Janumet

1.

NAME OF THE MEDICINAL PRODUCT

Janumet 50 mg/850 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 50 mg of sitagliptin (as phosphate monohydrate) and 850 mg of metformin

hydrochloride.

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet (tablet).

Capsule-shaped, pink film-coated tablet with “515” 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-on to insulin (i.e., triple combination therapy) as an adjunct to diet

and exercise to improve glycaemic control in patients when stable dose of insulin and metformin alone

do not provide adequate glycaemic control.

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-administration of sitagliptin and metformin

For patients switching from co-administration of sitagliptin and metformin, Janumet should be

initiated at the dose of sitagliptin and metformin already being taken.

2

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;

-

acute conditions with the potential to alter renal function such as:

-

dehydration,

3

-

moderate and severe renal impairment (creatinine clearance < 60 ml/min) (see section 4.4);

-

severe infection,

-

intravascular administration of iodinated contrast agents (see section 4.4);

-

acute or chronic disease which may cause tissue hypoxia such as:

-

cardiac or respiratory failure,

-

recent myocardial infarction,

-

shock;

-

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 nonsteroidal 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.

4

-

shock,

Hypersensitivity reactions

Postmarketing 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 3 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-administration of multiple doses of sitagliptin (50 mg twice daily) and metformin (1,000 mg twice

daily) did not meaningfully alter the pharmacokinetics of either sitagliptin or metformin in patients

with type 2 diabetes.

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 C max 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-administered.

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).

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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-administration of other medicinal products is low.

Ciclosporin: A study was conducted to assess the effect of ciclosporin, a potent inhibitor of

p-glycoprotein, on the pharmacokinetics of sitagliptin. Co-administration of a single 100 mg oral dose

of sitagliptin and a single 600 mg oral dose of ciclosporin increased the AUC and C max 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-glycoprotein inhibitors.

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 sitagliptin daily for 10 days, the plasma AUC of

digoxin was increased on average by 11 %, and the plasma C max 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 Fertility, 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

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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-administered sitagliptin and metformin has been demonstrated (see section 5.2).

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 (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon

(≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).

Table 1. The frequency of adverse reactions identified from placebo-controlled clinical studies

Adverse reaction

Frequency of adverse reaction by treatment regimen

Sitagliptin with

Metformin 1

Sitagliptin with

Metformin and a

Sulphonylurea 2

Sitagliptin with

Metformin and

a PPARγ Agent

(rosiglitazone) 3

Sitagliptin with

Metformin and

Insulin 4

Time-point

24-week

18-week

24-week

Metabolism and nutrition disorders

hypoglycaemia *

Very common

Common

Very common

Nervous system disorders

headache

Common

Uncommon

somnolence

Uncommon

Gastrointestinal disorders

diarrhoea

Uncommon

Common

nausea

Common

constipation

Common

upper abdominal

pain

Uncommon

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Adverse reaction

Frequency of adverse reaction by treatment regimen

Sitagliptin with

Metformin 1

Sitagliptin with

Metformin and a

Sulphonylurea 2

Sitagliptin with

Metformin and

a PPARγ Agent

(rosiglitazone) 3

Sitagliptin with

Metformin and

Insulin 4

Time-point

24-week

18-week

24-week

vomiting

Common

dry mouth

Uncommon

General disorders and administration site conditions

peripheral oedema

Common †

Investigations

blood glucose

decreased

Uncommon

* 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-related in patients treated with

sitagliptin added to ongoing metformin compared to treatment with placebo added to ongoing

metformin was 9.3 % and 10.1 %, respectively.

In an additional 1-year study of sitagliptin 100 mg once daily added to ongoing metformin, the

incidence of adverse reactions considered as drug-related in patients treated with sitagliptin added to

ongoing metformin compared to sulphonylurea added to ongoing metformin was 14.5 % and

30.3 %, respectively.

In pooled studies of up to 1 year in duration comparing sitagliptin added to ongoing metformin to a

sulphonylurea agent added to ongoing 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 placebo-controlled study of sitagliptin 100 mg once daily added to ongoing

combination treatment with glimepiride and metformin, the overall incidence of adverse reactions

considered as drug-related in patients treated with the addition of sitagliptin to the ongoing treatment

with glimepiride and metformin was 18.1 % compared to treatment with the addition of placebo to

the ongoing treatment with glimepiride and metformin which was 7.1 %.

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-related in

patients treated with sitagliptin combination compared to treatment with the placebo combination

was 15.3 % and 10.9 %, respectively. Other drug-related adverse reactions reported in the 54-week

analysis (frequency common) in patients treated with the sitagliptin combination occurring in excess

(> 0.2 % and difference > 1 patient) of that in patients treated with the placebo combination were:

headache, cough, vomiting, hypoglycaemia, fungal skin infection, and upper respiratory tract

infection.

4

In this 24-week placebo-controlled study of sitagliptin 100 mg once daily as add-on to insulin and

metformin, the incidence of adverse reactions considered as drug-related in patients treated with

sitagliptin in combination with insulin/metformin compared to treatment with placebo in

combination with insulin/metformin was 16.2 % and 9.0 %, respectively.

8

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/1,000 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.

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-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 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.

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Table 2. The frequency of metformin adverse reactions identified from clinical trial and

postmarketing data

Adverse reaction

Frequency

Metabolism and nutrition disorders

lactic acidosis Very rare

vitamin B12 deficiency a Very rare

Nervous system disorders

metallic taste Common

Gastrointestinal disorders

gastrointestinal symptoms b Very common

Hepatobiliary disorders

liver function disorders, hepatitis Very rare

Skin and subcutaneous tissue disorders

urticaria, erythema, pruritis Very rare

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).

b Gastrointestinal 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 dialyzable. In clinical studies, approximately 13.5 % of the dose was removed

over a 3- to 4-hour haemodialysis session. Prolonged haemodialysis may be considered if clinically

appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

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.

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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-1 (GLP-1) and glucose-dependent

insulinotropic polypeptide (GIP). The incretins are part of an endogenous system involved in the

physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or

elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells. GLP-1 also

lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production.

When blood glucose levels are low, insulin release is not enhanced and glucagon secretion is not

suppressed. Sitagliptin is a potent and highly selective inhibitor of the enzyme DPP-4 and does not

inhibit the closely-related enzymes DPP-8 or DPP-9 at therapeutic concentrations. Sitagliptin differs in

chemical structure and pharmacological action from GLP-1 analogues, insulin, sulphonylureas or

meglitinides, biguanides, peroxisome proliferator-activated receptor gamma (PPARγ) agonists, alpha-

glucosidase inhibitors, and amylin analogues.

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.

Co-administration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations.

Sitagliptin, but not metformin, increased active GIP concentrations.

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 A 1c (HbA 1c ) and fasting and postprandial glucose. Reduction in fasting plasma glucose

(FPG) was observed at 3 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-β (Homeostasis Model Assessment-β), proinsulin to insulin ratio, and

measures of beta cell responsiveness from the frequently-sampled meal tolerance test were observed.

Studies of sitagliptin in combination with metformin

In a 24-week, placebo-controlled clinical study to evaluate the efficacy and safety of the addition of

sitagliptin 100 mg once daily to ongoing metformin, sitagliptin provided significant improvements in

glycaemic parameters compared with placebo. Change from baseline in body weight was similar for

patients treated with sitagliptin relative to placebo. In this study there was a similar incidence of

hypoglycaemia reported for patients treated with sitagliptin or placebo.

In a 24-week placebo-controlled factorial study of initial therapy, sitagliptin 50 mg twice daily in

combination with metformin (500 mg or 1,000 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.

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Study of sitagliptin in combination with metformin and a sulphonylurea

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 in combination with metformin). The addition of

sitagliptin to glimepiride and metformin provided significant improvements in glycaemic parameters.

Patients treated with sitagliptin had a modest increase in body weight (+1.1 kg) compared to those

given placebo.

Study of sitagliptin in combination with metformin and a PPARγ agonist

A 54-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin

(100 mg once daily) added to the combination of rosiglitazone and metformin. The addition of

sitagliptin to rosiglitazone and metformin provided significant improvements in glycaemic parameters

at the primary timepoint of Week 18, with improvements sustained through the end of the study.

Change from baseline in body weight was similar for patients treated with sitagliptin relative to

placebo (1.9 vs. 1.3 kg).

Study of sitagliptin in combination with metformin and insulin

A 24-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin

(100 mg once daily) added to insulin (at a stable dose for at least 10 weeks) with or without metformin

(at least 1,500 mg). In patients taking pre-mixed insulin, the mean daily dose was 70.9 U/day. In

patients taking non-pre-mixed (intermediate/long-acting) insulin, the mean daily dose was 44.3 U/day.

Data from the 73 % of patients who were taking metformin are presented in Table 3. The addition of

sitagliptin to insulin provided significant improvements in glycaemic parameters. There was no

meaningful change from baseline in body weight in either group.

Table 3: HbA 1c results in placebo-controlled combination therapy studies of sitagliptin and

metformin *

Study

Mean baseline

HbA 1c (%)

Mean change from

baseline HbA 1c (%)

Placebo-corrected mean change

in HbA 1c (%)

(95 % CI)

Sitagliptin 100 mg once daily

added to ongoing metformin

therapy

(N=453)

8.0

-0.7 †

-0.7 †‡

(-0.8, -0.5)

Sitagliptin 100 mg once daily

added to ongoing glimepiride

+ metformin therapy

(N=115)

8.3

-0.6 †

-0.9 †‡

(-1.1, -0.7)

Sitagliptin 100 mg once daily

added to ongoing

rosiglitazone + metformin

therapy (N=170)

-0.7 †‡

(-0.9, -0.5)

-0.8 †‡

(-1.0, -0.5)

Week 18

8.8

-1.0 †

Week 54

8.8

-1.0 †

Sitagliptin 100 mg once daily

added to ongoing insulin +

metformin therapy

(N=223)

8.7

-0.7 §

-0.5 §,‡

(-0.7, -0.4)

Initial Therapy (twice daily) :

Sitagliptin 50 mg +

metformin 500 mg

(N=183)

8.8

-1.4 †

-1.6 †‡

(-1.8, -1.3)

12

Study

Mean baseline

HbA 1c (%)

Mean change from

baseline HbA 1c (%)

Placebo-corrected mean change

in HbA 1c (%)

(95 % CI)

Initial Therapy (twice daily) :

Sitagliptin 50 mg +

metformin 1,000 mg

(N=178)

8.8

-1.9 †

-2.1 †‡

(-2.3, -1.8)

* 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.

HbA 1c (%) at week 24.

§ Least squares mean adjusted for insulin use at Visit 1 (pre-mixed vs. non-pre-mixed [intermediate- or long-acting]), and

baseline value.

In a 52-week study, comparing the efficacy and safety of the addition of sitagliptin 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 HbA 1c (-0.7 % mean change from

baselines at week 52, with baseline HbA 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 ≤ 5 mg/day throughout the study. However, more patients in the sitagliptin group

discontinued due to lack of efficacy than in the glipizide group. Patients treated with sitagliptin

exhibited a significant mean decrease from baseline in body weight (-1.5 kg) compared to a significant

weight gain in patients administered glipizide (+1.1 kg). In this study, the proinsulin to insulin ratio, a

marker of efficiency of insulin synthesis and release, improved with sitagliptin and deteriorated with

glipizide treatment. The incidence of hypoglycaemia in the sitagliptin group (4.9 %) was significantly

lower than that in the glipizide group (32.0 %).

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)

13

-

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-administration of sitagliptin phosphate and

metformin hydrochloride as individual tablets.

The following statements reflect the pharmacokinetic properties of the individual active substances of

Janumet.

Sitagliptin

Absorption

Following oral administration of a 100-mg dose to healthy subjects, sitagliptin was rapidly absorbed,

with peak plasma concentrations (median T max ) occurring 1 to 4 hours post-dose, mean plasma AUC of

sitagliptin was 8.52 μM•hr, C max was 950 nM. The absolute bioavailability of sitagliptin is

approximately 87 %. Since co-administration of a high-fat meal with sitagliptin had no effect on the

pharmacokinetics, sitagliptin may be administered with or without food.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Dose-proportionality was not

established for C max and C 24hr (C max increased in a greater than dose-proportional manner and C 24hr

increased in a less than dose-proportional manner).

Distribution

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 %).

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 [ 14 C]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.

In vitro data showed that sitagliptin is not an inhibitor of CYP isoenzymes CYP3A4, 2C8, 2C9, 2D6,

1A2, 2C19 or 2B6, and is not an inducer of CYP3A4 and CYP1A2.

Elimination

Following administration of an oral [ 14 C]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 t ½ following a 100-mg oral dose of sitagliptin was approximately

12.4 hours. Sitagliptin accumulates only minimally with multiple doses. The 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

14

been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in

mediating the renal elimination of sitagliptin. However, ciclosporin, a p-glycoprotein inhibitor, did not

reduce the renal clearance of sitagliptin. Sitagliptin is not a substrate for OCT2 or OAT1 or PEPT1/2

transporters. In 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 mg) in patients with varying degrees of chronic renal impairment compared to normal

healthy control subjects. The study included patients with renal impairment classified on the basis of

creatinine clearance as mild (50 to < 80 ml/min), moderate (30 to < 50 ml/min), and severe

(< 30 ml/min), as well as patients with end-stage renal disease (ESRD) on haemodialysis.

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-fold

increase in the plasma AUC of sitagliptin was observed in patients with moderate renal impairment,

and an approximately 4-fold increase was observed in patients with severe renal impairment and in

patients with ESRD on haemodialysis, as compared to normal healthy control subjects. Sitagliptin was

modestly removed by haemodialysis (13.5 % over a 3- to 4-hour haemodialysis session starting

4 hours post-dose). Sitagliptin is not recommended for use in patients with moderate or severe renal

impairment including those with ESRD since experience in these patients is too limited (see

section 4.2).

Hepatic impairment

No dose adjustment for sitagliptin is necessary for patients with mild or moderate hepatic impairment

(Child-Pugh score ≤ 9). There is no clinical experience in patients 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.

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 sitagliptin 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.

Metformin

Absorption

After an oral dose of metformin, tmax is reached in 2.5 h. Absolute bioavailability of a 500 mg

metformin tablet is approximately 50-60 % in healthy subjects. After an oral dose, the non-absorbed

fraction recovered in faeces was 20-30 %.

15

After oral administration, metformin absorption is saturable and incomplete. It is assumed that the

pharmacokinetics of metformin absorption is non-linear. At the usual metformin doses and dosing

schedules, steady state plasma concentrations are reached within 24-48 h and are generally less than 1

µg/ml. In controlled clinical trials, maximum metformin plasma levels (C max ) did not exceed 4 µg/ml,

even at maximum doses.

Food decreases the extent and slightly delays the absorption of metformin. Following administration

of a dose of 850 mg, a 40 % lower plasma peak concentration, a 25 % decrease in AUC and a 35 min

prolongation of time to peak plasma concentration was observed. The clinical relevance of this

decrease is unknown.

Distribution

Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower

than the plasma peak and appears at approximately the same time. The red blood cells most likely

represent a secondary compartment of distribution. The mean Vd ranged between 63 – 276 l.

Biotransformation

Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.

Elimination

Renal clearance of metformin is > 400 ml/min, indicating that metformin is eliminated by glomerular

filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is

approximately 6.5 h. When renal function is impaired, renal clearance is decreased in proportion to

that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of

metformin in plasma.

5.3 Preclinical safety data

No animal studies have been conducted with Janumet.

In 16-week studies in which dogs were treated with either metformin alone or a combination of

metformin and sitagliptin, no additional toxicity was observed from the combination. The NOEL in

these studies was observed at exposures to sitagliptin of approximately 6 times the human exposure

and to metformin of approximately 2.5 times the human exposure.

The following data are findings in studies performed with sitagliptin or metformin individually.

Sitagliptin

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-fold based on the 14-week rat study. The relevance of these

findings for humans is unknown. Transient treatment-related physical signs, some of which suggest

neural toxicity, such as open-mouth breathing, salivation, white foamy emesis, ataxia, trembling,

decreased activity, and/or hunched posture were observed in dogs at exposure levels approximately

23 times the clinical exposure level. In addition, very slight to slight skeletal muscle degeneration was

also observed histologically at doses resulting in systemic exposure levels of approximately 23 times

the human exposure level. A no-effect level for these findings was found at an exposure 6-fold the

clinical exposure level.

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 tumors in rats

was likely secondary to chronic hepatic toxicity at this high dose. Because of the high safety margin

(19-fold at this no-effect level), these neoplastic changes are not considered relevant for the situation

in humans.

16

No treatment related effects on 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).

Metformin

Preclinical data for metformin reveal no special hazard for humans based on conventional studies of

safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to

reproduction.

6.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core :

microcrystalline cellulose (E460)

povidone K29/32 (E1201)

sodium lauril sulfate

sodium stearyl fumarate

Film coating :

polyvinyl alcohol

macrogol 3350

talc (E553b)

titanium dioxide (E171)

iron oxide red (E172)

iron oxide black (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

24 months.

6.4 Special precautions for storage

Do not store above 30°C.

6.5 Nature and contents of container

Opaque blisters (PVC/PE/PVDC and aluminum). Packs of 14, 28, 56, 112, 168, 196 film-coated

tablets, multi-packs containing 196 (2 packs of 98) film-coated tablets. Pack of 50 x 1 film-coated

tablets in perforated unit dose blisters.

Not all pack sizes may be marketed.

17

6.6 Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

7.

MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme Ltd.

Hertford Road, Hoddesdon

Hertfordshire EN11 9BU

United Kingdom

8.

MARKETING AUTHORISATION NUMBER(S)

EU/1/08/455/001

EU/1/08/455/002

EU/1/08/455/003

EU/1/08/455/004

EU/1/08/455/005

EU/1/08/455/006

EU/1/08/455/007

EU/1/08/455/015

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

16 July 2008

10. DATE OF REVISION OF THE TEXT

Detailed information on this product is available on the website of the European Medicines Agency

web site: http://www.ema.europa.eu/.

18

1.

NAME OF THE MEDICINAL PRODUCT

Janumet 50 mg/1,000 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

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).

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-on to insulin (i.e., triple combination therapy) as an adjunct to diet

and exercise to improve glycaemic control in patients when stable dose of insulin and metformin alone

do not provide adequate glycaemic control.

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-administration of sitagliptin and metformin

For patients switching from co-administration of sitagliptin and metformin, Janumet should be

initiated at the dose of sitagliptin and metformin already being taken.

19

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;

-

acute conditions with the potential to alter renal function such as:

-

dehydration,

20

-

moderate and severe renal impairment (creatinine clearance < 60 ml/min) (see section 4.4);

-

severe infection,

-

intravascular administration of iodinated contrast agents (see section 4.4);

-

acute or chronic disease which may cause tissue hypoxia such as:

-

cardiac or respiratory failure,

-

recent myocardial infarction,

-

shock;

-

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 nonsteroidal 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.

21