Tesavel

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

 



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1. NAME OF THE MEDICINAL PRODUCT

TESAVEL 25 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains sitagliptin phosphate monohydrate, equivalent to 25 mg sitagliptin.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet).

Round, pink film-coated tablet with “221” on one side.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

For adult patients with type 2 diabetes mellitus, TESAVEL is indicated to improve glycaemic control:

as monotherapy:

 in patients inadequately controlled by diet and exercise alone and for whom metformin is 
inappropriate due to contraindications or intolerance.

as dual oral therapy in combination with:

 metformin when diet and exercise plus metformin alone do not provide adequate glycaemic 
control.

 a sulphonylurea when diet and exercise plus maximal tolerated dose of a sulphonylurea alone 
do not provide adequate glycaemic control and when metformin is inappropriate due to 
contraindications or intolerance.

 a peroxisome proliferator-activated receptor gamma (PPAR) agonist (i.e. a thiazolidinedione) 
when use of a PPAR agonist is appropriate and when diet and exercise plus the PPAR 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 PPAR agonist and metformin when use of a PPAR agonist is appropriate and when diet and 
exercise plus dual therapy with these medicinal products do not provide adequate glycaemic 
control.

TESAVEL 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.

 



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4.2 Posology and method of administration

Posology
The dose is 100 mg sitagliptin once daily. When used in combination with metformin and/or a PPAR
agonist, the dose of metformin and/or PPAR agonist should be maintained, and TESAVEL 
administered concomitantly.

When TESAVEL 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 TESAVEL 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 medicinal product, 
its conditions for use in patients with renal impairment should be checked.

For patients with mild renal impairment (glomerular filtration rate [GFR]  60 to < 90 mL/min), no 
dose adjustment is required.

For patients with moderate renal impairment (GFR  45 to < 60 mL/min), no dosage adjustment is 
required.

For patients with moderate renal impairment (GFR  30 to < 45 mL/min), the dose of TESAVEL is 
50 mg once daily.

For patients with severe renal impairment (GFR ≥ 15 to <30 mL/min) or with end-stage renal disease 
(ESRD) (GFR < 15 mL/min), including those requiring haemodialysis or peritoneal dialysis, the dose 
of TESAVEL 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 TESAVEL and periodically thereafter.

Hepatic impairment
No dose adjustment is necessary for patients with mild to moderate hepatic impairment. TESAVEL
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
Sitagliptin should not be used in children and adolescents 10 to 17 years of age because of insufficient 
efficacy. Currently available data are described in sections 4.8, 5.1, and 5.2. Sitagliptin has not been 
studied in paediatric patients under 10 years of age.

Method of administration
TESAVEL can be taken with or without food.

 



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4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see 
sections 4.4 and 4.8).

4.4 Special warnings and precautions for use

General
TESAVEL 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, TESAVEL and other potentially suspect medicinal 
products should be discontinued; if acute pancreatitis is confirmed, TESAVEL 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 TESAVEL as monotherapy and as part of combination therapy with medicinal 
products not known to cause hypoglycaemia (i.e. metformin and/or a PPAR 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 GFR 
< 45 mL/min, as well as in ESRD patients requiring haemodialysis or peritoneal dialysis (see 
sections 4.2 and 5.2).

When considering the use of sitagliptin in combination with another anti-diabetic medicinal product, 
its conditions for use in patients with renal impairment should be checked.

Hypersensitivity reactions
Post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin have 
been reported. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions 
including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after 
initiation of treatment, with some reports occurring after the first dose. If a hypersensitivity reaction is 
suspected, TESAVEL should be discontinued. Other potential causes for the event should be 
assessed, and alternative treatment for diabetes initiated.

Bullous pemphigoid
There have been post-marketing reports of bullous pemphigoid in patients taking DPP-4 inhibitors 
including sitagliptin. If bullous pemphigoid is suspected, TESAVEL should be discontinued.

Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 
‘sodium-free’.

 



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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 pharmacokinetics 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 the risk of clinically meaningful interactions is considered to be 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 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 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, TESAVEL 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. TESAVEL should not be used during breast-feeding.

 



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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

TESAVEL 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 have been 
reported.

In addition, patients should be alerted to the risk of hypoglycaemia when TESAVEL 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. 
Hypoglycaemia 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

Blood and lymphatic system disorders
thrombocytopenia Rare

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

 



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Adverse reaction Frequency of adverse reaction

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 post-marketing 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)).

Paediatric population
In clinical trials with sitagliptin in paediatric patients with type 2 diabetes mellitus aged 10 to17 years, 
the profile of adverse reactions was comparable to that observed in adults.

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 m2), 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. 

 



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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 of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

4.9 Overdose

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.

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 haemodialysis session. Prolonged haemodialysis 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
TESAVEL 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) and glucose-dependent insulinotropic polypeptide (GIP), are 
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. The effects of GLP-1 and GIP are glucose-dependent such that when blood glucose 

 

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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 haemoglobin 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 in adult patients with type 2 diabetes (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-week studies of sitagliptin as add-on therapy, one in combination with 
metformin and one in combination with pioglitazone. Change from baseline in body weight was 
similar for patients treated with sitagliptin relative to placebo. In these studies there was a similar 
incidence of hypoglycaemia reported for patients treated with sitagliptin or placebo.

A 24-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin
(100 mg once daily) added to glimepiride alone or glimepiride in combination with metformin. The 
addition of sitagliptin to either glimepiride alone or to glimepiride and metformin provided significant 
improvements in glycaemic parameters. Patients treated with sitagliptin had a modest increase in body 
weight compared to those given placebo.

A 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 

 



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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)
8.0 -0.5

-0.6‡

(-0.8, -0.4)
Sitagliptin 100 mg once daily

(N= 229)
8.0 -0.6

-0.8‡

(-1.0, -0.6)

Combination Therapy Studies

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 pioglitazone therapy

(N=163)
8.1 -0.9

-0.7‡

(-0.9, -0.5)

Sitagliptin 100 mg once daily added to 
ongoing glimepiride therapy

(N=102)
8.4 -0.3

-0.6‡

(-0.8, -0.3)

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 pioglitazone + metformin 
therapy#

(N=152)

8.8 -1.2
-0.7‡

(-1.0, -0.5)

Initial therapy (twice daily):
Sitagliptin 50 mg + metformin 500 mg 
(N=183)

8.8 -1.4
-1.6‡

(-1.8, -1.3)

Initial therapy (twice daily): 
Sitagliptin 50 mg + metformin 
1,000 mg
(N=178)

8.8 -1.9
-2.1‡

(-2.3, -1.8)

 



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Study
Mean baseline 

HbA1c (%)

Mean change 
from baseline 
HbA1c (%)

†

Placebo-corrected 
mean change in 

HbA1c (%)
† 

(95 % CI)
Sitagliptin 100 mg once daily added to 
ongoing insulin (+/- metformin) 
therapy

(N=305)

8.7 -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.
HbA1c (%) at week 24.
# HbA1c (%) at week 26.
¶ Least squares mean adjusted for metformin use at Visit 1 (yes/no), insulin use at Visit 1 (pre-mixed vs. non-pre-mixed 
[intermediate- or long-acting]), and baseline value. Treatment by 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 
sitagliptin 100 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). The overall incidence of 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 100 mg once daily or 
glipizide (a sulphonylurea) in patients with inadequate glycaemic control on metformin monotherapy, 
sitagliptin was similar to glipizide in reducing HbA1c. The mean glipizide dose used in the comparator 
group was 10 mg per day with approximately 40 % of patients requiring a glipizide dose of 
 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 Week 24, the increase in daily insulin 
dose was 19 IU/day in 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. 19.1 %). 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

 



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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 50 mg 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 25 or 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 randomised 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 m2).

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, or hospitalisation for unstable angina. Secondary 
cardiovascular endpoints included the first occurrence of cardiovascular death, nonfatal myocardial 
infarction, or nonfatal stroke; first occurrence of the individual components of the primary composite; 
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 hospitalisation 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

Hazard Ratio

(95% CI) p-value†N (%)

Incidence 
rate per 

100 
patient-
years* N (%)

Incidence 
rate per 

100 
patient-
years*

Analysis in the Intention-to-Treat Population

Number of patients 7,332 7,339 0.98 (0.89–1.08) <0.001

 



13

Sitagliptin 100 mg Placebo

Hazard Ratio

(95% CI) p-value†N (%)

Incidence 
rate per 

100 
patient-
years* N (%)

Incidence 
rate per 

100 
patient-
years*

Primary Composite Endpoint
(Cardiovascular death, nonfatal 
myocardial infarction, nonfatal 
stroke, or hospitalisation for 
unstable angina) 839 (11.4) 4.1 851 (11.6) 4.2

Secondary Composite Endpoint
(Cardiovascular death, nonfatal 
myocardial infarction, or nonfatal 
stroke) 745 (10.2) 3.6 746 (10.2) 3.6 0.99 (0.89–1.10) <0.001

Secondary Outcome

Cardiovascular death 380 (5.2) 1.7 366 (5.0) 1.7 1.03 (0.89-1.19) 0.711

All myocardial infarction (fatal 
and non-fatal) 300 (4.1) 1.4 316 (4.3) 1.5 0.95 (0.81–1.11) 0.487

All stroke (fatal and non-fatal) 178 (2.4) 0.8 183 (2.5) 0.9 0.97 (0.79–1.19) 0.760

Hospitalisation for unstable 
angina 116 (1.6) 0.5 129 (1.8) 0.6 0.90 (0.70–1.16) 0.419

Death from any cause 547 (7.5) 2.5 537 (7.3) 2.5 1.01 (0.90–1.14) 0.875

Hospitalisation for heart failure‡ 228 (3.1) 1.1 229 (3.1) 1.1 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 hospitalisation for heart failure was adjusted for a history of heart failure at baseline.

Paediatric population
A 54-week, double-blind study was conducted to evaluate the efficacy and safety of sitagliptin 
100 mg once daily in paediatric patients (10 to 17 years of age) with type 2 diabetes who were not on 
anti-hyperglycaemic therapy for at least 12 weeks (with HbA1c 6.5% to 10%) or were on a stable 
dose of insulin for at least 12 weeks (with HbA1c 7% to 10%). Patients were randomised to sitagliptin 
100 mg once daily or placebo for 20 weeks.

Mean baseline HbA1c was 7.5%. Treatment with sitagliptin 100 mg did not provide significant 
improvement in HbA1c at 20 weeks. The reduction in HbA1c in patients treated with sitagliptin 
(N=95) was 0.0% compared to 0.2% in patients treated with placebo (N=95), a difference of -0.2%
(95% CI: -0.7, 0.3). See section 4.2.

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 8.52 M•hr, 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, TESAVEL may be administered with or without food.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Dose-proportionality was not 
established for Cmax and C24hr (Cmax increased in a greater than dose-proportional manner and C24hr
increased in a less than dose-proportional manner).

 



14

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 [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=160 M) or p-glycoprotein (up 
to 250 M) 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 mild, moderate, and severe renal 
impairment, as well as patients with ESRD on haemodialysis. In addition, the effects of renal 
impairment on sitagliptin pharmacokinetics in patients with type 2 diabetes and mild, moderate, or 
severe renal impairment (including ESRD) were assessed using population pharmacokinetic analyses.

Compared to normal healthy control subjects, plasma AUC of sitagliptin was increased by 
approximately 1.2-fold and 1.6-fold in patients with mild renal impairment (GFR ≥ 60 to 
< 90 mL/min) and patients with moderate renal impairment (GFR ≥ 45 to < 60 mL/min), respectively. 
Because increases of this magnitude are not clinically relevant, dosage adjustment in these patients is 
not necessary.

Plasma AUC of sitagliptin was increased approximately 2-fold in patients with moderate renal 
impairment (GFR ≥ 30 to < 45 mL/min), and approximately 4-fold in patients with severe renal 

 



15

impairment (GFR < 30 mL/min), including in patients with ESRD on haemodialysis. 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 are recommended in patients with GFR < 45 mL/min (see 
section 4.2).

Hepatic impairment
No dose adjustment for TESAVEL 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 population
The pharmacokinetics of sitagliptin (single dose of 50 mg, 100 mg or 200 mg) were investigated in 
paediatric patients (10 to 17 years of age) with type 2 diabetes. In this population, the dose-adjusted
AUC of sitagliptin in plasma was approximately 18 % lower compared to adult patients with type 2 
diabetes for a 100 mg dose. This is not considered to be a clinically meaningful difference compared 
to adult patients based on the flat PK/PD relationship between the dose of 50 mg and 100 mg. No 
studies with sitagliptin have been performed in paediatric patients with age <10 years.

Other patient characteristics
No dose adjustment is necessary based on gender, race, or body mass index (BMI). These 
characteristics had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a 
composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of 
Phase I and Phase II data.

5.3 Preclinical safety data

Renal and liver toxicity were observed in rodents at systemic exposure values 58 times the human 
exposure level, while the no-effect level was found at 19 times the human exposure level. Incisor teeth
abnormalities were observed in rats at exposure levels 67 times the clinical exposure level; the 
no-effect level for this finding was 58-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 tumours 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.

 



16

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 foetal 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 (E341)
croscarmellose sodium (E468)
magnesium stearate (E470b)
sodium stearyl fumarate

Film coating:
poly(vinyl alcohol)
macrogol 3350
talc (E553b)
titanium dioxide (E171)
red iron oxide (E172)
yellow iron oxide (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

Opaque blisters (PVC/PE/PVDC and aluminium). Packs of 14, 28, 30, 56, 84, 90 or 98 film-coated 
tablets and 50 x 1 film-coated tablets in perforated unit dose blisters.

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.

 



17

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/07/435/001
EU/1/07/435/002
EU/1/07/435/003
EU/1/07/435/004
EU/1/07/435/005
EU/1/07/435/006
EU/1/07/435/019
EU/1/07/435/020

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 10 January 2008
Date of latest renewal: 20 September 2012

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu.

 



18

1. NAME OF THE MEDICINAL PRODUCT

TESAVEL 50 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains sitagliptin phosphate monohydrate, equivalent to 50 mg sitagliptin.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet).

Round, light beige film-coated tablet with “112” on one side.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

For adult patients with type 2 diabetes mellitus, TESAVEL is indicated to improve glycaemic control:

as monotherapy:

 in patients inadequately controlled by diet and exercise alone and for whom metformin is 
inappropriate due to contraindications or intolerance.

as dual oral therapy in combination with:

 metformin when diet and exercise plus metformin alone do not provide adequate glycaemic 
control.

 a sulphonylurea when diet and exercise plus maximal tolerated dose of a sulphonylurea alone
do not provide adequate glycaemic control and when metformin is inappropriate due to 
contraindications or intolerance.

 a peroxisome proliferator-activated receptor gamma (PPAR) agonist (i.e. a thiazolidinedione) 
when use of a PPAR agonist is appropriate and when diet and exercise plus the PPAR 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 PPAR agonist and metformin when use of a PPAR agonist is appropriate and when diet and 
exercise plus dual therapy with these medicinal products do not provide adequate glycaemic 
control.

TESAVEL 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.

 



19

4.2 Posology and method of administration

Posology
The dose is 100 mg sitagliptin once daily. When used in combination with metformin and/or a PPAR
agonist, the dose of metformin and/or PPAR agonist should be maintained, and TESAVEL 
administered concomitantly.

When TESAVEL 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 TESAVEL 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 medicinal product, 
its conditions for use in patients with renal impairment should be checked.

For patients with mild renal impairment (glomerular filtration rate [GFR]  60 to < 90 mL/min), no 
dose adjustment is required.

For patients with moderate renal impairment (GFR  45 to < 60 mL/min), no dosage adjustment is 
required.

For patients with moderate renal impairment (GFR  30 to < 45 mL/min), the dose of TESAVEL is
50 mg once daily.

For patients with severe renal impairment (GFR ≥ 15 to <30 mL/min) or with end-stage renal disease 
(ESRD) (GFR < 15 mL/min), including those requiring haemodialysis or peritoneal dialysis, the dose 
of TESAVEL 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 TESAVEL and periodically thereafter.

Hepatic impairment
No dose adjustment is necessary for patients with mild to moderate hepatic impairment. TESAVEL
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
Sitagliptin should not be used in children and adolescents 10 to 17 years of age because of insufficient 
efficacy. Currently available data are described in sections 4.8, 5.1, and 5.2. Sitagliptin has not been 
studied in paediatric patients under 10 years of age.

Method of administration
TESAVEL can be taken with or without food.

 



20

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see 
sections 4.4 and 4.8).

4.4 Special warnings and precautions for use

General
TESAVEL 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, TESAVEL and other potentially suspect medicinal 
products should be discontinued; if acute pancreatitis is confirmed, TESAVEL 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 TESAVEL as monotherapy and as part of combination therapy with medicinal 
products not known to cause hypoglycaemia (i.e. metformin and/or a PPAR 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 GFR 
< 45 mL/min, as well as in ESRD patients requiring haemodialysis or peritoneal dialysis (see 
sections 4.2 and 5.2).

When considering the use of sitagliptin in combination with another anti-diabetic medicinal product, 
its conditions for use in patients with renal impairment should be checked.

Hypersensitivity reactions
Post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin have 
been reported. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions 
including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after 
initiation of treatment, with some reports occurring after the first dose. If a hypersensitivity reaction is 
suspected, TESAVEL should be discontinued. Other potential causes for the event should be 
assessed, and alternative treatment for diabetes initiated.

Bullous pemphigoid
There have been post-marketing reports of bullous pemphigoid in patients taking DPP-4 inhibitors 
including sitagliptin. If bullous pemphigoid is suspected, TESAVEL should be discontinued.

Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 
‘sodium-free’.

 



21

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 pharmacokinetics 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 the risk of clinically meaningful interactions is considered to be 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 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 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, TESAVEL 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. TESAVEL should not be used during breast-feeding.

 



22

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

TESAVEL 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 have been 
reported.

In addition, patients should be alerted to the risk of hypoglycaemia when TESAVEL 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. 
Hypoglycaemia 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

Blood and lymphatic system disorders
thrombocytopenia Rare

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

 



23

Adverse reaction Frequency of adverse reaction

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 post-marketing 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)).

Paediatric population
In clinical trials with sitagliptin in paediatric patients with type 2 diabetes mellitus aged 10 to17 years, 
the profile of adverse reactions was comparable to that observed in adults.

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 m2), 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. 

 



24

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 of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

4.9 Overdose

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.

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 haemodialysis session. Prolonged haemodialysis 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
TESAVEL 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) and glucose-dependent insulinotropic polypeptide (GIP), are 
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. The effects of GLP-1 and GIP are glucose-dependent such that when blood glucose 

 

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25

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 haemoglobin 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 in adult patients with type 2 diabetes (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-week studies of sitagliptin as add-on therapy, one in combination with 
metformin and one in combination with pioglitazone. Change from baseline in body weight was 
similar for patients treated with sitagliptin relative to placebo. In these studies there was a similar 
incidence of hypoglycaemia reported for patients treated with sitagliptin or placebo.

A 24-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin
(100 mg once daily) added to glimepiride alone or glimepiride in combination with metformin. The 
addition of sitagliptin to either glimepiride alone or to glimepiride and metformin provided significant 
improvements in glycaemic parameters. Patients treated with sitagliptin had a modest increase in body 
weight compared to those given placebo.

A 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 

 



26

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)
8.0 -0.5

-0.6‡

(-0.8, -0.4)
Sitagliptin 100 mg once daily

(N= 229)
8.0 -0.6

-0.8‡

(-1.0, -0.6)

Combination Therapy Studies

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 pioglitazone therapy

(N=163)
8.1 -0.9

-0.7‡

(-0.9, -0.5)

Sitagliptin 100 mg once daily added to 
ongoing glimepiride therapy

(N=102)
8.4 -0.3

-0.6‡

(-0.8, -0.3)

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 pioglitazone + metformin 
therapy#

(N=152)

8.8 -1.2
-0.7‡

(-1.0, -0.5)

Initial therapy (twice daily):
Sitagliptin 50 mg + metformin 500 mg 
(N=183)

8.8 -1.4
-1.6‡

(-1.8, -1.3)

Initial therapy (twice daily): 
Sitagliptin 50 mg + metformin 
1,000 mg
(N=178)

8.8 -1.9
-2.1‡

(-2.3, -1.8)

 



27

Study
Mean baseline 

HbA1c (%)

Mean change 
from baseline 
HbA1c (%)

†

Placebo-corrected 
mean change in 

HbA1c (%)
† 

(95 % CI)
Sitagliptin 100 mg once daily added to 
ongoing insulin (+/- metformin) 
therapy

(N=305)

8.7 -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.
HbA1c (%) at week 24.
# HbA1c (%) at week 26.
¶ Least squares mean adjusted for metformin use at Visit 1 (yes/no), insulin use at Visit 1 (pre-mixed vs. non-pre-mixed 
[intermediate- or long-acting]), and baseline value. Treatment by 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 
sitagliptin 100 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). The overall incidence of 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 100 mg once daily or 
glipizide (a sulphonylurea) in patients with inadequate glycaemic control on metformin monotherapy, 
sitagliptin was similar to glipizide in reducing HbA1c. The mean glipizide dose used in the comparator 
group was 10 mg per day with approximately 40 % of patients requiring a glipizide dose of 
 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 Week 24, the increase in daily insulin 
dose was 19 IU/day in 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. 19.1 %). 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

 



28

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 50 mg 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 25 or 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 randomised 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 m2).

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, or hospitalisation for unstable angina. Secondary 
cardiovascular endpoints included the first occurrence of cardiovascular death, nonfatal myocardial 
infarction, or nonfatal stroke; first occurrence of the individual components of the primary composite; 
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 hospitalisation 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

Hazard Ratio

(95% CI) p-value†N (%)

Incidence 
rate per 

100 
patient-
years* N (%)

Incidence 
rate per 

100 
patient-
years*

Analysis in the Intention-to-Treat Population

Number of patients 7,332 7,339 0.98 (0.89–1.08) <0.001

 



29

Sitagliptin 100 mg Placebo

Hazard Ratio

(95% CI) p-value†N (%)

Incidence 
rate per 

100 
patient-
years* N (%)

Incidence 
rate per 

100 
patient-
years*

Primary Composite Endpoint
(Cardiovascular death, nonfatal 
myocardial infarction, nonfatal 
stroke, or hospitalisation for 
unstable angina) 839 (11.4) 4.1 851 (11.6) 4.2

Secondary Composite Endpoint
(Cardiovascular death, nonfatal 
myocardial infarction, or nonfatal 
stroke) 745 (10.2) 3.6 746 (10.2) 3.6 0.99 (0.89–1.10) <0.001

Secondary Outcome

Cardiovascular death 380 (5.2) 1.7 366 (5.0) 1.7 1.03 (0.89-1.19) 0.711

All myocardial infarction (fatal 
and non-fatal) 300 (4.1) 1.4 316 (4.3) 1.5 0.95 (0.81–1.11) 0.487

All stroke (fatal and non-fatal) 178 (2.4) 0.8 183 (2.5) 0.9 0.97 (0.79–1.19) 0.760

Hospitalisation for unstable 
angina 116 (1.6) 0.5 129 (1.8) 0.6 0.90 (0.70–1.16) 0.419

Death from any cause 547 (7.5) 2.5 537 (7.3) 2.5 1.01 (0.90–1.14) 0.875

Hospitalisation for heart failure‡ 228 (3.1) 1.1 229 (3.1) 1.1 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 hospitalisation for heart failure was adjusted for a history of heart failure at baseline.

Paediatric population
A 54-week, double-blind study was conducted to evaluate the efficacy and safety of sitagliptin 
100 mg once daily in paediatric patients (10 to 17 years of age) with type 2 diabetes who were not on 
anti-hyperglycaemic therapy for at least 12 weeks (with HbA1c 6.5% to 10%) or were on a stable 
dose of insulin for at least 12 weeks (with HbA1c 7% to 10%). Patients were randomised to sitagliptin 
100 mg once daily or placebo for 20 weeks.

Mean baseline HbA1c was 7.5%. Treatment with sitagliptin 100 mg did not provide significant 
improvement in HbA1c at 20 weeks. The reduction in HbA1c in patients treated with sitagliptin 
(N=95) was 0.0% compared to 0.2% in patients treated with placebo (N=95), a difference of -0.2%
(95% CI: -0.7, 0.3). See section 4.2.

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 8.52 M•hr, 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, TESAVEL may be administered with or without food.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Dose-proportionality was not 
established for Cmax and C24hr (Cmax increased in a greater than dose-proportional manner and C24hr
increased in a less than dose-proportional manner).

 



30

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 [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=160 M) or p-glycoprotein (up 
to 250 M) 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 mild, moderate, and severe renal 
impairment, as well as patients with ESRD on haemodialysis. In addition, the effects of renal 
impairment on sitagliptin pharmacokinetics in patients with type 2 diabetes and mild, moderate, or 
severe renal impairment (including ESRD) were assessed using population pharmacokinetic analyses.

Compared to normal healthy control subjects, plasma AUC of sitagliptin was increased by 
approximately 1.2-fold and 1.6-fold in patients with mild renal impairment (GFR ≥ 60 to 
< 90 mL/min) and patients with moderate renal impairment (GFR ≥ 45 to < 60 mL/min), respectively. 
Because increases of this magnitude are not clinically relevant, dosage adjustment in these patients is 
not necessary.

 



31

Plasma AUC of sitagliptin was increased approximately 2-fold in patients with moderate renal 
impairment (GFR ≥ 30 to < 45 mL/min), and approximately 4-fold in patients with severe renal 
impairment (GFR < 30 mL/min), including in patients with ESRD on haemodialysis. 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 are recommended in patients with GFR < 45 mL/min (see 
section 4.2).

Hepatic impairment
No dose adjustment for TESAVEL 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 population
The pharmacokinetics of sitagliptin (single dose of 50 mg, 100 mg or 200 mg) were investigated in 
paediatric patients (10 to 17 years of age) with type 2 diabetes. In this population, the dose-adjusted
AUC of sitagliptin in plasma was approximately 18 % lower compared to adult patients with type 2 
diabetes for a 100 mg dose. This is not considered to be a clinically meaningful difference compared 
to adult patients based on the flat PK/PD relationship between the dose of 50 mg and 100 mg. No 
studies with sitagliptin have been performed in paediatric patients with age <10 years.

Other patient characteristics
No dose adjustment is necessary based on gender, race, or body mass index (BMI). These 
characteristics had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a 
composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of 
Phase I and Phase II data.

5.3 Preclinical safety data

Renal and liver toxicity were observed in rodents at systemic exposure values 58 times the human 
exposure level, while the no-effect level was found at 19 times the human exposure level. Incisor teeth
abnormalities were observed in rats at exposure levels 67 times the clinical exposure level; the 
no-effect level for this finding was 58-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 tumours 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.

 



32

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 foetal 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 (E341)
croscarmellose sodium (E468)
magnesium stearate (E470b)
sodium stearyl fumarate

Film coating:
poly(vinyl alcohol)
macrogol 3350
talc (E553b)
titanium dioxide (E171)
red iron oxide (E172)
yellow iron oxide (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

Opaque blisters (PVC/PE/PVDC and aluminium). Packs of 14, 28, 30, 56, 84, 90 or 98 film-coated 
tablets and 50 x 1 film-coated tablets in perforated unit dose blisters.

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.

 



33

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/07/435/007
EU/1/07/435/008
EU/1/07/435/009
EU/1/07/435/010
EU/1/07/435/011
EU/1/07/435/012
EU/1/07/435/021
EU/1/07/435/022

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 10 January 2008
Date of latest renewal: 20 September 2012

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu.

 



34

1. NAME OF THE MEDICINAL PRODUCT

TESAVEL 100 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 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 (tablet).

Round, beige film-coated tablet with “277” on one side.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

For adult patients with type 2 diabetes mellitus, TESAVEL is indicated to improve glycaemic control:

as monotherapy:

 in patients inadequately controlled by diet and exercise alone and for whom metformin is 
inappropriate due to contraindications or intolerance.

as dual oral therapy in combination with:

 metformin when diet and exercise plus metformin alone do not provide adequate glycaemic 
control.

 a sulphonylurea when diet and exercise plus maximal tolerated dose of a sulphonylurea alone
do not provide adequate glycaemic control and when metformin is inappropriate due to 
contraindications or intolerance.

 a peroxisome proliferator-activated receptor gamma (PPAR) agonist (i.e. a thiazolidinedione) 
when use of a PPAR agonist is appropriate and when diet and exercise plus the PPAR 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 PPAR agonist and metformin when use of a PPAR agonist is appropriate and when diet and 
exercise plus dual therapy with these medicinal products do not provide adequate glycaemic 
control.

TESAVEL 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.

 



35

4.2 Posology and method of administration

Posology
The dose is 100 mg sitagliptin once daily. When used in combination with metformin and/or a PPAR
agonist, the dose of metformin and/or PPAR agonist should be maintained, and TESAVEL 
administered concomitantly.

When TESAVEL 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 TESAVEL 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 medicinal product, 
its conditions for use in patients with renal impairment should be checked.

For patients with mild renal impairment (glomerular filtration rate [GFR]  60 to < 90 ml/min), no 
dose adjustment is required.

For patients with moderate renal impairment (GFR  45 to < 60 mL/min), no dosage adjustment is 
required.

For patients with moderate renal impairment (GFR  30 to < 45 mL/min), the dose of TESAVEL is
50 mg once daily.

For patients with severe renal impairment (GFR ≥ 15 to <30 mL/min) or with end-stage renal disease 
(ESRD) (GFR < 15 mL/min), including those requiring haemodialysis or peritoneal dialysis, the dose 
of TESAVEL 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 TESAVEL and periodically thereafter.

Hepatic impairment
No dose adjustment is necessary for patients with mild to moderate hepatic impairment. TESAVEL
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
Sitagliptin should not be used in children and adolescents 10 to 17 years of age because of insufficient 
efficacy. Currently available data are described in sections 4.8, 5.1, and 5.2. Sitagliptin has not been 
studied in paediatric patients under 10 years of age.

Method of administration
TESAVEL can be taken with or without food.

 



36

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see 
sections 4.4 and 4.8).

4.4 Special warnings and precautions for use

General
TESAVEL 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, TESAVEL and other potentially suspect medicinal 
products should be discontinued; if acute pancreatitis is confirmed, TESAVEL 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 TESAVEL as monotherapy and as part of combination therapy with medicinal 
products not known to cause hypoglycaemia (i.e. metformin and/or a PPAR 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 GFR 
< 45 mL/min, as well as in ESRD patients requiring haemodialysis or peritoneal dialysis (see 
sections 4.2 and 5.2).

When considering the use of sitagliptin in combination with another anti-diabetic medicinal product, 
its conditions for use in patients with renal impairment should be checked.

Hypersensitivity reactions
Post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin have 
been reported. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions 
including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after 
initiation of treatment, with some reports occurring after the first dose. If a hypersensitivity reaction is 
suspected, TESAVEL should be discontinued. Other potential causes for the event should be 
assessed, and alternative treatment for diabetes initiated.

Bullous pemphigoid
There have been post-marketing reports of bullous pemphigoid in patients taking DPP-4 inhibitors 
including sitagliptin. If bullous pemphigoid is suspected, TESAVEL should be discontinued.

Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 
‘sodium-free’.

 



37

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 pharmacokinetics 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 the risk of clinically meaningful interactions is considered to be 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 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 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, TESAVEL 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. TESAVEL should not be used during breast-feeding.

 



38

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

TESAVEL 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 have been 
reported.

In addition, patients should be alerted to the risk of hypoglycaemia when TESAVEL 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. 
Hypoglycaemia 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

Blood and lymphatic system disorders
thrombocytopenia Rare

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

 



39

Adverse reaction Frequency of adverse reaction

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 post-marketing 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)).

Paediatric population
In clinical trials with sitagliptin in paediatric patients with type 2 diabetes mellitus aged 10 to17 years, 
the profile of adverse reactions was comparable to that observed in adults.

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 m2), 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. 

 



40

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 of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

4.9 Overdose

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.

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 haemodialysis session. Prolonged haemodialysis 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
TESAVEL 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) and glucose-dependent insulinotropic polypeptide (GIP), are 
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. The effects of GLP-1 and GIP are glucose-dependent such that when blood glucose 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


41

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 haemoglobin 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 in adult patients with type 2 diabetes (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-week studies of sitagliptin as add-on therapy, one in combination with 
metformin and one in combination with pioglitazone. Change from baseline in body weight was 
similar for patients treated with sitagliptin relative to placebo. In these studies there was a similar 
incidence of hypoglycaemia reported for patients treated with sitagliptin or placebo.

A 24-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin
(100 mg once daily) added to glimepiride alone or glimepiride in combination with metformin. The 
addition of sitagliptin to either glimepiride alone or to glimepiride and metformin provided significant 
improvements in glycaemic parameters. Patients treated with sitagliptin had a modest increase in body 
weight compared to those given placebo.

A 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 

 



42

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)
8.0 -0.5

-0.6‡

(-0.8, -0.4)
Sitagliptin 100 mg once daily

(N= 229)
8.0 -0.6

-0.8‡

(-1.0, -0.6)

Combination Therapy Studies

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 pioglitazone therapy

(N=163)
8.1 -0.9

-0.7‡

(-0.9, -0.5)

Sitagliptin 100 mg once daily added to 
ongoing glimepiride therapy

(N=102)
8.4 -0.3

-0.6‡

(-0.8, -0.3)

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 pioglitazone + metformin 
therapy#

(N=152)

8.8 -1.2
-0.7‡

(-1.0, -0.5)

Initial therapy (twice daily):
Sitagliptin 50 mg + metformin 500 mg 
(N=183)

8.8 -1.4
-1.6‡

(-1.8, -1.3)

Initial therapy (twice daily): 
Sitagliptin 50 mg + metformin 
1,000 mg
(N=178)

8.8 -1.9
-2.1‡

(-2.3, -1.8)

 



43

Study
Mean baseline 

HbA1c (%)

Mean change 
from baseline 
HbA1c (%)

†

Placebo-corrected 
mean change in 

HbA1c (%)
† 

(95 % CI)
Sitagliptin 100 mg once daily added to 
ongoing insulin (+/- metformin) 
therapy

(N=305)

8.7 -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.
HbA1c (%) at week 24.
# HbA1c (%) at week 26.
¶ Least squares mean adjusted for metformin use at Visit 1 (yes/no), insulin use at Visit 1 (pre-mixed vs. non-pre-mixed 
[intermediate- or long-acting]), and baseline value. Treatment by 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 
sitagliptin 100 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). The overall incidence of 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 100 mg once daily or 
glipizide (a sulphonylurea) in patients with inadequate glycaemic control on metformin monotherapy, 
sitagliptin was similar to glipizide in reducing HbA1c. The mean glipizide dose used in the comparator 
group was 10 mg per day with approximately 40 % of patients requiring a glipizide dose of 
 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 Week 24, the increase in daily insulin 
dose was 19 IU/day in 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. 19.1 %). 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

 



44

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 50 mg 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 25 or 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 randomised 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 m2).

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, or hospitalisation for unstable angina. Secondary 
cardiovascular endpoints included the first occurrence of cardiovascular death, nonfatal myocardial 
infarction, or nonfatal stroke; first occurrence of the individual components of the primary composite; 
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 hospitalisation 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

Hazard Ratio

(95% CI) p-value†N (%)

Incidence 
rate per 

100 
patient-
years* N (%)

Incidence 
rate per 

100 
patient-
years*

Analysis in the Intention-to-Treat Population

Number of patients 7,332 7,339 0.98 (0.89–1.08) <0.001

 



45

Sitagliptin 100 mg Placebo

Hazard Ratio

(95% CI) p-value†N (%)

Incidence 
rate per 

100 
patient-
years* N (%)

Incidence 
rate per 

100 
patient-
years*

Primary Composite Endpoint
(Cardiovascular death, nonfatal 
myocardial infarction, nonfatal 
stroke, or hospitalisation for 
unstable angina) 839 (11.4) 4.1 851 (11.6) 4.2

Secondary Composite Endpoint
(Cardiovascular death, nonfatal 
myocardial infarction, or nonfatal 
stroke) 745 (10.2) 3.6 746 (10.2) 3.6 0.99 (0.89–1.10) <0.001

Secondary Outcome

Cardiovascular death 380 (5.2) 1.7 366 (5.0) 1.7 1.03 (0.89-1.19) 0.711

All myocardial infarction (fatal 
and non-fatal) 300 (4.1) 1.4 316 (4.3) 1.5 0.95 (0.81–1.11) 0.487

All stroke (fatal and non-fatal) 178 (2.4) 0.8 183 (2.5) 0.9 0.97 (0.79–1.19) 0.760

Hospitalisation for unstable 
angina 116 (1.6) 0.5 129 (1.8) 0.6 0.90 (0.70–1.16) 0.419

Death from any cause 547 (7.5) 2.5 537 (7.3) 2.5 1.01 (0.90–1.14) 0.875

Hospitalisation for heart failure‡ 228 (3.1) 1.1 229 (3.1) 1.1 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 hospitalisation for heart failure was adjusted for a history of heart failure at baseline.

Paediatric population
A 54-week, double-blind study was conducted to evaluate the efficacy and safety of sitagliptin 
100 mg once daily in paediatric patients (10 to 17 years of age) with type 2 diabetes who were not on 
anti-hyperglycaemic therapy for at least 12 weeks (with HbA1c 6.5% to 10%) or were on a stable 
dose of insulin for at least 12 weeks (with HbA1c 7% to 10%). Patients were randomised to sitagliptin 
100 mg once daily or placebo for 20 weeks.

Mean baseline HbA1c was 7.5%. Treatment with sitagliptin 100 mg did not provide significant 
improvement in HbA1c at 20 weeks. The reduction in HbA1c in patients treated with sitagliptin 
(N=95) was 0.0% compared to 0.2% in patients treated with placebo (N=95), a difference of -0.2%
(95% CI: -0.7, 0.3). See section 4.2.

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 8.52 M•hr, 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, TESAVEL may be administered with or without food.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Dose-proportionality was not 
established for Cmax and C24hr (Cmax increased in a greater than dose-proportional manner and C24hr
increased in a less than dose-proportional manner).

 



46

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 [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=160 M) or p-glycoprotein (up 
to 250 M) 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 mild, moderate, and severe renal 
impairment, as well as patients with ESRD on haemodialysis. In addition, the effects of renal 
impairment on sitagliptin pharmacokinetics in patients with type 2 diabetes and mild, moderate, or 
severe renal impairment (including ESRD) were assessed using population pharmacokinetic analyses.

Compared to normal healthy control subjects, plasma AUC of sitagliptin was increased by 
approximately 1.2-fold and 1.6-fold in patients with mild renal impairment (GFR ≥ 60 to 
< 90 mL/min) and patients with moderate renal impairment (GFR ≥ 45 to < 60 mL/min), respectively. 
Because increases of this magnitude are not clinically relevant, dosage adjustment in these patients is 
not necessary.

Plasma AUC of sitagliptin was increased approximately 2-fold in patients with moderate renal 
impairment (GFR ≥ 30 to < 45 mL/min), and approximately 4-fold in patients with severe renal 

 



47

impairment (GFR < 30 mL/min), including in patients with ESRD on haemodialysis. 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 are recommended in patients with GFR < 45 mL/min (see 
section 4.2).

Hepatic impairment
No dose adjustment for TESAVEL 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 population
The pharmacokinetics of sitagliptin (single dose of 50 mg, 100 mg or 200 mg) were investigated in 
paediatric patients (10 to 17 years of age) with type 2 diabetes. In this population, the dose-adjusted
AUC of sitagliptin in plasma was approximately 18 % lower compared to adult patients with type 2 
diabetes for a 100 mg dose. This is not considered to be a clinically meaningful difference compared 
to adult patients based on the flat PK/PD relationship between the dose of 50 mg and 100 mg. No 
studies with sitagliptin have been performed in paediatric patients with age <10 years.

Other patient characteristics
No dose adjustment is necessary based on gender, race, or body mass index (BMI). These 
characteristics had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a 
composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of 
Phase I and Phase II data.

5.3 Preclinical safety data

Renal and liver toxicity were observed in rodents at systemic exposure values 58 times the human 
exposure level, while the no-effect level was found at 19 times the human exposure level. Incisor teeth
abnormalities were observed in rats at exposure levels 67 times the clinical exposure level; the 
no-effect level for this finding was 58-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 tumours 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.

 



48

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 foetal 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 (E341)
croscarmellose sodium (E468)
magnesium stearate (E470b)
sodium stearyl fumarate

Film coating:
poly(vinyl alcohol)
macrogol 3350
talc (E553b)
titanium dioxide (E171)
red iron oxide (E172)
yellow iron oxide (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

Opaque blisters (PVC/PE/PVDC and aluminium). Packs of 14, 28, 30, 56, 84, 90 or 98 film-coated 
tablets and 50 x 1 film-coated tablets in perforated unit dose blisters.

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.

 



49

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/07/435/013
EU/1/07/435/014
EU/1/07/435/015
EU/1/07/435/016
EU/1/07/435/017
EU/1/07/435/018
EU/1/07/435/023
EU/1/07/435/024

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 10 January 2008
Date of latest renewal: 20 September 2012

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu.

 



50

ANNEX II

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 
RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT

 



51

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer(s) responsible for batch release

Merck Sharp & Dohme Ltd.
Shotton Lane, Cramlington
Northumberland NE23 3JU
United Kingdom

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch.

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to medical prescription.

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

 Periodic safety update reports (PSURs)

The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT

 Risk management plan (RMP)

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing 
authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:
 At the request of the European Medicines Agency;
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached.

 



52

ANNEX III

LABELLING AND PACKAGE LEAFLET

 



53

A. LABELLING

 



54

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

TESAVEL 25 mg film-coated tablets
sitagliptin

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains sitagliptin phosphate monohydrate equivalent to 25 mg of sitagliptin.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

14 film-coated tablets
28 film-coated tablets
30 film-coated tablets
56 film-coated tablets
84 film-coated tablets
90 film-coated tablets
98 film-coated tablets
50 x 1 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

 



55

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/07/435/001 14 film-coated tablets
EU/1/07/435/002 28 film-coated tablets
EU/1/07/435/019 30 film-coated tablets
EU/1/07/435/003 56 film-coated tablets
EU/1/07/435/004 84 film-coated tablets
EU/1/07/435/020 90 film-coated tablets
EU/1/07/435/005 98 film-coated tablets
EU/1/07/435/006 50 x 1 film-coated tablets

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

TESAVEL 25 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

 



56

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTERS

1. NAME OF THE MEDICINAL PRODUCT

TESAVEL 25 mg tablets
sitagliptin

2. NAME OF THE MARKETING AUTHORISATION HOLDER

MSD

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

 



57

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

TESAVEL 50 mg film-coated tablets
sitagliptin

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains sitagliptin phosphate monohydrate equivalent to 50 mg of sitagliptin.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

14 film-coated tablets
28 film-coated tablets
30 film-coated tablets
56 film-coated tablets
84 film-coated tablets
90 film-coated tablets
98 film-coated tablets
50 x 1 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

 



58

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/07/435/007 14 film-coated tablets
EU/1/07/435/008 28 film-coated tablets
EU/1/07/435/021 30 film-coated tablets
EU/1/07/435/009 56 film-coated tablets
EU/1/07/435/010 84 film-coated tablets
EU/1/07/435/022 90 film-coated tablets
EU/1/07/435/011 98 film-coated tablets
EU/1/07/435/012 50 x 1 film-coated tablets

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

TESAVEL 50 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

 



59

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTERS

1. NAME OF THE MEDICINAL PRODUCT

TESAVEL 50 mg tablets
sitagliptin

2. NAME OF THE MARKETING AUTHORISATION HOLDER

MSD

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

 



60

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

TESAVEL 100 mg film-coated tablets
sitagliptin

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains sitagliptin phosphate monohydrate equivalent to 100 mg of sitagliptin.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

14 film-coated tablets
28 film-coated tablets
30 film-coated tablets
56 film-coated tablets
84 film-coated tablets
90 film-coated tablets
98 film-coated tablets
50 x 1 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

 



61

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/07/435/013 14 film-coated tablets
EU/1/07/435/014 28 film-coated tablets
EU/1/07/435/023 30 film-coated tablets
EU/1/07/435/015 56 film-coated tablets
EU/1/07/435/016 84 film-coated tablets
EU/1/07/435/024 90 film-coated tablets
EU/1/07/435/017 98 film-coated tablets
EU/1/07/435/018 50 x 1 film-coated tablets

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

TESAVEL 100 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

 



62

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTERS

1. NAME OF THE MEDICINAL PRODUCT

TESAVEL 100 mg tablets
sitagliptin

2. NAME OF THE MARKETING AUTHORISATION HOLDER

MSD

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

 



63

B. PACKAGE LEAFLET

 



64

Package leaflet: Information for the patient

TESAVEL 25 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, pharmacist, or nurse.
- 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, pharmacist, or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What TESAVEL is and what it is used for
2. What you need to know before you take TESAVEL
3. How to take TESAVEL
4. Possible side effects
5. How to store TESAVEL
6. Contents of the pack and other information

1. What TESAVEL is and what it is used for

TESAVEL 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 increase the levels of insulin produced 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 TESAVEL

Do not take TESAVEL
- if you are allergic to sitagliptin or any of the other ingredients of this medicine (listed in 

section 6).

Warnings and precautions
Cases of inflammation of the pancreas (pancreatitis) have been reported in patients receiving 
TESAVEL (see section 4).

 



65

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 TESAVEL.

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 TESAVEL (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 TESAVEL
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 
TESAVEL.

Pregnancy and breast-feeding
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 or negligible 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.

TESAVEL contains sodium
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 
‘sodium-free’.

3. How to take TESAVEL

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure.

 



66

The usual 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 and 
exercise recommended by your doctor while taking TESAVEL.

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

If you forget to take TESAVEL
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 TESAVEL
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 TESAVEL 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

 



67

Common: constipation

Some patients have experienced the following side effects while taking sitagliptin and pioglitazone:
Common: flatulence, swelling of the hands or legs

Some patients have experienced the following side effects while taking sitagliptin in combination 
with pioglitazone and metformin:
Common: 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: flu
Uncommon: 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: low blood sugar, headache, upper respiratory infection, stuffy or runny nose and sore 
throat, osteoarthritis, arm or leg pain
Uncommon: dizziness, constipation, itching
Rare: reduced number of platelets
Frequency not known: 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, pharmacist, or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.

5. How to store TESAVEL

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

Do not use this medicine after the expiry date which is stated on the blister and the carton after 'EXP'. 
The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not throw away 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 TESAVEL contains

- The active substance is sitagliptin. Each film-coated tablet (tablet) contains sitagliptin 
phosphate monohydrate, equivalent to 25 mg sitagliptin.

- The other ingredients are: In the tablet core: microcrystalline cellulose (E460), calcium 
hydrogen phosphate, anhydrous (E341), croscarmellose sodium (E468), magnesium stearate 
(E470b), and sodium stearyl fumarate. The tablet film coating contains: poly(vinyl alcohol), 
macrogol 3350, talc (E553b), titanium dioxide (E171), red iron oxide (E172), and yellow iron 
oxide (E172).

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


68

What TESAVEL looks like and contents of the pack

Round, pink film-coated tablet with “221” on one side.

Opaque blisters (PVC/PE/PVDC and aluminium). Packs of 14, 28, 30, 56, 84, 90 or 98 film-coated 
tablets and 50 x 1 film-coated tablets in perforated unit dose blisters.

Not all pack sizes may be marketed.

Marketing Authorisation Holder
Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

Manufacturer
Merck Sharp & Dohme Ltd.
Shotton Lane, Cramlington
Northumberland NE23 3JU
United Kingdom

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

Belgique/België/Belgien
MSD Belgium BVBA/SPRL
Tél/Tel: +32 (0)27766211
dpoc_belux@merck.com

Lietuva
UAB Merck Sharp & Dohme
Tel.: +370 5 278 02 47
msd_lietuva@merck.com

България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3737
info-msdbg@merck.com

Luxembourg/Luxemburg
MSD Belgium BVBA/SPRL
Tél: +32 (0)27766211
dpoc_belux@merck.com

Česká republika
Merck Sharp & Dohme s.r.o.
Tel.: +420 233 010 111
dpoc_czechslovak@merck.com

Magyarország
MSD Pharma Hungary Kft.
Tel.: +36 1 888 53 00
hungary_msd@merck.com

Danmark
MSD Danmark ApS
Tlf: +45 4482 4000
dkmail@merck.com

Malta
Merck Sharp & Dohme Cyprus Limited
Tel: 8007 4433 (+356 99917558)
malta_info@merck.com

Deutschland
MSD SHARP & DOHME GMBH
Tel: 0800 673 673 673 (+49 (0) 89 4561 2612)
e-mail@msd.de

Nederland
Merck Sharp & Dohme B.V.
Tel.: 0800 9999000 (+31 23 5153153)
medicalinfo.nl@merck.com

 



69

Eesti
Merck Sharp & Dohme OÜ
Tel: +372 6144 200
msdeesti@merck.com

Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no

Eλλάδα
MSD Α.Φ.Β.Ε.Ε.
Τηλ: + 30 210 98 97 300
dpoc_greece@merck.com

Österreich
Merck Sharp & Dohme Ges.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com

España
Almirall, S.A.
Tel: +34 93 291 30 00
info.spain@almirall.com

Polska
MSD Polska Sp. z o.o.
Tel.: +48 22 549 51 00
msdpolska@merck.com

France
MSD France
Tél: + 33 (0) 1 80 46 40 40

Portugal
Merck Sharp & Dohme, Lda
Tel: +351 21 4465700
inform_pt@merck.com

Hrvatska
Merck Sharp & Dohme d.o.o.
Tel: + 385 1 66 11 333
croatia_info@merck.com

România
Merck Sharp & Dohme Romania S.R.L.
Tel: + 4021 529 29 00
msdromania@merck.com

Ireland
Merck Sharp & Dohme Ireland (Human Health) 
Limited
Tel: +353 (0)1 2998700
medinfo_ireland@merck.com

Slovenija
Merck Sharp & Dohme, inovativna zdravila
d.o.o. 
Tel: + 386 1 5204 201
msd_slovenia@merck.com

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
Merck Sharp & Dohme, s. r. o.
Tel.: +421 2 58282010
dpoc_czechslovak@merck.com

Ιtalia
Addenda Pharma S.r.l.
Tel.: +39 06 91393303
addendapharma@legalmail.it

Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0) 9 804 650
info@msd.fi

Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ: 80000 673 (+357 22866700)
cyprus_info@merck.com

Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 77 5700488
medicinskinfo@merck.com

Latvija
SIA Merck Sharp & Dohme Latvija
Tel: +371 67364 224
msd_lv@merck.com

United Kingdom
Merck Sharp & Dohme Limited
Tel: +44 (0) 1992 467272
medicalinformationuk@merck.com

This leaflet was last revised in {MM/YYYY}.

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

 



70

Package leaflet: Information for the patient

TESAVEL 50 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, pharmacist, or nurse.
- 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, pharmacist, or nurse. This includes any possible

side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What TESAVEL is and what it is used for
2. What you need to know before you take TESAVEL
3. How to take TESAVEL
4. Possible side effects
5 How to store TESAVEL
6. Contents of the pack and other information

1. What TESAVEL is and what it is used for

TESAVEL 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 increase the levels of insulin produced 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 TESAVEL

Do not take TESAVEL
- if you are allergic to sitagliptin or any of the other ingredients of this medicine (listed in 

section 6).

Warnings and precautions
Cases of inflammation of the pancreas (pancreatitis) have been reported in patients receiving 
TESAVEL (see section 4).

 



71

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 TESAVEL.

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 TESAVEL (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 TESAVEL
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 
TESAVEL.

Pregnancy and breast-feeding
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 use 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 or negligible 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.

TESAVEL contains sodium
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 
‘sodium-free’.

3. How to take TESAVEL

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure.

 



72

The usual 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 and
exercise recommended by your doctor while taking TESAVEL.

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

If you forget to take TESAVEL
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 TESAVEL
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 TESAVEL 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

 



73

Common: constipation

Some patients have experienced the following side effects while taking sitagliptin and pioglitazone:
Common: flatulence, swelling of the hands or legs

Some patients have experienced the following side effects while taking sitagliptin in combination 
with pioglitazone and metformin:
Common: 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: flu
Uncommon: 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: low blood sugar, headache, upper respiratory infection, stuffy or runny nose and sore
throat, osteoarthritis, arm or leg pain
Uncommon: dizziness, constipation, itching
Rare: reduced number of platelets
Frequency not known: 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, pharmacist, or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.

5. How to store TESAVEL

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

Do not use this medicine after the expiry date which is stated on the blister and the carton after 'EXP'. 
The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not throw away 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 TESAVEL contains

- The active substance is sitagliptin. Each film-coated tablet (tablet) contains sitagliptin 
phosphate monohydrate, equivalent to 50 mg sitagliptin.

- The other ingredients are: In the tablet core: microcrystalline cellulose (E460), calcium 
hydrogen phosphate, anhydrous (E341), croscarmellose sodium (E468), magnesium stearate 
(E470b), and sodium stearyl fumarate. The tablet film coating contains: poly(vinyl alcohol), 
macrogol 3350, talc (E553b), titanium dioxide (E171), red iron oxide (E172), and yellow iron 
oxide (E172).

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


74

What TESAVEL looks like and contents of the pack

Round, light beige film-coated tablet with “112”on one side.

Opaque blisters (PVC/PE/PVDC and aluminium). Packs of 14, 28, 30, 56, 84, 90 or 98 film-coated 
tablets and 50 x 1 film-coated tablets in perforated unit dose blisters.

Not all pack sizes may be marketed.

Marketing Authorisation Holder
Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

Manufacturer
Merck Sharp & Dohme Ltd.
Shotton Lane, Cramlington
Northumberland NE23 3JU
United Kingdom

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

Belgique/België/Belgien
MSD Belgium BVBA/SPRL
Tél/Tel: +32 (0)27766211
dpoc_belux@merck.com

Lietuva
UAB Merck Sharp & Dohme
Tel.: +370 5 278 02 47
msd_lietuva@merck.com

България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3737
info-msdbg@merck.com

Luxembourg/Luxemburg
MSD Belgium BVBA/SPRL
Tél: +32 (0)27766211
dpoc_belux@merck.com

Česká republika
Merck Sharp & Dohme s.r.o.
Tel.: +420 233 010 111
dpoc_czechslovak@merck.com

Magyarország
MSD Pharma Hungary Kft.
Tel.: +36 1 888 53 00
hungary_msd@merck.com

Danmark
MSD Danmark ApS
Tlf: +45 4482 4000
dkmail@merck.com

Malta
Merck Sharp & Dohme Cyprus Limited
Tel: 8007 4433 (+356 99917558)
malta_info@merck.com

Deutschland
MSD SHARP & DOHME GMBH
Tel: 0800 673 673 673 (+49 (0) 89 4561 2612)
e-mail@msd.de

Nederland
Merck Sharp & Dohme B.V.
Tel.: 0800 9999000 (+31 23 5153153)
medicalinfo.nl@merck.com

 



75

Eesti
Merck Sharp & Dohme OÜ
Tel: +372 6144 200
msdeesti@merck.com

Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no

Eλλάδα
MSD Α.Φ.Β.Ε.Ε.
Τηλ: + 30 210 98 97 300
dpoc_greece@merck.com

Österreich
Merck Sharp & Dohme Ges.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com

España
Almirall, S.A.
Tel: +34 93 291 30 00
info.spain@almirall.com

Polska
MSD Polska Sp. z o.o.
Tel.: +48 22 549 51 00
msdpolska@merck.com

France
MSD France
Tél: + 33 (0) 1 80 46 40 40

Portugal
Merck Sharp & Dohme, Lda
Tel: +351 21 4465700
inform_pt@merck.com

Hrvatska
Merck Sharp & Dohme d.o.o.
Tel: + 385 1 66 11 333
croatia_info@merck.com

România
Merck Sharp & Dohme Romania S.R.L.
Tel: + 4021 529 29 00
msdromania@merck.com

Ireland
Merck Sharp & Dohme Ireland (Human Health) 
Limited
Tel: +353 (0)1 2998700
medinfo_ireland@merck.com

Slovenija
Merck Sharp & Dohme, inovativna zdravila 
d.o.o. 
Tel: + 386 1 5204 201
msd_slovenia@merck.com

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
Merck Sharp & Dohme, s. r. o.
Tel.: +421 2 58282010
dpoc_czechslovak@merck.com

Ιtalia
Addenda Pharma S.r.l.
Tel.: +39 06 91393303
addendapharma@legalmail.it

Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0) 9 804 650
info@msd.fi

Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ: 80000 673 (+357 22866700)
cyprus_info@merck.com

Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 77 5700488
medicinskinfo@merck.com

Latvija
SIA Merck Sharp & Dohme Latvija
Tel: +371 67364 224
msd_lv@merck.com

United Kingdom
Merck Sharp & Dohme Limited
Tel: +44 (0) 1992 467272
medicalinformationuk@merck.com

This leaflet was last revised in {MM/YYYY}.

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

 



76

Package leaflet: Information for the patient

TESAVEL 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, pharmacist, or nurse.
- 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, pharmacist, or nurse. This includes any possible

side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What TESAVEL is and what it is used for
2. What you need to know before you take TESAVEL
3. How to take TESAVEL
4. Possible side effects
5. How to store TESAVEL
6. Contents of the pack and other information

1. What TESAVEL is and what it is used for

TESAVEL 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 increase the levels of insulin produced 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 TESAVEL

Do not take TESAVEL
- if you are allergic to sitagliptin or any of the other ingredients of this medicine (listed in 

section 6).

Warnings and precautions
Cases of inflammation of the pancreas (pancreatitis) have been reported in patients receiving 
TESAVEL (see section 4).

 



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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 TESAVEL.

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 TESAVEL (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 TESAVEL
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 
TESAVEL.

Pregnancy and breast-feeding
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 or negligible 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.

TESAVEL contains sodium
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 
‘sodium-free’.

3. How to take TESAVEL

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure.

 



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The usual 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 and
exercise recommended by your doctor while taking TESAVEL.

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

If you forget to take TESAVEL
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 TESAVEL
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 TESAVEL 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

 



79

Common: constipation

Some patients have experienced the following side effects while taking sitagliptin and pioglitazone:
Common: flatulence, swelling of the hands or legs

Some patients have experienced the following side effects while taking sitagliptin in combination 
with pioglitazone and metformin:
Common: 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: flu
Uncommon: 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: low blood sugar, headache, upper respiratory infection, stuffy or runny nose and sore 
throat, osteoarthritis, arm or leg pain
Uncommon: dizziness, constipation, itching
Rare: reduced number of platelets
Frequency not known: 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, pharmacist, or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.

5. How to store TESAVEL

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

Do not use this medicine after the expiry date which is stated on the blister and the carton after ‘EXP’. 
The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not throw away 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 TESAVEL contains

- The active substance is sitagliptin. Each film-coated tablet (tablet) contains sitagliptin 
phosphate monohydrate, equivalent to 100 mg sitagliptin.

- The other ingredients are: In the tablet core: microcrystalline cellulose (E460), calcium 
hydrogen phosphate, anhydrous (E341), croscarmellose sodium (E468), magnesium stearate 
(E470b), and sodium stearyl fumarate. The tablet film coating contains: poly(vinyl alcohol), 
macrogol 3350, talc (E553b), titanium dioxide (E171), red iron oxide (E172), and yellow iron 
oxide (E172).

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


80

What TESAVEL looks like and contents of the pack

Round, beige film-coated tablet with “277” on one side.

Opaque blisters (PVC/PE/PVDC and aluminium). Packs of 14, 28, 30, 56, 84, 90 or 98 film-coated 
tablets and 50 x 1 film-coated tablets in perforated unit dose blisters.

Not all pack sizes may be marketed.

Marketing Authorisation Holder
Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

Manufacturer
Merck Sharp & Dohme Ltd.
Shotton Lane, Cramlington
Northumberland NE23 3JU
United Kingdom

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

Belgique/België/Belgien
MSD Belgium BVBA/SPRL
Tél/Tel: +32 (0)27766211
dpoc_belux@merck.com

Lietuva
UAB Merck Sharp & Dohme
Tel.: +370 5 278 02 47
msd_lietuva@merck.com

България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3737
info-msdbg@merck.com

Luxembourg/Luxemburg
MSD Belgium BVBA/SPRL
Tél: +32 (0)27766211
dpoc_belux@merck.com

Česká republika
Merck Sharp & Dohme s.r.o.
Tel.: +420 233 010 111
dpoc_czechslovak@merck.com

Magyarország
MSD Pharma Hungary Kft.
Tel.: +36 1 888 53 00
hungary_msd@merck.com

Danmark
MSD Danmark ApS
Tlf: +45 4482 4000
dkmail@merck.com

Malta
Merck Sharp & Dohme Cyprus Limited
Tel: 8007 4433 (+356 99917558)
malta_info@merck.com

Deutschland
MSD SHARP & DOHME GMBH
Tel: 0800 673 673 673 (+49 (0) 89 4561 2612)
e-mail@msd.de

Nederland
Merck Sharp & Dohme B.V.
Tel.: 0800 9999000 (+31 23 5153153)
medicalinfo.nl@merck.com

 



81

Eesti
Merck Sharp & Dohme OÜ
Tel: +372 6144 200
msdeesti@merck.com

Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no

Eλλάδα
MSD Α.Φ.Β.Ε.Ε.
Τηλ: + 30 210 98 97 300
dpoc_greece@merck.com

Österreich
Merck Sharp & Dohme Ges.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com

España
Almirall, S.A.
Tel: +34 93 291 30 00
info.spain@almirall.com

Polska
MSD Polska Sp. z o.o.
Tel.: +48 22 549 51 00
msdpolska@merck.com

France
MSD France
Tél: + 33 (0) 1 80 46 40 40

Portugal
Merck Sharp & Dohme, Lda
Tel: +351 21 4465700
inform_pt@merck.com

Hrvatska
Merck Sharp & Dohme d.o.o.
Tel: + 385 1 66 11 333
croatia_info@merck.com

România
Merck Sharp & Dohme Romania S.R.L.
Tel: + 4021 529 29 00
msdromania@merck.com

Ireland
Merck Sharp & Dohme Ireland (Human Health) 
Limited
Tel: +353 (0)1 2998700
medinfo_ireland@merck.com

Slovenija
Merck Sharp & Dohme, inovativna zdravila 
d.o.o.
Tel: + 386 1 5204 201
msd_slovenia@merck.com

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
Merck Sharp & Dohme, s. r. o.
Tel.: +421 2 58282010
dpoc_czechslovak@merck.com

Ιtalia
Addenda Pharma S.r.l.
Tel.: +39 06 91393303
addendapharma@legalmail.it

Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0) 9 804 650
info@msd.fi

Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ: 80000 673 (+357 22866700)
cyprus_info@merck.com

Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 77 5700488
medicinskinfo@merck.com

Latvija
SIA Merck Sharp & Dohme Latvija
Tel: +371 67364 224
msd_lv@merck.com

United Kingdom
Merck Sharp & Dohme Limited
Tel: +44 (0) 1992 467272
medicalinformationuk@merck.com

This leaflet was last revised in {MM/YYYY}.

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET