natgillin/translations-raw huggingface dataset:
10, 1%
Adverse Reaction
.
Frequency of adverse reaction by treatment regimen
(> 0, 2%
Sitagliptin with
11. 3%
Metformin
18. 1%
a Sulfonylurea
7. 1%
Metformin and a a PPARγ Agent Sulfonylurea3 (pioglitazone)4
.
Metabolism and nutrition disorders
100 mg
hypoglycaemia*
100 mg
Very common
(> 0, 2%
Very common Common
> 1
Nervous system disorders somnolence
TESAVEL,
Uncommon
TESAVEL (
Gastrointestinal disorders
,
diarrhea nausea flatulence constipation upper abdominal pain
,
Uncommon Common Uncommon
> 0. 5%
Common
TESAVEL
Common
50 mg / 1000 mg),
General disorders peripheral oedema
14. 0% "
Common
9. 7%
Investigations blood glucose decreased *
(14. 0%
Uncommon
.
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.
,
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.
(6. 7%) $
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.
$
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.
$,
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.
200
Across clinical studies, a small increase in white blood cell count (approximately 200 cells/ microl difference in WBC vs. placebo; mean baseline WBC approximately 6600 cells/ microl) was observed due to an increase in neutrophils.
TESAVEL.
This observation was seen in most but not all studies.
Stevens- Johnson (4. 4).
No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed with TESAVEL treatment.
4. 9 $% $'! $&
6 Post-marketing Experience:
QTc,
4.9 Overdose
800 mg
During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were generally well tolerated.
800 mg.
Minimal increases in QTc, not considered to be clinically relevant, were observed in one study at a dose of 800 mg sitagliptin.
.)
In the event of an overdose, it is reasonable to employ the usual supportive measures, e. g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required.
!
It is not known if sitagliptin is dialyzable by peritoneal dialysis.
..
5.
DPP- 4,
DPP-4 Inhibitor, ATC code:
DPP- 4
TESAVEL is a member of a class of oral anti-hyperglycaemic agents called dipeptidyl peptidase 4 (DPP-4) inhibitors.
"
7 Overall, sitagliptin improved glycaemic control when given as monotherapy, when used in combination with metformin (initial or add-on therapy), in combination with a sulphonylurea (with or without metformin), and in combination with a thiazolidinedione, as measured by clinically relevant reductions in HbA1c from baseline at study endpoint (see Table 2).
"$
Body weight did not increase from baseline with sitagliptin therapy in either study, compared to a small reduction in patients given placebo.
2,
The number of patients with moderate to severe renal insufficiency was too low to confirm safe use of sitagliptin in this type of patients.
#
In these studies there was a similar incidence of hypoglycaemia reported for patients treated with sitagliptin or placebo.
$
Patients treated with sitagliptin had a modest increase in body weight compared to those given placebo.
. 3
The incidence of hypoglycaemia was similar across treatment groups.
2
Table 2.
DPP- 4,
Placebo-corrected mean
$# # $
Mean
GLP- 1
Mean change from
A1c (HbA1c),
change in HbA1c (%) at
DPP- 9
Study
(add- on
baseline HbA1c (%)
HbA1c
baseline HbA1c (%) † at Week 24
) # TESAVEL
Week 24† (95% CI)
100 mg
Monotherapy Studies Sitagliptin 100 mg once daily§
! < 50 ml/ min),
8.0
HbA1c
-0.5
5
-0.6‡
100
(N= 193) Sitagliptin 100 mg once daily (N= 229) Combination Therapy Studies Sitagliptin 100 mg once daily added to
50 mg)
8.0
& ').
-0.6
HbA1c (%) *
(-0.8, -0.4) -0.8‡ (-1.0, -0.6) -0.7‡
+ HbA1c (%) +
ongoing metformin therapy (N=453)
&
8.0
. $2 $
-0.7
HbA1c (%)
(-0.8, -0.5)
- 0. 6 ‡ (- 0. 8, - 0. 4)
Placebo-corrected mean
# (2 +.
Mean
, -. $+.% + & '* &
Mean change from
HbA1c (%) *
change in HbA1c (%) at
+ HbA1c (%) +
Study
(N= 193)
baseline HbA1c (%)
7 $. - 24 † (95% CI)
Week 24† (95% CI)
100 mg
Sitagliptin 100 mg once daily added to -0.7‡ ongoing pioglitazone therapy (N=163) Sitagliptin 100 mg once daily added to
8. 4
8.1
- 0. 3
-0.9
8. 3
8.4
- 0. 6
-0.3
(- 1. 1, - 0. 7)
(-0.8, -0.3)
(N=115) +
ongoing glimepiride + metformin therapy (N=115) Initial therapy (twice daily):
)
8.3
- 1. 6 ‡
-0.6
(- 1. 8, - 1. 3)
-0.9‡ (-1.1, -0.7) -1.6‡
500 mg (N=183) + () - 2. 1 ‡!
Sitagliptin 50 mg + metformin 500 mg (N=183) Initial therapy (twice daily):
- 1. 9
-1.4
(- 2. 3, - 1. 8)
(-1.8, -1.3)
1000 mg (N=178) * / † Least squares ‡
Sitagliptin 50 mg + metformin 1000 mg (N=178)
p < 0. 001 §
-1.9
18
* All Patients Treated Population (an intention-to-treat analysis). † Least squares means adjusted for prior antihyperglycaemic therapy status and baseline value. ‡ p < 0.001 compared to placebo or placebo + combination treatment. § HbA1c (%) at week 18.
TESAVEL 100 mg
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 HbA1c.
(32. 0%).
5.2 Pharmacokinetic properties
(4. 9%)
Absorption Following oral administration of a 100-mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours post-dose, mean plasma AUC of sitagliptin was 8.52 μ M• hr, Cmax was 950 nM.
8. 52 M. hr, 87%.
The absolute bioavailability of sitagliptin is approximately 87%.
Cmax
Dose-proportionality was not established for Cmax and C24hr (Cmax increased in a greater than dose-proportional manner and C24hr increased in a less than dose-proportional manner).
3
9 Metabolism Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway.
CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 2B6, CYP3A4
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.
100%
Elimination Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in faeces (13%) or urine (87%) within one week of dosing.
. 5 100- mg
Sitagliptin accumulates only minimally with multiple doses.
%
However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.
In vitro,
Sitagliptin is not a substrate for OCT2 or OAT1 or PEPT1/ 2 transporters.
250 3)
In vitro, sitagliptin did not inhibit OAT3 (IC50=160 μ M) or p-glycoprotein (up to 250 μ M) mediated transport at therapeutically relevant plasma concentrations.
OAT3 $
Characteristics in patients The pharmacokinetics of sitagliptin were generally similar in healthy subjects and in patients with type 2 diabetes.
(IC50=160
The study included patients with renal insufficiency 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.
3).!
An approximately 2-fold increase in the plasma AUC of sitagliptin was observed in patients with moderate renal insufficiency, and an approximately 4-fold increase was observed in patients with severe renal insufficiency and in patients with ESRD on hemodialysis, as compared to normal healthy control subjects.
4 -
Sitagliptin was modestly removed by hemodialysis (13.5% over a 3- to 4-hour hemodialysis session starting 4 hours postdose).
(4. 2).
(See section 4.2.)
() TESAVEL (Child- Pugh score ≤ 9).)
Hepatic insufficiency No dosage adjustment for TESAVEL is necessary for patients with mild or moderate hepatic insufficiency (Child-Pugh score ≤ 9).
(Child- Pugh score > 9). /,.
There is no clinical experience in patients with severe hepatic insufficiency (Child-Pugh score > 9).
19% '
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.
;
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.
’
Sitagliptin was not carcinogenic in mice.
'
No adverse effects upon fertility were observed in male and female rats given sitagliptin prior to and throughout mating.
14
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.
6. 1 - $' $
6.1 List of excipients
,
11 calcium hydrogen phosphate, anhydrous (E341) croscarmellose sodium (E468) magnesium stearate (E470b) sodium stearyl fumarate
(E171) (E172) (E172)
6.2 Incompatibilities
(+ 7
Not applicable.
- +, 0 "$& +
6.3 Shelf life
6. 5 0+
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
(PVC/ PE/ PVDC
Opaque blisters (PVC/ PE/ PVDC and aluminum).
14, 28, 56, 84
Not all pack sizes may be marketed.
98 '
6.6 Special precautions for disposal
3
Any unused product or waste material should be disposed of in accordance with local requirements.
8+
7.
Hertford Road, Hoddesdon Hertfordshire EN11 9BU% (
Hertford Road, Hoddesdon Hertfordshire EN11 9BU United Kingdom
() # EU/ 1/ 07/ 435/ 001 EU/ 1/ 07/ 435/ 002EU/ 1/ 07/ 435/ 003 EU/ 1/ 07/ 435/ 004 EU/ 1/ 07/ 435/ 005 EU/ 1/ 07/ 435/ 006
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
:
12 9.
10;
DATE OF FIRST AUTHORISATION/ RENEWAL OF THE AUTHORISATION
2008
10 January 2008
,
Each tablet contains sitagliptin phosphate monohydrate, equivalent to 50 mg sitagliptin.
50 mg
For a full list of excipients, see section 6.1.
# “ 112 ”
Round, light beige film-coated tablet with “ 112” on one side.
($) *% $'+ +
4.2 Posology and method of administration
% TESAVEL
14 Patients with renal insufficiency For patients with mild renal insufficiency (creatinine clearance [CrCl] ≥ 50 ml/ min), no dosage adjustment for TESAVEL is required.
TESAVEL
4.4 Special warnings and precautions for use
,
Therefore, to reduce the risk of hypoglycaemia, a lower dose of sulphonylurea may be considered (see section 4.2).
Stevens- Johnson.%
The use of sitagliptin in combination with insulin has not been adequately studied.
$
Renal insufficiency As the experience is limited, patients with moderate to severe renal insufficiency should not be treated with TESAVEL (see section 5.2).
$
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).
3
4.5 Interaction with other medicinal products and other forms of interaction
$
Effects of other medicinal products on sitagliptin Clinical data described below suggest that the risk for clinically meaningful interactions by co- administered medicinal products is low.
TESAVEL,
15 Metformin:
3 (OAT3).%
Cyclosporine:
OAT3
The effects of potent CYP3A4 inhibitors in the setting of renal insufficiency has not been assessed in a clinical study.
#
OAT3 mediated transport of sitagliptin was inhibited in vitro by probenecid, although the risk of clinically meaningful interactions is considered to be low.
vitro in vivo.
Concomitant administration of OAT3 inhibitors has not been evaluated in vivo.
,. *
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).
OAT3
Sitagliptin had a small effect on plasma digoxin concentrations, and may be a mild inhibitor of p- glycoprotein in vivo.
vitro
Digoxin:
CYP450.
No dosage adjustment of digoxin is recommended.
CYP3A4, CYP2C8, CYP2C9
4.6 Pregnancy and lactation
TESAVEL
Pregnancy There are no adequate data from the use of TESAVEL in pregnant women.
TESAVEL '. 7
The potential risk for humans is unknown.
TESAVEL
Due to lack of human data, TESAVEL should not be used during pregnancy.
.
Animal studies have shown excretion of sitagliptin in breast milk.
. * TESAVEL
TESAVEL should not be used during breast-feeding.
-%
However, when driving or operating machines, it should be taken into account that dizziness and somnolence have been reported.
9 TESAVEL
16 4.8 Undesirable effects
100 mg)
In 9 large clinical trials of up to 2 years in duration, over 2700 patients have received treatment with TESAVEL 100 mg per day alone or in combination with metformin, a sulphonylurea (with or without metformin) or a PPARγ agent.
30, 3%
Sitagliptin with
100 mg
Metformin
(> 0, 2%
a Sulfonylurea
> 1
Metformin and a a PPARγ Agent Sulfonylurea3 (pioglitazone)4
)
Metabolism and nutrition disorders
100 mg $
hypoglycaemia*
)
17 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.
4. 9 $% $'! $&
18 Post-marketing Experience:
A1c (HbA1c),
With higher insulin levels, tissue glucose uptake is enhanced.
, ",
19 Overall, sitagliptin improved glycaemic control when given as monotherapy, when used in combination with metformin (initial or add-on therapy), in combination with a sulphonylurea (with or without metformin), and in combination with a thiazolidinedione, as measured by clinically relevant reductions in HbA1c from baseline at study endpoint (see Table 2).
$
Body weight did not increase from baseline with sitagliptin therapy in either study, compared to a small reduction in patients given placebo.
". 5
The number of patients with moderate to severe renal insufficiency was too low to confirm safe use of sitagliptin in this type of patients.
"#
In these studies there was a similar incidence of hypoglycaemia reported for patients treated with sitagliptin or placebo.
100 mg
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 incidence of hypoglycaemia was similar across treatment groups.
HbA1c
Table 2.
"
Placebo-corrected mean
(FPG)
Mean
(2- $
Mean change from
PPG),
change in HbA1c (%) at
. /
Study
$(surrogate
baseline
markers) Model Assessment -),.%
baseline HbA1c (%)
TESAVEL
Week 24†
! < 50 ml/ min),
Monotherapy Studies
5
at Week 24†
%
(95% CI)
100
Sitagliptin 100 mg once daily§ (N= 193) Sitagliptin 100 mg once daily (N= 229) Combination Therapy Studies Sitagliptin 100 mg once daily added to
24
8.0 8.0
# (100 mg
-0.5 -0.6
)
-0.6‡ (-0.8, -0.4) -0.8‡ (-1.0, -0.6) -0.7‡
24 - 1000 mg
ongoing metformin therapy (N=453)
.%
-0.7
(500 mg
(-0.8, -0.5)
2:
20
HbA1c $&%.% + 2.! *
Placebo-corrected mean
& ').
Mean
HbA1c (%)
Study
+ 7 $. - 24 †
baseline
7 $. - 24 † (95% CI)
baseline HbA1c (%)
100 mg §
Week 24†
100 mg
Sitagliptin 100 mg once daily added to
(- 1. 0, - 0. 6) (N= 229)
HbA1c (%)
(- 0. 8, - 0. 5)
at Week 24†
(N=453)
(95% CI) -0.7‡
(- 0. 9, - 0. 5)
(-0.9, -0.5) -0.6‡
(- 0. 8, - 0. 3)
(-0.8, -0.3)
(N=102)
ongoing glimepiride + metformin therapy (N=115) Initial therapy (twice daily):
(- 1. 1, - 0. 7)
-0.9‡ (-1.1, -0.7) -1.6‡
(N=183) +
Sitagliptin 50 mg + metformin 500 mg (N=183) Initial therapy (twice daily):
(- 1. 8, - 1. 3)
(-1.8, -1.3)
(N=178)
Sitagliptin 50 mg + metformin 1000 mg (N=178)
24 † Least squares ‡ §
* All Patients Treated Population (an intention-to-treat analysis). † Least squares means adjusted for prior antihyperglycaemic therapy status and baseline value. ‡ p < 0.001 compared to placebo or placebo + combination treatment. § HbA1c (%) at week 18.
3
21 Metabolism Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway.
79
Approximately 79% of sitagliptin is excreted unchanged in the urine.
) TESAVEL (Child- Pugh score ≤ 9).)
Hepatic insufficiency No dosage adjustment for TESAVEL is necessary for patients with mild or moderate hepatic insufficiency (Child-Pugh score ≤ 9).
19
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.
58
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
,
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.
23
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.
'
Sitagliptin was not carcinogenic in mice.
#
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.
,
23 calcium hydrogen phosphate, anhydrous (E341) croscarmellose sodium (E468) magnesium stearate (E470b) sodium stearyl fumarate
) #
8.
EU/ 1/ 07/ 435/ 007
MARKETING AUTHORISATION NUMBER(S)
EU/ 1/ 07/ 435/ 008EU/ 1/ 07/ 435/ 009 EU/ 1/ 07/ 435/ 010 EU/ 1/ 07/ 435/ 011 EU/ 1/ 07/ 435/ 012
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
:
24 9.
# “ 277 ”
Round, beige film-coated tablet with “ 277” on one side.
% TESAVEL
26 Patients with renal insufficiency For patients with mild renal insufficiency (creatinine clearance [CrCl] ≥ 50 ml/ min), no dosage adjustment for TESAVEL is required.
TESAVEL,
27 Metformin:
9 TESAVEL
28 4.8 Undesirable effects
4. 9 $% $'! $&
30 Post-marketing Experience:
, ",
31 Overall, sitagliptin improved glycaemic control when given as monotherapy, when used in combination with metformin (initial or add-on therapy), in combination with a sulphonylurea (with or without metformin), and in combination with a thiazolidinedione, as measured by clinically relevant reductions in HbA1c from baseline at study endpoint (see Table 2).
2:
32
(- 1. 0, - 0. 6)
HbA1c (%)
38 * / † Least squares ‡
* All Patients Treated Population (an intention-to-treat analysis). † Least squares means adjusted for prior antihyperglycaemic therapy status and baseline value. ‡ p < 0.001 compared to placebo or placebo + combination treatment. § HbA1c (%) at week 18.
3
33 Metabolism Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway.
,
35 calcium hydrogen phosphate, anhydrous (E341) croscarmellose sodium (E468) magnesium stearate (E470b) sodium stearyl fumarate
EU/ 1/ 07/ 435/ 013
MARKETING AUTHORISATION NUMBER(S)
EU/ 1/ 07/ 435/ 014EU/ 1/ 07/ 435/ 015 EU/ 1/ 07/ 435/ 016 EU/ 1/ 07/ 435/ 017 EU/ 1/ 07/ 435/ 018
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
:
36 9.
43.
37 ANNEX II
) (
A.
) 5
B.
5 5
38 A.
,
Name and address of the manufacturer responsible for batch release
Via Emilia 21 IT- 27100 Pavia;
Via Emilia 21 IT-27100 Pavia Italy
0 +
B.
%.
• CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON THE MARKETING AUTHORISATION HOLDER
Module 1. 8. 1.
Medicinal product subject to medical prescription.
+ +
• CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
+ CHMP.
Not applicable.
$
Risk Management Plan The MAH commits to performing the studies and additional pharmacovigilance activities detailed in the Pharmacovigilance Plan, as agreed in version 1.1 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, the updated RMP should be submitted at the same time as the next 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 EMEA
• 3 +.
39 ANNEX III
45
LABELLING AND PACKAGE LEAFLET
# 5
40 A.
46.
LABELLING
47
41 PARTICULARS TO APPEAR ON THE OUTER PACKAGING
($! $TESAVEL 25 mg
Outer carton for TESAVEL 25 mg film-coated tablets
TESAVEL 25 mg!
TESAVEL 25 mg film-coated tablets Sitagliptin
55;
7.
7% <% {MM/ XXXX}
EXPIRY DATE
48 10.
42 10.
Merck Sharp & Dohme
NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Ltd.
Merck Sharp & Dohme Ltd.
EU/ 1/ 07/ 435/ 001
MARKETING AUTHORISATION NUMBER(S)
EU/ 1/ 07/ 435/ 002EU/ 1/ 07/ 435/ 003 EU/ 1/ 07/ 435/ 004 EU/ 1/ 07/ 435/ 005 EU/ 1/ 07/ 435/ 006
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
5
Batch
9
Medicinal product subject to medical prescription.
.
15.
49
43 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
8 & $TESAVEL 25 mg
Blister for TESAVEL 25 mg film-coated tablets
%!
1.
TESAVEL 25 mg!
TESAVEL 25 mg tablets Sitagliptin
7% <% {33 /::::}
EXPIRY DATE
4. #
EXP
/
4.
5.
Batch
50
5.
#:
OTHER
5
44 PARTICULARS TO APPEAR ON THE OUTER PACKAGING
($! $TESAVEL 50 mg
Outer carton for TESAVEL 50 mg film-coated tablets
TESAVEL 50 mg!
TESAVEL 50 mg film-coated tablets Sitagliptin
#
Each tablet contains sitagliptin phosphate monohydrate equivalent to 50 mg of sitagliptin.
51 9.
EXP
52
46 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
8 & $TESAVEL 50 mg
Blister for TESAVEL 50 mg film-coated tablets
TESAVEL 50 mg!
TESAVEL 50 mg tablets Sitagliptin
5
47 PARTICULARS TO APPEAR ON THE OUTER PACKAGING
($! $TESAVEL 100 mg
Outer carton for TESAVEL 100 mg film-coated tablets
TESAVEL 100 mg!
TESAVEL 100 mg film-coated tablets Sitagliptin
54 9.
EXP