1. Name Of The Medicinal Product
JANUVIA®
2. Qualitative And Quantitative Composition
Each tablet contains sitagliptin phosphate monohydrate, equivalent to 100 mg sitagliptin.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Film-coated tablet (tablet)
Round, beige film-coated tablet with “277” on one side.
4. Clinical Particulars
4.1 Therapeutic Indications
For patients with type 2 diabetes mellitus, Januvia is indicated to improve glycaemic control :
as monotherapy
• in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to contraindications or intolerance.
as dual oral therapy in combination with
• metformin when diet and exercise plus metformin alone do not provide adequate glycaemic control.
• a sulphonylurea when diet and exercise plus maximal tolerated dose of a sulphonylurea alone do not provide adequate glycaemic control and when metformin is inappropriate due to contraindications or intolerance.
• a peroxisome proliferator-activated receptor gamma (PPARγ) agonist (i.e. a thiazolidinedione) when use of a PPARγ agonist is appropriate and when diet and exercise plus the PPARγ agonist alone do not provide adequate glycaemic control.
as triple oral therapy in combination with
• a sulphonylurea and metformin when diet and exercise plus dual therapy with these agents do not provide adequate glycaemic control.
• a PPARγ agonist and metformin when use of a PPARγ agonist is appropriate and when diet and exercise plus dual therapy with these agents do not provide adequate glycaemic control.
Januvia is also indicated as add
4.2 Posology And Method Of Administration
Posology
The dose of Januvia is 100 mg once daily. When Januvia is used in combination with metformin and/or a PPARγ agonist, the dose of metformin and/or PPARγ agonist should be maintained, and Januvia administered concomitantly.
When Januvia is used in combination with a sulphonylurea or with insulin, a lower dose of the sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia. (See section 4.4.)
If a dose of Januvia is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day.
Special populations
Renal impairment
For patients with mild renal impairment (creatinine clearance [CrCl]
Clinical study experience with Januvia in patients with moderate or severe renal impairment is limited. Therefore, use of Januvia is not recommended in this patient population (see section 5.2).
Hepatic impairment
No dose adjustment is necessary for patients with mild to moderate hepatic impairment. Januvia has not been studied in patients with severe hepatic impairment.
Elderly
No dose adjustment is necessary based on age. Limited safety data is available in patients
Paediatric population
Januvia is not recommended for use in children below 18 years of age due to a lack of data on its safety and efficacy.
Method of administration
Januvia can be taken with or without food.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients (see section 4.4 and 4.8).
4.4 Special Warnings And Precautions For Use
General
Januvia should not be used in patients with type 1 diabetes or 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, Januvia and other potentially suspect medicinal products should be discontinued.
Hypoglycaemia when used in combination with other anti-hyperglycaemic agents
In clinical trials of Januvia as monotherapy and as part of combination therapy with agents not known to cause hypoglycaemia (i.e. metformin and/or a PPARγ agonist), rates of hypoglycaemia reported with sitagliptin were similar to rates in patients taking placebo. When sitagliptin was added to a sulphonylurea, or to insulin, the incidence of hypoglycaemia was increased over that of placebo (see section 4.8). Therefore, to reduce the risk of hypoglycaemia, a lower dose of sulphonylurea or insulin may be considered (see section 4.2).
Renal impairment
As the experience is limited, patients with moderate to severe renal impairment should not be treated with Januvia (see section 5.2).
Hypersensitivity Reactions
Postmarketing reports of serious hypersensitivity reactions in patients treated with Januvia have been reported. 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 Januvia, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue Januvia, assess for other potential causes for the event, and institute alternative treatment for diabetes. (See section 4.8).
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Effects of other medicinal products on sitagliptin
Clinical data described below suggest that the risk for clinically meaningful interactions by co-administered medicinal products is low.
Metformin: Co-administration of multiple twice-daily doses of 1000 mg metformin with 50 mg sitagliptin did not meaningfully alter the pharmacokinetics of sitagliptin in patients with type 2 diabetes.
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 p-glycoprotein and organic anion transporter-3 (OAT3). OAT3 mediated transport of sitagliptin was inhibited in 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 p-glycoprotein in vivo.
Digoxin: Sitagliptin had a small effect on plasma digoxin concentrations. Following administration of 0.25 mg digoxin concomitantly with 100 mg of Januvia 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
Pregnancy
There are no adequate data from the use of Januvia in pregnant women. Studies in animals have shown reproductive toxicity at high doses (see section 5.3). The potential risk for humans is unknown. Due to lack of human data, Januvia should not be used during pregnancy.
Lactation
It is unknown whether sitagliptin is excreted in human breast milk. Animal studies have shown excretion of sitagliptin in breast milk. Januvia should not be used during breast-feeding.
4.7 Effects On Ability To Drive And Use Machines
Januvia 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.
In addition, patients should be alerted to the risk of hypoglycaemia when Januvia is used in combination with sulphonylurea agents or with insulin.
4.8 Undesirable Effects
In 11 large clinical trials of up to 2 years in duration, over 3,200 patients have received treatment with Januvia 100 mg per day alone or in combination with metformin, a sulphonylurea (with or without metformin), insulin (with or without metformin), or a PPARγ agent (with or without metformin). In a pooled analysis of 9 of these trials, the rate of discontinuation due to adverse experiences considered drug-related was 0.8 % with 100 mg per day and 1.5 % with other treatments. No adverse reactions considered as drug-related were reported in patients treated with sitagliptin occurring in excess (> 0.2 % and difference > 1 patient) of that in patients treated with control. In an additional combination study with a PPARγ agent (rosiglitazone) and metformin, no patients were discontinued due to adverse experiences considered as drug
Adverse reactions considered as drug-related reported in patients treated with sitagliptin occurring in excess (> 0.2 % and difference> 1 patient) of that in patients treated with placebo are listed below (Table 1) by system organ class and frequency. 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 Januvia as monotherapy and sitagliptin as part of combination therapy with metformin and/or a PPARγ agent, rates of hypoglycaemia reported with sitagliptin were similar to rates in patients taking placebo.
1 In this placebo-controlled 24-week study of sitagliptin 100 mg once daily in combination with metformin, the incidence of adverse reactions considered as drug-related in patients treated with sitagliptin/metformin compared to treatment with placebo/metformin was 9.3 % and 10.1 %, respectively.
In an additional 1-year study of sitagliptin 100 mg once daily in combination with metformin, the incidence of adverse reactions considered as drug-related in patients treated with sitagliptin/metformin compared to sulphonylurea/metformin was 14.5 % and 30.3 %, respectively.
In pooled studies of up to 1 year in duration comparing sitagliptin/metformin to a sulphonylurea agent/metformin, adverse reactions considered as drug-related reported in patients treated with sitagliptin 100 mg occurring in excess (> 0.2 % and difference> 1 patient) of that in patients receiving the sulphonylurea agent are as follows: anorexia (Metabolism and nutritional disorders; frequency uncommon) and weight decreased (Investigations; frequency uncommon).
2 In this 24-week study of sitagliptin 100 mg once daily in combination with glimepiride, the incidence of adverse reactions considered as drug-related in patients treated with sitagliptin/glimepiride compared to treatment with placebo/glimepiride was 11.3 % and 6.6 %, respectively.
3 In this 24-week study of sitagliptin 100 mg once daily in combination with glimepiride and metformin, the incidence of adverse reactions considered as drug-related in patients treated with sitagliptin in combination with glimepiride/metformin compared to treatment with placebo in combination with glimepiride/metformin was 18.1 % and 7.1 %, respectively.
4 In this 24-week study of the combination of sitagliptin 100 mg once daily and pioglitazone, the incidence of adverse reactions considered as drug-related in patients treated with sitagliptin/pioglitazone compared to patients treated with placebo/pioglitazone was 9.1 % and 9.0 %, respectively.
5 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
6 In this 24
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-related reported in patients treated with sitagliptin in excess (> 0.2 % and difference> 1 patient) of that in patients receiving placebo are headache, hypoglycaemia, constipation, and dizziness.
In addition to the drug-related adverse experiences described above, adverse experiences reported regardless of causal relationship to medication and occurring in at least 5 % and more commonly in patients treated with Januvia included upper respiratory tract infection and nasopharyngitis. Additional adverse experiences reported regardless of causal relationship to medication that occurred more frequently in patients treated with Januvia (not reaching the 5 % level, but occurring with an incidence of> 0.5 % higher with Januvia than that in the control group) included osteoarthritis and pain in extremity.
In an additional 24
In a 24-week study of initial combination therapy with sitagliptin and metformin administered twice daily (sitagliptin/metformin 50 mg/500 mg or 50 mg/1000 mg), the overall incidence of adverse reactions considered as drug-related in patients treated with the combination of sitagliptin and metformin compared to patients treated with placebo was 14.0 % and 9.7 %, respectively. The overall incidence of adverse reactions considered as drug-related in patients treated with the combination of sitagliptin and metformin was comparable to metformin alone (14.0 % each) and greater than sitagliptin alone (6.7 %), with the differences relative to sitagliptin alone primarily due to gastrointestinal adverse reactions.
Across clinical 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 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 Januvia treatment.
Post-marketing Experience:
During post-approval use of Januvia as monotherapy and/or in combination with other antihyperglycaemic agents, additional side effects have been reported (frequency not known): 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.
4.9 Overdose
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
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 if required.
Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5 % of the dose was removed over a 3- to 4
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Medicines used in diabetes, Dipeptidyl peptidase 4 (DPP-4) inhibitors, ATC code: A10BH01.
Januvia is a member of a class of oral anti-hyperglycaemic agents called dipeptidyl peptidase 4 (DPP1c (HbA1c) and lower fasting and postprandial glucose concentrations. The glucose-dependent mechanism of sitagliptin is distinct from the mechanism of sulphonylureas, which increase insulin secretion even when glucose levels are low and can lead to hypoglycaemia in patients with type 2 diabetes and in normal subjects. Sitagliptin is a potent and highly selective inhibitor of the enzyme DPP
In a two
Overall, sitagliptin improved glycaemic control when used as monotherapy or in combination treatment (see Table 2).
Two studies were conducted to evaluate the efficacy and safety of Januvia monotherapy. Treatment with sitagliptin at 100 mg once daily as monotherapy provided significant improvements in HbA1c, fasting plasma glucose (FPG), and 2
In a study in patients with type 2 diabetes and chronic renal impairment (creatinine clearance < 50 ml/min), the safety and tolerability of reduced doses of sitagliptin were investigated and generally similar to placebo. In addition, the reductions in HbA1c and FPG with sitagliptin compared to placebo were generally similar to those observed in other monotherapy studies in patients with normal renal function (see section 5.2). The number of patients with moderate to severe renal impairment was too low to confirm safe use of sitagliptin in this type of patients.
Sitagliptin 100 mg once daily provided significant improvements in glycaemic parameters compared with placebo in two 24-week studies of sitagliptin as add-on therapy, one in combination with metformin and one in combination with pioglitazone. Change from baseline in body weight was similar for patients treated with sitagliptin relative to placebo. In these studies there was a similar incidence of hypoglycaemia reported for patients treated with sitagliptin or placebo.
A 24-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin (100 mg once daily) added to glimepiride alone or glimepiride in combination with metformin. The addition of sitagliptin to either glimepiride alone or to glimepiride and metformin provided significant improvements in glycaemic parameters. Patients treated with sitagliptin had a modest increase in body weight compared to those given placebo.
A 54
A 24
In a 24-week placebo-controlled factorial study of initial therapy, sitagliptin 50 mg twice daily in combination with metformin (500 mg or 1000 mg twice daily) provided significant improvements in glycaemic parameters compared with either monotherapy. The decrease in body weight with the combination of sitagliptin and metformin was similar to that observed with metformin alone or placebo; there was no change from baseline for patients on sitagliptin alone. The incidence of hypoglycaemia was similar across treatment groups.
Table 2. HbA1c results in placebo-controlled monotherapy and combination therapy studies*
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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 18.
% HbA1c (%) at week 24.
¶ Least squares mean adjusted for metformin use at Visit 1 (yes/no), insulin use at Visit 1 (pre
A 241c from mean baseline values of 7.2 % was
In a study comparing the efficacy and safety of the addition of Januvia 100 mg once daily or glipizide (a sulphonylurea agent) in patients with inadequate glycaemic control on metformin monotherapy, sitagliptin was similar to glipizide in reducing HbA1c . The mean glipizide dose used in the comparator group was 10 mg per day with approximately 40 % of patients requiring a glipizide dose of
The European Medicines Agency has deferred the obligation to submit the results of studies with Januvia in one or more subsets of the paediatric population in type 2 diabetes mellitus (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic Properties
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 coadministration of a high-fat meal with Januvia had no effect on the pharmacokinetics, Januvia may be administered with or without food.
Plasma AUC of sitagliptin increased in a dose-proportional manner. Dose-proportionality was not established for Cmax and C24hr (Cmax increased in a greater than dose-proportional manner and C24hr increased in a less than dose-proportional manner).
Distribution
The mean volume of distribution at steady state following a single 100
Biotransformation
Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway. Approximately 79 % of sitagliptin is excreted unchanged in the urine.
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 DPPIn vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.
In vitro data showed that sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is not an inducer of CYP3A4 and CYP1A2.
Elimination
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
Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporterIn vitro, sitagliptin did not inhibit OAT3 (IC50=160 μM) or p-glycoprotein (up to 250 μM) mediated transport at therapeutically relevant plasma concentrations. In a clinical study sitagliptin had a small effect on plasma digoxin concentrations indicating that sitagliptin may be a mild inhibitor of p-glycoprotein.
Characteristics in patients
The pharmacokinetics of sitagliptin were generally similar in healthy subjects and in patients with type 2 diabetes.
Renal impairment
A single-dose, open-label study was conducted to evaluate the pharmacokinetics of a reduced dose of sitagliptin (50
Patients with mild renal impairment did not have a clinically meaningful increase in the plasma concentration of sitagliptin as compared to normal healthy control subjects. An approximately 2
Hepatic impairment
No dose adjustment for Januvia is necessary for patients with mild or moderate hepatic impairment (Child-Pugh score
Elderly
No dose adjustment is required based on age. Age did not have a clinically meaningful impact on the pharmacokinetics of sitagliptin based on a population pharmacokinetic analysis of Phase I and Phase II data. Elderly subjects (65 to 80 years) had approximately 19 % higher plasma concentrations of sitagliptin compared to younger subjects.
Paediatric
No studies with Januvia have been performed in paediatric patients.
Other patient characteristics
No dose adjustment is necessary based on gender, race, or body mass index (BMI). These characteristics had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.
5.3 Preclinical Safety Data
Renal and liver toxicity were observed in rodents at systemic exposure values 58 times the human exposure level, while the no-effect level was found at 19 times the human exposure level. Incisor teeth abnormalities were observed in rats at exposure levels 67 times the clinical exposure level; the no-effect level for this finding was 58
Sitagliptin has not been demonstrated to be genotoxic in preclinical studies. Sitagliptin was not carcinogenic in mice. In rats, there was an increased incidence of hepatic adenomas and carcinomas at systemic exposure levels 58 times the human exposure level. Since hepatotoxicity has been shown to correlate with induction of hepatic neoplasia in rats, this increased incidence of hepatic tumours in rats was likely secondary to chronic hepatic toxicity at this high dose. Because of the high safety margin (19
No adverse effects upon fertility were observed in male and female rats given sitagliptin prior to and throughout mating.
In a pre-/postnatal development study performed in rats sitagliptin showed no adverse effects.
Reproductive toxicity studies showed a slight treatment-related increased incidence of fetal rib malformations (absent, hypoplastic and wavy ribs) in the offspring of rats at systemic exposure levels more than 29 times the human exposure levels. Maternal toxicity was seen in rabbits at more than 29 times the human exposure levels. Because of the high safety margins, these findings do not suggest a relevant risk for human reproduction. Sitagliptin is secreted in considerable amounts into the milk of lactating rats (milk/plasma ratio: 4:1).
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