1. Name Of The Medicinal Product
Janumet®
2. Qualitative And Quantitative Composition
'Janumet' 50 mg/1,000 mg film-coated tablets
Each tablet contains 50 mg of sitagliptin (as phosphate monohydrate) and 1,000 mg of metformin hydrochloride.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Film-coated tablet (tablet).
'Janumet' 50 mg/1,000 mg: Capsule-shaped, red film-coated tablet with “577” debossed on one side.
4. Clinical Particulars
4.1 Therapeutic Indications
For patients with type 2 diabetes mellitus:
'Janumet' is indicated as an adjunct to diet and exercise to improve glycaemic control in patients inadequately controlled on their maximal tolerated dose of metformin alone or those already being treated with the combination of sitagliptin and metformin.
'Janumet' is indicated in combination with a sulphonylurea (i.e., triple combination therapy) as an adjunct to diet and exercise in patients inadequately controlled on their maximal tolerated dose of metformin and a sulphonylurea.
'Janumet' is indicated as triple combination therapy with a peroxisome proliferator-activated receptor gamma (PPARγ) agonist (i.e., a thiazolidinedione) as an adjunct to diet and exercise in patients inadequately controlled on their maximal tolerated dose of metformin and a PPARγ agonist.
'Janumet' is also indicated as add
4.2 Posology And Method Of Administration
Posology
The dose of antihyperglycaemic therapy with 'Janumet' should be individualised on the basis of the patient's current regimen, effectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin.
For patients inadequately controlled on maximal tolerated dose of metformin monotherapy
For patients not adequately controlled on metformin alone, the usual starting dose of 'Janumet' should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) plus the dose of metformin already being taken.
For patients switching from co
For patients switching from co
For patients inadequately controlled on dual combination therapy with the maximal tolerated dose of metformin and a sulphonylurea
The dose of 'Janumet' should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and a dose of metformin similar to the dose already being taken. When 'Janumet' is used in combination with a sulphonylurea, a lower dose of the sulphonylurea may be required to reduce the risk of hypoglycaemia (see section 4.4).
For patients inadequately controlled on dual combination therapy with the maximal tolerated dose of metformin and a PPARγ agonist
The dose of 'Janumet' should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and a dose of metformin similar to the dose already being taken.
For patients inadequately controlled on dual combination therapy with insulin and the maximal tolerated dose of metformin
The dose of 'Janumet' should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and a dose of metformin similar to the dose already being taken. When 'Janumet' is used in combination with insulin, a lower dose of insulin may be required to reduce the risk of hypoglycaemia (see section 4.4).
For the different doses on metformin, 'Janumet' is available in strengths of 50 mg sitagliptin and 850 mg metformin hydrochloride or 1,000 mg metformin hydrochloride.
All patients should continue their diet with an adequate distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet.
Special populations
Renal impairment
'Janumet' should not be used in patients with moderate or severe renal impairment (creatinine clearance < 60 ml/min) (see sections 4.3 and 4.4).
Hepatic impairment
'Janumet' should not be used in patients with hepatic impairment (see sections 4.3 and 5.2).
Elderly
As metformin and sitagliptin are excreted by the kidney, 'Janumet' 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 (see sections 4.3 and 4.4). Limited safety data on sitagliptin is available in patients> 75 years of age and care should be exercised.
Paediatric population
'Janumet' is not recommended for use in children below 18 years of age due to a lack of data on its safety and efficacy in this population.
Method of administration
'Janumet' should be given twice daily with meals to reduce the gastrointestinal undesirable effects associated with metformin.
4.3 Contraindications
'Janumet' is contraindicated in patients with:
- hypersensitivity to the active substances or to any of the excipients (see sections 4.4 and 4.8);
- diabetic ketoacidosis, diabetic pre-coma;
- moderate and severe renal impairment (creatinine clearance < 60 ml/min) (see section 4.4);
- acute conditions with the potential to alter renal function such as:
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- acute or chronic disease which may cause tissue hypoxia such as:
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- hepatic impairment;
- acute alcohol intoxication, alcoholism;
- lactation.
4.4 Special Warnings And Precautions For Use
General
'Janumet' should not be used in patients with type 1 diabetes and must not be used for the treatment of diabetic ketoacidosis.
Pancreatitis
In post-marketing experience there have been spontaneously reported adverse reactions of acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of sitagliptin (with or without supportive treatment), but very rare cases of necrotizing or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, Janumet and other potentially suspect medicinal products should be discontinued.
Lactic acidosis
Lactic acidosis is a very rare, but serious (high mortality in the absence of prompt treatment), metabolic complication that can occur due to metformin accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by also assessing other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any conditions associated with hypoxia.
Diagnosis
Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/l, and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, treatment with the medicinal product should be discontinued and the patient hospitalised immediately (see section 4.9).
Renal function
Metformin and sitagliptin are known to be substantially excreted by the kidney. Metformin-related lactic acidosis increases with the degree of impairment of renal function, therefore, serum creatinine concentrations should be determined regularly:
- at least once a year in patients with normal renal function
- at least two to four times a year in patients with serum creatinine levels at or above the upper limit of normal and in elderly patients.
Decreased renal function in elderly patients 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 non-steroidal anti-inflammatory drug (NSAID).
Hypoglycaemia
Patients receiving 'Janumet' in combination with a sulphonylurea or with insulin may be at risk for hypoglycaemia. Therefore, a reduction in the dose of the sulphonylurea or insulin may be necessary.
Hypersensitivity reactions
Post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin have been reported. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first three months after initiation of treatment with sitagliptin, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue 'Janumet', assess for other potential causes of the event, and institute alternative treatment for diabetes (see section 4.8).
Surgery
As 'Janumet' contains metformin hydrochloride, the treatment should be discontinued 48 hours before elective surgery with general, spinal or epidural anaesthesia. 'Janumet' should not usually be resumed earlier than 48 hours afterwards and only after renal function has been re-evaluated and found to be normal.
Administration of iodinated contrast agent
The intravascular administration of iodinated contrast agents in radiological studies can lead to renal failure which has been associated with lactic acidosis in patients receiving metformin. Therefore, 'Janumet' should be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal (see section 4.5).
Change in clinical status of patients with previously controlled type 2 diabetes
A patient with type 2 diabetes previously well controlled on 'Janumet' 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, 'Janumet' must be stopped immediately and other appropriate corrective measures initiated.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Co
Pharmacokinetic drug interaction studies with 'Janumet' have not been performed; however, such studies have been conducted with the individual active substances of 'Janumet', sitagliptin and metformin.
There is increased risk of lactic acidosis in acute alcohol intoxication (particularly in the case of fasting, malnutrition or hepatic insufficiency) due to the metformin active substance of 'Janumet' (see section 4.4). Consumption of alcohol and medicinal products containing alcohol should be avoided.
Cationic agents that are eliminated by renal tubular secretion (e.g., cimetidine) may interact with metformin by competing for common renal tubular transport systems. A study conducted in seven normal healthy volunteers showed that cimetidine, administered as 400 mg twice daily, increased metformin systemic exposure (AUC) by 50 % and Cmax by 81 %. Therefore, close monitoring of glycaemic control, dose adjustment within the recommended posology and changes in diabetic treatment should be considered when cationic agents that are eliminated by renal tubular secretion are co
The intravascular administration of iodinated contrast agents in radiological studies may lead to renal failure, resulting in metformin accumulation and a risk of lactic acidosis. Therefore, 'Janumet' should be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal (see section 4.4).
Combination requiring precautions for use
Glucocorticoids (given by systemic and local routes) beta-2-agonists, and diuretics have intrinsic hyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoring performed, especially at the beginning of treatment with such medicinal products. If necessary, the dose of the anti-hyperglycaemic medicinal product should be adjusted during therapy with the other medicinal product and on its discontinuation.
ACE-inhibitors may decrease the blood glucose levels. If necessary, the dose of the antihyperglycaemic medicinal product should be adjusted during therapy with the other medicinal product and on its discontinuation.
Effects of other medicinal products on sitagliptin
Clinical data described below suggest that the risk for clinically meaningful interactions following co
Ciclosporin: A study was conducted to assess the effect of ciclosporin, a potent inhibitor of pmax of sitagliptin by approximately 29 % and 68 %, respectively. These changes in sitagliptin pharmacokinetics were not considered to be clinically meaningful. The renal clearance of sitagliptin was not meaningfully altered. Therefore, meaningful interactions would not be expected with other p
In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin is CYP3A4, with contribution from CYP2C8. In patients with normal renal function, metabolism, including via CYP3A4, plays only a small role in the clearance of sitagliptin. Metabolism may play a more significant role in the elimination of sitagliptin in the setting of severe renal impairment or end-stage renal disease (ESRD). For this reason, it is possible that potent CYP3A4 inhibitors (i.e., ketoconazole, itraconazole, ritonavir, clarithromycin) could alter the phamacokinetics of sitagliptin in patients with severe renal impairment or ESRD. The effects of potent CYP3A4 inhibitors in the setting of renal impairment has not been assessed in a clinical study.
In vitro transport studies showed that sitagliptin is a substrate for pin vitro by probenecid, although the risk of clinically meaningful interactions is considered to be low. Concomitant administration of OAT3 inhibitors has not been evaluated in vivo.
Effects of sitagliptin on other medicinal products
In vitro data suggest that sitagliptin does not inhibit nor induce CYP450 isoenzymes. In clinical studies, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low propensity for causing interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic cationic transporter (OCT). Sitagliptin had a small effect on plasma digoxin concentrations, and may be a mild inhibitor of pin vivo.
Digoxin: Sitagliptin had a small effect on plasma digoxin concentrations. Following administration of 0.25 mg digoxin concomitantly with 100 mg of sitagliptin daily for 10 days, the plasma AUC of digoxin was increased on average by 11 %, and the plasma Cmax on average by 18 %. No dose adjustment of digoxin is recommended. However, patients at risk of digoxin toxicity should be monitored for this when sitagliptin and digoxin are administered concomitantly.
4.6 Pregnancy And Lactation
There are no adequate data from the use of sitagliptin in pregnant women. Studies in animals have shown reproductive toxicity at high doses of sitagliptin (see section 5.3).
A limited amount of data suggest the use of metformin in pregnant women is not associated with an increased risk of congenital malformations. Animal studies with metformin do not indicate harmful effects with respect to pregnancy, embryonic or foetal development, parturition or postnatal development (see also section 5.3).
'Janumet' should not be used during pregnancy. If a patient wishes to become pregnant or if a pregnancy occurs, treatment with 'Janumet' should be discontinued and switched to insulin treatment as soon as possible.
No studies in lactating animals have been conducted with the combined active substances of 'Janumet' In studies performed with the individual active substances, both sitagliptin and metformin are excreted in the milk of lactating rats. Metformin is excreted in human milk in small amounts. It is not known whether sitagliptin is excreted in human milk. 'Janumet' must therefore not be used in women who are breast-feeding (see section 4.3).
4.7 Effects On Ability To Drive And Use Machines
'Janumet' has no known influence on the ability to drive and use machines. However, when driving or operating 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 'Janumet' is used in combination with sulphonylurea agents or with insulin.
4.8 Undesirable Effects
There have been no therapeutic clinical trials conducted with 'Janumet' tablets however bioequivalence of 'Janumet' with co
Sitagliptin and metformin
Adverse reactions considered as drug related reported in excess (> 0.2 % and difference> 1 patient) of placebo and in patients receiving sitagliptin in combination with metformin in double-blind studies are listed below as MedDRA preferred term by system organ class and absolute frequency (Table 1). Frequencies are defined as: very common (
Table 1. The frequency of adverse reactions identified from placebo-controlled clinical studies
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* In clinical trials of sitagliptin as monotherapy and sitagliptin as part of combination therapy with metformin or metformin and a PPARγ agent, rates of hypoglycaemia reported with sitagliptin were similar to rates in patients taking placebo.
† Observed in the 54-week analysis.
1 In this placebo-controlled 24-week study of sitagliptin 100 mg once daily added to ongoing metformin, the incidence of adverse reactions considered as drug
In an additional 1-year study of sitagliptin 100 mg once daily added to ongoing metformin, the incidence of adverse reactions considered as drug
In pooled studies of up to one year in duration comparing sitagliptin added to ongoing metformin to a sulphonylurea agent added to ongoing metformin, adverse reactions considered as drug
2 In this 24
3 In this study of sitagliptin 100 mg once daily in combination with rosiglitazone and metformin, which continued through 54 weeks, the incidence of adverse reactions considered as drug
4 In this 24
In a 24
Additional information on the individual active substances of the fixed dose combination
Sitagliptin
In addition, in monotherapy studies of up to 24 weeks in duration of sitagliptin 100 mg once daily alone compared to placebo, adverse reactions considered as drug
In addition to the drug related adverse reactions described above, adverse events (reported regardless of causal relationship to medicinal product) occurring in at least 5 % and more commonly in patients treated with sitagliptin included upper respiratory tract infection and nasopharyngitis. Additional adverse events that occurred more frequently in patients treated with sitagliptin (not reaching the 5 % level, but occurring with an incidence of> 0.5 % higher with sitagliptin than that in the control group) included osteoarthritis and pain in extremity.
Across clinical studies, a small increase in white blood cell (WBC) count (approximately 200 cells/microl difference in WBC vs placebo; mean baseline WBC approximately 6,600 cells/microl) was observed due to an increase in neutrophils. This observation was seen in most but not all studies. This change in laboratory parameters is not considered to be clinically relevant.
No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed with sitagliptin treatment.
Post-marketing data
During post-approval use of 'Janumet' or sitagliptin, one of the active substances of 'Janumet', additional adverse reactions have been reported (frequency not known). These reactions have been reported when 'Janumet' or sitagliptin have been used alone and/or in combination with other antihyperglycaemic agents: hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin conditions including Stevens-Johnson syndrome (see section 4.4); acute pancreatitis, including fatal and non-fatal haemorrhagic and necrotizing pancreatitis (see section 4.4); impaired renal function, including acute renal failure (sometimes requiring dialysis); vomiting.
Metformin
Clinical Trial Data and Post-marketing data
Table 2 presents adverse reactions by system organ class and by frequency category. Frequency categories are based on information available from metformin Summary of Product Characteristics available in the EU.
Table 2. The frequency of metformin adverse reactions identified from clinical trial and postmarketing data
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a Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption which may very rarely result in clinically significant vitamin B12 deficiency (e.g., megaloblastic anaemia).
bGastro-intestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite occur most frequently during initiation of therapy and resolve spontaneously in most cases.
4.9 Overdose
No data are available with regard to overdose of 'Janumet'.
During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were generally well tolerated. Minimal increases in QTc, not considered to be clinically relevant, were observed in one study at a dose of 800 mg sitagliptin. 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 600 mg per day for periods of up to 10 days and 400 mg per day for periods of up to 28 days.
A large overdose of metformin (or co-existing risks of lactic acidosis) may lead to lactic acidosis which is a medical emergency and must be treated in hospital. The most effective method to remove lactate and metformin is haemodialysis.
Sitagliptin is modestly dialysable. In clinical studies, approximately 13.5 % of the dose was removed over a 3- to 4
In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastro-intestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Medicines used in diabetes, combinations of oral blood glucose lowering drugs, ATC code: A10BD07
'Janumet' combines two antihyperglycaemic agents with complementary mechanisms of action to improve glycaemic control in patients with type 2 diabetes: sitagliptin phosphate, a dipeptidyl peptidase 4 (DPP-4) inhibitor, and metformin hydrochloride, a member of the biguanide class.
Sitagliptin
Sitagliptin phosphate is an orally-active, potent, and highly selective inhibitor of the dipeptidyl peptidase 4 (DPP-4) enzyme for the treatment of type 2 diabetes. The DPP-4 inhibitors are a class of agents that act as incretin enhancers. By inhibiting the DPP-4 enzyme, sitagliptin increases the levels of two known active incretin hormones, glucagon-like peptide
In a two
Overall, sitagliptin improved glycaemic control when used as monotherapy or in combination treatment.
In clinical trials, sitagliptin as monotherapy improved glycaemic control with significant reductions in haemoglobin A1c (HbA1c) and fasting and postprandial glucose. Reduction in fasting plasma glucose (FPG) was observed at three weeks, the first time point at which FPG was measured. The observed incidence of hypoglycaemia in patients treated with sitagliptin was similar to placebo. Body weight did not increase from baseline with sitagliptin therapy. Improvements in surrogate markers of beta cell function, including HOMA
Studies of sitagliptin in combination with metformin
In a 24
In a 24
Study of sitagliptin in combination with metformin and a sulphonylurea
A 24
Study of sitagliptin in combination with metformin and a PPARγ agonist
A 54
Study of sitagliptin in combination with metformin and insulin
A 24
Table 3: HbA1c results in placebo-controlled combination therapy studies of sitagliptin and metformin*
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* All Patients Treated Population (an intention-to-treat analysis).
† Least squares means adjusted for prior antihyperglycaemic therapy status and baseline value.
‡ p< 0.001 compared to placebo or placebo + combination treatment.
% HbA1c (%) at week 24.
§Least squares mean adjusted for insulin use at Visit 1 (pre
In a 521c (1c of approximately 7.5 % in both groups). The mean glipizide dose used in the comparator group was 10 mg per day with approximately 40 % of patients requiring a glipizide dose of
Metformin
Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.
Metformin may act via three mechanisms:
- by reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis
- in muscle, by modestly increasing insulin sensitivity, improving peripheral glucose uptake and utilisation
- by delaying intestinal glucose absorption.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin increases the transport capacity of specific types of membrane glucose transporters (GLUT-1 and GLUT-4).
In humans, independently of its action on glycaemia, metformin has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: metformin reduces total cholesterol, LDLc and triglyceride levels.
The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood glucose control in type 2 diabetes. Analysis of the results for overweight patients treated with metformin after failure of diet alone showed:
- a significant reduction of the absolute risk of any diabetes-related complication in the metformin group (29.8 events/1,000 patient-years) versus diet alone (43.3 events/1,000 patient-years), p=0.0023, and versus the combined sulphonylurea and insulin monotherapy groups (40.1 events/1,000 patient-years), p=0.0034
- a significant reduction of the absolute risk of any diabetes-related mortality: metformin 7.5 events/1,000 patient-years, diet alone 12.7 events/1,000 patient-years, p=0.017
- a significant reduction of the absolute risk of overall mortality: metformin 13.5 events/1,000 patient-years versus diet alone 20.6 events/1,000 patient-years, (p=0.011), and versus the combined sulphonylurea and insulin monotherapy groups 18.9 events/1,000 patient-years (p=0.021)
- a significant reduction in the absolute risk of myocardial infarction: metformin 11 events/1,000 patient-years, diet alone 18 events/1,000 patient-years, (p=0.01).
The European Medicines Agency has waived the obligation to submit the results of studies with 'Janumet' in all subsets of the paediatric population in type 2 diabetes mellitus (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic Properties
'Janumet'
A bioequivalence study in healthy subjects demonstrated that the 'Janumet' (sitagliptin/metformin hydrochloride) combination tablets are bioequivalent to co
The following statements reflect the pharmacokinetic properties of the individual active substances of 'Janumet'
Sitagliptin
Absorption
Following oral administration of a 100max) occurring 1 to 4 hours post-dose, mean plasma AUC of sitagliptin was 8.52 μM•hr, Cmax was 950 nM. The absolute bioavailability of sitagliptin is approximately 87 %. Since co
Plasma AUC of sitagliptin increased in a dose-proportional manner. Dose-proportionality was not established for C
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