Sitagliptin phosphate monohydrate/metformin hydrochloride
- JANUMET XR is available for oral administration as film-coated tablets containing sitagliptin phosphate monohydrate equivalent to 50 mg sitagliptin as free base and either 500 mg metformin hydrochloride modified release (JANUMET XR 50 mg/500 mg*), or 1000 mg metformin hydrochloride modified release (JANUMET XR 50 mg/1000 mg).
- Additionally, JANUMET XR is available for oral administration as tablets containing sitagliptin phosphate monohydrate equivalent to 100 mg sitagliptin as free base and 1000 mg metformin hydrochloride modified release (JANUMET XR 100 mg/1000 mg).
- JANUMET XR is indicated as an adjunct to healthy eating and physical activity to improve glycaemic management in adults with type 2 diabetes mellitus when treatment with both sitagliptin and metformin is appropriate.
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Life threatening lactic acidosis can occur due to accumulation of metformin. The main risk factor is renal impairment, other risk factors include old age associated with reduced renal function and high doses of metformin above 2g per day.
- The dosage of antihyperglycemic therapy with JANUMET XR should be individualised on the basis of a person’s current regimen, effectiveness and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin. (Person centred care)
- JANUMET XR should be given once daily with a meal preferably in the evening. The dose should be escalated gradually to reduce the gastrointestinal (GI) side effects due to metformin. Additionally, administration of JANUMET XR with food enhances plasma concentrations of metformin. To preserve the modified-release properties, the tablets must not be split, broken, crushed, or chewed before swallowing. There have been reports of incompletely dissolved JANUMET XR tablets being eliminated in the faeces. It is not known whether this material seen in faeces contains active drug. If an individual reports repeatedly seeing tablets in faeces, the healthcare provider should assess adequacy of glycaemic management.
- As initial therapy:-For individuals with type 2 diabetes mellitus, whose hyperglycaemia is inadequately managed with healthy eating and physical activity, when dual therapy is appropriate, the recommended total daily starting dose of JANUMET XR is 100 mg sitagliptin and 1000 mg metformin hydrochloride. Individuals with inadequate glycaemic management on this dose should have their metformin dose increased up to a maximum of 100 mg sitagliptin/2000 mg metformin hydrochloride daily. -For individuals inadequately managed on sitagliptin monotherapy. For those whose diabetes is inadequately on sitagliptin alone, the recommended starting dose of JANUMET XR is 100 mg sitagliptin and 1000 mg metformin hydrochloride daily. Individuals may be titrated up to 100 mg sitagliptin/2000 mg metformin hydrochloride daily to achieve healthy glycaemia. Individuals taking sitagliptin monotherapy dose-adjusted for renal impairment should not be switched to JANUMET XR. -For individuals, whose diabetes is inadequately managed on metformin monotherapy. For those whose diabetes is not adequately managed on metformin alone, the usual starting dose of JANUMET XR should provide sitagliptin 100 mg total daily dose plus the dose of metformin already being taken. -For individuals switching from sitagliptin co-administered with metformin. For individuals switching from sitagliptin co-administered with metformin, JANUMET XR may be initiated at the dose of sitagliptin, and metformin already being taken. -For individuals who diabetes is inadequately managed on dual combination therapy with metformin and a sulfonylurea. The usual starting dose of JANUMET XR should provide sitagliptin 100 mg total daily dose and the dose of metformin already being taken. Individuals may require lower sulfonylurea doses to reduce the risk of sulfonylurea-induced hypoglycaemia. Note: Diabetes MedsCheck with counselling on managing hypoglycaemia and referral for blood glucose monitoring. -For individuals, whose diabetes is inadequately managed on dual combination therapy with metformin and insulin. The usual starting dose of JANUMETXR should provide 100 mg total daily dose of sitagliptin. In determining the starting dose of the metformin component, an individual’s level of glycaemia and current dose of metformin should be considered. Individuals currently on or initiating insulin therapy may require lower doses of insulin to reduce the risk of hypoglycaemia Note: Diabetes MedsCheck with counselling on managing hypoglycaemia and referral for blood glucose monitoring.
- Renal impairment: No dose adjustment is needed in mild renal impairment (estimated glomerular filtration rate [eGFR] ≥ 60 mL/min/1.73 m2). An eGFR should be assessed before initiation of treatment with JANUMET XR and at least annually thereafter. In those at increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g., every 3-6 months.
- Factors that may increase risk of lactic acidosis should be reviewed before considering initiation of metformin in those with eGFR < 60 mL/min/1.73 m2. JANUMET XR is prescribed once daily. JANUMET XR is contraindicated in those with eGFR < 30 mL/min/1.73 m2 Discontinue JANUMET XR if the eGFR later falls below 30 mL/min/1.73 m2 Initiation of JANUMET XR in individuals with an eGFR ≥ 30 mL/min/1.73 m2 and < 45 mL/min/1.73 m2 is not recommended. In those taking JANUMET XR whose eGFR later falls below 45 mL/min/1.73 m2 the benefit and risk of continuing therapy should be assessed and dose of the sitagliptin component limited to 50 mg once day.
- Hepatic Impairment-Sitagliptin phosphate monohydrate: In individuals with moderate hepatic impairment (Child-Pugh score 7 to 9), mean AUC and Cmax of sitagliptin increased approximately 21% and 13%, respectively, compared to healthy matched controls following administration of a single 100 mg dose of sitagliptin. These differences are not considered to be clinically meaningful. There is no clinical experience in those with severe hepatic impairment (Child-Pugh score > 9). However, because sitagliptin is primarily renally eliminated, severe hepatic impairment is not expected to affect the pharmacokinetics of sitagliptin. -Metformin hydrochloride: No pharmacokinetic studies of metformin have been conducted in those with hepatic impairment. Impaired hepatic function has been associated with some cases of lactic acidosis in those taking metformin, however.
- JANUMET XR should be temporarily discontinued in those undergoing radiological studies involving intravascular administration of iodinated contrast materials, because the use of such products may result in acute alteration of renal function.
As metformin and sitagliptin are excreted by the kidney, JANUMET XR should be used with caution as age increases. Monitoring of renal function is necessary to aid in prevention of metformin-associated lactic acidosis, particularly in the elderly.
JANUMET XR are not currently indicated for use in children below 18 years.
- Severe renal impairment (eGFR < 30 mL/min/1.73 m2)
- Known hypersensitivity to sitagliptin phosphate monohydrate, metformin hydrochloride or any other component of JANUMET XR.
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
- General - JANUMET XR should not be used in individuals with type 1 diabetes mellitus.
-Lactic acidosis: Lactic acidosis is a rare, but serious metabolic complication that can occur due to metformin accumulation during treatment with metformin. When it occurs, it is fatal in approximately 50% of cases. Lactic acidosis is a medical emergency and must be treated in hospital immediately. The risk of lactic acidosis increases with the degree of renal dysfunction. Reported cases of lactic acidosis in individuals on metformin have occurred primarily in those with diabetes with significant renal insufficiency, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Special caution should be taken in the elderly due to the decrease of renal function with age.
Note: Diabetes MedsCheck for referral to healthcare team for education on lactic acidosis.
-Surgery: Metformin must be discontinued at the time of surgery under general, spinal or epidural anaesthesia. Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and provided that renal function has been re-evaluated and found to be stable.
- Monitoring of renal function: Renal function should be confirmed before initiation of JANUMET therapy, and then at least once a year in those with normal renal function and at least two to four times a year if serum creatinine levels are at or above the upper limit of normal and in elderly individuals.
Decreased renal function in the elderly is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive or diuretic therapy or when starting treatment with a nonsteroidal anti-inflammatory drug (NSAID).
Note: Diabetes MedsCheck with referral for annual cycle of care.
- Alcohol Intake: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Individuals, therefore, should be warned against excessive alcohol intake while receiving JANUMET XR.
-Gastrointestinal disorders: Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain, and loss of appetite are very common (>10%): these occur most frequently during initiation of therapy and resolve spontaneously in most cases. To prevent these gastrointestinal symptoms, it is recommended that this medicinal product be taken in 2 or 3 daily doses. A slow increase of the dose may also improve gastrointestinal tolerability.
-Metabolism and nutrition disorders: Lactic acidosis is a very rare (<0.01%) but serious metabolic complication that can occur due to metformin accumulation during treatment with metformin. The onset of lactic acidosis is often subtle and accompanied only by non-specific symptoms such as malaise, myalgia, respiratory distress, increasing somnolence and non-specific abdominal distress. There may be associated hypothermia, hypotension and resistant bradyarrhythmias with more marked acidosis.
Note: Diabetes MedsCheck with referral to healthcare team for education on lactic acidosis.
-Hepatobiliary disorders: Very rare: liver function test abnormalities or hepatitis requiring treatment discontinuation.
-Skin and subcutaneous tissue disorders: Skin reactions such as erythema, pruritus and urticaria have been reported but the incidence is very rare (<0.01%).
-Nervous system disorders
-Taste disturbance (3 %) is common.
-Vitamin B12 Levels: In controlled, 29-week clinical trials of immediate release metformin, 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 anaemia and appears to be rapidly reversible with discontinuation of metformin or Vitamin B12 supplementation. Measurement of haematologic parameters on an annual basis is advised in patients on JANUMET XR 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). See interventions for further information.
- The results of a definitive bioequivalence study in healthy subjects demonstrated that the JANUMET XR (sitagliptin phosphate monohydrate/metformin hydrochloride) 50 mg/500 mg and 50 mg/1000 mg combination tablets are bioequivalent to coadministration of corresponding doses of sitagliptin phosphate monohydrate (JANUVIA®) and metformin hydrochloride as individual tablets. Because bioequivalence is demonstrated at the lowest and highest combination tablet dose strengths available, bioequivalence is conferred to the (sitagliptin/metformin) 50 mg/850 mg fixed dose combination (FDC) tablet.
- After administration of JANUMET XR 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 JANUMET XR 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 phosphate monohydrate: The mean volume of distribution at steady state following a single 100 mg intravenous dose of sitagliptin to healthy subjects is approximately 198 litres. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).
- Metformin hydrochloride: The apparent volume of distribution (V/F) of metformin following single oral doses of metformin hydrochloride tablets 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. 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 microgram/mL.
- Sitagliptin phosphate monohydrate: Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway. Approximately 79% of sitagliptin is excreted unchanged in the urine.
- 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.
- Sitagliptin phosphate monohydrate: Following administration of an oral [14C] sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in faeces (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.
- 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.
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