patients with type 2 diabetes administered sitagliptin 100 mg (N=81) or sitagliptin 200 mg (N=63) daily, there were no meaningful changes in QTc interval based on ECG data obtained at the time of expected peak plasma concentration.
Ristfor (Metformin hydrochloride_Sitagliptin)
The results of a study in healthy subjects demonstrated that the Ristfor (Metformin hydrochloride_Sitagliptin) (sitagliptin and metformin HCl extended-release) 50 mg/500 mg and 100 mg/1000 mg tablets are bioequivalent to coadministration of corresponding doses of sitagliptin and metformin hydrochloride extended-release.
Bioequivalence between two Ristfor (Metformin hydrochloride_Sitagliptin) 50 mg/500 mg tablets and one Ristfor (Metformin hydrochloride_Sitagliptin) 100 mg/1000 mg tablet was also demonstrated.
After administration of two Ristfor (Metformin hydrochloride_Sitagliptin) 50 mg/1000 mg tablets once daily with the evening meal for 7 days in healthy adult subjects, steady-state for sitagliptin and metformin is reached by Day 4 and 5, respectively. The median Tmax value for sitagliptin and metformin at steady state is approximately 3 and 8 hours postdose, respectively. The median Tmax value for sitagliptin and metformin after administration of a single tablet of JANUMET is 3 and 3.5 hours postdose, respectively.
Absorption
Ristfor (Metformin hydrochloride_Sitagliptin)
After administration of Ristfor (Metformin hydrochloride_Sitagliptin) tablets with a high-fat breakfast, the AUC for sitagliptin was not altered. The mean Cmax was decreased by 17%, although the median Tmax was unchanged relative to the fasted state. After administration of Ristfor (Metformin hydrochloride_Sitagliptin) with a high-fat breakfast, the AUC for metformin increased 62%, the Cmax for metformin decreased by 9%, and the median Tmax for metformin occurred 2 hours later relative to the fasted state.
Sitagliptin
The absolute bioavailability of sitagliptin is approximately 87%. Coadministration of a high-fat meal with sitagliptin had no effect on the pharmacokinetics of sitagliptin.
Distribution
Sitagliptin
The mean volume of distribution at steady state following a single 100-mg intravenous dose of sitagliptin to healthy subjects is approximately 198 liters. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).
Metformin hydrochloride
Distribution studies with extended-release metformin have not been conducted; however, the apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin hydrochloride tablets 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin hydrochloride tablets, steady-state plasma concentrations of metformin are reached within 24-48 hours and are generally <1 mcg/mL. During controlled clinical trials of metformin, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.
Metabolism
Sitagliptin
Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.
Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.
Metformin hydrochloride
Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion. Metabolism studies with extended-release metformin tablets have not been conducted.
Excretion
Sitagliptin
Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100-mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.
Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.
Metformin hydrochloride
Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
