ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
TESAVEL 25 mg film-coated tablets
2.
Each tablet contains sitagliptin phosphate monohydrate, equivalent to 25 mg sitagliptin.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet (tablet)
Round, pink film-coated tablet with “221” on one side.
4.
For 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 (PPARγ) agonist (i.e. a thiazolidinedione)
when use of a PPARγ agonist is appropriate and when diet and exercise plus the PPARγ agonist
alone do not provide adequate glycaemic control.
as
triple oral therapy
in combination with
•
a sulphonylurea and metformin when diet and exercise plus dual therapy with these agents do
not provide adequate glycaemic control.
•
a PPARγ agonist and metformin when use of a PPARγ agonist is appropriate and when diet and
exercise plus dual therapy with these agents do not provide adequate glycaemic control.
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.
2
Posology
The dose of TESAVEL is 100 mg once daily. When TESAVEL is used in combination with
metformin and/or a PPARγ agonist, the dose of metformin and/or PPARγ 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
For patients with mild renal impairment (creatinine clearance [CrCl] ≥ 50 ml/min), no dose adjustment
for TESAVEL is required.
Clinical study experience with TESAVEL in patients with moderate or severe renal impairment is
limited. Therefore, use of TESAVEL is not recommended in this patient population (see section 5.2).
Hepatic impairment
No dose adjustment is necessary for patients with mild to moderate hepatic impairment. TESAVEL
has not been studied in patients with severe hepatic impairment.
Elderly
No dose adjustment is necessary based on age. Limited safety data is available in patients ≥ 75 years
of age and care should be exercised.
Paediatric population
TESAVEL is not recommended for use in children below 18 years of age due to a lack of data on its
safety and efficacy.
Method of administration
TESAVEL can be taken with or without food.
Hypersensitivity to the active substance or to any of the excipients (see section 4.4 and 4.8).
General
TESAVEL should not be used in patients with type 1 diabetes or for the treatment of diabetic
ketoacidosis.
Pancreatitis
In post-marketing experience there have been spontaneously reported adverse reactions of acute
pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis:
persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation
of sitagliptin (with or without supportive treatment), but very rare cases of necrotizing or
haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, TESAVEL and
other potentially suspect medicinal products should be discontinued.
Hypoglycaemia when used in combination with other anti-hyperglycaemic agents
In clinical trials of TESAVEL as monotherapy and as part of combination therapy with agents not
known to cause hypoglycaemia (i.e. metformin and/or a PPARγ agonist), rates of hypoglycaemia
3
reported with sitagliptin were similar to rates in patients taking placebo. When sitagliptin was added to
a sulphonylurea or to insulin, the incidence of hypoglycaemia was increased over that of placebo (see
section 4.8). Therefore, to reduce the risk of hypoglycaemia, a lower dose of sulphonylurea or insulin
may be considered (see section 4.2).
Renal impairment
As the experience is limited, patients with moderate to severe renal impairment should not be treated
with TESAVEL (see section 5.2).
Hypersensitivity Reactions
Postmarketing reports of serious hypersensitivity reactions in patients treated with TESAVEL 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 TESAVEL, with some reports occurring after the first dose. If a
hypersensitivity reaction is suspected, discontinue TESAVEL, assess for other potential causes for the
event, and institute alternative treatment for diabetes (see section 4.8).
Effects of other medicinal products on sitagliptin
Clinical data described below suggest that the risk for clinically meaningful interactions by co-
administered medicinal products is low.
Metformin:
Co-administration of multiple twice-daily doses of 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 C
max
of sitagliptin by
approximately 29 % and 68 %, respectively. These changes in sitagliptin pharmacokinetics were not
considered to be clinically meaningful. The renal clearance of sitagliptin was not meaningfully altered.
Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors.
In vitro
studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin
is CYP3A4, with contribution from CYP2C8. In patients with normal renal function, metabolism,
including via CYP3A4, plays only a small role in the clearance of sitagliptin. Metabolism may play a
more significant role in the elimination of sitagliptin in the setting of severe renal impairment or end-
stage renal disease (ESRD). For this reason, it is possible that potent CYP3A4 inhibitors (i.e.
ketoconazole, itraconazole, ritonavir, clarithromycin) could alter the phamacokinetics of sitagliptin in
patients with severe renal impairment or ESRD. The effects of potent CYP3A4 inhibitors in the setting
of renal impairment has not been assessed in a clinical study.
In vitro
transport studies showed that sitagliptin is a substrate for p-glycoprotein and organic anion
transporter-3 (OAT3). OAT3 mediated transport of sitagliptin was inhibited
in vitro
by probenecid,
although the risk of clinically meaningful interactions is considered to be low. Concomitant
administration of OAT3 inhibitors has not been evaluated
in vivo
.
Effects of sitagliptin on other medicinal products
In vitro
data suggest that sitagliptin does not inhibit nor induce CYP450 isoenzymes. In clinical
studies, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide,
simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing
in vivo
evidence of a low
propensity for causing interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic
cationic transporter (OCT).
Sitagliptin had a small effect on plasma digoxin concentrations, and may be a mild inhibitor of p-
glycoprotein
in vivo
.
4
Digoxin:
Sitagliptin had a small effect on plasma digoxin concentrations. Following administration of
0.25 mg digoxin concomitantly with 100 mg of TESAVEL daily for 10 days, the plasma AUC of
digoxin was increased on average by 11 %, and the plasma C
max
on average by 18 %. No dose
adjustment of digoxin is recommended. However, patients at risk of digoxin toxicity should be
monitored for this when sitagliptin and digoxin are administered concomitantly.
Pregnancy
There are no adequate data from the use of TESAVEL 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.
Lactation
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.
TESAVEL has no known influence on the ability to drive and use machines. However, when driving
or operating machines, it should be taken into account that dizziness and somnolence have been
reported.
In addition, patients should be alerted to the risk of hypoglycaemia when TESAVEL is used in
combination with sulphonylurea agents or with insulin.
In 11 large clinical trials of up to 2 years in duration, over 3,200 patients have received treatment with
TESAVEL 100 mg per day alone or in combination with metformin, a sulphonylurea (with or without
metformin), insulin (with or without metformin), or a PPARγ agent (with or without metformin). In a
pooled analysis of 9 of these trials, the rate of discontinuation due to adverse experiences considered
drug-related was 0.8 % with 100 mg per day and 1.5 % with other treatments. No adverse reactions
considered as drug-related were reported in patients treated with sitagliptin occurring in excess
(> 0.2 % and difference > 1 patient) of that in patients treated with control. In an additional
combination study with a PPARγ agent (rosiglitazone) and metformin, no patients were discontinued
due to adverse experiences considered as drug-related.
Adverse reactions considered as drug-related reported in patients treated with sitagliptin occurring in
excess (> 0.2 % and difference > 1 patient) of that in patients treated with placebo are listed below
(Table 1) by system organ class and frequency. Frequencies are defined as: very common (≥ 1/10);
common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); and
very rare (< 1/10,000).
5
Table 1. The frequency of adverse reactions identified from placebo-controlled clinical studies
Adverse
reaction
Frequency of adverse reaction by treatment regimen
Sitagliptin
with
Metformin
1
Sitagliptin
with a
Sulphonylure
a
2
Sitagliptin
with a
Sulphonylure
a
and
Metformin
3
Sitagliptin
with a PPAR
γ
Agent
(pioglitazone)
4
Sitagliptin
with a
PPAR
γ
Agent
(rosiglitazone
)
and
Metformin
5
Sitagliptin
with Insulin
(+/-)
Metformin)
6
Time-point
24-week
24-week
24-week
24-week
18-week
24-week
Infections and infestations
influenza
Common
Metabolism and nutrition disorders
hypoglycaemia*
Common
Very common
Common
Common
Common
Nervous system disorders
headache
Common
Common
somnolence
Uncommon
Gastrointestinal disorders
diarrhoea
Uncommon
Common
dry mouth
Uncommon
nausea
Common
flatulence
Common
constipation
Common
Uncommon
upper
abdominal pain
Uncommon
vomiting
Common
General disorders and administration site conditions
peripheral
oedema
Common
Common
Investigations
blood glucose
decreased
Uncommon
*
In clinical trials of TESAVEL as monotherapy and sitagliptin as part of combination therapy with
metformin and/or a PPARγ agent, rates of hypoglycaemia reported with sitagliptin were similar to
rates in patients taking placebo.
1
In this placebo-controlled 24-week study of sitagliptin 100 mg once daily in combination with
metformin, the incidence of adverse reactions considered as drug-related in patients treated with
sitagliptin/metformin compared to treatment with placebo/metformin was 9.3 % and 10.1 %,
respectively.
In an additional 1-year study of sitagliptin 100 mg once daily in combination with metformin, the
incidence of adverse reactions considered as drug-related in patients treated with
sitagliptin/metformin compared to sulphonylurea/metformin was 14.5 % and 30.3 %, respectively.
In pooled studies of up to 1 year in duration comparing sitagliptin/metformin to a sulphonylurea
agent/metformin, adverse reactions considered as drug-related reported in patients treated with
sitagliptin 100 mg occurring in excess (> 0.2 % and difference > 1 patient) of that in patients
6
receiving the sulphonylurea agent are as follows: anorexia (Metabolism and nutritional disorders;
frequency uncommon) and weight decreased (Investigations; frequency uncommon).
2
In this 24-week study of sitagliptin 100 mg once daily in combination with glimepiride, the
incidence of adverse reactions considered as drug-related in patients treated with
sitagliptin/glimepiride compared to treatment with placebo/glimepiride was 11.3 % and 6.6 %,
respectively.
3
In this 24-week study of sitagliptin 100 mg once daily in combination with glimepiride and
metformin, the incidence of adverse reactions considered as drug-related in patients treated with
sitagliptin in combination with glimepiride/metformin compared to treatment with placebo in
combination with glimepiride/metformin was 18.1 % and 7.1 %, respectively.
4
In this 24-week study of the combination of sitagliptin 100 mg once daily and pioglitazone, the
incidence of adverse reactions considered as drug-related in patients treated with
sitagliptin/pioglitazone compared to patients treated with placebo/pioglitazone was 9.1 % and 9.0 %,
respectively.
5
In this study of sitagliptin 100 mg once daily in combination with rosiglitazone and metformin,
which continued through 54 weeks, the incidence of adverse reactions considered as drug-related in
patients treated with the sitagliptin combination compared to treatment with the placebo
combination was 15.3 % and 10.9 %, respectively. Other drug-related adverse reactions reported in
the 54-week analysis (frequency common) in patients treated with the sitagliptin combination
occurring in excess (> 0.2 % and difference > 1 patient) of that in patients treated with the placebo
combination were: headache, cough, vomiting, hypoglycaemia, fungal skin infection, and upper
respiratory tract infection.
6
In this 24-week study of sitagliptin 100 mg once daily as add-on to insulin therapy (with or without
metformin), the incidence of adverse reactions considered as drug-related in patients treated with
sitagliptin/insulin (with or without metformin) compared to treatment with placebo/insulin (with or
without metformin) was 15.5 % and 8.5 %, respectively. In this study 0.9 % of patients treated with
sitagliptin/insulin and 0.0 % of patients treated with placebo/insulin were discontinued due to
adverse experiences considered as drug-related.
In addition, in monotherapy studies of up to 24 weeks in duration of sitagliptin 100 mg once daily
alone compared to placebo, adverse reactions considered as drug-related reported in patients treated
with sitagliptin in excess (> 0.2 % and difference > 1 patient) of that in patients receiving placebo are
headache, hypoglycaemia, constipation, and dizziness.
In addition to the drug-related adverse experiences described above, adverse experiences reported
regardless of causal relationship to medication and occurring in at least 5 % and more commonly in
patients treated with TESAVEL 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 TESAVEL (not reaching the 5 % level, but occurring with an
incidence of > 0.5 % higher with TESAVEL than that in the control group) included osteoarthritis and
pain in extremity.
In an additional 24-week study of sitagliptin 100 mg once daily compared to metformin, the incidence
of adverse reactions considered as drug-related in patients treated with sitagliptin compared to
metformin was 5.9 % and 16.7 %, respectively, primarily due to a higher incidence of gastrointestinal
adverse reactions in the metformin group. In this study 0.6 % of patients treated with sitagliptin and
2.3 % of patients treated with metformin were discontinued due to adverse experiences considered as
drug-related.
In a 24-week study of initial combination therapy with sitagliptin and metformin administered twice
daily (sitagliptin/metformin 50 mg/500 mg or 50 mg/1,000 mg), the overall incidence of adverse
reactions considered as drug-related in patients treated with the combination of sitagliptin and
7
metformin compared to patients treated with placebo was 14.0 % and 9.7 %, respectively. The overall
incidence of adverse reactions considered as drug-related in patients treated with the combination of
sitagliptin and metformin was comparable to metformin alone (14.0 % each) and greater than
sitagliptin alone (6.7 %), with the differences relative to sitagliptin alone primarily due to
gastrointestinal adverse reactions.
Across clinical studies, a small increase in white blood cell count (approximately 200 cells/microl
difference in WBC vs. placebo; mean baseline WBC approximately 6,600 cells/microl) was observed
due to an increase in neutrophils. This observation was seen in most but not all studies. This change in
laboratory parameters is not considered to be clinically relevant.
No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed
with TESAVEL treatment.
Post-marketing Experience:
During post-approval use of TESAVEL as monotherapy and/or in combination with other
antihyperglycaemic agents, additional side effects have been reported (frequency not known):
hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and
exfoliative skin conditions including Stevens-Johnson syndrome (see section 4.4); acute pancreatitis,
including fatal and non-fatal haemorrhagic and necrotizing pancreatitis (see section 4.4); impaired
renal function, including acute renal failure (sometimes requiring dialysis); vomiting.
During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were
generally well tolerated. Minimal increases in QTc, not considered to be clinically relevant, were
observed in one study at a dose of 800 mg sitagliptin. There is no experience with doses above 800 mg
in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse
reactions observed with sitagliptin with doses of up to 600 mg per day for periods of up to 10 days and
400 mg per day for periods of up to 28 days.
In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove
unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an
electrocardiogram), and institute supportive therapy if required.
Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5 % of the dose was removed
over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically
appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Medicines used in diabetes, Dipeptidyl peptidase 4 (DPP-4 ) inhibitors,
ATC code: A10BH01.
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 agent 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
8
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 concentrations are low,
stimulation of insulin release and suppression of glucagon secretion by GLP-1 are not observed. For
both GLP-1 and GIP, stimulation of insulin release is enhanced as glucose rises above normal
concentrations. Further, GLP-1 does not impair the normal glucagon response to hypoglycaemia. The
activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly hydrolyzes the incretin
hormones to produce inactive products. Sitagliptin prevents the hydrolysis of incretin hormones by
DPP-4, thereby increasing plasma concentrations of the active forms of GLP-1 and GIP. By enhancing
active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in a glucose-
dependent manner. In patients with type 2 diabetes with hyperglycaemia, these changes in insulin and
glucagon levels lead to lower hemoglobin A
1c
(HbA
1c
) 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.
Overall, sitagliptin improved glycaemic control when used as monotherapy or in combination
treatment (see Table 2).
Two studies were conducted to evaluate the efficacy and safety of TESAVEL monotherapy. Treatment
with sitagliptin at 100 mg once daily as monotherapy provided significant improvements in HbA
1c
,
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 TESAVEL 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.
In a study in patients with type 2 diabetes and chronic renal impairment (creatinine clearance
< 50 ml/min), the safety and tolerability of reduced doses of sitagliptin were investigated and
generally similar to placebo. In addition, the reductions in HbA
1c
and FPG with sitagliptin compared
to placebo were generally similar to those observed in other monotherapy studies in patients with
normal renal function (see section 5.2). The number of patients with moderate to severe renal
impairment was too low to confirm safe use of sitagliptin in this type of patients.
Sitagliptin 100 mg once daily provided significant improvements in glycaemic parameters compared
with placebo in two 24-week studies of sitagliptin as add-on therapy, one in combination with
metformin and one in combination with pioglitazone. Change from baseline in body weight was
similar for patients treated with sitagliptin relative to placebo. In these studies there was a similar
incidence of hypoglycaemia reported for patients treated with sitagliptin or placebo.
A 24-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin
(100 mg once daily) added to glimepiride alone or glimepiride in combination with metformin. The
addition of sitagliptin to either glimepiride alone or to glimepiride and metformin provided significant
improvements in glycaemic parameters. Patients treated with sitagliptin had a modest increase in body
weight compared to those given placebo.
9
A 54-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin
(100 mg once daily) added to the combination of rosiglitazone and metformin. The addition of
sitagliptin to rosiglitazone and metformin provided significant improvements in glycaemic parameters
at the primary timepoint of Week 18, with improvements sustained through the end of the study.
Change from baseline in body weight was similar for patients treated with sitagliptin relative to
placebo (1.9 vs. 1.3 kg).
A 24-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin
(100 mg once daily) added to insulin (at a stable dose for at least 10 weeks) with or without metformin
(at least 1,500 mg). In patients taking pre-mixed insulin, the mean daily dose was 70.9 U/day. In
patients taking non-pre-mixed (intermediate/long-acting) insulin, the mean daily dose was 44.3 U/day.
The addition of sitagliptin to insulin provided significant improvements in glycaemic parameters.
There was no meaningful change from baseline in body weight in either group.
In a 24-week placebo-controlled factorial study of initial therapy, sitagliptin 50 mg twice daily in
combination with metformin (500 mg or 1,000 mg twice daily) provided significant improvements in
glycaemic parameters compared with either monotherapy. The decrease in body weight with the
combination of sitagliptin and metformin was similar to that observed with metformin alone or
placebo; there was no change from baseline for patients on sitagliptin alone.
The incidence of
hypoglycaemia was similar across treatment groups.
Table 2. HbA
1c
results in placebo-controlled monotherapy and combination therapy studies*
Study
Mean
baseline
HbA
1c
(%)
Mean change from
baseline HbA
1c
(%)
†
Placebo-corrected
mean change in
HbA
1c
(%)
†
(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 rosiglitazone + metformin
therapy (N=170)
Week 18
8.8
-1.0
-0.7
‡
(-0.9, -0.5)
-0.8
‡
(-1.0, -0.5
Week 54
8.8
-1.0
10
Study
Mean
baseline
HbA
1c
(%)
Mean change from
baseline HbA
1c
(%)
†
Placebo-corrected
mean change in
HbA
1c
(%)
†
(95 % CI)
Initial therapy (twice daily)
:
Sitagliptin 50 mg + metformin 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)
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.
§
HbA
1c
(%) at week 18.
HbA
1c
(%) at week 24.
¶
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 HbA
1c
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 TESAVEL 100 mg once daily or
glipizide (a sulphonylurea agent) in patients with inadequate glycaemic control on metformin
monotherapy, sitagliptin was similar to glipizide in reducing HbA
1c
. 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 %).
The European Medicines Agency has deferred the obligation to submit the results of studies with
TESAVEL in one or more subsets of the paediatric population in type 2 diabetes mellitus (see
section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Absorption
Following oral administration of a 100-mg dose to healthy subjects, sitagliptin was rapidly absorbed,
with peak plasma concentrations (median T
max
) occurring 1 to 4 hours post-dose, mean plasma AUC of
sitagliptin was 8.52 μM•hr, C
max
was 950 nM. The absolute bioavailability of sitagliptin is
approximately 87 %. Since co-administration of a high-fat meal with TESAVEL had no effect on the
pharmacokinetics, TESAVEL may be administered with or without food.
11
Plasma AUC of sitagliptin increased in a dose-proportional manner. Dose-proportionality was not
established for C
max
and C
24hr
(C
max
increased in a greater than dose-proportional manner and C
24hr
increased in a less than dose-proportional manner).
Distribution
The mean volume of distribution at steady state following a single 100-mg intravenous dose of
sitagliptin to healthy subjects is approximately 198 liters. The fraction of sitagliptin reversibly bound
to plasma proteins is low (38 %).
Biotransformation
Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway.
Approximately 79 % of sitagliptin is excreted unchanged in the urine.
Following a [
14
C]sitagliptin oral dose, approximately 16 % of the radioactivity was excreted as
metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to
contribute to the plasma DPP-4 inhibitory activity of sitagliptin.
In vitro
studies indicated that the
primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution
from CYP2C8.
In vitro
data showed that sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6,
1A2, 2C19 or 2B6, and is not an inducer of CYP3A4 and CYP1A2.
Elimination
Following administration of an oral [
14
C]sitagliptin dose to healthy subjects, approximately 100 % of
the administered radioactivity was eliminated in faeces (13 %) or urine (87 %) within one week of
dosing. The apparent terminal t
1/2
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 μM) or p-glycoprotein (up to 250
μM) mediated transport at therapeutically relevant plasma concentrations. In a clinical study sitagliptin
had a small effect on plasma digoxin concentrations indicating that sitagliptin may be a mild inhibitor
of p-glycoprotein.
Characteristics in patients
The pharmacokinetics of sitagliptin were generally similar in healthy subjects and in patients with type
2 diabetes.
Renal impairment
A single-dose, open-label study was conducted to evaluate the pharmacokinetics of a reduced dose of
sitagliptin (50-mg) in patients with varying degrees of chronic renal impairment compared to normal
healthy control subjects. The study included patients with renal impairment classified on the basis of
creatinine clearance as mild (50 to < 80 ml/min), moderate (30 to < 50 ml/min), and severe
(< 30 ml/min), as well as patients with end-stage renal disease (ESRD) on hemodialysis.
Patients with mild renal impairment did not have a clinically meaningful increase in the plasma
concentration of sitagliptin as compared to normal healthy control subjects. An approximately 2-fold
increase in the plasma AUC of sitagliptin was observed in patients with moderate renal impairment,
and an approximately 4-fold increase was observed in patients with severe renal impairment and in
patients with ESRD on hemodialysis, as compared to normal healthy control subjects. Sitagliptin was
12
modestly removed by hemodialysis (13.5 % over a 3- to 4-hour hemodialysis session starting 4 hours
postdose). TESAVEL is not recommended for use in patients with moderate or severe renal
impairment including those with ESRD since experience in these patients is too limited (see
section 4.2).
Hepatic impairment
No dose adjustment for 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
No studies with TESAVEL have been performed in paediatric patients.
Other patient characteristics
No dose adjustment is necessary based on gender, race, or body mass index (BMI). These
characteristics had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a
composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of
Phase I and Phase II data.
5.3 Preclinical safety data
Renal and liver toxicity were observed in
rodents at systemic exposure values 58 times the human
exposure level, while the no-effect level was found at 19 times the human exposure level. Incisor teeth
abnormalities were observed in rats at exposure levels 67 times the clinical exposure level; the no-
effect level for this finding was 58-fold based on the 14-week rat study. The relevance of these
findings for humans is unknown. Transient
treatment-related physical signs,
some of which suggest
neural toxicity, such as open-mouth breathing, salivation, white foamy emesis, ataxia, trembling,
decreased activity, and/or hunched posture were observed in dogs at exposure levels approximately
23 times the clinical exposure level. In addition, very slight to slight skeletal muscle degeneration was
also observed histologically at doses resulting in systemic exposure levels of approximately 23 times
the human exposure level. A no-effect level for these findings was found at an exposure 6-fold the
clinical exposure level.
Sitagliptin has not been demonstrated to be genotoxic in preclinical studies. Sitagliptin was not
carcinogenic in mice. In rats, there was an increased incidence of hepatic adenomas and carcinomas at
systemic exposure levels 58 times the human exposure level. Since hepatotoxicity has been shown to
correlate with induction of hepatic neoplasia in rats, this increased incidence of hepatic tumors in rats
was likely secondary to chronic hepatic toxicity at this high dose. Because of the high safety margin
(19-fold at this no-effect level), these neoplastic changes are not considered relevant for the situation
in humans.
No adverse effects upon fertility were observed in male and female rats given sitagliptin prior to and
throughout mating.
In a pre-/postnatal development study performed in rats sitagliptin showed no adverse effects.
Reproductive toxicity studies showed a slight treatment-related increased incidence of fetal rib
malformations (absent, hypoplastic and wavy ribs) in the offspring of rats at systemic exposure levels
more than 29 times the human exposure levels. Maternal toxicity was seen in rabbits at more than
29 times the human exposure levels. Because of the high safety margins, these findings do not suggest
13
a relevant risk for human reproduction. Sitagliptin is secreted in considerable amounts into the milk of
lactating rats (milk/plasma ratio: 4:1).
6.
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
:
polyvinyl 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 aluminum). Packs of 14, 28, 56, 84 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 product or waste material should be disposed of in accordance with local requirements.
7.
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
14
8.
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
9.
Date of first authorisation: 10 January 2008
Detailed information on this product is available on the website of the European Medicines Agency
web site: http://www.ema.europa.eu/.
15
1.
TESAVEL 50 mg film-coated tablets
2.
Each tablet contains sitagliptin phosphate monohydrate, equivalent to 50 mg sitagliptin.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet (tablet)
Round, light beige film-coated tablet with “112” on one side.
4.
For 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 (PPARγ) agonist (i.e. a thiazolidinedione)
when use of a PPARγ agonist is appropriate and when diet and exercise plus the PPARγ agonist
alone do not provide adequate glycaemic control.
as
triple oral therapy
in combination with
•
a sulphonylurea and metformin when diet and exercise plus dual therapy with these agents do
not provide adequate glycaemic control.
•
a PPARγ agonist and metformin when use of a PPARγ agonist is appropriate and when diet and
exercise plus dual therapy with these agents do not provide adequate glycaemic control.
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.
16
Posology
The dose of TESAVEL is 100 mg once daily. When TESAVEL is used in combination with
metformin and/or a PPARγ agonist, the dose of metformin and/or PPARγ 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
For patients with mild renal impairment (creatinine clearance [CrCl] ≥ 50 ml/min), no dose adjustment
for TESAVEL is required.
Clinical study experience with TESAVEL in patients with moderate or severe renal impairment is
limited. Therefore, use of TESAVEL is not recommended in this patient population (see section 5.2).
Hepatic impairment
No dose adjustment is necessary for patients with mild to moderate hepatic impairment. TESAVEL
has not been studied in patients with severe hepatic impairment.
Elderly
No dose adjustment is necessary based on age. Limited safety data is available in patients ≥ 75 years
of age and care should be exercised.
Paediatric population
TESAVEL is not recommended for use in children below 18 years of age due to a lack of data on its
safety and efficacy.
Method of administration
TESAVEL can be taken with or without food.
Hypersensitivity to the active substance or to any of the excipients (see section 4.4 and 4.8).
General
TESAVEL should not be used in patients with type 1 diabetes or for the treatment of diabetic
ketoacidosis.
Pancreatitis
In post-marketing experience there have been spontaneously reported adverse reactions of acute
pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis:
persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation
of sitagliptin (with or without supportive treatment), but very rare cases of necrotizing or
haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, TESAVEL and
other potentially suspect medicinal products should be discontinued.
Hypoglycaemia when used in combination with other anti-hyperglycaemic agents
In clinical trials of TESAVEL as monotherapy and as part of combination therapy with agents not
known to cause hypoglycaemia (i.e. metformin and/or a PPARγ agonist), rates of hypoglycaemia
17
reported with sitagliptin were similar to rates in patients taking placebo. When sitagliptin was added to
a sulphonylurea or to insulin, the incidence of hypoglycaemia was increased over that of placebo (see
section 4.8). Therefore, to reduce the risk of hypoglycaemia, a lower dose of sulphonylurea or insulin
may be considered (see section 4.2).
Renal impairment
As the experience is limited, patients with moderate to severe renal impairment should not be treated
with TESAVEL (see section 5.2).
Hypersensitivity Reactions
Postmarketing reports of serious hypersensitivity reactions in patients treated with TESAVEL 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 TESAVEL, with some reports occurring after the first dose. If a
hypersensitivity reaction is suspected, discontinue TESAVEL, assess for other potential causes for the
event, and institute alternative treatment for diabetes (see section 4.8).
Effects of other medicinal products on sitagliptin
Clinical data described below suggest that the risk for clinically meaningful interactions by co-
administered medicinal products is low.
Metformin:
Co-administration of multiple twice-daily doses of 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 C
max
of sitagliptin by
approximately 29 % and 68 %, respectively. These changes in sitagliptin pharmacokinetics were not
considered to be clinically meaningful. The renal clearance of sitagliptin was not meaningfully altered.
Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors.
In vitro
studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin
is CYP3A4, with contribution from CYP2C8. In patients with normal renal function, metabolism,
including via CYP3A4, plays only a small role in the clearance of sitagliptin. Metabolism may play a
more significant role in the elimination of sitagliptin in the setting of severe renal impairment or end-
stage renal disease (ESRD). For this reason, it is possible that potent CYP3A4 inhibitors (i.e.
ketoconazole, itraconazole, ritonavir, clarithromycin) could alter the phamacokinetics of sitagliptin in
patients with severe renal impairment or ESRD. The effects of potent CYP3A4 inhibitors in the setting
of renal impairment has not been assessed in a clinical study.
In vitro
transport studies showed that sitagliptin is a substrate for p-glycoprotein and organic anion
transporter-3 (OAT3). OAT3 mediated transport of sitagliptin was inhibited
in vitro
by probenecid,
although the risk of clinically meaningful interactions is considered to be low. Concomitant
administration of OAT3 inhibitors has not been evaluated
in vivo
.
Effects of sitagliptin on other medicinal products
In vitro
data suggest that sitagliptin does not inhibit nor induce CYP450 isoenzymes. In clinical
studies, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide,
simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing
in vivo
evidence of a low
propensity for causing interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic
cationic transporter (OCT).
Sitagliptin had a small effect on plasma digoxin concentrations, and may be a mild inhibitor of p-
glycoprotein
in vivo
.
18
Digoxin:
Sitagliptin had a small effect on plasma digoxin concentrations. Following administration of
0.25 mg digoxin concomitantly with 100 mg of TESAVEL daily for 10 days, the plasma AUC of
digoxin was increased on average by 11 %, and the plasma C
max
on average by 18 %. No dose
adjustment of digoxin is recommended. However, patients at risk of digoxin toxicity should be
monitored for this when sitagliptin and digoxin are administered concomitantly.
Pregnancy
There are no adequate data from the use of TESAVEL 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.
Lactation
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.
TESAVEL has no known influence on the ability to drive and use machines. However, when driving
or operating machines, it should be taken into account that dizziness and somnolence have been
reported.
In addition, patients should be alerted to the risk of hypoglycaemia when TESAVEL is used in
combination with sulphonylurea agents or with insulin.
In 11 large clinical trials of up to 2 years in duration, over 3,200 patients have received treatment with
TESAVEL 100 mg per day alone or in combination with metformin, a sulphonylurea (with or without
metformin), insulin (with or without metformin), or a PPARγ agent (with or without metformin). In a
pooled analysis of 9 of these trials, the rate of discontinuation due to adverse experiences considered
drug-related was 0.8 % with 100 mg per day and 1.5 % with other treatments. No adverse reactions
considered as drug-related were reported in patients treated with sitagliptin occurring in excess
(> 0.2 % and difference > 1 patient) of that in patients treated with control. In an additional
combination study with a PPARγ agent (rosiglitazone) and metformin, no patients were discontinued
due to adverse experiences considered as drug-related.
Adverse reactions considered as drug-related reported in patients treated with sitagliptin occurring in
excess (> 0.2 % and difference > 1 patient) of that in patients treated with placebo are listed below
(Table 1) by system organ class and frequency. Frequencies are defined as: very common (≥ 1/10);
common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); and
very rare (< 1/10,000).
19
Table 1. The frequency of adverse reactions identified from placebo-controlled clinical studies
Adverse
reaction
Frequency of adverse reaction by treatment regimen
Sitagliptin
with
Metformin
1
Sitagliptin
with a
Sulphonylure
a
2
Sitagliptin
with a
Sulphonylure
a
and
Metformin
3
Sitagliptin
with a PPAR
γ
Agent
(pioglitazone)
4
Sitagliptin
with a
PPAR
γ
Agent
(rosiglitazone
)
and
Metformin
5
Sitagliptin
with Insulin
(+/-)
Metformin)
6
Time-point
24-week
24-week
24-week
24-week
18-week
24-week
Infections and infestations
influenza
Common
Metabolism and nutrition disorders
hypoglycaemia*
Common
Very common
Common
Common
Common
Nervous system disorders
headache
Common
Common
somnolence
Uncommon
Gastrointestinal disorders
diarrhoea
Uncommon
Common
dry mouth
Uncommon
nausea
Common
flatulence
Common
constipation
Common
Uncommon
upper
abdominal pain
Uncommon
vomiting
Common
General disorders and administration site conditions
peripheral
oedema
Common
Common
Investigations
blood glucose
decreased
Uncommon
*
In clinical trials of TESAVEL as monotherapy and sitagliptin as part of combination therapy with
metformin and/or a PPARγ agent, rates of hypoglycaemia reported with sitagliptin were similar to
rates in patients taking placebo.
1
In this placebo-controlled 24-week study of sitagliptin 100 mg once daily in combination with
metformin, the incidence of adverse reactions considered as drug-related in patients treated with
sitagliptin/metformin compared to treatment with placebo/metformin was 9.3 % and 10.1 %,
respectively.
In an additional 1-year study of sitagliptin 100 mg once daily in combination with metformin, the
incidence of adverse reactions considered as drug-related in patients treated with
sitagliptin/metformin compared to sulphonylurea/metformin was 14.5 % and 30.3 %, respectively.
In pooled studies of up to 1 year in duration comparing sitagliptin/metformin to a sulphonylurea
agent/metformin, adverse reactions considered as drug-related reported in patients treated with
sitagliptin 100 mg occurring in excess (> 0.2 % and difference > 1 patient) of that in patients
20
receiving the sulphonylurea agent are as follows: anorexia (Metabolism and nutritional disorders;
frequency uncommon) and weight decreased (Investigations; frequency uncommon).
2
In this 24-week study of sitagliptin 100 mg once daily in combination with glimepiride, the
incidence of adverse reactions considered as drug-related in patients treated with
sitagliptin/glimepiride compared to treatment with placebo/glimepiride was 11.3 % and 6.6 %,
respectively.
3
In this 24-week study of sitagliptin 100 mg once daily in combination with glimepiride and
metformin, the incidence of adverse reactions considered as drug-related in patients treated with
sitagliptin in combination with glimepiride/metformin compared to treatment with placebo in
combination with glimepiride/metformin was 18.1 % and 7.1 %, respectively.
4
In this 24-week study of the combination of sitagliptin 100 mg once daily and pioglitazone, the
incidence of adverse reactions considered as drug-related in patients treated with
sitagliptin/pioglitazone compared to patients treated with placebo/pioglitazone was 9.1 % and 9.0 %,
respectively.
5
In this study of sitagliptin 100 mg once daily in combination with rosiglitazone and metformin,
which continued through 54 weeks, the incidence of adverse reactions considered as drug-related in
patients treated with the sitagliptin combination compared to treatment with the placebo
combination was 15.3 % and 10.9 %, respectively. Other drug-related adverse reactions reported in
the 54-week analysis (frequency common) in patients treated with the sitagliptin combination
occurring in excess (> 0.2 % and difference > 1 patient) of that in patients treated with the placebo
combination were: headache, cough, vomiting, hypoglycaemia, fungal skin infection, and upper
respiratory tract infection.
6
In this 24-week study of sitagliptin 100 mg once daily as add-on to insulin therapy (with or without
metformin), the incidence of adverse reactions considered as drug-related in patients treated with
sitagliptin/insulin (with or without metformin) compared to treatment with placebo/insulin (with or
without metformin) was 15.5 % and 8.5 %, respectively. In this study 0.9 % of patients treated with
sitagliptin/insulin and 0.0 % of patients treated with placebo/insulin were discontinued due to
adverse experiences considered as drug-related.
In addition, in monotherapy studies of up to 24 weeks in duration of sitagliptin 100 mg once daily
alone compared to placebo, adverse reactions considered as drug-related reported in patients treated
with sitagliptin in excess (> 0.2 % and difference > 1 patient) of that in patients receiving placebo are
headache, hypoglycaemia, constipation, and dizziness.
In addition to the drug-related adverse experiences described above, adverse experiences reported
regardless of causal relationship to medication and occurring in at least 5 % and more commonly in
patients treated with TESAVEL 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 TESAVEL (not reaching the 5 % level, but occurring with an
incidence of > 0.5 % higher with TESAVEL than that in the control group) included osteoarthritis and
pain in extremity.
In an additional 24-week study of sitagliptin 100 mg once daily compared to metformin, the incidence
of adverse reactions considered as drug-related in patients treated with sitagliptin compared to
metformin was 5.9 % and 16.7 %, respectively, primarily due to a higher incidence of gastrointestinal
adverse reactions in the metformin group. In this study 0.6 % of patients treated with sitagliptin and
2.3 % of patients treated with metformin were discontinued due to adverse experiences considered as
drug-related.
In a 24-week study of initial combination therapy with sitagliptin and metformin administered twice
daily (sitagliptin/metformin 50 mg/500 mg or 50 mg/1,000 mg), the overall incidence of adverse
reactions considered as drug-related in patients treated with the combination of sitagliptin and
21
metformin compared to patients treated with placebo was 14.0 % and 9.7 %, respectively. The overall
incidence of adverse reactions considered as drug-related in patients treated with the combination of
sitagliptin and metformin was comparable to metformin alone (14.0 % each) and greater than
sitagliptin alone (6.7 %), with the differences relative to sitagliptin alone primarily due to
gastrointestinal adverse reactions.
Across clinical studies, a small increase in white blood cell count (approximately 200 cells/microl
difference in WBC vs. placebo; mean baseline WBC approximately 6,600 cells/microl) was observed
due to an increase in neutrophils. This observation was seen in most but not all studies. This change in
laboratory parameters is not considered to be clinically relevant.
No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed
with TESAVEL treatment.
Post-marketing Experience:
During post-approval use of TESAVEL as monotherapy and/or in combination with other
antihyperglycaemic agents, additional side effects have been reported (frequency not known):
hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and
exfoliative skin conditions including Stevens-Johnson syndrome (see section 4.4); acute pancreatitis,
including fatal and non-fatal haemorrhagic and necrotizing pancreatitis (see section 4.4); impaired
renal function, including acute renal failure (sometimes requiring dialysis); vomiting.
During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were
generally well tolerated. Minimal increases in QTc, not considered to be clinically relevant, were
observed in one study at a dose of 800 mg sitagliptin. There is no experience with doses above 800 mg
in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse
reactions observed with sitagliptin with doses of up to 600 mg per day for periods of up to 10 days and
400 mg per day for periods of up to 28 days.
In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove
unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an
electrocardiogram), and institute supportive therapy if required.
Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5 % of the dose was removed
over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically
appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Medicines used in diabetes, Dipeptidyl peptidase 4 (DPP-4 ) inhibitors,
ATC code: A10BH01.
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 agent 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
22
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 concentrations are low,
stimulation of insulin release and suppression of glucagon secretion by GLP-1 are not observed. For
both GLP-1 and GIP, stimulation of insulin release is enhanced as glucose rises above normal
concentrations. Further, GLP-1 does not impair the normal glucagon response to hypoglycaemia. The
activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly hydrolyzes the incretin
hormones to produce inactive products. Sitagliptin prevents the hydrolysis of incretin hormones by
DPP-4, thereby increasing plasma concentrations of the active forms of GLP-1 and GIP. By enhancing
active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in a glucose-
dependent manner. In patients with type 2 diabetes with hyperglycaemia, these changes in insulin and
glucagon levels lead to lower hemoglobin A
1c
(HbA
1c
) 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.
Overall, sitagliptin improved glycaemic control when used as monotherapy or in combination
treatment (see Table 2).
Two studies were conducted to evaluate the efficacy and safety of TESAVEL monotherapy. Treatment
with sitagliptin at 100 mg once daily as monotherapy provided significant improvements in HbA
1c
,
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 TESAVEL 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.
In a study in patients with type 2 diabetes and chronic renal impairment (creatinine clearance
< 50 ml/min), the safety and tolerability of reduced doses of sitagliptin were investigated and
generally similar to placebo. In addition, the reductions in HbA
1c
and FPG with sitagliptin compared
to placebo were generally similar to those observed in other monotherapy studies in patients with
normal renal function (see section 5.2). The number of patients with moderate to severe renal
impairment was too low to confirm safe use of sitagliptin in this type of patients.
Sitagliptin 100 mg once daily provided significant improvements in glycaemic parameters compared
with placebo in two 24-week studies of sitagliptin as add-on therapy, one in combination with
metformin and one in combination with pioglitazone. Change from baseline in body weight was
similar for patients treated with sitagliptin relative to placebo. In these studies there was a similar
incidence of hypoglycaemia reported for patients treated with sitagliptin or placebo.
A 24-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin
(100 mg once daily) added to glimepiride alone or glimepiride in combination with metformin. The
addition of sitagliptin to either glimepiride alone or to glimepiride and metformin provided significant
improvements in glycaemic parameters. Patients treated with sitagliptin had a modest increase in body
weight compared to those given placebo.
23
A 54-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin
(100 mg once daily) added to the combination of rosiglitazone and metformin. The addition of
sitagliptin to rosiglitazone and metformin provided significant improvements in glycaemic parameters
at the primary timepoint of Week 18, with improvements sustained through the end of the study.
Change from baseline in body weight was similar for patients treated with sitagliptin relative to
placebo (1.9 vs. 1.3 kg).
A 24-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin
(100 mg once daily) added to insulin (at a stable dose for at least 10 weeks) with or without metformin
(at least 1,500 mg). In patients taking pre-mixed insulin, the mean daily dose was 70.9 U/day. In
patients taking non-pre-mixed (intermediate/long-acting) insulin, the mean daily dose was 44.3 U/day.
The addition of sitagliptin to insulin provided significant improvements in glycaemic parameters.
There was no meaningful change from baseline in body weight in either group.
In a 24-week placebo-controlled factorial study of initial therapy, sitagliptin 50 mg twice daily in
combination with metformin (500 mg or 1,000 mg twice daily) provided significant improvements in
glycaemic parameters compared with either monotherapy. The decrease in body weight with the
combination of sitagliptin and metformin was similar to that observed with metformin alone or
placebo; there was no change from baseline for patients on sitagliptin alone.
The incidence of
hypoglycaemia was similar across treatment groups.
Table 2. HbA
1c
results in placebo-controlled monotherapy and combination therapy studies*
Study
Mean
baseline
HbA
1c
(%)
Mean change from
baseline HbA
1c
(%)
†
Placebo-corrected
mean change in
HbA
1c
(%)
†
(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 rosiglitazone + metformin
therapy (N=170)
Week 18
8.8
-1.0
-0.7
‡
(-0.9, -0.5)
-0.8
‡
(-1.0, -0.5
Week 54
8.8
-1.0
24
Study
Mean
baseline
HbA
1c
(%)
Mean change from
baseline HbA
1c
(%)
†
Placebo-corrected
mean change in
HbA
1c
(%)
†
(95 % CI)
Initial therapy (twice daily)
:
Sitagliptin 50 mg + metformin 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)
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.
§
HbA
1c
(%) at week 18.
HbA
1c
(%) at week 24.
¶
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 HbA
1c
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 TESAVEL 100 mg once daily or
glipizide (a sulphonylurea agent) in patients with inadequate glycaemic control on metformin
monotherapy, sitagliptin was similar to glipizide in reducing HbA
1c
. 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 %).
The European Medicines Agency has deferred the obligation to submit the results of studies with
TESAVEL in one or more subsets of the paediatric population in type 2 diabetes mellitus (see
section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Absorption
Following oral administration of a 100-mg dose to healthy subjects, sitagliptin was rapidly absorbed,
with peak plasma concentrations (median T
max
) occurring 1 to 4 hours post-dose, mean plasma AUC of
sitagliptin was 8.52 μM•hr, C
max
was 950 nM. The absolute bioavailability of sitagliptin is
approximately 87 %. Since coadministration of a high-fat meal with TESAVEL had no effect on the
pharmacokinetics, TESAVEL may be administered with or without food.
25
Plasma AUC of sitagliptin increased in a dose-proportional manner. Dose-proportionality was not
established for C
max
and C
24hr
(C
max
increased in a greater than dose-proportional manner and C
24hr
increased in a less than dose-proportional manner).
Distribution
The mean volume of distribution at steady state following a single 100-mg intravenous dose of
sitagliptin to healthy subjects is approximately 198 liters. The fraction of sitagliptin reversibly bound
to plasma proteins is low (38 %).
Biotransformation
Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway.
Approximately 79 % of sitagliptin is excreted unchanged in the urine.
Following a [
14
C]sitagliptin oral dose, approximately 16 % of the radioactivity was excreted as
metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to
contribute to the plasma DPP-4 inhibitory activity of sitagliptin.
In vitro
studies indicated that the
primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution
from CYP2C8.
In vitro
data showed that sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6,
1A2, 2C19 or 2B6, and is not an inducer of CYP3A4 and CYP1A2.
Elimination
Following administration of an oral [
14
C]sitagliptin dose to healthy subjects, approximately 100 % of
the administered radioactivity was eliminated in faeces (13 %) or urine (87 %) within one week of
dosing. The apparent terminal t
1/2
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 μM) or p-glycoprotein (up to 250
μM) mediated transport at therapeutically relevant plasma concentrations. In a clinical study sitagliptin
had a small effect on plasma digoxin concentrations indicating that sitagliptin may be a mild inhibitor
of p-glycoprotein.
Characteristics in patients
The pharmacokinetics of sitagliptin were generally similar in healthy subjects and in patients with type
2 diabetes.
Renal impairment
A single-dose, open-label study was conducted to evaluate the pharmacokinetics of a reduced dose of
sitagliptin (50-mg) in patients with varying degrees of chronic renal impairment compared to normal
healthy control subjects. The study included patients with renal impairment classified on the basis of
creatinine clearance as mild (50 to < 80 ml/min), moderate (30 to < 50 ml/min), and severe
(< 30 ml/min), as well as patients with end-stage renal disease (ESRD) on hemodialysis.
26
Patients with mild renal impairment did not have a clinically meaningful increase in the plasma
concentration of sitagliptin as compared to normal healthy control subjects. An approximately 2-fold
increase in the plasma AUC of sitagliptin was observed in patients with moderate renal impairment,
and an approximately 4-fold increase was observed in patients with severe renal impairment and in
patients with ESRD on hemodialysis, as compared to normal healthy control subjects. Sitagliptin was
modestly removed by hemodialysis (13.5 % over a 3- to 4-hour hemodialysis session starting 4 hours
postdose). TESAVEL is not recommended for use in patients with moderate or severe renal
impairment including those with ESRD since experience in these patients is too limited. (See
section 4.2.)
Hepatic impairment
No dose adjustment for 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
No studies with TESAVEL have been performed in paediatric patients.
Other patient characteristics
No dose adjustment is necessary based on gender, race, or body mass index (BMI). These
characteristics had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a
composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of
Phase I and Phase II data.
5.3 Preclinical safety data
Renal and liver toxicity were observed in
rodents at systemic exposure values 58 times the human
exposure level, while the no-effect level was found at 19 times the human exposure level. Incisor teeth
abnormalities were observed in rats at exposure levels 67 times the clinical exposure level; the no-
effect level for this finding was 58-fold based on the 14-week rat study. The relevance of these
findings for humans is unknown. Transient
treatment-related physical signs,
some of which suggest
neural toxicity, such as open-mouth breathing, salivation, white foamy emesis, ataxia, trembling,
decreased activity, and/or hunched posture were observed in dogs at exposure levels approximately
23 times the clinical exposure level. In addition, very slight to slight skeletal muscle degeneration was
also observed histologically at doses resulting in systemic exposure levels of approximately 23 times
the human exposure level. A no-effect level for these findings was found at an exposure 6-fold the
clinical exposure level.
Sitagliptin has not been demonstrated to be genotoxic in preclinical studies. Sitagliptin was not
carcinogenic in mice. In rats, there was an increased incidence of hepatic adenomas and carcinomas at
systemic exposure levels 58 times the human exposure level. Since hepatotoxicity has been shown to
correlate with induction of hepatic neoplasia in rats, this increased incidence of hepatic tumors in rats
was likely secondary to chronic hepatic toxicity at this high dose. Because of the high safety margin
(19-fold at this no-effect level), these neoplastic changes are not considered relevant for the situation
in humans.
No adverse effects upon fertility were observed in male and female rats given sitagliptin prior to and
throughout mating.
In a pre-/postnatal development study performed in rats sitagliptin showed no adverse effects.
27
Reproductive toxicity studies showed a slight treatment-related increased incidence of fetal rib
malformations (absent, hypoplastic and wavy ribs) in the offspring of rats at systemic exposure levels
more than 29 times the human exposure levels. Maternal toxicity was seen in rabbits at more than
29 times the human exposure levels. Because of the high safety margins, these findings do not suggest
a relevant risk for human reproduction. Sitagliptin is secreted in considerable amounts into the milk of
lactating rats (milk/plasma ratio: 4:1).
6.
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
:
polyvinyl 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 aluminum). Packs of 14, 28, 56, 84 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 product or waste material should be disposed of in accordance with local requirements.
28
7.
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
8.
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
9.
Date of first authorisation: 10 January 2008
Detailed information on this product is available on the website of the European Medicines Agency
web site: http://www.ema.europa.eu/.
29
1.
TESAVEL 100 mg film-coated tablets
2.
Each tablet contains sitagliptin phosphate monohydrate, equivalent to 100 mg sitagliptin.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet (tablet)
Round, beige film-coated tablet with “277” on one side.
4.
For 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 (PPARγ) agonist (i.e. a thiazolidinedione)
when use of a PPARγ agonist is appropriate and when diet and exercise plus the PPARγ agonist
alone do not provide adequate glycaemic control.
as
triple oral therapy
in combination with
•
a sulphonylurea and metformin when diet and exercise plus dual therapy with these agents do
not provide adequate glycaemic control.
•
a PPARγ agonist and metformin when use of a PPARγ agonist is appropriate and when diet and
exercise plus dual therapy with these agents do not provide adequate glycaemic control.
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.
30
Posology
The dose of TESAVEL is 100 mg once daily. When TESAVEL is used in combination with
metformin and/or a PPARγ agonist, the dose of metformin and/or PPARγ 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
For patients with mild renal impairment (creatinine clearance [CrCl] ≥50 ml/min), no dose adjustment
for TESAVEL is required.
Clinical study experience with TESAVEL in patients with moderate or severe renal impairment is
limited. Therefore, use of TESAVEL is not recommended in this patient population (see section 5.2).
Hepatic impairment
No dose adjustment is necessary for patients with mild to moderate hepatic impairment. TESAVEL
has not been studied in patients with severe hepatic impairment.
Elderly
No dose adjustment is necessary based on age. Limited safety data is available in patients ≥ 75 years
of age and care should be exercised.
Paediatric population
TESAVEL is not recommended for use in children below 18 years of age due to a lack of data on its
safety and efficacy.
Method of administration
TESAVEL can be taken with or without food.
Hypersensitivity to the active substance or to any of the excipients (see section 4.4 and 4.8).
General
TESAVEL should not be used in patients with type 1 diabetes or for the treatment of diabetic
ketoacidosis.
Pancreatitis
In post-marketing experience there have been spontaneously reported adverse reactions of acute
pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis:
persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation
of sitagliptin (with or without supportive treatment), but very rare cases of necrotizing or
haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, TESAVEL and
other potentially suspect medicinal products should be discontinued.
Hypoglycaemia when used in combination with other anti-hyperglycaemic agents
In clinical trials of TESAVEL as monotherapy and as part of combination therapy with agents not
known to cause hypoglycaemia (i.e. metformin and/or a PPARγ agonist), rates of hypoglycaemia
31
reported with sitagliptin were similar to rates in patients taking placebo. When sitagliptin was added to
a sulphonylurea or to insulin, the incidence of hypoglycaemia was increased over that of placebo (see
section 4.8). Therefore, to reduce the risk of hypoglycaemia, a lower dose of sulphonylurea or insulin
may be considered (see section 4.2).
Renal impairment
As the experience is limited, patients with moderate to severe renal impairment should not be treated
with TESAVEL (see section 5.2).
Hypersensitivity Reactions
Postmarketing reports of serious hypersensitivity reactions in patients treated with TESAVEL 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 TESAVEL, with some reports occurring after the first dose. If a
hypersensitivity reaction is suspected, discontinue TESAVEL, assess for other potential causes for the
event, and institute alternative treatment for diabetes (see section 4.8).
Effects of other medicinal products on sitagliptin
Clinical data described below suggest that the risk for clinically meaningful interactions by co-
administered medicinal products is low.
Metformin:
Co-administration of multiple twice-daily doses of 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 C
max
of sitagliptin by
approximately 29 % and 68 %, respectively. These changes in sitagliptin pharmacokinetics were not
considered to be clinically meaningful. The renal clearance of sitagliptin was not meaningfully altered.
Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors.
In vitro
studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin
is CYP3A4, with contribution from CYP2C8. In patients with normal renal function, metabolism,
including via CYP3A4, plays only a small role in the clearance of sitagliptin. Metabolism may play a
more significant role in the elimination of sitagliptin in the setting of severe renal impairment or
ESRD. For this reason, it is possible that potent CYP3A4 inhibitors (i.e. ketoconazole, itraconazole,
ritonavir, clarithromycin) could alter the phamacokinetics of sitagliptin in patients with severe renal
impairment or end-stage renal disease (ESRD). The effects of potent CYP3A4 inhibitors in the setting
of renal impairment has not been assessed in a clinical study.
In vitro
transport studies showed that sitagliptin is a substrate for p-glycoprotein and organic anion
transporter-3 (OAT3). OAT3 mediated transport of sitagliptin was inhibited
in vitro
by probenecid,
although the risk of clinically meaningful interactions is considered to be low. Concomitant
administration of OAT3 inhibitors has not been evaluated
in vivo
.
Effects of sitagliptin on other medicinal products
In vitro
data suggest that sitagliptin does not inhibit nor induce CYP450 isoenzymes. In clinical
studies, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide,
simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing
in vivo
evidence of a low
propensity for causing interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic
cationic transporter (OCT).
Sitagliptin had a small effect on plasma digoxin concentrations, and may be a mild inhibitor of p-
glycoprotein
in vivo
.
32
Digoxin:
Sitagliptin had a small effect on plasma digoxin concentrations. Following administration of
0.25 mg digoxin concomitantly with 100 mg of TESAVEL daily for 10 days, the plasma AUC of
digoxin was increased on average by 11 %, and the plasma C
max
on average by 18 %. No dose
adjustment of digoxin is recommended. However, patients at risk of digoxin toxicity should be
monitored for this when sitagliptin and digoxin are administered concomitantly.
Pregnancy
There are no adequate data from the use of TESAVEL 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.
Lactation
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.
TESAVEL has no known influence on the ability to drive and use machines. However, when driving
or operating machines, it should be taken into account that dizziness and somnolence have been
reported.
In addition, patients should be alerted to the risk of hypoglycaemia when TESAVEL is used in
combination with sulphonylurea agents or with insulin.
In 11 large clinical trials of up to 2 years in duration, over 3,200 patients have received treatment with
TESAVEL 100 mg per day alone or in combination with metformin, a sulphonylurea (with or without
metformin), insulin (with or without metformin), or a PPARγ agent (with or without metformin). In a
pooled analysis of 9 of these trials, the rate of discontinuation due to adverse experiences considered
drug-related was 0.8 % with 100 mg per day and 1.5 % with other treatments. No adverse reactions
considered as drug-related were reported in patients treated with sitagliptin occurring in excess
(> 0.2 % and difference > 1 patient) of that in patients treated with control. In an additional
combination study with a PPARγ agent (rosiglitazone) and metformin, no patients were discontinued
due to adverse experiences considered as drug-related.
Adverse reactions considered as drug-related reported in patients treated with sitagliptin occurring in
excess (> 0.2 % and difference > 1 patient) of that in patients treated with placebo are listed below
(Table 1) by system organ class and frequency. Frequencies are defined as: very common (≥ 1/10);
common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); and
very rare (< 1/10,000).
33
Table 1. The frequency of adverse reactions identified from placebo-controlled clinical studies
Adverse
reaction
Frequency of adverse reaction by treatment regimen
Sitagliptin
with
Metformin
1
Sitagliptin
with a
Sulphonylure
a
2
Sitagliptin
with a
Sulphonylure
a
and
Metformin
3
Sitagliptin
with a PPAR
γ
Agent
(pioglitazone)
4
Sitagliptin
with a
PPAR
γ
Agent
(rosiglitazone
)
and
Metformin
5
Sitagliptin
with Insulin
(+/-)
Metformin)
6
Time-point
24-week
24-week
24-week
24-week
18-week
24-week
Infections and infestations
influenza
Common
Metabolism and nutrition disorders
hypoglycaemia*
Common
Very common
Common
Common
Common
Nervous system disorders
headache
Common
Common
somnolence
Uncommon
Gastrointestinal disorders
diarrhoea
Uncommon
Common
dry mouth
Uncommon
nausea
Common
flatulence
Common
constipation
Common
Uncommon
upper
abdominal pain
Uncommon
vomiting
Common
General disorders and administration site conditions
peripheral
oedema
Common
Common
Investigations
blood glucose
decreased
Uncommon
*
In clinical trials of TESAVEL as monotherapy and sitagliptin as part of combination therapy with
metformin and/or a PPARγ agent, rates of hypoglycaemia reported with sitagliptin were similar to
rates in patients taking placebo.
1
In this placebo-controlled 24-week study of sitagliptin 100 mg once daily in combination with
metformin, the incidence of adverse reactions considered as drug-related in patients treated with
sitagliptin/metformin compared to treatment with placebo/metformin was 9.3 % and 10.1 %,
respectively.
In an additional 1-year study of sitagliptin 100 mg once daily in combination with metformin, the
incidence of adverse reactions considered as drug-related in patients treated with
sitagliptin/metformin compared to sulphonylurea/metformin was 14.5 % and 30.3 %, respectively.
In pooled studies of up to 1 year in duration comparing sitagliptin/metformin to a sulphonylurea
agent/metformin, adverse reactions considered as drug-related reported in patients treated with
sitagliptin 100 mg occurring in excess (> 0.2 % and difference > 1 patient) of that in patients
34
receiving the sulphonylurea agent are as follows: anorexia (Metabolism and nutritional disorders;
frequency uncommon) and weight decreased (Investigations; frequency uncommon).
2
In this 24-week study of sitagliptin 100 mg once daily in combination with glimepiride, the
incidence of adverse reactions considered as drug-related in patients treated with
sitagliptin/glimepiride compared to treatment with placebo/glimepiride was 11.3 % and 6.6 %,
respectively.
3
In this 24-week study of sitagliptin 100 mg once daily in combination with glimepiride and
metformin, the incidence of adverse reactions considered as drug-related in patients treated with
sitagliptin in combination with glimepiride/metformin compared to treatment with placebo in
combination with glimepiride/metformin was 18.1 % and 7.1 %, respectively.
4
In this 24-week study of the combination of sitagliptin 100 mg once daily and pioglitazone, the
incidence of adverse reactions considered as drug-related in patients treated with
sitagliptin/pioglitazone compared to patients treated with placebo/pioglitazone was 9.1 % and 9.0 %,
respectively.
5
In this study of sitagliptin 100 mg once daily in combination with rosiglitazone and metformin,
which continued through 54 weeks, the incidence of adverse reactions considered as drug-related in
patients treated with the sitagliptin combination compared to treatment with the placebo
combination was 15.3 % and 10.9 %, respectively. Other drug-related adverse reactions reported in
the 54-week analysis (frequency common) in patients treated with the sitagliptin combination
occurring in excess (> 0.2 % and difference > 1 patient) of that in patients treated with the placebo
combination were: headache, cough, vomiting, hypoglycaemia, fungal skin infection, and upper
respiratory tract infection.
6
In this 24-week study of sitagliptin 100 mg once daily as add-on to insulin therapy (with or without
metformin), the incidence of adverse reactions considered as drug-related in patients treated with
sitagliptin/insulin (with or without metformin) compared to treatment with placebo/insulin (with or
without metformin) was 15.5 % and 8.5 %, respectively. In this study 0.9 % of patients treated with
sitagliptin/insulin and 0.0 % of patients treated with placebo/insulin were discontinued due to
adverse experiences considered as drug-related.
In addition, in monotherapy studies of up to 24 weeks in duration of sitagliptin 100 mg once daily
alone compared to placebo, adverse reactions considered as drug-related reported in patients treated
with sitagliptin in excess (> 0.2 % and difference > 1 patient) of that in patients receiving placebo are
headache, hypoglycaemia, constipation, and dizziness.
In addition to the drug-related adverse experiences described above, adverse experiences reported
regardless of causal relationship to medication and occurring in at least 5 % and more commonly in
patients treated with TESAVEL 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 TESAVEL (not reaching the 5 % level, but occurring with an
incidence of > 0.5 % higher with TESAVEL than that in the control group) included osteoarthritis and
pain in extremity.
In an additional 24-week study of sitagliptin 100 mg once daily compared to metformin, the incidence
of adverse reactions considered as drug-related in patients treated with sitagliptin compared to
metformin was 5.9 % and 16.7 %, respectively, primarily due to a higher incidence of gastrointestinal
adverse reactions in the metformin group. In this study 0.6 % of patients treated with sitagliptin and
2.3 % of patients treated with metformin were discontinued due to adverse experiences considered as
drug-related.
In a 24-week study of initial combination therapy with sitagliptin and metformin administered twice
daily (sitagliptin/metformin 50 mg/500 mg or 50 mg/1,000 mg), the overall incidence of adverse
reactions considered as drug-related in patients treated with the combination of sitagliptin and
35
metformin compared to patients treated with placebo was 14.0 % and 9.7 %, respectively. The overall
incidence of adverse reactions considered as drug-related in patients treated with the combination of
sitagliptin and metformin was comparable to metformin alone (14.0 % each) and greater than
sitagliptin alone (6.7 %), with the differences relative to sitagliptin alone primarily due to
gastrointestinal adverse reactions.
Across clinical studies, a small increase in white blood cell count (approximately 200 cells/microl
difference in WBC vs. placebo; mean baseline WBC approximately 6,600 cells/microl) was observed
due to an increase in neutrophils. This observation was seen in most but not all studies. This change in
laboratory parameters is not considered to be clinically relevant.
No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed
with TESAVEL treatment.
Post-marketing Experience:
During post-approval use of TESAVEL as monotherapy and/or in combination with other
antihyperglycaemic agents, additional side effects have been reported (frequency not known):
hypersensitivity reactions, including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis,
and exfoliative skin conditions including Stevens-Johnson syndrome (see section 4.4); acute
pancreatitis, including fatal and non-fatal haemorrhagic and necrotizing pancreatitis (see section 4.4);
impaired renal function, including acute renal failure (sometimes requiring dialysis); vomiting.
During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were
generally well tolerated. Minimal increases in QTc, not considered to be clinically relevant, were
observed in one study at a dose of 800 mg sitagliptin. There is no experience with doses above 800 mg
in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse
reactions observed with sitagliptin with doses of up to 600 mg per day for periods of up to 10 days and
400 mg per day for periods of up to 28 days.
In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove
unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an
electrocardiogram), and institute supportive therapy if required.
Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5 % of the dose was removed
over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically
appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Medicines used in diabetes, Dipeptidyl peptidase 4 (DPP-4 )
inhibitorsInhibitor, ATC code: A10BH01.
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 agent 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
36
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 concentrations are low,
stimulation of insulin release and suppression of glucagon secretion by GLP-1 are not observed. For
both GLP-1 and GIP, stimulation of insulin release is enhanced as glucose rises above normal
concentrations. Further, GLP-1 does not impair the normal glucagon response to hypoglycaemia. The
activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly hydrolyzes the incretin
hormones to produce inactive products. Sitagliptin prevents the hydrolysis of incretin hormones by
DPP-4, thereby increasing plasma concentrations of the active forms of GLP-1 and GIP. By enhancing
active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in a glucose-
dependent manner. In patients with type 2 diabetes with hyperglycaemia, these changes in insulin and
glucagon levels lead to lower hemoglobin A
1c
(HbA
1c
) 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.
Overall, sitagliptin improved glycaemic control when used as monotherapy or in combination
treatment (see Table 2).
Two studies were conducted to evaluate the efficacy and safety of TESAVEL monotherapy. Treatment
with sitagliptin at 100 mg once daily as monotherapy provided significant improvements in HbA
1c
,
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 TESAVEL 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.
In a study in patients with type 2 diabetes and chronic renal impairment (creatinine clearance
< 50 ml/min), the safety and tolerability of reduced doses of sitagliptin were investigated and
generally similar to placebo. In addition, the reductions in HbA
1c
and FPG with sitagliptin compared
to placebo were generally similar to those observed in other monotherapy studies in patients with
normal renal function (see section 5.2). The number of patients with moderate to severe renal
impairment was too low to confirm safe use of sitagliptin in this type of patients.
Sitagliptin 100 mg once daily provided significant improvements in glycaemic parameters compared
with placebo in two 24-week studies of sitagliptin as add-on therapy, one in combination with
metformin and one in combination with pioglitazone. Change from baseline in body weight was
similar for patients treated with sitagliptin relative to placebo. In these studies there was a similar
incidence of hypoglycaemia reported for patients treated with sitagliptin or placebo.
A 24-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin
(100 mg once daily) added to glimepiride alone or glimepiride in combination with metformin. The
addition of sitagliptin to either glimepiride alone or to glimepiride and metformin provided significant
improvements in glycaemic parameters. Patients treated with sitagliptin had a modest increase in body
weight compared to those given placebo.
37
A 54-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin
(100 mg once daily) added to the combination of rosiglitazone and metformin. The addition of
sitagliptin to rosiglitazone and metformin provided significant improvements in glycaemic parameters
at the primary timepoint of Week 18, with improvements sustained through the end of the study.
Change from baseline in body weight was similar for patients treated with sitagliptin relative to
placebo (1.9 vs. 1.3 kg).
A 24-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin
(100 mg once daily) added to insulin (at a stable dose for at least 10 weeks) with or without metformin
(at least 1,500 mg). In patients taking pre-mixed insulin, the mean daily dose was 70.9 U/day. In
patients taking non-pre-mixed (intermediate/long-acting) insulin, the mean daily dose was 44.3 U/day.
The addition of sitagliptin to insulin provided significant improvements in glycaemic parameters.
There was no meaningful change from baseline in body weight in either group.
In a 24-week placebo-controlled factorial study of initial therapy, sitagliptin 50 mg twice daily in
combination with metformin (500 mg or 1,000 mg twice daily) provided significant improvements in
glycaemic parameters compared with either monotherapy. The decrease in body weight with the
combination of sitagliptin and metformin was similar to that observed with metformin alone or
placebo; there was no change from baseline for patients on sitagliptin alone.
The incidence of
hypoglycaemia was similar across treatment groups.
Table 2. HbA
1c
results in placebo-controlled monotherapy and combination therapy studies*
Study
Mean
baseline
HbA
1c
(%)
Mean change from
baseline HbA
1c
(%)
†
Placebo-corrected
mean change in
HbA
1c
(%)
†
(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 rosiglitazone + metformin
therapy (N=170)
Week 18
8.8
-1.0
-0.7
‡
(-0.9, -0.5)
-0.8
‡
(-1.0, -0.5)
Week 54
8.8
-1.0
38
Study
Mean
baseline
HbA
1c
(%)
Mean change from
baseline HbA
1c
(%)
†
Placebo-corrected
mean change in
HbA
1c
(%)
†
(95 % CI)
Initial therapy (twice daily)
:
Sitagliptin 50 mg + metformin 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)
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.
§
HbA
1c
(%) at week 18.
HbA
1c
(%) at week 24.
¶
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 HbA
1c
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 TESAVEL 100 mg once daily or
glipizide (a sulphonylurea agent) in patients with inadequate glycaemic control on metformin
monotherapy, sitagliptin was similar to glipizide in reducing HbA
1c
. 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 %).
The European Medicines Agency has deferred the obligation to submit the results of studies with
TESAVEL in one or more subsets of the paediatric population in type 2 diabetes mellitus (see
section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Absorption
Following oral administration of a 100-mg dose to healthy subjects, sitagliptin was rapidly absorbed,
with peak plasma concentrations (median T
max
) occurring 1 to 4 hours post-dose, mean plasma AUC of
sitagliptin was 8.52 μM•hr, C
max
was 950 nM. The absolute bioavailability of sitagliptin is
approximately 87 %. Since co-administration of a high-fat meal with TESAVEL had no effect on the
pharmacokinetics, TESAVEL may be administered with or without food.
39
Plasma AUC of sitagliptin increased in a dose-proportional manner. Dose-proportionality was not
established for C
max
and C
24hr
(C
max
increased in a greater than dose-proportional manner and C
24hr
increased in a less than dose-proportional manner).
Distribution
The mean volume of distribution at steady state following a single 100-mg intravenous dose of
sitagliptin to healthy subjects is approximately 198 liters. The fraction of sitagliptin reversibly bound
to plasma proteins is low (38 %).
Biotransformation
Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway.
Approximately 79 % of sitagliptin is excreted unchanged in the urine.
Following a [
14
C]sitagliptin oral dose, approximately 16 % of the radioactivity was excreted as
metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to
contribute to the plasma DPP-4 inhibitory activity of sitagliptin.
In vitro
studies indicated that the
primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution
from CYP2C8.
In vitro
data showed that sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6,
1A2, 2C19 or 2B6, and is not an inducer of CYP3A4 and CYP1A2.
Elimination
Following administration of an oral [
14
C]sitagliptin dose to healthy subjects, approximately 100 % of
the administered radioactivity was eliminated in faeces (13 %) or urine (87 %) within one week of
dosing. The apparent terminal t
1/2
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 μM) or p-glycoprotein (up to 250
μM) mediated transport at therapeutically relevant plasma concentrations. In a clinical study sitagliptin
had a small effect on plasma digoxin concentrations indicating that sitagliptin may be a mild inhibitor
of p-glycoprotein.
Characteristics in patients
The pharmacokinetics of sitagliptin were generally similar in healthy subjects and in patients with type
2 diabetes.
Renal impairment
A single-dose, open-label study was conducted to evaluate the pharmacokinetics of a reduced dose of
sitagliptin (50-mg) in patients with varying degrees of chronic renal impairment compared to normal
healthy control subjects. The study included patients with renal impairment classified on the basis of
creatinine clearance as mild (50 to < 80 ml/min), moderate (30 to < 50 ml/min), and severe
(< 30 ml/min), as well as patients with end-stage renal disease (ESRD) on hemodialysis.
Patients with mild renal impairment did not have a clinically meaningful increase in the plasma
concentration of sitagliptin as compared to normal healthy control subjects. An approximately 2-fold
increase in the plasma AUC of sitagliptin was observed in patients with moderate renal impairment,
and an approximately 4-fold increase was observed in patients with severe renal impairment and in
patients with ESRD on hemodialysis, as compared to normal healthy control subjects. Sitagliptin was
40
modestly removed by hemodialysis (13.5 % over a 3- to 4-hour hemodialysis session starting 4 hours
postdose). TESAVEL is not recommended for use in patients with moderate or severe renal
impairment including those with ESRD since experience in these patients is too limited (see
section 4.2).
Hepatic impairment
No dose adjustment for 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
No studies with TESAVEL have been performed in paediatric patients.
Other patient characteristics
No dose adjustment is necessary based on gender, race, or body mass index (BMI). These
characteristics had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a
composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of
Phase I and Phase II data.
5.3 Preclinical safety data
Renal and liver toxicity were observed in
rodents at systemic exposure values 58 times the human
exposure level, while the no-effect level was found at 19 times the human exposure level. Incisor teeth
abnormalities were observed in rats at exposure levels 67 times the clinical exposure level; the no-
effect level for this finding was 58-fold based on the 14-week rat study. The relevance of these
findings for humans is unknown. Transient
treatment-related physical signs,
some of which suggest
neural toxicity, such as open-mouth breathing, salivation, white foamy emesis, ataxia, trembling,
decreased activity, and/or hunched posture were observed in dogs at exposure levels approximately
23 times the clinical exposure level. In addition, very slight to slight skeletal muscle degeneration was
also observed histologically at doses resulting in systemic exposure levels of approximately 23 times
the human exposure level. A no-effect level for these findings was found at an exposure 6-fold the
clinical exposure level.
Sitagliptin has not been demonstrated to be genotoxic in preclinical studies. Sitagliptin was not
carcinogenic in mice. In rats, there was an increased incidence of hepatic adenomas and carcinomas at
systemic exposure levels 58 times the human exposure level. Since hepatotoxicity has been shown to
correlate with induction of hepatic neoplasia in rats, this increased incidence of hepatic tumors in rats
was likely secondary to chronic hepatic toxicity at this high dose. Because of the high safety margin
(19-fold at this no-effect level), these neoplastic changes are not considered relevant for the situation
in humans.
No adverse effects upon fertility were observed in male and female rats given sitagliptin prior to and
throughout mating.
In a pre-/postnatal development study performed in rats sitagliptin showed no adverse effects.
Reproductive toxicity studies showed a slight treatment-related increased incidence of fetal rib
malformations (absent, hypoplastic and wavy ribs) in the offspring of rats at systemic exposure levels
more than 29 times the human exposure levels. Maternal toxicity was seen in rabbits at more than
29 times the human exposure levels. Because of the high safety margins, these findings do not suggest
41
a relevant risk for human reproduction. Sitagliptin is secreted in considerable amounts into the milk of
lactating rats (milk/plasma ratio: 4:1).
6.
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
:
polyvinyl 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 aluminum). Packs of 14, 28, 56, 84 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 product or waste material should be disposed of in accordance with local requirements.
7.
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
42
8.
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
9.
Date of first authorisation: 10 January 2008
Detailed information on this product is available on the website of the European Medicines Agency
web site: http://www.ema.europa.eu/.
43
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
44
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Merck Sharp & Dohme (Italia) S.p.A.
Via Emilia 21
IT-27100 Pavia
Italy
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to medical prescription.
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 7.0 presented in
Module 1.8.1. of the Marketing Authorisation Application and any subsequent updates, is in place and
functioning before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 2.0 of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any
updated RMP should be submitted at the same time as the following Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the European Medicines Agency
45
ANNEX III
LABELLING AND PACKAGE LEAFLET
46
A. LABELLING
47
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Outer carton for TESAVEL 25 mg film-coated tablets
1.
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.
14 film-coated tablets
28 film-coated tablets
56 film-coated tablets
84 film-coated tablets
98 film-coated tablets
50 x 1 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
48
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
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
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
TESAVEL 25 mg
49
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister for TESAVEL 25 mg film-coated tablets
1.
TESAVEL 25 mg tablets
Sitagliptin
2.
MSD
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
OTHER
50
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Outer carton for TESAVEL 50 mg film-coated tablets
1.
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.
14 film-coated tablets
28 film-coated tablets
56 film-coated tablets
84 film-coated tablets
98 film-coated tablets
50 x 1 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
51
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
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
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
TESAVEL 50 mg
52
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister for TESAVEL 50 mg film-coated tablets
1.
TESAVEL 50 mg tablets
Sitagliptin
2.
MSD
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
OTHER
53
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Outer carton for TESAVEL 100 mg film-coated tablets
1.
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.
14 film-coated tablets
28 film-coated tablets
56 film-coated tablets
84 film-coated tablets
98 film-coated tablets
50 x 1 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
54
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
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
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
TESAVEL 100 mg
55
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister for TESAVEL 100 mg film-coated tablets
1.
TESAVEL 100 mg tablets
Sitagliptin
2.
MSD
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
OTHER
56
B. PACKAGE LEAFLET
57
PACKAGE LEAFLET: INFORMATION FOR THE USER
TESAVEL 25 mg film-coated tablets
Sitagliptin
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What TESAVEL is and what it is used for
2.
Before you take TESAVEL
3.
How to take TESAVEL
4.
How to store TESAVEL
6.
Further information
1.
WHAT TESAVEL IS AND WHAT IT IS USED FOR
TESAVEL is a member of a class of medicines you take by mouth called DPP-4 inhibitors (dipeptidyl
peptidase-4 inhibitors) that lowers blood sugar levels in patients with type 2 diabetes mellitus. Type 2
diabetes is also called non-insulin-dependent diabetes mellitus, or NIDDM.
TESAVEL helps to improve the levels of insulin after a meal and decreases the amount of sugar made
by the body. It is unlikely to cause low blood sugar because it does not work when your blood sugar is
low. However, when TESAVEL is used in combination with a sulphonylurea medicine or with insulin,
low blood sugar (hypoglycaemia) can occur.
Your doctor has prescribed TESAVEL to help lower your blood sugar, which is too high because of
your type 2 diabetes. TESAVEL 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.
BEFORE YOU TAKE TESAVEL
Do not take TESAVEL
-
if you are allergic (hypersensitive) to sitagliptin or any of the other ingredients of TESAVEL.
58
5.
Possible side effects
Take special care with TESAVEL
Cases of inflammation of the pancreas (pancreatitis) have been reported in patients receiving
TESAVEL. Pancreatitis can be a serious, potentially life-threatening medical condition. Stop taking
TESAVEL and call your doctor if you experience severe and persistent stomach pain, with or without
vomiting, because you could have pancreatitis.
Tell your doctor if you have or have had:
-
pancreatitis, gallstones, alcoholism or very high triglycerides. These medical conditions can
increase your chance of getting pancreatitis, or getting it again.
-
diabetic ketoacidosis (a complication of diabetes with high blood sugar, rapid weight loss,
nausea or vomiting)
-
any kidney problems, or any past or present medical problems. If you have kidney problems,
TESAVEL may not be the right medicine for you.
-
an allergic reaction to TESAVEL
If you are taking a sulphonylurea or insulin with TESAVEL you may experience low blood sugar.
Your doctor may reduce the dose of your sulphonylurea or insulin medicine.
Taking other medicines
TESAVEL may be taken with most medicines. Tell your doctor or pharmacist about all the medicines
you take or have recently taken. This includes prescription and non-prescription medicines, and herbal
supplements.
Taking TESAVEL with food and drink
You can take TESAVEL with or without food and drink.
Pregnancy and breast-feeding
Women who are pregnant or plan to become pregnant should consult their doctor before taking
TESAVEL. You should not use TESAVEL during pregnancy.
It is not known if TESAVEL passes into breast milk. You should not use TESAVEL if you are breast-
feeding or plan to breast-feed.
Driving and using machines
TESAVEL has no known influence on the ability to drive and use machines. However, when driving
or operating machinery, it should be taken into account that dizziness and drowsiness have been
reported.
Taking TESAVEL in combination with medicines called sulphonylureas or with insulin can cause
hypoglycaemia, which may affect your ability to drive and use machines or work without safe
foothold.
3.
HOW TO TAKE TESAVEL
Always take TESAVEL exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
The usual dose is:
−
one 100 mg film-coated tablet
−
once a day
−
by mouth
Your doctor may prescribe TESAVEL alone or with certain other medicines that lower blood sugar.
59
-
type 1 diabetes
Continue to take TESAVEL as long as your doctor prescribes it so you can continue to help control
your blood sugar.
Diet and exercise can help your body use its blood sugar better. It is important to stay on the diet,
exercise and weight loss program recommended by your doctor while taking TESAVEL.
If you take more TESAVEL than you should
If you take more than the prescribed dosage of TESAVEL, 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
TESAVEL.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, TESAVEL may cause side effects, although not everybody gets them.
Very common side effects (more than 1 per 10 patients)
Common side effects (less than 1 per 10 but more than 1 per 100 patients)
Uncommon side effects (less than 1 per 100 but more than 1 per 1,000 patients)
Some patients have experienced the following side effects after adding sitagliptin to metformin:
Common: nausea
Uncommon: weight loss, loss of appetite, abdominal pain, diarrhoea, low blood sugar, drowsiness.
Some patients have experienced stomach discomfort when starting the combination of sitagliptin and
metformin together.
Some patients have experienced the following side effects while taking TESAVEL in combination
with a sulphonylurea:
Common: low blood sugar
Some patients have experienced the following side effects while taking TESAVEL in combination
with a sulphonylurea and metformin:
Very common: low blood sugar
Common: constipation
Some patients have experienced the following side effects while taking TESAVEL and pioglitazone:
Common: low blood sugar and flatulence. In addition, some patients have reported foot swelling while
taking TESAVEL and pioglitazone. These side effects may be seen with sitagliptin and any glitazone
(e.g., rosiglitazone).
Some patients have experienced the following side effects while taking TESAVEL in combination
with rosiglitazone and metformin:
Common: headache, cough, diarrhoea, vomiting, low blood sugar, fungal skin infection, upper
respiratory infection, swelling of the hands or legs.
Some patients have experienced the following side effects while taking TESAVEL in combination
with insulin (with or without metformin):
Common: headache, low blood sugar and flu
Uncommon: dry mouth, constipation
Some patients have experienced the following side effects while taking TESAVEL alone:
Common: low blood sugar, headache
Uncommon: dizziness, constipation
60
In addition, some patients have reported the following side effects while taking TESAVEL:
Common: upper respiratory infection, stuffy or runny nose and sore throat, osteoarthritis, arm or leg
pain.
During post-approval use of TESAVEL by itself and/or with other diabetes medicines additional side
effects have also been reported (frequency not known): allergic reactions, which may be serious,
including rash, hives, and swelling of the face, lips, tongue, and throat that may cause difficulty in
breathing or swallowing. If you have an allergic reaction, stop taking TESAVEL and call your doctor
right away. Your doctor may prescribe a medicine to treat your allergic reaction and a different
medicine for your diabetes. Other side effects that have been reported include: inflammation of the
pancreas; kidney problems (sometimes requiring dialysis); vomiting.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE TESAVEL
Keep out of the reach and sight of children.
Do not use TESAVEL after the expiry date which is stated on the blister and the carton. The expiry
date refers to the last day of that month.
This medicine does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What TESAVEL contains
-
The active substance is sitagliptin. Each film-coated tablet contains sitagliptin phosphate
monohydrate, equivalent to 25 mg sitagliptin.
-
The other ingredients are: microcrystalline cellulose (E460), calcium hydrogen phosphate,
anhydrous (E341), croscarmellose sodium (E468), magnesium stearate (E470b), and sodium
stearyl fumarate. The tablet film coating contains: polyvinyl alcohol, macrogol 3350, talc
(E553b), titanium dioxide (E171), red iron oxide (E172), and yellow iron oxide (E172).
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 aluminum). Packs of 14, 28, 56, 84 or 98 film-coated tablets and
50 x 1 film-coated tablets in perforated unit dose blisters.
Not all pack sizes may be marketed.
61
Marketing Authorisation Holder and Manufacturer
The
Marketing Authorisation
Holder
is:
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
The
Manufacturer
is:
Merck Sharp & Dohme (Italia) S.p.A.
Via Emilia, 21
27100 - Pavia
Italy
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
Belgique/België/Belgien
Merck Sharp & Dohme B.V.
Succursale belge/Belgisch bijhuis
Tél/Tel: +32 (0) 800 38693
MSDBelgium_info@merck.com
Luxembourg/Luxemburg
Merck Sharp & Dohme B.V.
Succursale belge/Belgisch bijhuis
Tél: +32 (0) 800 38693
MSDBelgium_info@merck.com
България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3740
info-msdbg@merck.com
Magyarország
MSD Magyarország Kft.
Tel.: +36 1 888 53 00
hungary_msd@merck.com
Česká republika
Merck Sharp & Dohme IDEA, Inc., org. sl.
Tel.: +420 233 010 111
msd_cr@merck.com
Malta
Merck Sharp & Dohme Cyprus Limited
Tel: +357 22866700
malta_info@merck.com
Ċipru
Danmark
Merck Sharp & Dohme
Tlf: +45 43 28 77 66
dkmail@merck.com
Nederland
Merck Sharp & Dohme BV
Tel: 0800 99 99 000
medicalinfo.nl@merck.com
Deutschland
MSD SHARP & DOHME GMBH
Tel: +49 (0) 89 4561 2612
Infocenter@msd.de
Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no
Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 613 9750
msdeesti@merck.com
Österreich
Merck Sharp & Dohme G.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com
Eλλάδα
BIANEΞ Α.Ε
Τηλ: +3 0210 80091 11
Mailbox@vianex.gr
Polska
MSD Polska Sp. z o.o.
Tel.: +48 22 549 51 00
msdpolska@merck.com
Portugal
Merck Sharp & Dohme, Lda
Tel: +351 21 4465700
informacao_doente@merck.com
62
France
Laboratoires Merck Sharp & Dohme – Chibret
Tél: +33 (0) 1 47 54 87 00
contact@msd-france.com
România
Merck Sharp & Dohme Romania S.R.L.
Tel: + 4021 529 29 00
msdromania@merck.com
Ireland
Merck Sharp and 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 5204201
msd_slovenia@merck.com
Ísland
Icepharma hf.
Sími: +354 540 8000
ISmail@merck.com
Slovenská republika
Merck Sharp & Dohme IDEA, Inc.
Tel.: +421 2 58282010
msd_sk@merck.com
Ιtalia
Addenda Pharma S.r.l.
Tel.: +39 06 91393303
info@addenda.it
Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0) 9 804650
info@msd.fi
Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ: +357 22866700
cyprus_info@merck.com
Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 (0) 8 626 14 00
medicinskinfo@merck.com
Latvija
SIA “Merck Sharp & Dohme Latvija”
Tel: +371 67364 224
msd_lv@merck.com
United Kingdom
Merck Sharp and Dohme Limited
Tel: +44 (0) 1992 467272
medicalinformationuk@merck.com
Lietuva
UAB “Merck Sharp & Dohme”
Tel.: +370 5 278 02 47
msd_lietuva@merck.com
This leaflet was last approved in
{MM/YYYY}.
Detailed information on this medicine is available on the website of the European Medicines Agency
web site: http://www.ema.europa.eu/.
63
PACKAGE LEAFLET: INFORMATION FOR THE USER
TESAVEL 50 mg film-coated tablets
Sitagliptin
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What TESAVEL is and what it is used for
2.
Before you take TESAVEL
3.
How to take TESAVEL
4.
How to store TESAVEL
6.
Further information
1.
WHAT TESAVEL IS AND WHAT IT IS USED FOR
TESAVEL is a member of a class of medicines you take by mouth called DPP-4 inhibitors (dipeptidyl
peptidase-4 inhibitors) that lowers blood sugar levels in patients with type 2 diabetes mellitus. Type 2
diabetes is also called non-insulin-dependent diabetes mellitus, or NIDDM.
TESAVEL helps to improve the levels of insulin after a meal and decreases the amount of sugar made
by the body. It is unlikely to cause low blood sugar because it does not work when your blood sugar is
low. However, when TESAVEL is used in combination with a sulphonylurea medicine or with insulin,
low blood sugar (hypoglycaemia) can occur.
Your doctor has prescribed TESAVEL to help lower your blood sugar, which is too high because of
your type 2 diabetes. TESAVEL 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.
BEFORE YOU TAKE TESAVEL
Do not take TESAVEL
-
if you are allergic (hypersensitive) to sitagliptin or any of the other ingredients of TESAVEL.
64
5
Possible side effects
Take special care with TESAVEL
Cases of inflammation of the pancreas (pancreatitis) have been reported in patients receiving
TESAVEL. Pancreatitis can be a serious, potentially life-threatening medical condition. Stop taking
TESAVEL and call your doctor if you experience severe and persistent stomach pain, with or without
vomiting, because you could have pancreatitis.
Tell your doctor if you have or have had:
-
pancreatitis, gallstones, alcoholism or very high triglycerides. These medical conditions can
increase your chance of getting pancreatitis, or getting it again.
-
diabetic ketoacidosis (a complication of diabetes with high blood sugar, rapid weight loss,
nausea or vomiting)
-
any kidney problems, or any past or present medical problems. If you have kidney problems,
TESAVEL may not be the right medicine for you.
-
an allergic reaction to TESAVEL
If you are taking a sulphonylurea or insulin with TESAVEL you may experience low blood sugar.
Your doctor may reduce the dose of your sulphonylurea or insulin medicine.
Taking other medicines
TESAVEL may be taken with most medicines. Tell your doctor or pharmacist about all the medicines
you take or have recently taken. This includes prescription and non-prescription medicines, and herbal
supplements.
Taking TESAVEL with food and drink
You can take TESAVEL with or without food and drink.
Pregnancy and breast-feeding
Women who are pregnant or plan to become pregnant should consult their doctor before taking
TESAVEL. You should not use TESAVEL during pregnancy.
It is not known if TESAVEL passes into breast milk. You should not use TESAVEL if you are breast-
feeding or plan to breast-feed.
Driving and using machines
TESAVEL has no known influence on the ability to drive and use machines. However, when driving
or operating machinery, it should be taken into account that dizziness and drowsiness have been
reported.
Taking TESAVEL in combination with medicines called sulphonylureas or with insulin can cause
hypoglycaemia, which may affect your ability to drive and use machines or work without safe
foothold.
3.
HOW TO TAKE TESAVEL
Always take TESAVEL exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
The usual dose is:
−
one 100 mg film-coated tablet
−
once a day
−
by mouth
Your doctor may prescribe TESAVEL alone or with certain other medicines that lower blood sugar.
65
-
type 1 diabetes
Continue to take TESAVEL as long as your doctor prescribes it so you can continue to help control
your blood sugar.
Diet and exercise can help your body use its blood sugar better. It is important to stay on the diet,
exercise and weight loss program recommended by your doctor while taking TESAVEL.
If you take more TESAVEL than you should
If you take more than the prescribed dosage of TESAVEL, 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
TESAVEL.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, TESAVEL may cause side effects, although not everybody gets them.
Very common side effects (more than 1 per 10 patients)
Common side effects (less than 1 per 10 but more than 1 per 100 patients)
Uncommon side effects (less than 1 per 100 but more than 1 per 1,000 patients)
Some patients have experienced the following side effects after adding sitagliptin to metformin:
Common: nausea
Uncommon: weight loss, loss of appetite, abdominal pain, diarrhoea, low blood sugar, drowsiness.
Some patients have experienced stomach discomfort when starting the combination of sitagliptin and
metformin together.
Some patients have experienced the following side effects while taking TESAVEL in combination
with a sulphonylurea:
Common: low blood sugar
Some patients have experienced the following side effects while taking TESAVEL in combination
with a sulphonylurea and metformin:
Very common: low blood sugar
Common: constipation
Some patients have experienced the following side effects while taking TESAVEL and pioglitazone:
Common: low blood sugar and flatulence. In addition, some patients have reported foot swelling while
taking TESAVEL and pioglitazone. These side effects may be seen with sitagliptin and any glitazone
(e.g., rosiglitazone).
Some patients have experienced the following side effects while taking TESAVEL in combination
with rosiglitazone and metformin:
Common: headache, cough, diarrhoea, vomiting, low blood sugar, fungal skin infection, upper
respiratory infection, swelling of the hands or legs.
Some patients have experienced the following side effects while taking TESAVEL in combination
with insulin (with or without metformin):
Common: headache, low blood sugar and flu
Uncommon: dry mouth, constipation
Some patients have experienced the following side effects while taking TESAVEL alone:
Common: low blood sugar, headache
Uncommon: dizziness, constipation
66
In addition, some patients have reported the following side effects while taking TESAVEL:
Common: upper respiratory infection, stuffy or runny nose and sore throat, osteoarthritis, arm or leg
pain.
During post-approval use of TESAVEL by itself and/or with other diabetes medicines additional side
effects have also been reported (frequency not known): allergic reactions, which may be serious,
including rash, hives, and swelling of the face, lips, tongue, and throat that may cause difficulty in
breathing or swallowing. If you have an allergic reaction, stop taking TESAVEL and call your doctor
right away. Your doctor may prescribe a medicine to treat your allergic reaction and a different
medicine for your diabetes. Other side effects that have been reported include: inflammation of the
pancreas; kidney problems (sometimes requiring dialysis); vomiting.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE TESAVEL
Keep out of the reach and sight of children.
Do not use TESAVEL after the expiry date which is stated on the blister and the carton. The expiry
date refers to the last day of that month.
This medicine does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What TESAVEL contains
-
The active substance is sitagliptin. Each film-coated tablet contains sitagliptin phosphate
monohydrate, equivalent to 50 mg sitagliptin.
-
The other ingredients are: microcrystalline cellulose (E460), calcium hydrogen phosphate,
anhydrous (E341), croscarmellose sodium (E468), magnesium stearate (E470b), and sodium
stearyl fumarate. The tablet film coating contains: polyvinyl alcohol, macrogol 3350, talc
(E553b), titanium dioxide (E171), red iron oxide (E172), and yellow iron oxide (E172).
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 aluminum). Packs of 14, 28, 56, 84 or 98 film-coated tablets and
50 x 1 film-coated tablets in perforated unit dose blisters.
Not all pack sizes may be marketed.
67
Marketing Authorisation Holder and Manufacturer
The
Marketing Authorisation
Holder
is:
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
The
Manufacturer
is:
Merck Sharp & Dohme (Italia) S.p.A.
Via Emilia, 21
27100 - Pavia
Italy
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
Belgique/België/Belgien
Merck Sharp & Dohme B.V.
Succursale belge/Belgisch bijhuis
Tél/Tel: +32 (0) 800 38693
MSDBelgium_info@merck.com
Luxembourg/Luxemburg
Merck Sharp & Dohme B.V.
Succursale belge/Belgisch bijhuis
Tél: +32 (0) 800 38693
MSDBelgium_info@merck.com
България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3740
info-msdbg@merck.com
Magyarország
MSD Magyarország Kft.
Tel.: +36 1 888 53 00
hungary_msd@merck.com
Česká republika
Merck Sharp & Dohme IDEA, Inc., org. sl.
Tel.: +420 233 010 111
msd_cr@merck.com
Malta
Merck Sharp & Dohme Cyprus Limited
Tel: +357 22866700
malta_info@merck.com
Ċipru
Danmark
Merck Sharp & Dohme
Tlf: +45 43 28 77 66
dkmail@merck.com
Nederland
Merck Sharp & Dohme BV
Tel: 0800 99 99 000
medicalinfo.nl@merck.com
Deutschland
MSD SHARP & DOHME GMBH
Tel: +49 (0) 89 4561 2612
Infocenter@msd.de
Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no
Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 613 9750
msdeesti@merck.com
Österreich
Merck Sharp & Dohme G.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com
Eλλάδα
BIANEΞ Α.Ε
Τηλ: +3 0210 80091 11
Mailbox@vianex.gr
Polska
MSD Polska Sp. z o.o.
Tel.: +48 22 549 51 00
msdpolska@merck.com
Portugal
Merck Sharp & Dohme, Lda
Tel: +351 21 4465700
informacao_doente@merck.com
68
France
Laboratoires Merck Sharp & Dohme – Chibret
Tél: +33 (0) 1 47 54 87 00
contact@msd-france.com
România
Merck Sharp & Dohme Romania S.R.L.
Tel: + 4021 529 29 00
msdromania@merck.com
Ireland
Merck Sharp and 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 5204201
msd_slovenia@merck.com
Ísland
Icepharma hf.
Sími: +354 540 8000
ISmail@merck.com
Slovenská republika
Merck Sharp & Dohme IDEA, Inc.
Tel.: +421 2 58282010
msd_sk@merck.com
Ιtalia
Addenda Pharma S.r.l.
Tel.: +39 06 91393303
info@addenda.it
Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0) 9 804650
info@msd.fi
Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ: +357 22866700
cyprus_info@merck.com
Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 (0) 8 626 14 00
medicinskinfo@merck.com
Latvija
SIA “Merck Sharp & Dohme Latvija”
Tel: +371 67364 224
msd_lv@merck.com
United Kingdom
Merck Sharp and Dohme Limited
Tel: +44 (0) 1992 467272
medicalinformationuk@merck.com
Lietuva
UAB “Merck Sharp & Dohme”
Tel.: +370 5 278 02 47
msd_lietuva@merck.com
This leaflet was last approved in
{MM/YYYY}.
Detailed information on this medicine is available on the website of the European Medicines Agency
web site: http://www.ema.europa.eu/.
69
PACKAGE LEAFLET: INFORMATION FOR THE USER
TESAVEL 100 mg film-coated tablets
Sitagliptin
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What TESAVEL is and what it is used for
2.
Before you take TESAVEL
3.
How to take TESAVEL
4.
How to store TESAVEL
6.
Further information
1.
WHAT TESAVEL IS AND WHAT IT IS USED FOR
TESAVEL is a member of a class of medicines you take by mouth called DPP-4 inhibitors (dipeptidyl
peptidase-4 inhibitors) that lowers blood sugar levels in patients with type 2 diabetes mellitus. Type 2
diabetes is also called non-insulin-dependent diabetes mellitus, or NIDDM.
TESAVEL helps to improve the levels of insulin after a meal and decreases the amount of sugar made
by the body. It is unlikely to cause low blood sugar because it does not work when your blood sugar is
low. However, when TESAVEL is used in combination with a sulphonylurea medicine or with insulin,
low blood sugar (hypoglycaemia) can occur.
Your doctor has prescribed TESAVEL to help lower your blood sugar, which is too high because of
your type 2 diabetes. TESAVEL 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.
BEFORE YOU TAKE TESAVEL
Do not take TESAVEL
-
if you are allergic (hypersensitive) to sitagliptin or any of the other ingredients of TESAVEL.
70
5.
Possible side effects
Take special care with TESAVEL
Cases of inflammation of the pancreas (pancreatitis) have been reported in patients receiving
TESAVEL. Pancreatitis can be a serious, potentially life-threatening medical condition. Stop taking
TESAVEL and call your doctor if you experience severe and persistent stomach pain, with or without
vomiting, because you could have pancreatitis.
Tell your doctor if you have or have had:
-
pancreatitis, gallstones, alcoholism or very high triglycerides. These medical conditions can
increase your chance of getting pancreatitis, or getting it again.
-
diabetic ketoacidosis (a complication of diabetes with high blood sugar, rapid weight loss,
nausea or vomiting)
-
any kidney problems, or any past or present medical problems. If you have kidney problems,
TESAVEL may not be the right medicine for you.
-
an allergic reaction to TESAVEL
If you are taking a sulphonylurea or insulin with TESAVEL you may experience low blood sugar.
Your doctor may reduce the dose of your sulphonylurea or insulin medicine.
Taking other medicines
TESAVEL may be taken with most medicines. Tell your doctor or pharmacist about all the medicines
you take or have recently taken. This includes prescription and non-prescription medicines, and herbal
supplements.
Taking TESAVEL with food and drink
You can take TESAVEL with or without food and drink.
Pregnancy and breast-feeding
Women who are pregnant or plan to become pregnant should consult their doctor before taking
TESAVEL. You should not use TESAVEL during pregnancy.
It is not known if TESAVEL passes into breast milk. You should not use TESAVEL if you are breast-
feeding or plan to breast-feed.
Driving and using machines
TESAVEL has no known influence on the ability to drive and use machines. However, when driving
or operating machinery, it should be taken into account that dizziness and drowsiness have been
reported.
Taking TESAVEL in combination with medicines called sulphonylureas or with insulin can cause
hypoglycaemia, which may affect your ability to drive and use machines or work without safe
foothold.
3.
HOW TO TAKE TESAVEL
Always take TESAVEL exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
The usual dose is:
−
one 100 mg film-coated tablet
−
once a day
−
by mouth
Your doctor may prescribe TESAVEL alone or with certain other medicines that lower blood sugar.
71
-
type 1 diabetes
Continue to take TESAVEL as long as your doctor prescribes it so you can continue to help control
your blood sugar.
Diet and exercise can help your body use its blood sugar better. It is important to stay on the diet,
exercise and weight loss program recommended by your doctor while taking TESAVEL.
If you take more TESAVEL than you should
If you take more than the prescribed dosage of TESAVEL, 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
TESAVEL.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, TESAVEL may cause side effects, although not everybody gets them.
Very common side effects (more than 1 per 10 patients)
Common side effects (less than 1 per 10 but more than 1 per 100 patients)
Uncommon side effects (less than 1 per 100 but more than 1 per 1,000 patients)
Some patients have experienced the following side effects after adding sitagliptin to metformin:
Common: nausea
Uncommon: weight loss, loss of appetite, abdominal pain, diarrhoea, low blood sugar, drowsiness.
Some patients have experienced stomach discomfort when starting the combination of sitagliptin and
metformin together.
Some patients have experienced the following side effects while taking TESAVEL in combination
with a sulphonylurea:
Common: low blood suga
Some patients have experienced the following side effects while taking TESAVEL in combination
with a sulphonylurea and metformin:
Very common: low blood sugar
Common: constipation
Some patients have experienced the following side effects while taking TESAVEL and pioglitazone:
Common: low blood sugar and flatulence. In addition, some patients have reported foot swelling while
taking TESAVEL and pioglitazone. These side effects may be seen with sitagliptin and any glitazone
(e.g., rosiglitazone).
Some patients have experienced the following side effects while taking TESAVEL in combination
with rosiglitazone and metformin:
Common: headache, cough, diarrhoea, vomiting, low blood sugar, fungal skin infection, upper
respiratory infection, swelling of the hands or legs.
Some patients have experienced the following side effects while taking TESAVEL in combination
with insulin (with or without metformin):
Common: headache, low blood sugar and flu
Uncommon: dry mouth, constipation
Some patients have experienced the following side effects while taking TESAVEL alone:
Common: low blood sugar, headache
Uncommon: dizziness, constipation
72
In addition, some patients have reported the following side effects while taking TESAVEL:
Common: upper respiratory infection, stuffy or runny nose and sore throat, osteoarthritis, arm or leg
pain.
During post-approval use of TESAVEL by itself and/or with other diabetes medicines additional side
effects have also been reported (frequency not known): allergic reactions, which may be serious,
including rash, hives, and swelling of the face, lips, tongue, and throat that may cause difficulty in
breathing or swallowing. If you have an allergic reaction, stop taking TESAVEL and call your doctor
right away. Your doctor may prescribe a medicine to treat your allergic reaction and a different
medicine for your diabetes. Other side effects that have been reported include: inflammation of the
pancreas; kidney problems (sometimes requiring dialysis); vomiting.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE TESAVEL
Keep out of the reach and sight of children.
Do not use TESAVEL after the expiry date which is stated on the blister and the carton. The expiry
date refers to the last day of that month.
This medicine does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What TESAVEL contains
-
The active substance is sitagliptin. Each film-coated tablet contains sitagliptin phosphate
monohydrate, equivalent to 100 mg sitagliptin.
-
The other ingredients are: microcrystalline cellulose (E460), calcium hydrogen phosphate,
anhydrous (E341), croscarmellose sodium (E468), magnesium stearate (E470b), and sodium
stearyl fumarate. The tablet film coating contains: polyvinyl alcohol, macrogol 3350, talc
(E553b), titanium dioxide (E171), red iron oxide (E172), and yellow iron oxide (E172).
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 aluminum). Packs of 14, 28, 56, 84 or 98 film-coated tablets and
50 x 1 film-coated tablets in perforated unit dose blisters.
Not all pack sizes may be marketed.
73
Marketing Authorisation Holder and Manufacturer
The
Marketing Authorisation
Holder
is:
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
The
Manufacturer
is:
Merck Sharp & Dohme (Italia) S.p.A.
Via Emilia, 21
27100 - Pavia
Italy
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
Belgique/België/Belgien
Merck Sharp & Dohme B.V.
Succursale belge/Belgisch bijhuis
Tél/Tel: +32 (0) 800 38693
MSDBelgium_info@merck.com
Luxembourg/Luxemburg
Merck Sharp & Dohme B.V.
Succursale belge/Belgisch bijhuis
Tél: +32 (0) 800 38693
MSDBelgium_info@merck.com
България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3740
info-msdbg@merck.com
Magyarország
MSD Magyarország Kft.
Tel.: +36 1 888 53 00
hungary_msd@merck.com
Česká republika
Merck Sharp & Dohme IDEA, Inc., org. sl.
Tel.: +420 233 010 111
msd_cr@merck.com
Malta
Merck Sharp & Dohme Cyprus Limited
Tel: +357 22866700
malta_info@merck.com
Ċipru
Danmark
Merck Sharp & Dohme
Tlf: +45 43 28 77 66
dkmail@merck.com
Nederland
Merck Sharp & Dohme BV
Tel: 0800 99 99 000
medicalinfo.nl@merck.com
Deutschland
MSD SHARP & DOHME GMBH
Tel: +49 (0) 89 4561 2612
Infocenter@msd.de
Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no
Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 613 9750
msdeesti@merck.com
Österreich
Merck Sharp & Dohme G.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com
Eλλάδα
BIANEΞ Α.Ε
Τηλ: +3 0210 80091 11
Mailbox@vianex.gr
Polska
MSD Polska Sp. z o.o.
Tel.: +48 22 549 51 00
msdpolska@merck.com
Portugal
Merck Sharp & Dohme, Lda
Tel: +351 21 4465700
informacao_doente@merck.com
74
France
Laboratoires Merck Sharp & Dohme – Chibret
Tél: +33 (0) 1 47 54 87 00
contact@msd-france.com
România
Merck Sharp & Dohme Romania S.R.L.
Tel: + 4021 529 29 00
msdromania@merck.com
Ireland
Merck Sharp and 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 5204201
msd_slovenia@merck.com
Ísland
Icepharma hf.
Sími: +354 540 8000
ISmail@merck.com
Slovenská republika
Merck Sharp & Dohme IDEA, Inc.
Tel.: +421 2 58282010
msd_sk@merck.com
Ιtalia
Addenda Pharma S.r.l.
Tel.: +39 06 91393303
info@addenda.it
Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0) 9 804650
info@msd.fi
Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ: +357 22866700
cyprus_info@merck.com
Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 (0) 8 626 14 00
medicinskinfo@merck.com
Latvija
SIA “Merck Sharp & Dohme Latvija”
Tel: +371 67364 224
msd_lv@merck.com
United Kingdom
Merck Sharp and Dohme Limited
Tel: +44 (0) 1992 467272
medicalinformationuk@merck.com
Lietuva
UAB “Merck Sharp & Dohme”
Tel.: +370 5 278 02 47
msd_lietuva@merck.com
This leaflet was last approved in
{MM/YYYY}.
Detailed information on this medicine is available on the website of the European Medicines Agency
web site: http://www.ema.europa.eu/.
75
Source: European Medicines Agency
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