Jimandin 100 mg Filmdragerad tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

21-04-2018

Produktens egenskaper Produktens egenskaper (SPC)

21-04-2018

Aktiva substanser:
sitagliptinfosfatmonohydrat
Tillgänglig från:
Medochemie Ltd,
ATC-kod:
A10BH01
INN (International namn):
sitagliptin phosphate monohydrate
Dos:
100 mg
Läkemedelsform:
Filmdragerad tablett
Sammansättning:
sitagliptinfosfatmonohydrat 128,5 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Blister, 14 tabletter; Blister, 28 tabletter; Blister, 30 tabletter; Blister, 56 tabletter; Blister, 84 tabletter; Blister, 90 tabletter; Blister, 98 tabletter
Bemyndigande status:
Godkänd
Godkännandenummer:
53338
Tillstånd datum:
2017-08-18

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

27-08-2020

Produktens egenskaper Produktens egenskaper - engelska

21-06-2017

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

18-08-2017

Läs hela dokumentet

Package leaflet: Information for the patient

Jimandin 25 mg film-coated tablets

Jimandin 50 mg film-coated tablets

Jimandin 100 mg film-coated tablets

Sitagliptin

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet

What Jimandin is and what it is used for

What you need to know before you take Jimandin

How to take Jimandin

Possible side effects

How to store Jimandin

Contents of the pack and other information

1.

What Jimandin is and what it is used for

Jimandin contains the active substance sitagliptin which is a member of a class of medicines called

DPP-4 inhibitors (dipeptidyl peptidase-4 inhibitors) that lowers blood sugar levels in adult patients

with type 2 diabetes mellitus.

This medicine helps to improve the levels of insulin after a meal and decreases the amount of sugar

made by the body.

Your doctor has prescribed this medicine to help lower your blood sugar, which is too high because of

your type 2 diabetes. This medicine can be used alone or in combination with certain other medicines

(insulin, metformin, sulphonylureas, or glitazones) that lower blood sugar, which you may already be

taking for your diabetes together with a food and exercise plan.

What is type 2 diabetes?

Type 2 diabetes is a condition in which your body does not make enough insulin, and the insulin that

your body produces does not work as well as it should. Your body can also make too much sugar.

When this happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems

like heart disease, kidney disease, blindness, and amputation.

2.

What you need to know before you take Jimandin

Do not take Jimandin:

if you are allergic to sitagliptin or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions

Talk to your doctor or pharmacist before taking Jimandin.

Cases of inflammation of the pancreas (pancreatitis) have been reported in patients receiving Jimandin

(see section 4).

If you encounter blistering of the skin it may be a sign for a condition called bullous pemphigoid.

Your doctor may ask you to stop Jimandin.

Tell your doctor if you have or have had:

a disease of the pancreas (such as pancreatitis)

gallstones, alcohol dependence or very high levels of triglycerides (a form of fat) in your blood.

These medical conditions can increase your chance of getting pancreatitis (see section 4).

type 1 diabetes

diabetic ketoacidosis (a complication of diabetes with high blood sugar, rapid weight loss, nausea

or vomiting)

any past or present kidney problems.

an allergic reaction to Jimandin (see section 4).

This medicine is unlikely to cause low blood sugar because it does not work when your blood sugar is

low. However, when this medicine is used in combination with a sulphonylurea medicine or with

insulin, low blood sugar (hypoglycaemia) can occur. Your doctor may reduce the dose of your

sulphonylurea or insulin medicine.

Children and adolescents

Children and adolescents below 18 years should not use this medicine. It is not effective in children

and adolescents between the ages of 10 and 17 years. It is not known if this medicine is safe and

effective when used in children younger than 10 years.

Other medicines and Jimandin

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other

medicines.

In particular, tell your doctor if you are taking digoxin (a medicine used to treat irregular heart beat

and other heart problems). The level of digoxin in your blood may need to be checked if taking with

Jimandin.

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask

your doctor or pharmacist for advice before taking this medicine.

You should not take this medicine during pregnancy.

It is not known if this medicine passes into breast milk. You should not take this medicine if you are

breast-feeding or plan to breast-feed.

Driving and using machines

This medicine has no known influence on the ability to drive and use machines. However, dizziness

and drowsiness have been reported, which may affect your ability to drive or use machines.

Taking this medicine in combination with medicines called sulphonylureas or with insulin can cause

hypoglycaemia, which may affect your ability to drive and use machines or work without safe

foothold.

3.

How to take Jimandin

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist

if you are not sure.

The recommended dose is:

one 100 mg film-coated tablet

once a day

by mouth

If you have kidney problems, your doctor may prescribe lower doses (such as 25 mg or 50 mg).

You can take this medicine with or without food and drink.

Your doctor may prescribe this medicine alone or with certain other medicines that lower blood sugar.

Diet and exercise can help your body use its blood sugar better. It is important to stay on the diet,

exercise and weight loss program recommended by your doctor while taking Jimandin.

If you take more Jimandin than you should

If you take more than the prescribed dosage of this medicine, contact your doctor immediately.

If you forget to take Jimandin

If you miss a dose, take it as soon as you remember. If you do not remember until it is time for your

next dose, skip the missed dose and go back to your regular schedule. Do not take a double dose of

this medicine.

If you stop taking Jimandin

Continue to take this medicine as long as your doctor prescribes it so you can continue to help control

your blood sugar. You should not stop taking this medicine without talking to your doctor first.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

STOP taking Jimandin and contact a doctor immediately if you notice any of the following

serious side effects:

Severe and persistent pain in the abdomen (stomach area) which might reach through to your back

with or without nausea and vomiting, as these could be signs of an inflamed pancreas

(pancreatitis).

If you have a serious allergic reaction (frequency not known), including rash, hives, blisters on the

skin/peeling skin and swelling of the face, lips, tongue, and throat that may cause difficulty in

breathing or swallowing, stop taking this medicine and call your doctor right away. Your doctor may

prescribe a medicine to treat your allergic reaction and a different medicine for your diabetes.

Some patients have experienced the following side effects after adding sitagliptin to metformin:

Common (may affect up to 1 in 10 people): low blood sugar, nausea, flatulence, vomiting

Uncommon (may affect up to 1 in 100 people): stomach ache, diarrhoea, constipation, drowsiness.

Some patients have experienced different types of stomach discomfort when starting the combination

of sitagliptin and metformin together (frequency is common).

Some patients have experienced the following side effects while taking sitagliptin in combination

with a sulphonylurea and metformin:

Very common (may affect more than 1 in 10 people): low blood sugar

Common (may affect up to 1 in 10 people): constipation.

Some patients have experienced the following side effects while taking sitagliptin and

pioglitazone:

Common (may affect up to 1 in 10 people): flatulence, swelling of hands or legs.

Some patients have experienced the following side effects while taking sitagliptin in combination

with pioglitazone and metformin:

Common (may affect up to 1 in 10 people): swelling of the hands or legs.

Some patients have experienced the following side effects while taking sitagliptin in combination

with insulin (with or without metformin):

Common (may affect up to 1 in 10 people): flu

Uncommon (may affect up to 1 in 100 people): dry mouth.

Some patients have experienced the following side effects while taking sitagliptin alone in clinical

studies, or during post-approval use alone and/or with other diabetes medicines:

Common (may affect up to 1 in 10 people): low blood sugar, headache, upper respiratory infection,

stuffy or runny nose and sore throat, osteoarthritis, arm or leg pain

Uncommon (may affect up to 1 in 100 people): dizziness, constipation, itching

Rare (may affect up to 1 in 1,000 people): reduced number of platelets

Frequency not known (frequency cannot be estimated from the available data): kidney problems

(sometimes requiring dialysis), vomiting, joint pain, muscle pain, back pain, interstitial lung disease,

bullous pemphigoid (a type of skin blister).

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet. You can also report side effects directly via the national reporting system.

By reporting side effects you can help provide more information on the safety of this medicine.

5.

How to store Jimandin

Keep this medicine out of the sight and reach of children.

This medicinal product does not require any special storage conditions.

Do not use this medicine after the expiry date, which is stated on the carton. It is also on each blister of

tablets. The expiry date refers to the last day of that month.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to

throw away medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Jimandin contains

The active substance is sitagliptin. Each tablet contains sitagliptin phosphate monohydrate,

equivalent to 25 mg, 50 mg or 100 mg sitagliptin.

The other ingredients are:

Tablet core - Microcrystalline cellulose (E460), Calcium hydrogen phosphate, anhydrous,

Croscarmellose sodium, Magnesium stearate, Sodium stearyl fumarate.

Coating - Polyvinyl alcohol (E1203), Titanium dioxide (E171), Macrogol (E1521), Talc

(E553b), for 25mg tablet Iron oxide yellow (E172), for 50mg tablet Iron oxide red (E172), for

100mg tablet Iron oxide yellow (E172) and Iron oxide red (E172).

What Jimandin looks like and contents of the pack

Jimandin 25 mg tablet: Yellow round, biconvex film coated tablets, with diameter approximately

6mm.

Jimandin 50 mg tablet: Pale red round, biconvex film coated tablets, with diameter approximately

8mm.

Jimandin 100 mg tablet: Light brown, round, biconvex film coated tablets with diameter

approximately 10.3mm.

PA/Al/PVC//Al blisters containing 14, 28, 30, 56, 84, 90, 98 tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Medochemie Ltd., 1-10 Constantinoupoleos street, 3011 Limassol, Cyprus

Manufacturer

Medochemie Ltd (Central Factory),

1-10 Constantinoupoleos street, 3011 Limassol, Cyprus

This leaflet was last revised in August 2020.

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Jimandin 25 mg film-coated tablets

Jimandin 50 mg film-coated tablets

Jimandin 100 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Jimandin 25 mg film-coated tablet contains sitagliptin phosphate monohydrate, equivalent to

25mg sitagliptin.

Each Jimandin 50 mg film-coated tablet contains sitagliptin phosphate monohydrate, equivalent to 50

mg sitagliptin.

Each Jimandin 100 mg film-coated tablet contains sitagliptin phosphate monohydrate, equivalent to

100 mg sitagliptin.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet.

25 mg/tablet: Yellow round, biconvex film coated tablets, with diameter approximately 6mm

50 mg/tablet: Pale red round, biconvex film coated tablets, with diameter approximately 8mm

100 mg/tablet: Light brown, round, biconvex film coated tablets with diameter approximately 10.3mm

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

For adult patients with type 2 diabetes mellitus, Jimandin 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.

peroxisome

proliferator-activated

receptor

gamma

(PPARγ)

agonist

(i.e.

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 medicinal

products 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 medicinal products do not provide adequate

glycaemic control.

Jimandin is also indicated as add-on to insulin (with or without metformin) when diet and exercise

plus stable dose of insulin do not provide adequate glycaemic control.

4.2

Posology and method of administration

Posology

The dose is 100mg sitagliptin once daily. When used in combination with metformin and/or a PPARγ

agonist,

dose

metformin

and/or

PPARγ

agonist

should

maintained,

Jimandin

administered concomitantly.

When Jimandin 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 Jimandin 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

When considering the use of sitagliptin in combination with another anti-diabetic product, its

conditions for use in patients with renal impairment should be checked.

For patients with mild renal impairment (creatinine clearance [CrCl] ≥50 ml/min), no dose adjustment

is required.

For patients with moderate renal impairment (CrCl ≥30 to <50 mL/min), the dose of Jimandin is 50

mg once daily.

For patients with severe renal impairment (CrCl <30 mL/min) or with end-stage renal disease (ESRD)

requiring haemodialysis or peritoneal dialysis, the dose of Jimandin is 25 mg once daily. Treatment

may be administered without regard to the timing of dialysis.

Because there is a dosage adjustment based upon renal function, assessment of renal function is

recommended prior to initiation of Jimandin and periodically thereafter.

Hepatic impairment

No dose adjustment is necessary for patients with mild to moderate hepatic impairment. Sitagliptin

has not been studied in patients with severe hepatic impairment and care should be exercised (see

section 5.2).

However, because sitagliptin is primarily renally eliminated, severe hepatic impairment is not

expected to affect the pharmacokinetics of sitagliptin.

Elderly

No dose adjustment is necessary based on age.

Paediatric population

The safety and efficacy of sitagliptin in children and adolescents under 18 years of age have not yet

been established. No data are available.

Method of administration

Jimandin can be taken with or without food.

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see section 4.4

and 4.8).

4.4

Special warnings and precautions for use

General

Jimandin should not be used in patients with type 1 diabetes or for the treatment of diabetic

ketoacidosis.

Acute pancreatitis

Use of DPP-4 inhibitors has been associated with a risk of developing 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 necrotising or haemorrhagic pancreatitis and/or death

have been reported. If pancreatitis is suspected, Jimandin and other potentially suspect medicinal

products should be discontinued; if acute pancreatitis is confirmed, Jimandin should not be restarted.

Caution should be exercised in patients with a history of pancreatitis.

Hypoglycaemia when used in combination with other anti-hyperglycaemic medicinal products

In clinical trials of sitagliptin as monotherapy and as part of combination therapy with medicinal

products 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.

Hypoglycaemia has been observed when sitagliptin was used in combination with insulin or a

sulphonylurea. Therefore, to reduce the risk of hypoglycaemia, a lower dose of sulphonylurea or

insulin may be considered (see section 4.2).

Renal impairment

Sitagliptin is renally excreted. To achieve plasma concentrations of sitagliptin similar to those in

patients with normal renal function, lower dosages are recommended in patients with moderate and

severe renal impairment, as well as in ESRD patients requiring haemodialysis or peritoneal dialysis

(see section 4.2 and 5.2).

When considering the use of sitagliptin in combination with another anti-diabetic product, its

conditions for use in patients with renal impairment should be checked.

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 some reports occurring after the first dose. If a hypersensitivity reaction is

suspected, Jimandin should be discontinued. Other potential causes for the event should be assessed,

and alternative treatment for diabetes initiated.

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.

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 effect 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

risk

clinically

meaningful

interactions

considered

low.

Concomitant

administration of OAT3 inhibitors has not been evaluated in vivo.

Metformin

: Co-administration of multiple twice-daily doses of 1,000 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 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 Cmax 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.

Effects of sitagliptin on other medicinal products

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.

In vitro data suggest that sitagliptin does not inhibit nor induce CYP450 isoenzymes. In clinical

studies,

sitagliptin

meaningfully

alter

pharmacokinetics

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 may be a mild inhibitor of p-glycoprotein in vivo.

4.6

Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of sitagliptin 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, Jimandin should not be used during pregnancy.

Breast-feeding

It is unknown whether sitagliptin is excreted in human breast milk. Animal studies have shown

excretion of sitagliptin in breast milk. Jimandin should not be used during breast-feeding.

Fertility

Animal data do not suggest an effect of treatment with sitagliptin on male and female fertility. Human

data are lacking.

4.7

Effects on ability to drive and use machines

Jimandin has no or negligible influence on the ability to drive and use machines. However, when

driving or using machines, it should be taken into account that dizziness and somnolence has been

reported.

In addition, patients should be alerted to the risk of hypoglycaemia when Jimandin is used in

combination with a sulphonylurea or with insulin.

4.8

Undesirable effects

Summary of the safety profile

Serious adverse reactions including pancreatitis and hypersensitivity reactions have been reported.

Hypoglycemia has been reported in combination with sulphonylurea (4.7%-13.8%) and insulin (9.6%)

(see section 4.4).

Tabulated list of adverse reactions

Adverse reactions are listed below (Table 1) by system organ class and frequency. 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) and not known (cannot be estimated from the

available data).

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

of sitagliptin monotherapy and post-marketing experience

Adverse reaction

Frequency of adverse reaction

Immune system disorders

hypersensitivity reactions including anaphylactic responses

*,†

Frequency not known

Metabolism and nutrition disorders

hypoglycaemia

Common

Nervous system disorders

headache

Common

dizziness

Uncommon

Respiratory, thoracic and mediastinal disorders

interstitial lung disease

Frequency not known

Gastrointestinal disorders

constipation

Uncommon

vomiting

Frequency not known

acute pancreatitis

*,†,‡

Frequency not known

fatal and non-fatal haemorrhagic and necrotizing pancreatitis

*,†

Frequency not known

Skin and subcutaneous tissue disorders

pruritus*

Uncommon

angioedema

*,†

Frequency not known

rash

*,†

Frequency not known

urticaria

*,†

Frequency not known

cutaneous vasculitis

*,†

Frequency not known

exfoliative skin conditions including Stevens-Johnson syndrome

*,†

Frequency not known

bullous pemphigoid*

Frequency not known

Musculoskeletal and connective tissue disorders

arthralgia

Frequency not known

myalgia

Frequency not known

back pain

Frequency not known

arthropathy*

Frequency not known

Renal and urinary disorders

impaired renal function

Frequency not known

acute renal failure

Frequency not known

*Adverse reactions were identified through postmarketing surveillance.

†See section 4.4.

See TECOS Cardiovascular Safety Study below.

Description of selected adverse reactions

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 sitagliptin 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 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.

Some adverse reactions were observed more frequently in studies of combination use of sitagliptin

with other anti-diabetic medicinal products than in studies of sitagliptin monotherapy. These included

hypoglycaemia (frequency very common with the combination of sulphonylurea and metformin),

influenza (common with insulin (with or without metformin)), nausea and vomiting (common with

metformin), flatulence (common with metformin or pioglitazone), constipation (common with the

combination of sulphonylurea and metformin), peripheral oedema (common with pioglitazone or the

combination of pioglitazone and metformin), somnolence and diarrhoea (uncommon with metformin),

and dry mouth (uncommon with insulin (with or without metformin)).

TECOS Cardiovascular Safety Study

The Trial Evaluating Cardiovascular Outcomes with sitagliptin (TECOS) included 7,332 patients

treated with sitagliptin, 100 mg daily (or 50 mg daily if the baseline eGFR was ≥ 30 and < 50

mL/min/1.73 m

), and 7,339 patients treated with placebo in the intention-to-treat population. Both

treatments were added to usual care targeting regional standards for HbA1c and CV risk factors. The

overall incidence of serious adverse events in patients receiving sitagliptin was similar to that in

patients receiving placebo.

In the intention-to-treat population, among patients who were using insulin and/or a sulfonylurea at

baseline, the incidence of severe hypoglycaemia was 2.7 % in sitagliptin-treated patients and 2.5 % in

placebo-treated patients; among patients who were not using insulin and/or a sulfonylurea at baseline,

the incidence of severe hypoglycaemia was 1.0 % in sitagliptin-treated patients and 0.7 % in placebo-

treated patients. The incidence of adjudication-confirmed pancreatitis events was 0.3 % in sitagliptin-

treated patients and 0.2 % in placebo-treated patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows

continued

monitoring

benefit/risk

balance

medicinal

product.

Healthcare

professionals are asked to report any suspected adverse reactions via the national reporting system.

4.9

Overdose

Symptoms

During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were

administered. 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.

Management

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 dialysable. In clinical studies, approximately 13.5% of the dose was removed

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

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

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in diabetes, Dipeptidyl peptidase 4 (DPP-4) inhibitors, ATC

code: A10BH01.

Mechanism of action

Sitagliptin is a member of a class of oral anti-hyperglycaemic agents called dipeptidyl peptidase 4

(DPP-4) inhibitors. The improvement in glycaemic control observed with this medicinal product may

be mediated by enhancing the levels of active incretin hormones. Incretin hormones, including

glucagon-like

peptide-1

(GLP-1)

glucose-dependent

insulinotropic

polypeptide

(GIP),

released by the intestine throughout the day, and levels are increased in response to a meal. 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 by intracellular signaling pathways involving

cyclic AMP.

Treatment with GLP-1 or with DPP-4 inhibitors in animal models of type 2 diabetes has been

demonstrated to improve beta cell responsiveness to glucose and stimulate insulin biosynthesis and

release. With higher insulin levels, tissue glucose uptake is enhanced. In addition, GLP-1 lowers

glucagon secretion from pancreatic alpha cells. Decreased glucagon concentrations, along with higher

insulin levels, lead to reduced hepatic glucose production, resulting in a decrease in blood glucose

levels.

effects

GLP-1

glucose-dependent

such

that

when

blood

glucose

concentrations are low, stimulation of insulin release and suppression of glucagon secretion by GLP-1

are not observed. For both GLP-1 and GIP, stimulation of insulin release is enhanced as glucose rises

above normal concentrations. Further, GLP-1 does not impair the normal glucagon response to

hypoglycaemia. The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly

hydrolyzes the incretin hormones to produce inactive products. Sitagliptin prevents the hydrolysis of

incretin hormones by DPP-4, thereby increasing plasma concentrations of the active forms of GLP-1

and GIP. By enhancing active incretin levels, sitagliptin increases insulin release and decreases

glucagon levels in a glucose-dependent manner. In patients with type 2 diabetes with hyperglycaemia,

these changes in insulin and glucagon levels lead to lower hemoglobin A1c (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-4 and does not inhibit the

closely-related enzymes DPP-8 or DPP-9 at therapeutic concentrations.

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.

Clinical efficacy and safety

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 sitagliptin monotherapy. Treatment

with sitagliptin at 100 mg once daily as monotherapy provided significant improvements in HbA1c,

fasting plasma glucose (FPG), and 2-hour post-prandial glucose (2-hour PPG), compared to placebo

in two studies, one of 18-and one of 24-weeks duration. Improvement of 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.

The observed incidence of hypoglycaemia in patients treated with sitagliptin was similar to placebo.

Body weight did not increase from baseline with sitagliptin therapy in either study, compared to a

small reduction in patients given placebo.

Sitagliptin 100 mg once daily provided significant improvements in glycaemic parameters compared

with placebo in two 24-weekstudies 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 26-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin

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

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

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

placebo. The incidence of hypoglycaemia was also similar in 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 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. 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.

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.

Table 2. HbA1c results in placebo-controlled monotherapy and combination therapy studies*

Study

Mean baseline

HbA1c (%)

Mean change from

baseline HbA1c

(%)†

Placebo-corrected

mean change in

HbA1c (%)†

(95 % CI)

Monotherapy Studies

Sitagliptin 100 mg once daily

(N=193)

-0.5

-0.6‡

(-0.8, -0.4)

Sitagliptin 100 mg once daily

(N=229)

-0.6

-0.8 ‡

(-1.0, -0.6)

Combination Therapy Studies

Sitagliptin 100 mg once daily added to

ongoing metformin therapy

(N=453)

-0.7

-0.7‡

(-0.8, -0.5)

Sitagliptin 100 mg once daily added to

ongoing pioglitazone therapy

(N=163)

-0.9

-0.7‡

(-0.9, -0.5)

Sitagliptin 100 mg once daily added to

ongoing glimepiride therapy

(N=102)

-0.3

-0.6‡

(-0.8, -0.3)

Sitagliptin 100 mg once daily added to

ongoing glimepiride + metformin

therapy

(N=115)

-0.6

-0.9‡

(-1.1, -0.7)

Sitagliptin 100 mg once daily added to

ongoing pioglitazone + metformin

therapy#

(N=152)

-1.2

-0.7‡

(-1.0, -0.5)

Initial therapy (twice daily)

Sitagliptin 50 mg + metformin 500 mg

(N=183)

-1.4

-1.6‡

(-1.8, -1.3)

Initial therapy (twice daily)

Sitagliptin 50 mg + metformin

1,000mg

(N=178)

-1.9

-2.1‡

(-2.3, -1.8)

Sitagliptin 100 mg once daily added to

ongoing insulin (+/- metformin)

therapy

(N=305)

-0.6

-0.6‡,¶

(-0.7, -0.4)

* 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.

II HbA 1c (%) at week 24.

# HbA1c (%) at week 26.

¶ Least squares mean adjusted for metformin use at Visit1 (yes/no), insulin use at Visit1 (pre-mixed

non-pre-mixed

[intermediate-

long-acting]),

baseline

value.

Treatment

stratum

(metformin and insulin use) interactions were not significant (p > 0.10).

A 24-week active (metformin)-controlled study was designed to evaluate the efficacy and safety of

sitagliptin100 mg once daily (N=528) compared to metformin (N=522) in patients with inadequate

glycaemic control on diet and exercise and who were not on anti-hyperglycaemic therapy (off therapy

for at least 4 months). The mean dose of metformin was approximately 1,900 mg per day. The

reduction in HbA1c from mean baseline values of 7.2% was -0.43 % for sitagliptin and -0.57 % for

metformin

(Per

Protocol

Analysis).

overall

incidence

gastrointestinal

adverse

reactions

considered as drug-related in patients treated with sitagliptin was 2.7% compared with 12.6 % in

patients treated with metformin. The incidence of hypoglycaemia was not significantly different

between the treatment groups (sitagliptin, 1.3%; metformin, 1.9 %). Body weight decreased from

baseline in both groups (sitagliptin, -0.6 kg; metformin -1.9 kg).

In a study comparing the efficacy and safety of the addition of sitagliptin 100mg once daily or

glipizide (a sulphonylurea) in patients with inadequate glycaemic control on metformin monotherapy,

sitagliptin was similar to glipizide in reducingHbA1c. 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 compared to a significant weight gain in patients administered

glipizide (-1.5 vs. +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 %).

A 24-week placebo-controlled study involving 660 patients was designed to evaluate the insulin

sparing efficacy and safety of sitagliptin (100 mg once daily) added to insulin glargine with or without

metformin (at least 1,500 mg) during intensification of insulin therapy. Baseline HbA1c was 8.74%

and baseline insulin dose was 37 IU/day. Patients were instructed to titrate their insulin glargine dose

based on fingerstick fasting glucose values. At Week24, the increase in daily insulin dose was 19

IU/dayin patients treated with sitagliptin and 24 IU/day in patients treated with placebo. The reduction

in HbA1c in patients treated with sitagliptin and insulin (with or without metformin) was -1.31 %

compared to -0.87 % in patients treated with placebo and insulin (with or without metformin), a

difference of -0.45 % [95% CI: -0.60, -0.29]. The incidence of hypoglycaemia was 25.2% in patients

treated with sitagliptin and insulin (with or without metformin) and 36.8% in patients treated with

placebo and insulin (with or without metformin). The difference was mainly due to a higher

percentage of patients in the placebo group experiencing 3 or more episodes of hypoglycaemia (9.4

vs. 19.2 %). There was no difference in the incidence of severe hypoglycaemia.

A study comparing sitagliptin at 25 or 50 mg once daily to glipizide at 2.5 to 20 mg/day was

conducted in patients with moderate to severe renal impairment. This study involved 423 patients with

chronic renal impairment (estimated glomerular filtration rate <50 ml/min). After 54 weeks, the mean

reduction from baseline in HbA1c was -0.76 % with sitagliptin and -0.64 % with glipizide (Per-

Protocol Analysis). In this study, the efficacy and safety profile of sitagliptin at 25 or 50mg once daily

was generally similar to that observed in other monotherapy studies in patients with normal renal

function. The incidence of hypoglycaemia in the sitagliptin group (6.2%) was significantly lower than

that in the glipizide group (17.0 %). There was also a significant difference between groups with

respect to change from baseline body weight (sitagliptin -0.6 kg; glipizide +1.2 kg).

Another study comparing sitagliptin at 25 mg once daily to glipizide at 2.5 to 20 mg/day was

conducted in 129 patients with ESRD who were on dialysis. After 54 weeks, the mean reduction from

baseline in HbA1c was -0.72 % with sitagliptin and -0.87 % with glipizide. In this study, the efficacy

and safety profile of sitagliptin at 25 mg once daily was generally similar to that observed in other

monotherapy studies in patients with normal renal function. The incidence of hypoglycaemia was not

significantly different between the treatment groups (sitagliptin, 6.3%; glipizide, 10.8 %).

In another study involving 91 patients with type 2 diabetes and chronic renal impairment (creatinine

clearance <50 ml/min), the safety and tolerability of treatment with sitagliptin at 25or 50 mg once

daily were generally similar to placebo. In addition, after 12 weeks, the mean reductions in HbA1c

(sitagliptin -0.59 %; placebo -0.18 %) and FPG (sitagliptin -25.5 mg/dL; placebo -3.0 mg/dL) were

generally similar to those observed in other monotherapy studies in patients with normal renal

function (see section 5.2).

The TECOS was a randomized study in 14,671 patients in the intention-to-treat population with an

HbA1c of ≥ 6.5 to 8.0 % with established CV disease who received sitagliptin (7,332) 100 mg daily

(or 50 mg daily if the baseline eGFR was ≥ 30 and < 50 mL/min/1.73 m2) or placebo (7,339) added to

usual care targeting regional standards for HbA1c and CV risk factors. Patients with an eGFR < 30

mL/min/1.73 m2 were not to be enrolled in the study. The study population included 2,004 patients ≥

75 years of age and 3,324 patients with renal impairment (eGFR < 60 mL/min/1.73 m

Over the course of the study, the overall estimated mean (SD) difference in HbA1c between the

sitagliptin and placebo groups was 0.29 % (0.01), 95 % CI (-0.32, -0.27); p < 0.001. The primary

cardiovascular endpoint was a composite of the first occurrence of cardiovascular death, nonfatal

myocardial

infarction,

nonfatal

stroke,

hospitalization

unstable

angina.

Secondary

cardiovascular endpoints included the first occurrence of cardiovascular death, nonfatal myocardial

all-cause mortality; and hospital admissions for congestive heart failure.

After a median follow up of 3 years, sitagliptin, when added to usual care, did not increase the risk of

major adverse cardiovascular events or the risk of hospitalization for heart failure compared to usual

care without sitagliptin in patients with type 2 diabetes (Table 3).

Table 3. Rates of Composite Cardiovascular Outcomes and Key Secondary Outcomes

Sitagliptin 100 mg

Placebo

N (%)

Incidence

rate per

100

patient-

years*

N (%)

Incidence

rate per

100

patient-

years*

Hazard

Ratio (95%

CI)

p-

value

Analysis in the Intention-to-Treat Population

Number of patients

7,332

7,339

Primary Composite

Endpoint

(Cardiovascular death,

nonfatal myocardial

infarction, nonfatal stroke, or

hospitalization for unstable

angina)

839 (11.4)

851 (11.6)

0.98

(0.89-1.08)

<0.001

Secondary Composite

Endpoint

(Cardiovascular death,

nonfatal myocardial

infarction, or nonfatal stroke)

745 (10.2)

746 (10.2)

0.99

(0.89-1.10)

<0.001

Sitagliptin 100 mg

Placebo

Hazard

Ratio (95%

CI)

p-

value

N (%)

Incidence

rate per

100

patient-

years*

N (%)

Incidence

rate per

100

patient-

years*

Secondary Outcome

Cardiovascular death

380 (5.2)

366 (5.0)

1.03

(0.89-1.19)

0.711

All myocardial infarction

(fatal and non-fatal)

300 (4.1)

316 (4.3)

0.95

(0.81-1.11)

0.487

All stroke (fatal and non-fatal)

178 (2.4)

183 (2.5)

0.97

(0.79-1.19)

0.760

Hospitalization for unstable

angina

116 (1.6)

129 (1.8)

0.90

(0.70-1.16)

0.419

Death from any cause

547 (7.5)

537 (7.3)

1.01

(0.90-1.14)

0.875

Hospitalization for heart

failure

228 (3.1)

229 (3.1)

1.00

(0.83-1.20)

0.983

* Incidence rate per 100 patient-years is calculated as 100 × (total number of patients with ≥ 1 event during

eligible exposure period per total patient-years of follow-up).

† Based on a Cox model stratified by region. For composite endpoints, the p-values correspond to a test of non-

inferiority seeking to show that the hazard ratio is less than 1.3. For all other endpoints, the p-values correspond

to a test of differences in hazard rates.

‡ The analysis of hospitalization for heart failure was adjusted for a history of heart failure at baseline.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with

sitagliptin 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 100-mg dose to healthy subjects, sitagliptin was rapidly absorbed,

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

of sitagliptin was 8.52μMhr, Cmax 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 Cmax and C 24hr (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-mg intravenous dose of

sitagliptin to healthy subjects is approximately 198 liters. The fraction of sitagliptin reversibly bound

to plasma proteins is low (38%).

Biotransformation

Sitagliptin

primarily

eliminated

unchanged

urine,

metabolism

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 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 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-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

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=160μM) 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 was 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 (50mg) 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 < 80ml/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

postdose). To achieve plasma concentrations of sitagliptin similar to those in patients with normal

renal

function,

lower

dosages

recommended

patients

with

moderate

severe

renal

impairment, as well as in ESRD patients requiring dialysis (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 PhaseI and Phase II

data. Elderly subjects (65 to 80 years) had approximately 19% higher plasma concentrations of

sitagliptin compared to younger subjects.

Paediatric population

No studies with sitagliptin have been performed in paediatric patients.

Other patient characteristics

dose

adjustment

necessary

based

gender,

race,

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

noeffect 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.

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).

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tablet core:

Microcrystalline cellulose (E460)

Calcium hydrogen phosphate, anhydrous

Croscarmellose sodium

Magnesium stearate

Sodium stearyl fumarate

Coating:

Polyvinyl alcohol (E1203)

Titanium dioxide (E171)

Macrogol (E1521)

Talc (E553b)

25mg: Iron oxide yellow (E172)

50mg: Iron oxide red (E172)

100mg: Iron oxide yellow (E172) and Iron oxide red (E172)

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

3 years

6.4

Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container

PA/Al/PVC//Al blisters containing 14, 28, 30, 56, 84, 90, 98 tablets.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

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

requirements.

7. MARKETING AUTHORISATION HOLDER

Medochemie Ltd, 1-10 Constantinoupoleos Street, 3011, Limassol Cyprus

8. MARKETING AUTHORISATION NUMBER

[to be completed nationally]

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

[to be completed nationally]

10.

DATE OF REVISION OF THE TEXT

21 June 2017

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