ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Onglyza 2.5 mg film-coated tablets
2.
Each tablet contains 2.5 mg saxagliptin (as hydrochloride).
Excipients
Each tablet contains 99 mg lactose monohydrate.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet (tablet).
Onglyza 2.5 mg tablets are pale yellow to light yellow, biconvex, round, film-coated tablets, with
“2.5” printed on one side and “4214” printed on the other side, in blue ink.
4.
Add-on combination therapy
Onglyza is indicated in adult patients aged 18 years and older with type 2 diabetes mellitus to improve
glycaemic control:
• in combination with metformin, when metformin alone, with diet and exercise, does not provide
adequate glycaemic control;
• in combination with a sulphonylurea, when the sulphonylurea alone, with diet and exercise,
does not provide adequate glycaemic control in patients for whom use of metformin is
considered inappropriate.
• in combination with a thiazolidinedione, when the thiazolidinedione alone with diet and
exercise, does not provide adequate glycaemic control in patients for whom use of a
thiazolidinedione is considered appropriate.
Posology
Add-on combination therapy
The recommended dose of Onglyza is 5 mg once daily as add-on combination therapy with metformin,
a thiazolidinedione or a sulphonylurea.
The safety and efficacy of saxagliptin as triple oral therapy in combination with metformin and a
thiazolidinedione, or with metformin and a sulphonylurea, has not been established.
Special populations
Elderly (≥ 65 years)
No dose adjustment is recommended based solely on age. Experience in patients aged 75 years and
older is very limited and caution should be exercised when treating this population (see also
sections 4.4, 5.1 and 5.2).
2
Renal impairment
No dose adjustment is recommended for patients with mild renal impairment.
The dose of Onglyza should be reduced to 2.5 mg once daily in patients with moderate or severe renal
impairment.
The experience in patients with severe renal impairment is very limited. Therefore, saxagliptin should
be used with caution in this population. Onglyza is not recommended for patients with end-stage renal
disease (ESRD) requiring haemodialysis (see section 4.4).
Because the dose of Onglyza should be limited to 2.5 mg based upon renal function, assessment of
renal function is recommended prior to initiation of Onglyza, and, in keeping with routine care, renal
assessment should be done periodically thereafter (see sections 4.4 and 5.2).
Hepatic impairment
No dose adjustment is necessary for patients with mild or moderate hepatic impairment (see
section 5.2). Saxagliptin should be used with caution in patients with moderate hepatic impairment,
and is not recommended for use in patients with severe hepatic impairment (see section 4.4).
Paediatric population
The safety and efficacy of Onglyza in children aged birth to < 18 years have not yet been established.
No data are available.
Method of administration
Onglyza can be taken with or without a meal at any time of the day. If a dose is missed, it should be
taken as soon as the patient remembers. A double dose should not be taken on the same day.
Hypersensitivity to the active substance or to any of the excipients.
General
Onglyza should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic
ketoacidosis.
Renal impairment
A single dosage adjustment is recommended in patients with moderate or severe renal impairment.
Saxagliptin should be used with caution in patients with severe renal impairment, and is not
recommended for use in patients with end-stage renal disease (ESRD) requiring haemodialysis.
Assessment of renal function is recommended prior to initiation of Onglyza, and in keeping with
routine care, renal assessment should be done periodically thereafter (see sections 4.2 and 5.2).
Hepatic impairment
Saxagliptin should be used with caution in patients with moderate hepatic impairment, and is not
recommended for use in patients with severe hepatic impairment (see section 4.2).
Use with sulphonylureas
Sulphonylureas are known to cause hypoglycaemia. Therefore, a lower dose of sulphonylurea may be
required to reduce the risk of hypoglycaemia when used in combination with Onglyza.
Hypersensitivity reactions
Onglyza should not be used in patients who have had any serious hypersensitivity reaction to a
dipeptidyl peptidase 4 (DPP4) inhibitor.
3
Elderly patients
Experience in patients aged 75 years and older is very limited and caution should be exercised when
treating this population (see sections 5.1 and 5.2).
Skin disorders
Ulcerative and necrotic skin lesions have been reported in extremities of monkeys in non-clinical
toxicology studies (see section 5.3). Although skin lesions were not observed at an increased incidence
in clinical trials, there is limited experience in patients with diabetic skin complications. Postmarketing
reports of rash have been described in the DPP4 inhibitor class. Rash is also noted as an adverse event
(AE) for Onglyza (see section 4.8). Therefore, in keeping with routine care of the diabetic patient,
monitoring for skin disorders, such as blistering, ulceration or rash, is recommended.
Cardiac failure
Experience in NYHA class I-II is limited, and there is no experience in clinical studies with
saxagliptin in NYHA class III-IV.
Immunocompromised patients
Immunocompromised patients, such as patients who have undergone organ transplantation or patients
diagnosed with human immunodeficiency syndrome, have not been studied in the Onglyza clinical
program. Therefore, the efficacy and safety profile of saxagliptin in these patients has not been
established.
Use with potent CYP 3A4 inducers
Using CYP3A4 inducers like carbamazepine, dexamethasone, phenobarbital, phenytoin, and
rifampicin may reduce the glycaemic lowering effect of Onglyza (see section 4.5).
Lactose
The tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this
medicinal product.
Clinical data described below suggest that the risk for clinically meaningful interactions with
co-administered medicinal products is low.
The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). In
in
vitro
studies, saxagliptin and its major metabolite neither inhibited CYP1A2, 2A6, 2B6, 2C9, 2C19,
2D6, 2E1, or 3A4, nor induced CYP1A2, 2B6, 2C9, or 3A4. In studies conducted in healthy subjects,
neither the pharmacokinetics of saxagliptin and its major metabolite, were meaningfully altered by
metformin, glibenclamide, pioglitazone, digoxin, simvastatin, omeprazole, antacids or famotidine. In
addition, saxagliptin did not meaningfully alter the pharmacokinetics of metformin, glibenclamide,
pioglitazone, digoxin, simvastatin, diltiazem or ketoconazole.
Concomitant administration of saxagliptin with the moderate inhibitor of CYP3A4/5 diltiazem,
increased the C
max
and AUC of saxagliptin by 63% and 2.1-fold, respectively, and the corresponding
values for the active metabolite were decreased by 44 and 34%, respectively.
Concomitant administration of saxagliptin with the potent inhibitor of CYP3A4/5 ketoconazole,
increased the C
max
and AUC of saxagliptin by 62% and 2.5-fold, respectively, and the corresponding
values for the active metabolite were decreased by 95% and 88%, respectively.
Concomitant administration of saxagliptin with the potent CYP3A4/5 inducer rifampicin, reduced C
max
and AUC of saxagliptin by 53% and 76%, respectively. The exposure of the active metabolite and the
plasma DPP4 activity inhibition over a dose interval were not influenced by rifampicin (see
section 4.4).
4
The co-administration of saxagliptin and CYP3A4/5 inducers, other than rifampicin (such as
carbamazepine, dexamethasone, phenobarbital and phenytoin) have not been studied and may result in
decreased plasma concentration of saxagliptin and increased concentration of its major metabolite.
Glycaemic control should be carefully assessed when saxagliptin is used concomitantly with a potent
CYP3A4 inducer.
The effects of smoking, diet, herbal products, and alcohol use on the pharmacokinetics of saxagliptin
have not been specifically studied.
Pregnancy
The use of saxagliptin has not been studied in pregnant women. Studies in animals have shown
reproductive toxicity at high doses (see section 5.3). The potential risk for humans is unknown.
Onglyza should not be used during pregnancy unless clearly necessary.
Breastfeeding
It is unknown whether saxagliptin is excreted in human breast milk. Animal studies have shown
excretion of saxagliptin and/or metabolite in milk. A risk to the suckling child cannot be excluded. A
decision must be made whether to discontinue breast-feeding or to discontinue therapy taking into
account the benefit of breast-feeding for the child and the benefit of therapy to the woman.
Fertility
The effect of saxagliptin on fertility in humans has not been studied. Effects on fertility were observed
in male and female rats at high doses producing overt signs of toxicity (see section 5.3).
Onglyza may have a negligible influence on the ability to drive and use machines.
No studies on the effects on the ability to drive and use machines have been performed. However,
when driving or using machines, it should be taken into account that dizziness has been reported in
studies with saxagliptin.
Summary of the safety profile
There were 4,148 patients with type 2 diabetes, including 3,021 patients treated with Onglyza,
randomised in six double-blind, controlled clinical safety and efficacy studies conducted to evaluate
the effects of saxagliptin on glycaemic control.
In a pooled analysis, the overall incidence of adverse events in patients treated with saxagliptin 5 mg
was similar to placebo. Discontinuation of therapy due to adverse events was higher in patients who
received saxagliptin 5 mg as compared to placebo (3.3% as compared to 1.8%).
Tabulated list of adverse reactions
Adverse reactions reported in ≥ 5% of patients treated with saxagliptin 5 mg and more commonly than
in patients treated with placebo or that were reported in ≥ 2% of patients treated with saxagliptin 5 mg
and ≥ 1% more frequently compared to placebo are shown in Table 1.
The adverse reactions are listed by system organ class and absolute 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), or Very rare (< 1/10,000), not known (cannot be estimated from the available
data).
5
Table 1
Frequency of adverse reactions by system organ class
System organ class
Adverse Reaction
Frequency of adverse reactions by treatment regimen
Saxagliptin
monotherapy
Saxagliptin
with
metformin
1
Saxagliptin
with a
sulphonylurea
(glibenclamide)
Saxagliptin with a
thiazolidinedione
Infections and
infestations
Upper respiratory
infection
Common
Common
Common
Common
Urinary tract
infection
Common
Common
Common
Common
Gastroenteritis
Common
Common
Common
Common
Sinusitis
Common
Common
Common
Common
Nasopharyngitis
Common
2
Metabolism and
nutrition disorders
Hypoglycaemia
Very common
3
Nervous system
disorders
Headache
Common
Common
Common
Common
Gastrointestinal
disorders
Vomiting
Common
Common
Common
Common
General disorders
and
administration site
conditions
Oedema peripheral
Common
4
1
Includes saxagliptin in add-on to metformin and initial combination with metformin.
2
Only in the initial combination therapy.
3
There was no statistically significant difference compared to placebo. The incidence of confirmed hypoglycaemia was
uncommon for Onglyza 5 mg (0.8%) and placebo (0.7%).
4
All of the reported adverse drug reactions of peripheral oedema were of mild to moderate intensity and none resulted in
study drug discontinuation.
Description of selected adverse reactions
In addition to the adverse reactions described above, adverse events reported regardless of causal
relationship to the medicinal product and occurring more commonly in patients treated with Onglyza
include hypersensitivity (0.6% vs. 0%) and rash (1.4% vs. 1.0%) as compared with placebo.
Adverse events, considered by the investigator to be at least possibly drug-related and reported in at
least two more patients treated with saxagliptin 5 mg compared to control, are described below by
treatment regimen.
As monotherapy: dizziness (common) and fatigue (common).
As add-on to metformin: dyspepsia (common) and myalgia (common).
As add-on to sulphonylurea (glibenclamide): fatigue (uncommon), dyslipidemia (uncommon) and
hypertriglyceridemia (uncommon).
6
As initial combination with metformin: gastritis (common), arthralgia (uncommon), myalgia
(uncommon), and erectile dysfunction (uncommon).
Investigations
Across clinical studies, the incidence of laboratory adverse events was similar in patients treated with
saxagliptin 5 mg compared to patients treated with placebo. A small decrease in absolute lymphocyte
count was observed. From a baseline mean absolute lymphocyte count of approximately
2,200 cells/μl, a mean decrease of approximately 100 cells/μl relative to placebo was observed in the
placebo-controlled-pooled analysis. Mean absolute lymphocyte counts remained stable with daily
dosing up to 102 weeks in duration. The decreases in lymphocyte count were not associated with
clinically relevant adverse reactions. The clinical significance of this decrease in lymphocyte count
relative to placebo is not known.
Onglyza has been shown to be safe and well-tolerated with no clinically meaningful effect on QTc
interval or heart rate at oral doses up to 400 mg daily for 2 weeks (80 times the recommended dose).
In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the
patient’s clinical status. Saxagliptin and its major metabolite can be removed by haemodialysis (23%
of dose over 4 hours).
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in diabetes. Dipeptidyl peptidase 4 (DPP-4) inhibitors, ATC
code: A10BH03
Mechanism of action and pharmacodynamic effects
Saxagliptin is a highly potent (Ki: 1.3 nM), selective, reversible, competitive, DPP-4 inhibitor. In
patients with type 2 diabetes, administration of saxagliptin led to inhibition of DPP-4 enzyme activity
for a 24-hour period. After an oral glucose load, this DPP-4 inhibition resulted in a 2- to 3-fold
increase in circulating levels of active incretin hormones, including glucagon-like peptide-1 (GLP-1)
and glucose-dependent insulinotropic polypeptide (GIP), decreased glucagon concentrations and
increased glucose-dependent beta-cell responsiveness, which resulted in higher insulin and C-peptide
concentrations. The rise in insulin from pancreatic beta-cells and the decrease in glucagon from
pancreatic alpha-cells were associated with lower fasting glucose concentrations and reduced glucose
excursion following an oral glucose load or a meal. Saxagliptin improves glycaemic control by
reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes.
Clinical safety and efficacy
A total of 4,148 patients with type 2 diabetes, including 3,021 patients treated with, saxagliptin were
randomised in 6 double-blind, controlled clinical safety and efficacy studies conducted to evaluate the
effects of saxagliptin on glycaemic control. In these studies 634 patients were 65 years and older,
while 59 patients were 75 years and older. Treatment with saxagliptin 5 mg once daily produced
clinically relevant and statistically significant improvements in haemoglobin A1c (HbA1c), fasting
plasma glucose (FPG) and postprandial glucose (PPG) compared to placebo in monotherapy, in
combination with metformin (initial or add-on therapy), in combination with a sulphonylurea, and in
combination with a thiazolidinedione (see Table 2). There was also no apparent change in body weight
associated with saxagliptin. Reductions in HbA1c were seen across subgroups including gender, age,
race, and baseline body mass index (BMI) and higher baseline HbA1c was associated with a greater
adjusted mean change from baseline with saxagliptin.
7
Saxagliptin as monotherapy
Two double-blind, placebo-controlled studies of 24-week duration were conducted to evaluate the
efficacy and safety of saxagliptin monotherapy in patients with type 2 diabetes. In both studies,
once-daily treatment with saxagliptin provided significant improvements in HbA1c.
Saxagliptin add-on to metformin therapy
An add-on to metformin placebo-controlled study of 24-week duration was conducted to evaluate the
efficacy and safety of saxagliptin in combination with metformin in patients with inadequate
glycaemic control (HbA1c 7-10%) on metformin alone. Saxagliptin (n=186) provided significant
improvements in HbA1c, FPG and PPG compared to placebo (n=175). Improvements in HbA1c, PPG,
and FPG following treatment with saxagliptin 5 mg plus metformin were sustained up to Week 102.
The HbA1c change for saxagliptin 5 mg plus metformin (n=31) compared to placebo plus metformin
(n=15) was -0.8% at Week 102.
Saxagliptin add-on to metformin compared with SU add-on to metformin
A 52-week study was conducted to evaluate the efficacy and safety of saxagliptin 5 mg in combination
with metformin (428 patients) compared with sulphonylurea (glipizide, 5 mg titrated as needed to
20 mg, mean dose of 15 mg) in combination with metformin (430 patients) in 858 patients with
inadequate glycaemic control (HbA1c 6.5%-10%) on metformin alone. The mean metformin dose was
approximately 1900 mg in each treatment group. After 52 weeks, the saxagliptin and glipizide groups
had similar mean reductions from baseline in HbA1c in the per-protocol analysis (-0.7% vs. –0.8%,
respectively, mean baseline HbA1c of 7.5% for both groups). The intent-to-treat analysis showed
consistent results. The reduction in FPG was slightly less in the saxagliptin-group and there were more
discontinuations (3.5% vs. 1.2%) due to lack of efficacy based on FPG criteria during the first
24 weeks of the study. Saxagliptin also resulted in a significantly lower proportion of patients with
hypoglycaemia, 3% (19 events in 13 subjects) vs. 36.3% (750 events in 156 patients) for glipizide.
Patients treated with saxagliptin exhibited a significant decrease from baseline in body weight
compared to a weight gain in patients administered glipizide (-1.1 vs. +1.1 kg).
Saxagliptin add-on to metformin compared with sitagliptin add-on to metformin
An 18-week study was conducted to evaluate the efficacy and safety of saxagliptin 5 mg in
combination with metformin (403 patients), compared with sitagliptin 100 mg in combination with
metformin (398 patients) in 801 patients with inadequate glycaemic control on metformin alone. After
18 weeks, saxagliptin was non-inferior to sitagliptin in mean reduction from baseline in HbA1c in both
the per-protocol and the full analysis sets . The reductions from baseline in HbA1c respectively for
saxagliptin and sitagliptin in the primary per-protocol analysis were -0.5% (mean and median) and
-0.6% (mean and median). In the confirmatory full analysis set, mean reductions were -0.4% and
-0.6% respectively for saxagliptin and sitagliptin, with median reductions of -0.5% for both groups.
Saxagliptin in combination with metformin as initial therapy
A 24-week study was conducted to evaluate the efficacy and safety of saxagliptin 5 mg in combination
with metformin as initial combination therapy in treatment-naïve patients with inadequate glycaemic
control (HbA1c 8-12%). Initial therapy with the combination of saxagliptin 5 mg plus metformin
(n=306) provided significant improvements in HbA1c, FPG and PPG compared to with either
saxagliptin (n=317) or metformin alone (n=313) as initial therapy. Reductions in HbA1c from baseline
to Week 24 were observed in all evaluated subgroups defined by baseline HbA1c, with greater
reductions observed in patients with a baseline HbA1c ≥ 10% (see Table 2). Improvements in HbA1c,
PPG and FPG following initial therapy with saxagliptin 5 mg plus metformin were sustained up to
Week 76. The HbA1c change for saxagliptin 5 mg plus metformin (n=177) compared to metformin
plus placebo (n=147) was -0.5% at Week 76.
Saxagliptin add-on to glibenclamide therapy
An add-on placebo-controlled study of 24-week duration was conducted to evaluate the efficacy and
safety of saxagliptin in combination with glibenclamide in patients with inadequate glycaemic control
at enrolment (HbA1c 7.5-10%) on a sub-maximal dose of glibenclamide alone. Saxagliptin in
combination with a fixed, intermediate dose of a sulphonylurea (glibenclamide 7.5 mg) was compared
to titration to a higher dose of glibenclamide (approximately 92% of patients in the placebo plus
8
glibenclamide group were up-titrated to a final total daily dose of 15 mg). Saxagliptin (n=250)
provided significant improvements in HbA1c, FPG and PPG compared to titration to a higher dose of
glibenclamide (n=264). Improvements in HbA1c and PPG following treatment with saxagliptin 5 mg
were sustained up to Week 76. The HbA1c change for saxagliptin 5 mg (n=56) compared to uptitrated
glibenclamide plus placebo (n=27) was -0.7% at Week 76.
Saxagliptin add-on to thiazolidinedione therapy
A placebo-controlled study of 24-week duration was conducted to evaluate the efficacy and safety of
saxagliptin in combination with a thiazolidinedione (TZD) in patients with inadequate glycaemic
control (HbA1c 7-10.5%) on TZD alone. Saxagliptin (n=183) provided significant improvements in
HbA1c, FPG and PPG compared to placebo (n=180). Improvements in HbA1c, PPG and FPG
following treatment with saxagliptin 5 mg were sustained up to Week 76. The HbA1c change for
saxagliptin 5 mg (n=82) compared to TZD plus placebo (n=53) was -0.9% at Week 76.
Patients with renal impairment
A 12-week, multi-centre, randomised, double-blind, placebo-controlled study was conducted to
evaluate the treatment effect of saxagliptin 2.5 mg once daily compared with placebo in 170 patients
(85 patients on saxagliptin and 85 on placebo) with type 2 diabetes (HbA1c 7.0-11%) and renal
impairment (moderate [N=90]; severe [N=41]; or ESRD [N=39]). In this study, 98.2% of the patients
were treated with other antihyperglycaemic medication (75.3% on insulin and 31.2% on oral
antihyperglycaemic drugs; some received both). Saxagliptin significantly decreased HbA1c compared
with placebo; the HbA1c change for saxagliptin was -0.9% at Week 12 (HbA1c change of -0.4% for
placebo). Improvements in HbA1c following treatment with saxagliptin 2.5 mg were sustained up to
Week 52, however the number of patients who completed 52 weeks without modification of other
antihyperglycaemic medications was low (26 subjects in the saxagliptin group versus 34 subjects in
the placebo group). The incidence of confirmed hypoglycaemic events was somewhat higher in the
saxagliptin group (9.4%) versus placebo group (4.7%) although the number of subjects with any
hypoglycaemic event did not differ between the treatment groups. There was no adverse effect on
renal function as determined by estimated glomerular filtration rate or CrCL at Week 12 and Week 52.
Table 2 Key efficacy results of Onglyza 5 mg per day in placebo-controlled monotherapy
trials and in add-on combination therapy trials
Mean
baseline
HbA1c
(%)
Mean change
2
from
baseline HbA1c (%)
at Week 24
Placebo-corrected
mean change in HbA1c
(%) at Week 24 (95%
CI)
MONOTHERAPY STUDIES
• Study CV181011 (n=103)
8.0
-0.5
-0.6 (-0.9, -0.4)
3
• Study CV181038 (n=69)
7.9
-0.7 (morning)
-0.4 (-0.7, -0.1)
4
(n=70)
7.9
-0.6 (evening)
-0.4 (-0.6, -0.1)
5
ADD-ON/COMBINATION STUDIES
• Study CV181014: add-on to metformin
(n=186)
8.1
-0.7
-0.8 (-1.0, -0.6)
3
• Study CV181040: add-on to SU
1
(n=250)
8.5
-0.6
-0.7 (-0.9, -0.6)
3
• Study CV181013: add-on to TZD (n=183)
8.4
-0.9
-0.6 (-0.8, -0.4)
3
• Study CV181039: initial combination with
metformin
6
Overall population (n=306)
Baseline HbA1c ≥ 10% strata (n=107)
9.4
10.8
-2.5
-3.3
-0.5 (-0.7, -0.4)
7
-0.6 (-0.9, -0.3)
8
n=Randomized patients (primary efficacy-intention-to-treat analysis).
1
Placebo group had uptitration of glibenclamide from 7.5 to 15 mg total daily dose.
2
Adjusted mean change from baseline adjusted for baseline value (ANCOVA).
3
p<0.0001 compared to placebo.
4
p=0.0059 compared to placebo.
5
p=0.0157 compared to placebo.
6
Metformin was uptitrated from 500 to 2000 mg per day as tolerated.
9
7
Mean HbA1c change is the difference between the saxagliptin+metformin and metformin alone groups (p<0.0001).
8
Mean HbA1c change is the difference between the saxagliptin+metformin and metformin alone groups.
5.2 Pharmacokinetic properties
The pharmacokinetics of saxagliptin and its major metabolite were similar in healthy subjects and in
patients with type 2 diabetes.
Absorption
Saxagliptin was rapidly absorbed after oral administration in the fasted state, with maximum plasma
concentrations (C
max
) of saxagliptin and its major metabolite attained within 2 and 4 hours (T
max
),
respectively. The C
max
and AUC values of saxagliptin and its major metabolite increased
proportionally with the increment in the saxagliptin dose, and this dose-proportionality was observed
in doses up to 400 mg. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean
plasma AUC values for saxagliptin and its major metabolite were 78 ng·h/ml and 214 ng·h/ml,
respectively. The corresponding plasma C
max
values were 24 ng/ml and 47 ng/ml, respectively. The
intra-subject coefficients of variation for saxagliptin C
max
and AUC were less than 12%.
The inhibition of plasma DPP-4 activity by saxagliptin for at least 24 hours after oral administration of
saxagliptin is due to high potency, high affinity, and extended binding to the active site.
Interaction with food
Food had relatively modest effects on the pharmacokinetics of saxagliptin in healthy subjects.
Administration with food (a high-fat meal) resulted in no change in saxagliptin C
max
and a 27%
increase in AUC compared with the fasted state. The time for saxagliptin to reach C
max
(T
max
) was
increased by approximately 0.5 hours with food compared with the fasted state. These changes were
not considered to be clinically meaningful.
Distribution
The
in vitro
protein binding of saxagliptin and its major metabolite in human serum is negligible.
Thus, changes in blood protein levels in various disease states (e.g., renal or hepatic impairment) are
not expected to alter the disposition of saxagliptin.
Biotransformation
The biotransformation of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5).
The major metabolite of saxagliptin is also a selective, reversible, competitive DPP-4 inhibitor, half as
potent as saxagliptin.
Elimination
The mean plasma terminal half-life (t
1/2
) values for saxagliptin and its major metabolite are 2.5 hours
and 3.1 hours respectively, and the mean t
1/2
value for plasma DPP-4 inhibition was 26.9 hours.
Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of
14
C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its major
metabolite, and total radioactivity respectively. The average renal clearance of saxagliptin
(~230 ml/min) was greater than the average estimated glomerular filtration rate (~120 ml/min),
suggesting some active renal excretion. For the major metabolite, renal clearance values were
comparable to estimated glomerular filtration rate. A total of 22% of the administered radioactivity
was recovered in faeces representing the fraction of the saxagliptin dose excreted in bile and/or
unabsorbed medicinal product from the gastrointestinal tract.
Linearity
The C
max
and AUC of saxagliptin and its major metabolite increased proportionally to the saxagliptin
dose. No appreciable accumulation of either saxagliptin or its major metabolite was observed with
repeated once-daily dosing at any dose level. No dose- and time-dependence was observed in the
clearance of saxagliptin and its major metabolite over 14 days of once-daily dosing with saxagliptin at
doses ranging from 2.5 mg to 400 mg.
Special populations
10
Renal impairment
A single-dose, open-label study was conducted to evaluate the pharmacokinetics of a 10 mg oral dose
of saxagliptin in subjects with varying degrees of chronic renal impairment compared to subjects with
normal renal function. The study included patients with renal impairment classified on the basis of
creatinine clearance (based on the Cockcroft-Gault formula) as mild (>50 to ≤80 ml/min), moderate
(≥30 to ≤50 ml/min), or severe (≤30 ml/min), as well as patients with ESRD on haemodialysis.
The degree of renal impairment did not affect the C
max
of saxagliptin or its major metabolite. In
subjects with mild renal impairment, the mean AUC values of saxagliptin and its major metabolite
were 1.2- and 1.7- fold higher, respectively, than mean AUC values in subjects with normal renal
function. Because increases of this magnitude are not clinically relevant, dose adjustment in patients
with mild renal impairment is not recommended. In subjects with moderate or severe renal impairment
or in subjects with ESRD on haemodialysis, the AUC values of saxagliptin and its major metabolite
were up to 2.1- and 4.5-fold higher, respectively, than AUC values in subjects with normal renal
function. The dose of Onglyza should be reduced to 2.5 mg once daily in patients with moderate or
severe renal impairment
(see sections 4.2 and 4.4).
Hepatic impairment
In subjects with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe (Child-Pugh
Class C) hepatic impairment the exposures to saxagliptin were 1.1-, 1.4- and 1.8-fold higher,
respectively, and the exposures to BMS-510849 were 22%, 7%, and 33% lower, respectively, than
those observed in healthy subjects.
Elderly patients (≥ 65 years)
Elderly patients (65-80 years) had about 60% higher saxagliptin AUC than young patients
(18-40 years). This is not considered clinically meaningful, therefore, no dose adjustment for Onglyza
is recommended on the basis of age alone.
5.3 Preclinical safety data
In cynomolgus monkeys saxagliptin produced reversible skin lesions (scabs, ulcerations and necrosis)
in extremities (tail, digits, scrotum and/or nose) at doses ≥ 3 mg/kg/day. The no effect level (NOEL)
for the lesions is 1 and 2 times the human exposure of saxagliptin and the major metabolite
respectively, at the recommended human dose of 5 mg/day (RHD).
The clinical relevance of the skin lesions is not known, however clinical correlates to skin lesions in
monkeys have not been observed in human clinical trials of saxagliptin.
Immune related findings of minimal, nonprogressive, lymphoid hyperplasia in spleen, lymph nodes
and bone marrow with no adverse sequelae have been reported in all species tested at exposures
starting from 7 times the RHD.
Saxagliptin produced gastrointestinal toxicity in dogs, including bloody/mucoid faeces and
enteropathy at higher doses with a NOEL 4 and 2 times the human exposure for saxagliptin and the
major metabolite, respectively, at RHD.
Saxagliptin was not genotoxic in a conventional battery of genotoxicity studies
in vitro
and
in vivo
. No
carcinogenic potential was observed in two-year carcinogenicity assays with mice and rats.
Effects on fertility were observed in male and female rats at high doses producing overt signs of
toxicity. Saxagliptin was not teratogenic at any doses evaluated in rats or rabbits. At high doses in rats,
saxagliptin caused reduced ossification (a developmental delay) of the foetal pelvis and decreased
foetal body weight (in the presence of maternal toxicity), with a NOEL 303 and 30 times the human
exposure for saxagliptin and the major metabolite, respectively, at RHD. In rabbits, the effects of
saxagliptin were limited to minor skeletal variations observed only at maternally toxic doses (NOEL
158 and 224 times the human exposure for saxagliptin and the major metabolite, respectively at RHD).
11
In a pre- and postnatal developmental study in rats, saxagliptin caused decreased pup weight at
maternally toxic doses, with NOEL 488 and 45 times the human exposure for saxagliptin and the
major metabolite, respectively at RHD. The effect on offspring body weights were noted until
postnatal day 92 and 120 in females and males, respectively.
6.
6.1 List of excipients
Tablet core
Lactose monohydrate
Cellulose microcrystalline (E460i)
Croscarmellose sodium (E468)
Magnesium stearate
Film coating
Polyvinyl alcohol
Macrogol/3350
Titanium dioxide (E171)
Talc (E553b)
Iron oxide yellow (E172)
Printing ink
Shellac
Indigo carmine aluminium lake (E132)
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
Alu/Alu blister.
Pack sizes of 14, 28, and 98 film-coated tablets in non-perforated calendar blisters.
Pack sizes of 30x1 and 90x1 film-coated tablets in perforated unit dose blisters.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Bristol-Myers Squibb/AstraZeneca EEIG
Bristol-Myers Squibb House
12
Uxbridge Business Park
Sanderson Road
Uxbridge
Middlesex
UB8 1DH
United Kingdom
8.
9.
Date of first authorisation: 01 October 2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
www.ema.europa.eu
13
1.
Onglyza 5 mg film-coated tablets
2.
Each tablet contains 5 mg saxagliptin (as hydrochloride).
Excipients
Each tablet contains 99 mg lactose monohydrate.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet (tablet).
Onglyza 5 mg tablets are pink, biconvex, round, film-coated tablets, with “5” printed on one side and
“4215” printed on the other side, in blue ink.
4.
Add-on combination therapy
Onglyza is indicated in adult patients aged 18 years and older with type 2 diabetes mellitus to improve
glycaemic control:
• in combination with metformin, when metformin alone, with diet and exercise, does not provide
adequate glycaemic control;
• in combination with a sulphonylurea, when the sulphonylurea alone, with diet and exercise,
does not provide adequate glycaemic control in patients for whom use of metformin is
considered inappropriate.
• in combination with a thiazolidinedione, when the thiazolidinedione alone with diet and
exercise, does not provide adequate glycaemic control in patients for whom use of a
thiazolidinedione is considered appropriate.
Posology
Add-on combination therapy
The recommended dose of Onglyza is 5 mg once daily as add-on combination therapy with metformin,
a thiazolidinedione or a sulphonylurea.
The safety and efficacy of saxagliptin as triple oral therapy in combination with metformin and a
thiazolidinedione, or with metformin and a sulphonylurea, has not been established.
Special populations
Elderly (≥ 65 years)
No dose adjustment is recommended based solely on age. Experience in patients aged 75 years and
older is very limited and caution should be exercised when treating this population (see also
sections 4.4, 5.1 and 5.2).
14
Renal impairment
No dose adjustment is recommended for patients with mild renal impairment.
The dose of Onglyza should be reduced to 2.5 mg once daily in patients with moderate or severe renal
impairment.
The experience in patients with severe renal impairment is very limited. Therefore, saxagliptin should
be used with caution in this population. Onglyza is not recommended for patients with end-stage renal
disease (ESRD) requiring haemodialysis (see section 4.4).
Because the dose of Onglyza should be limited to 2.5 mg based upon renal function, assessment of
renal function is recommended prior to initiation of Onglyza, and, in keeping with routine care, renal
assessment should be done periodically thereafter (see sections 4.4 and 5.2).
Hepatic impairment
No dose adjustment is necessary for patients with mild or moderate hepatic impairment (see
section 5.2). Saxagliptin should be used with caution in patients with moderate hepatic impairment,
and is not recommended for use in patients with severe hepatic impairment (see section 4.4).
Paediatric population
The safety and efficacy of Onglyza in children aged birth to < 18 years have not yet been established.
No data are available.
Method of administration
Onglyza can be taken with or without a meal at any time of the day. If a dose is missed, it should be
taken as soon as the patient remembers. A double dose should not be taken on the same day.
Hypersensitivity to the active substance or to any of the excipients.
General
Onglyza should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic
ketoacidosis.
Renal impairment
A single dosage adjustment is recommended in patients with moderate or severe renal impairment.
Saxagliptin should be used with caution in patients with severe renal impairment, and is not
recommended for use in patients with end-stage renal disease (ESRD) requiring haemodialysis.
Assessment of renal function is recommended prior to initiation of Onglyza, and, in keeping with
routine care, renal assessment should be done periodically thereafter (see sections 4.2 and 5.2).
Hepatic impairment
Saxagliptin should be used with caution in patients with moderate hepatic impairment, and is not
recommended for use in patients with severe hepatic impairment (see section 4.2).
Use with sulphonylureas
Sulphonylureas are known to cause hypoglycaemia. Therefore, a lower dose of sulphonylurea may be
required to reduce the risk of hypoglycaemia when used in combination with Onglyza.
Hypersensitivity reactions
Onglyza should not be used in patients who have had any serious hypersensitivity reaction to a
dipeptidyl peptidase 4 (DPP4) inhibitor.
15
Elderly patients
Experience in patients aged 75 years and older is very limited and caution should be exercised when
treating this population (see sections 5.1 and 5.2).
Skin disorders
Ulcerative and necrotic skin lesions have been reported in extremities of monkeys in non-clinical
toxicology studies (see section 5.3). Although skin lesions were not observed at an increased incidence
in clinical trials, there is limited experience in patients with diabetic skin complications. Postmarketing
reports of rash have been described in the DPP4 inhibitor class. Rash is also noted as an adverse event
(AE) for Onglyza (see section 4.8). Therefore, in keeping with routine care of the diabetic patient,
monitoring for skin disorders, such as blistering, ulceration or rash, is recommended.
Cardiac failure
Experience in NYHA class I-II is limited, and there is no experience in clinical studies with
saxagliptin in NYHA class III-IV.
Immunocompromised patients
Immunocompromised patients, such as patients who have undergone organ transplantation or patients
diagnosed with human immunodeficiency syndrome, have not been studied in the Onglyza clinical
program. Therefore, the efficacy and safety profile of saxagliptin in these patients has not been
established.
Use with potent CYP 3A4 inducers
Using CYP3A4 inducers like carbamazepine, dexamethasone, phenobarbital, phenytoin, and
rifampicin may reduce the glycaemic lowering effect of Onglyza (see section 4.5).
Lactose
The tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this
medicinal product.
Clinical data described below suggest that the risk for clinically meaningful interactions with
co-administered medicinal products is low.
The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). In
in
vitro
studies, saxagliptin and its major metabolite neither inhibited CYP1A2, 2A6, 2B6, 2C9, 2C19,
2D6, 2E1, or 3A4, nor induced CYP1A2, 2B6, 2C9, or 3A4. In studies conducted in healthy subjects,
neither the pharmacokinetics of saxagliptin and its major metabolite, were meaningfully altered by
metformin, glibenclamide, pioglitazone, digoxin, simvastatin, omeprazole, antacids or famotidine. In
addition, saxagliptin did not meaningfully alter the pharmacokinetics of metformin, glibenclamide,
pioglitazone, digoxin, simvastatin, diltiazem or ketoconazole.
Concomitant administration of saxagliptin with the moderate inhibitor of CYP3A4/5 diltiazem,
increased the C
max
and AUC of saxagliptin by 63% and 2.1-fold, respectively, and the corresponding
values for the active metabolite were decreased by 44 and 34%, respectively.
Concomitant administration of saxagliptin with the potent inhibitor of CYP3A4/5 ketoconazole,
increased the C
max
and AUC of saxagliptin by 62% and 2.5-fold, respectively, and the corresponding
values for the active metabolite were decreased by 95% and 88%, respectively.
Concomitant administration of saxagliptin with the potent CYP3A4/5 inducer rifampicin, reduced C
max
and AUC of saxagliptin by 53% and 76%, respectively. The exposure of the active metabolite and the
plasma DPP4 activity inhibition over a dose interval were not influenced by rifampicin (see
section 4.4).
16
The co-administration of saxagliptin and CYP3A4/5 inducers, other than rifampicin (such as
carbamazepine, dexamethasone, phenobarbital and phenytoin) have not been studied and may result in
decreased plasma concentration of saxagliptin and increased concentration of its major metabolite.
Glycaemic control should be carefully assessed when saxagliptin is used concomitantly with a potent
CYP3A4 inducer.
The effects of smoking, diet, herbal products, and alcohol use on the pharmacokinetics of saxagliptin
have not been specifically studied.
Pregnancy
The use of saxagliptin has not been studied in pregnant women. Studies in animals have shown
reproductive toxicity at high doses (see section 5.3). The potential risk for humans is unknown.
Onglyza should not be used during pregnancy unless clearly necessary.
Breastfeeding
It is unknown whether saxagliptin is excreted in human breast milk. Animal studies have shown
excretion of saxagliptin and/or metabolite in milk. A risk to the suckling child cannot be excluded. A
decision must be made whether to discontinue breast-feeding or to discontinue therapy taking into
account the benefit of breast-feeding for the child and the benefit of therapy to the woman.
Fertility
The effect of saxagliptin on fertility in humans has not been studied. Effects on fertility were observed
in male and female rats at high doses producing overt signs of toxicity (see section 5.3).
Onglyza may have a negligible influence on the ability to drive and use machines.
No studies on the effects on the ability to drive and use machines have been performed. However,
when driving or using machines, it should be taken into account that dizziness has been reported in
studies with saxagliptin.
Summary of the safety profile
There were 4,148 patients with type 2 diabetes, including 3,021 patients treated with Onglyza,
randomised in six double-blind, controlled clinical safety and efficacy studies conducted to evaluate
the effects of saxagliptin on glycaemic control.
In a pooled analysis, the overall incidence of adverse events in patients treated with saxagliptin 5 mg
was similar to placebo. Discontinuation of therapy due to adverse events was higher in patients who
received saxagliptin 5 mg as compared to placebo (3.3% as compared to 1.8%).
Tabulated list of adverse reactions
Adverse reactions reported in ≥ 5% of patients treated with saxagliptin 5 mg and more commonly than
in patients treated with placebo or that were reported in ≥ 2% of patients treated with saxagliptin 5 mg
and ≥ 1% more frequently compared to placebo are shown in Table 1.
The adverse reactions are listed by system organ class and absolute 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), or Very rare (< 1/10,000), not known (cannot be estimated from the available
data).
17
Table 1
Frequency of adverse reactions by system organ class
System organ class
Adverse Reaction
Frequency of adverse reactions by treatment regimen
Saxagliptin
monotherapy
Saxagliptin
with
metformin
1
Saxagliptin
with a
sulphonylurea
(glibenclamide)
Saxagliptin with a
thiazolidinedione
Infections and
infestations
Upper respiratory
infection
Common
Common
Common
Common
Urinary tract
infection
Common
Common
Common
Common
Gastroenteritis
Common
Common
Common
Common
Sinusitis
Common
Common
Common
Common
Nasopharyngitis
Common
2
Metabolism and
nutrition disorders
Hypoglycaemia
Very common
3
Nervous system
disorders
Headache
Common
Common
Common
Common
Gastrointestinal
disorders
Vomiting
Common
Common
Common
Common
General disorders
and
administration site
conditions
Oedema peripheral
Common
4
1
Includes saxagliptin in add-on to metformin and initial combination with metformin.
2
Only in the initial combination therapy.
3
There was no statistically significant difference compared to placebo. The incidence of confirmed hypoglycaemia was
uncommon for Onglyza 5 mg (0.8%) and placebo (0.7%).
4
All of the reported adverse drug reactions of peripheral oedema were of mild to moderate intensity and none resulted in
study drug discontinuation.
Description of selected adverse reactions
In addition to the adverse reactions described above, adverse events reported regardless of causal
relationship to the medicinal product and occurring more commonly in patients treated with Onglyza
include hypersensitivity (0.6% vs. 0%) and rash (1.4% vs. 1.0%) as compared with placebo.
Adverse events, considered by the investigator to be at least possibly drug-related and reported in at
least two more patients treated with saxagliptin 5 mg compared to control, are described below by
treatment regimen.
As monotherapy: dizziness (common) and fatigue (common).
As add-on to metformin: dyspepsia (common) and myalgia (common).
As add-on to sulphonylurea (glibenclamide): fatigue (uncommon), dyslipidemia (uncommon) and
hypertriglyceridemia (uncommon).
18
As initial combination with metformin: gastritis (common), arthralgia (uncommon), myalgia
(uncommon), and erectile dysfunction (uncommon).
Investigations
Across clinical studies, the incidence of laboratory adverse events was similar in patients treated with
saxagliptin 5 mg compared to patients treated with placebo. A small decrease in absolute lymphocyte
count was observed. From a baseline mean absolute lymphocyte count of approximately
2,200 cells/μl, a mean decrease of approximately 100 cells/μl relative to placebo was observed in the
placebo-controlled-pooled analysis. Mean absolute lymphocyte counts remained stable with daily
dosing up to 102 weeks in duration. The decreases in lymphocyte count were not associated with
clinically relevant adverse reactions. The clinical significance of this decrease in lymphocyte count
relative to placebo is not known.
Onglyza has been shown to be safe and well-tolerated with no clinically meaningful effect on QTc
interval or heart rate at oral doses up to 400 mg daily for 2 weeks (80 times the recommended dose).
In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the
patient’s clinical status. Saxagliptin and its major metabolite can be removed by haemodialysis (23%
of dose over 4 hours).
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in diabetes. Dipeptidyl peptidase 4 (DPP-4) inhibitors, ATC
code: A10BH03
Mechanism of action and pharmacodynamic effects
Saxagliptin is a highly potent (Ki: 1.3 nM), selective, reversible, competitive, DPP-4 inhibitor. In
patients with type 2 diabetes, administration of saxagliptin led to inhibition of DPP-4 enzyme activity
for a 24-hour period. After an oral glucose load, this DPP-4 inhibition resulted in a 2- to 3-fold
increase in circulating levels of active incretin hormones, including glucagon-like peptide-1 (GLP-1)
and glucose-dependent insulinotropic polypeptide (GIP), decreased glucagon concentrations and
increased glucose-dependent beta-cell responsiveness, which resulted in higher insulin and C-peptide
concentrations. The rise in insulin from pancreatic beta-cells and the decrease in glucagon from
pancreatic alpha-cells were associated with lower fasting glucose concentrations and reduced glucose
excursion following an oral glucose load or a meal. Saxagliptin improves glycaemic control by
reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes.
Clinical safety and efficacy
A total of 4,148 patients with type 2 diabetes, including 3,021 patients treated with, saxagliptin were
randomised in 6 double-blind, controlled clinical safety and efficacy studies conducted to evaluate the
effects of saxagliptin on glycaemic control. In these studies 634 patients were 65 years and older,
while 59 patients were 75 years and older. Treatment with saxagliptin 5 mg once daily produced
clinically relevant and statistically significant improvements in haemoglobin A1c (HbA1c), fasting
plasma glucose (FPG) and postprandial glucose (PPG) compared to placebo in monotherapy, in
combination with metformin (initial or add-on therapy), in combination with a sulphonylurea, and in
combination with a thiazolidinedione (see Table 2). There was also no apparent change in body weight
associated with saxagliptin. Reductions in HbA1c were seen across subgroups including gender, age,
race, and baseline body mass index (BMI) and higher baseline HbA1c was associated with a greater
adjusted mean change from baseline with saxagliptin.
19
Saxagliptin as monotherapy
Two double-blind, placebo-controlled studies of 24-week duration were conducted to evaluate the
efficacy and safety of saxagliptin monotherapy in patients with type 2 diabetes. In both studies,
once-daily treatment with saxagliptin provided significant improvements in HbA1c.
Saxagliptin add-on to metformin therapy
An add-on to metformin placebo-controlled study of 24-week duration was conducted to evaluate the
efficacy and safety of saxagliptin in combination with metformin in patients with inadequate
glycaemic control (HbA1c 7-10%) on metformin alone. Saxagliptin (n=186) provided significant
improvements in HbA1c, FPG and PPG compared to placebo (n=175). Improvements in HbA1c, PPG,
and FPG following treatment with saxagliptin 5 mg plus metformin were sustained up to Week 102.
The HbA1c change for saxagliptin 5 mg plus metformin (n=31) compared to placebo plus metformin
(n=15) was -0.8% at Week 102.
Saxagliptin add-on to metformin compared with SU add-on to metformin
A 52-week study was conducted to evaluate the efficacy and safety of saxagliptin 5 mg in combination
with metformin (428 patients) compared with sulphonylurea (glipizide, 5 mg titrated as needed to
20 mg, mean dose of 15 mg) in combination with metformin (430 patients) in 858 patients with
inadequate glycaemic control (HbA1c 6.5%-10%) on metformin alone. The mean metformin dose was
approximately 1900 mg in each treatment group. After 52 weeks, the saxagliptin and glipizide groups
had similar mean reductions from baseline in HbA1c in the per-protocol analysis (-0.7% vs. –0.8%,
respectively, mean baseline HbA1c of 7.5% for both groups). The intent-to-treat analysis showed
consistent results. The reduction in FPG was slightly less in the saxagliptin-group and there were more
discontinuations (3.5% vs. 1.2%) due to lack of efficacy based on FPG criteria during the first
24 weeks of the study. Saxagliptin also resulted in a significantly lower proportion of patients with
hypoglycaemia, 3% (19 events in 13 subjects) vs. 36.3% (750 events in 156 patients) for glipizide.
Patients treated with saxagliptin exhibited a significant decrease from baseline in body weight
compared to a weight gain in patients administered glipizide (-1.1 vs. +1.1 kg).
Saxagliptin add-on to metformin compared with sitagliptin add-on to metformin
An 18-week study was conducted to evaluate the efficacy and safety of saxagliptin 5 mg in
combination with metformin (403 patients), compared with sitagliptin 100 mg in combination with
metformin (398 patients) in 801 patients with inadequate glycaemic control on metformin alone. After
18 weeks, saxagliptin was non-inferior to sitagliptin in mean reduction from baseline in HbA1c in both
the per-protocol and the full analysis sets . The reductions from baseline in HbA1c respectively for
saxagliptin and sitagliptin in the primary per-protocol analysis were -0.5% (mean and median) and
-0.6% (mean and median). In the confirmatory full analysis set, mean reductions were -0.4% and
-0.6% respectively for saxagliptin and sitagliptin, with median reductions of -0.5% for both groups.
Saxagliptin in combination with metformin as initial therapy
A 24-week study was conducted to evaluate the efficacy and safety of saxagliptin 5 mg in combination
with metformin as initial combination therapy in treatment-naïve patients with inadequate glycaemic
control (HbA1c 8-12%). Initial therapy with the combination of saxagliptin 5 mg plus metformin
(n=306) provided significant improvements in HbA1c, FPG and PPG compared to with either
saxagliptin (n=317) or metformin alone (n=313) as initial therapy. Reductions in HbA1c from baseline
to Week 24 were observed in all evaluated subgroups defined by baseline HbA1c, with greater
reductions observed in patients with a baseline HbA1c ≥ 10% (see Table 2). Improvements in HbA1c,
PPG and FPG following initial therapy with saxagliptin 5 mg plus metformin were sustained up to
Week 76. The HbA1c change for saxagliptin 5 mg plus metformin (n=177) compared to metformin
plus placebo (n=147) was -0.5% at Week 76.
Saxagliptin add-on to glibenclamide therapy
An add-on placebo-controlled study of 24-week duration was conducted to evaluate the efficacy and
safety of saxagliptin in combination with glibenclamide in patients with inadequate glycaemic control
at enrolment (HbA1c 7.5-10%) on a sub-maximal dose of glibenclamide alone. Saxagliptin in
combination with a fixed, intermediate dose of a sulphonylurea (glibenclamide 7.5 mg) was compared
to titration to a higher dose of glibenclamide (approximately 92% of patients in the placebo plus
20
glibenclamide group were up-titrated to a final total daily dose of 15 mg). Saxagliptin (n=250)
provided significant improvements in HbA1c, FPG and PPG compared to titration to a higher dose of
glibenclamide (n=264). Improvements in HbA1c and PPG following treatment with saxagliptin 5 mg
were sustained up to Week 76. The HbA1c change for saxagliptin 5 mg (n=56) compared to uptitrated
glibenclamide plus placebo (n=27) was -0.7% at Week 76.
Saxagliptin add-on to thiazolidinedione therapy
A placebo-controlled study of 24-week duration was conducted to evaluate the efficacy and safety of
saxagliptin in combination with a thiazolidinedione (TZD) in patients with inadequate glycaemic
control (HbA1c 7-10.5%) on TZD alone. Saxagliptin (n=183) provided significant improvements in
HbA1c, FPG and PPG compared to placebo (n=180). Improvements in HbA1c, PPG and FPG
following treatment with saxagliptin 5 mg were sustained up to Week 76. The HbA1c change for
saxagliptin 5 mg (n=82) compared to TZD plus placebo (n=53) was -0.9% at Week 76.
Patients with renal impairment
A 12-week, multi-centre, randomised, double-blind, placebo-controlled study was conducted to
evaluate the treatment effect of saxagliptin 2.5 mg once daily compared with placebo in 170 patients
(85 patients on saxagliptin and 85 on placebo) with type 2 diabetes (HbA1c 7.0-11%) and renal
impairment (moderate [N=90]; severe [N=41]; or ESRD [N=39]). In this study, 98.2% of the patients
were treated with other antihyperglycaemic medication (75.3% on insulin and 31.2% on oral
antihyperglycaemic drugs; some received both). Saxagliptin significantly decreased HbA1c compared
with placebo; the HbA1c change for saxagliptin was -0.9% at Week 12 (HbA1c change of -0.4% for
placebo). Improvements in HbA1c following treatment with saxagliptin 2.5 mg were sustained up to
Week 52, however the number of patients who completed 52 weeks without modification of other
antihyperglycaemic medications was low (26 subjects in the saxagliptin group versus 34 subjects in
the placebo group). The incidence of confirmed hypoglycaemic events was somewhat higher in the
saxagliptin group (9.4%) versus placebo group (4.7%) although the number of subjects with any
hypoglycaemic event did not differ between the treatment groups. There was no adverse effect on
renal function as determined by estimated glomerular filtration rate or CrCL at Week 12 and Week 52.
Table 2 Key efficacy results of Onglyza 5 mg per day in placebo-controlled monotherapy
trials and in add-on combination therapy trials
Mean
baseline
HbA1c
(%)
Mean change
2
from
baseline HbA1c (%)
at Week 24
Placebo-corrected
mean change in HbA1c
(%) at Week 24 (95%
CI)
MONOTHERAPY STUDIES
• Study CV181011 (n=103)
8.0
-0.5
-0.6 (-0.9, -0.4)
3
• Study CV181038 (n=69)
7.9
-0.7 (morning)
-0.4 (-0.7, -0.1)
4
(n=70)
7.9
-0.6 (evening)
-0.4 (-0.6, -0.1)
5
ADD-ON/COMBINATION STUDIES
• Study CV181014: add-on to metformin
(n=186)
8.1
-0.7
-0.8 (-1.0, -0.6)
3
• Study CV181040: add-on to SU
1
(n=250)
8.5
-0.6
-0.7 (-0.9, -0.6)
3
• Study CV181013: add-on to TZD (n=183)
8.4
-0.9
-0.6 (-0.8, -0.4)
3
• Study CV181039: initial combination with
metformin
6
Overall population (n=306)
Baseline HbA1c ≥ 10% strata (n=107)
9.4
10.8
-2.5
-3.3
-0.5 (-0.7, -0.4)
7
-0.6 (-0.9, -0.3)
8
n=Randomized patients (primary efficacy-intention-to-treat analysis).
1
Placebo group had uptitration of glibenclamide from 7.5 to 15 mg total daily dose.
2
Adjusted mean change from baseline adjusted for baseline value (ANCOVA).
3
p<0.0001 compared to placebo.
4
p=0.0059 compared to placebo.
5
p=0.0157 compared to placebo.
6
Metformin was uptitrated from 500 to 2000 mg per day as tolerated.
21
7
Mean HbA1c change is the difference between the saxagliptin+metformin and metformin alone groups (p<0.0001).
8
Mean HbA1c change is the difference between the saxagliptin+metformin and metformin alone groups.
5.2 Pharmacokinetic properties
The pharmacokinetics of saxagliptin and its major metabolite were similar in healthy subjects and in
patients with type 2 diabetes.
Absorption
Saxagliptin was rapidly absorbed after oral administration in the fasted state, with maximum plasma
concentrations (C
max
) of saxagliptin and its major metabolite attained within 2 and 4 hours (T
max
),
respectively. The C
max
and AUC values of saxagliptin and its major metabolite increased
proportionally with the increment in the saxagliptin dose, and this dose-proportionality was observed
in doses up to 400 mg. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean
plasma AUC values for saxagliptin and its major metabolite were 78 ng·h/ml and 214 ng·h/ml,
respectively. The corresponding plasma C
max
values were 24 ng/ml and 47 ng/ml, respectively. The
intra-subject coefficients of variation for saxagliptin C
max
and AUC were less than 12%.
The inhibition of plasma DPP-4 activity by saxagliptin for at least 24 hours after oral administration of
saxagliptin is due to high potency, high affinity, and extended binding to the active site.
Interaction with food
Food had relatively modest effects on the pharmacokinetics of saxagliptin in healthy subjects.
Administration with food (a high-fat meal) resulted in no change in saxagliptin C
max
and a 27%
increase in AUC compared with the fasted state. The time for saxagliptin to reach C
max
(T
max
) was
increased by approximately 0.5 hours with food compared with the fasted state. These changes were
not considered to be clinically meaningful.
Distribution
The
in vitro
protein binding of saxagliptin and its major metabolite in human serum is negligible.
Thus, changes in blood protein levels in various disease states (e.g., renal or hepatic impairment) are
not expected to alter the disposition of saxagliptin.
Biotransformation
The biotransformation of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5).
The major metabolite of saxagliptin is also a selective, reversible, competitive DPP-4 inhibitor, half as
potent as saxagliptin.
Elimination
The mean plasma terminal half-life (t
1/2
) values for saxagliptin and its major metabolite are 2.5 hours
and 3.1 hours respectively, and the mean t
1/2
value for plasma DPP-4 inhibition was 26.9 hours.
Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of
14
C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its major
metabolite, and total radioactivity respectively. The average renal clearance of saxagliptin
(~230 ml/min) was greater than the average estimated glomerular filtration rate (~120 ml/min),
suggesting some active renal excretion. For the major metabolite, renal clearance values were
comparable to estimated glomerular filtration rate. A total of 22% of the administered radioactivity
was recovered in faeces representing the fraction of the saxagliptin dose excreted in bile and/or
unabsorbed medicinal product from the gastrointestinal tract.
Linearity
The C
max
and AUC of saxagliptin and its major metabolite increased proportionally to the saxagliptin
dose. No appreciable accumulation of either saxagliptin or its major metabolite was observed with
repeated once-daily dosing at any dose level. No dose- and time-dependence was observed in the
clearance of saxagliptin and its major metabolite over 14 days of once-daily dosing with saxagliptin at
doses ranging from 2.5 mg to 400 mg.
Special populations
22
Renal impairment
A single-dose, open-label study was conducted to evaluate the pharmacokinetics of a 10 mg oral dose
of saxagliptin in subjects with varying degrees of chronic renal impairment compared to subjects with
normal renal function. The study included patients with renal impairment classified on the basis of
creatinine clearance (based on the Cockcroft-Gault formula) as mild (>50 to ≤80 ml/min), moderate
(≥30 to ≤50 ml/min), or severe (≤30 ml/min), as well as patients with ESRD on haemodialysis.
The degree of renal impairment did not affect the C
max
of saxagliptin or its major metabolite. In
subjects with mild renal impairment, the mean AUC values of saxagliptin and its major metabolite
were 1.2- and 1.7- fold higher, respectively, than mean AUC values in subjects with normal renal
function. Because increases of this magnitude are not clinically relevant, dose adjustment in patients
with mild renal impairment is not recommended. In subjects with moderate or severe renal impairment
or in subjects with ESRD on haemodialysis, the AUC values of saxagliptin and its major metabolite
were up to 2.1- and 4.5-fold higher, respectively, than AUC values in subjects with normal renal
function. The dose of Onglyza should be reduced to 2.5 mg once daily in patients with moderate or
severe renal impairment
(see sections 4.2 and 4.4).
Hepatic impairment
In subjects with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe (Child-Pugh
Class C) hepatic impairment the exposures to saxagliptin were 1.1-, 1.4- and 1.8-fold higher,
respectively, and the exposures to BMS-510849 were 22%, 7%, and 33% lower, respectively, than
those observed in healthy subjects.
Elderly patients (≥ 65 years)
Elderly patients (65-80 years) had about 60% higher saxagliptin AUC than young patients
(18-40 years). This is not considered clinically meaningful, therefore, no dose adjustment for Onglyza
is recommended on the basis of age alone.
5.3 Preclinical safety data
In cynomolgus monkeys saxagliptin produced reversible skin lesions (scabs, ulcerations and necrosis)
in extremities (tail, digits, scrotum and/or nose) at doses ≥ 3 mg/kg/day. The no effect level (NOEL)
for the lesions is 1 and 2 times the human exposure of saxagliptin and the major metabolite
respectively, at the recommended human dose of 5 mg/day (RHD).
The clinical relevance of the skin lesions is not known, however clinical correlates to skin lesions in
monkeys have not been observed in human clinical trials of saxagliptin.
Immune related findings of minimal, nonprogressive, lymphoid hyperplasia in spleen, lymph nodes
and bone marrow with no adverse sequelae have been reported in all species tested at exposures
starting from 7 times the RHD.
Saxagliptin produced gastrointestinal toxicity in dogs, including bloody/mucoid faeces and
enteropathy at higher doses with a NOEL 4 and 2 times the human exposure for saxagliptin and the
major metabolite, respectively, at RHD.
Saxagliptin was not genotoxic in a conventional battery of genotoxicity studies
in vitro
and
in vivo
. No
carcinogenic potential was observed in two-year carcinogenicity assays with mice and rats.
Effects on fertility were observed in male and female rats at high doses producing overt signs of
toxicity. Saxagliptin was not teratogenic at any doses evaluated in rats or rabbits. At high doses in rats,
saxagliptin caused reduced ossification (a developmental delay) of the foetal pelvis and decreased
foetal body weight (in the presence of maternal toxicity), with a NOEL 303 and 30 times the human
exposure for saxagliptin and the major metabolite, respectively, at RHD. In rabbits, the effects of
saxagliptin were limited to minor skeletal variations observed only at maternally toxic doses (NOEL
158 and 224 times the human exposure for saxagliptin and the major metabolite, respectively at RHD).
23
In a pre- and postnatal developmental study in rats, saxagliptin caused decreased pup weight at
maternally toxic doses, with NOEL 488 and 45 times the human exposure for saxagliptin and the
major metabolite, respectively at RHD. The effect on offspring body weights were noted until
postnatal day 92 and 120 in females and males, respectively.
6.
6.1 List of excipients
Tablet core
Lactose monohydrate
Cellulose microcrystalline (E460i)
Croscarmellose sodium (E468)
Magnesium stearate
Film coating
Polyvinyl alcohol
Macrogol/3350
Titanium dioxide (E171)
Talc (E553b)
Iron oxide red (E172)
Printing ink
Shellac
Indigo carmine aluminium lake (E132)
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
Alu/Alu blister.
Pack sizes of 14, 28, 56 and 98 film-coated tablets in non-perforated blisters.
Pack sizes of 14, 28, 56 and 98 film-coated tablets in non-perforated calendar blisters.
Pack sizes of 30x1 and 90x1 film-coated tablets in perforated unit dose blisters.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Bristol-Myers Squibb/AstraZeneca EEIG
Bristol-Myers Squibb House
24
Uxbridge Business Park
Sanderson Road
Uxbridge
Middlesex
UB8 1DH
United Kingdom
8.
EU/1/09/545/001-010
9.
Date of first authorisation: 01 October 2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
www.ema.europa.eu
25
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER(S)
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
26
A. MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer(s) responsible for batch release
Bristol-Myers Squibb Company
Contrada Fontana del Ceraso
IT-03012 Anagni (FR)
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, presented in Module 1.8.1. of the
Marketing Authorisation, 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 5 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 European Medicines Agency
27
ANNEX III
LABELLING AND PACKAGE LEAFLET
28
A. LABELLING
29
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON Onglyza 2.5 mg film-coated tablets
1.
Onglyza 2.5 mg film-coated tablets
saxagliptin
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 2.5 mg saxagliptin (as hydrochloride)
3.
LIST OF EXCIPIENTS
Contains lactose. See leaflet for further information.
4.
14 film-coated tablets
28 film-coated tablets
30x1 film-coated tablets
90x1 film-coated tablets
98 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Oral use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE 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
30
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Bristol-Myers Squibb/AstraZeneca EEIG
Bristol-Myers Squibb House
Uxbridge Business Park
Sanderson Road
Uxbridge
Middlesex
UB8 1DH
United Kingdom
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
onglyza 2.5 mg
31
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON Onglyza 5 mg film-coated tablets
1.
Onglyza 5 mg film-coated tablets
saxagliptin
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 5 mg saxagliptin (as hydrochloride).
3.
LIST OF EXCIPIENTS
Contains lactose. See leaflet for further information.
4.
14 film-coated tablets
28 film-coated tablets
30x1 film-coated tablets
56 film-coated tablets
90x1 film-coated tablets
98 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Oral use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE 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
32
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Bristol-Myers Squibb/AstraZeneca EEIG
Bristol-Myers Squibb House
Uxbridge Business Park
Sanderson Road
Uxbridge
Middlesex
UB8 1DH
United Kingdom
EU/1/09/545/001
EU/1/09/545/002
EU/1/09/545/003
EU/1/09/545/004
EU/1/09/545/005
EU/1/09/545/006
EU/1/09/545/007
EU/1/09/545/008
EU/1/09/545/009
EU/1/09/545/010
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
onglyza 5 mg
33
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTERS (PERFORATED) for Onglyza 2.5 mg tablets
1.
Onglyza 2.5 mg tablets
saxagliptin
2.
Bristol-Myers Squibb/AstraZeneca EEIG
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
34
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTERS (PERFORATED/NON-PERFORATED) for Onglyza 5 mg tablets
1.
Onglyza 5 mg tablets
saxagliptin
2.
Bristol-Myers Squibb/AstraZeneca EEIG
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
35
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
CALENDAR BLISTERS (NON-PERFORATED) for Onglyza 2.5 mg tablets
1.
Onglyza 2.5 mg tablets
saxagliptin
2.
Bristol-Myers Squibb/AstraZeneca EEIG
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
Monday Tuesday Wednesday Thursday Friday Saturday Sunday
36
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
CALENDAR BLISTERS (NON-PERFORATED) for Onglyza 5 mg tablets
1.
Onglyza 5 mg tablets
saxagliptin
2.
Bristol-Myers Squibb/AstraZeneca EEIG
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
Monday Tuesday Wednesday Thursday Friday Saturday Sunday
37
B. PACKAGE LEAFLET
38
PACKAGE LEAFLET: INFORMATION FOR THE USER
Onglyza 2.5 mg film-coated tablets
Saxagliptin
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
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 Onglyza is and what it is used for
2.
Before you take Onglyza
4.
Possible side effects
5.
How to store Onglyza
6.
Further information
1.
WHAT ONGLYZA IS AND WHAT IT IS USED FOR
Onglyza contains the active substance saxagliptin, which belongs to a group of medicines called ‘oral
anti-diabetics’. They work by helping to control the level of sugar in your blood.
Onglyza is used for adult patients aged 18 years and older with ‘type 2 diabetes’, if the disease cannot
be adequately controlled with one oral anti-diabetic medicine, diet and exercise. Onglyza is used
together with another oral anti-diabetic medicine.
It is important to keep following the advice about diet and exercise that you have been given by your
doctor or nurse.
2.
BEFORE YOU TAKE ONGLYZA
Do not take Onglyza
-
if you are allergic (hypersensitive) to saxagliptin or any of the other ingredients of Onglyza
(listed in section 6, ‘What Onglyza contains’).
Take special care with Onglyza
Check with your doctor or pharmacist before taking Onglyza if you:
• have type 1 diabetes (your body does not produce any insulin) or diabetic ketoacidos (a
complication of diabetes with high blood sugar, rapid weight loss, nausea or vomiting). Onglyza
should not be used to treat these conditions;
• are taking an anti-diabetic medicine known as ‘sulphonylurea’, your doctor may want to reduce
your dose of sulphonylurea when you take it together with Onglyza in order to avoid low blood
sugar;
• have had allergic reactions to any other medicines that you take to control the amount of sugar
in your blood;
• have a condition that reduces your defense against infections, such as a disease like AIDS or
from medicines that you might take after an organ transplant;
39
-
If you have any further questions, ask your doctor, nurse, or pharmacist.
3.
How to take Onglyza
• suffer from heart failure;
• have moderate to severe kidney problems, you will need to take a lower dose of Onglyza;
• have moderate or severe liver problems. If you have severe liver problems, then Onglyza is not
recommended for you
Diabetic skin lesions are a common complication of diabetes. Rash has been seen with Onglyza and
with certain anti-diabetic medicines in the same class as Onglyza. You are advised to follow the
recommendations for skin and foot care that you are given by your doctor or nurse.
Onglyza is not recommended for children and adolescents under 18 years.
Using other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This
includes medicines that you buy without a prescription.
In particular, you should tell your doctor if you are using medicines containing any of the following
active substances:
• Carbamazepine, phenobarbital or phenytoin. These may be used to control fits (seizures) or
chronic pain.
• Dexamethasone – a steroid medicine. This may be used to treat inflammation in different body
parts and organs.
• Rifampicin. This is an antibiotic used to treat infections such as tuberculosis
• Ketoconazole. This may be used to treat fungal infections.
• Diltiazem. This is a medicine used to lower blood pressure.
Taking Onglyza with food and drink
You can take Onglyza with or without food.
Pregnancy and breast-feeding
Talk to your doctor before you take Onglyza if you are pregnant or plan to become pregnant. You
should not use Onglyza if you are pregnant.
Talk to your doctor if you want to breast-feed while taking this medicine. It is not known if Onglyza
passes into human breast milk.
Driving and using machines
If you feel dizzy while taking Onglyza, do not drive or use any tools or machines.
Important information about some of the ingredients of Onglyza
Onglyza contains lactose (milk sugar). If you have been told by your doctor that you have an
intolerance to some sugars, contact your doctor before taking this medicine.
3.
HOW TO TAKE ONGLYZA
Always take Onglyza exactly as your doctor has told you. Check with your doctor or pharmacist if you
are not sure.
The usual dose of Onglyza is one 5 mg tablet once a day.
If you have kidney problems, your doctor may prescribe a lower dose. This is one 2.5 mg tablet once a
day.
Your doctor will prescribe Onglyza together with another oral anti-diabetic medicine. Remember to
take this other medicine as directed by your doctor to achieve the best results for your health.
40
How to take Onglyza
Swallow the tablet whole with some water. You can take the tablet with or without food. The tablet
can be taken at any time of the day, however try to take your tablet at the same time each day. This
will help you to remember to take it.
If you take more Onglyza than you should
If you take more Onglyza tablets than you should, talk to a doctor straight away.
If you forget to take Onglyza
• If you forget to take a dose of Onglyza, take it as soon as you remember it. However, if it is
nearly time for the next dose, skip the missed dose.
• Do not take a double dose to make up for a forgotten dose. Never take two doses on the same
day.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Onglyza can cause side effects, although not everybody gets them.
Some symptoms need immediate medical attention:
You should stop taking Onglyza and see your doctor immediately if you experience the following
symptoms of low blood sugar: trembling, sweating, anxiety, blurred vision, tingling lips, paleness,
mood change, vagueness or confusion (hypoglycaemia).
Side effects below may occur with certain frequencies, which are defined as follows:
• Very common: affects more than 1 user in 10
• Common: affects 1 to 10 users in 100
• Uncommon: affects 1 to 10 users in 1,000
• Rare: affects 1 to 10 users in 10,000
• Very rare: affects less than 1 user in 10,000
• Not known: frequency cannot be estimated from the available data
Some patients have had the following side effects while taking Onglyza and metformin:
• Common: infection of the upper airways, infection of the urinary tract, inflamed stomach or gut
usually caused by an infection (gastroenteritis), infection of the upper airways with a feeling of
pain and fullness behind your cheeks and eyes (sinusitis), inflamed nose or throat
(nasopharyngitis) (signs of this may include a cold or a sore throat), headache, muscle pain
(myalgia), vomiting, inflammation of the stomach (gastritis) and indigestion (dyspepsia).
• Uncommon: joint pain (arthralgia) and difficulties in getting or maintaining an erection (erectile
dysfunction).
Some patients have had the following side effects while taking Onglyza and a sulphonylurea:
• Very common: low blood sugar (hypoglycaemia)
• Common: infection of the upper airways, infection of the urinary tract, inflamed stomach or gut
usually caused by an infection (gastroenteritis), infection of the upper airways with a feeling of
pain and fullness behind your cheeks and eyes (sinusitis), headache and vomiting.
• Uncommon: fatigue, abnormal lipid (fatty acids) levels (dyslipidemia, hypertriglyceridemia).
Some patients have had the following side effects while taking Onglyza and a thiazolidinedione:
• Common: infection of the upper airways, infection of the urinary tract, inflamed stomach or gut
usually caused by an infection (gastroenteritis), infection of the upper airways with a feeling of
pain and fullness behind your cheeks and eyes (sinusitis), headache, vomiting, swelling of the
hands, ankles or feet (peripheral oedema).
41
Some patients have had the following additional side effect while taking Onglyza alone: Common:
dizziness.
Some patients have had a small reduction in the number of one type of white blood cells (lymphocytes)
shown in a blood test. In addition, some patients have reported rash and skin reactions
(hypersensitivity) while taking Onglyza.
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 ONGLYZA
Keep out of the reach and sight of children.
Do not use Onglyza after the expiry date which is stated on the blister and the carton after EXP. The
expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Do not use Onglyza if the package is damaged or shows signs of tampering.
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 Onglyza contains
• The active substance is saxagliptin.
Each Onglyza 2.5 mg film-coated tablet contains 2.5 mg saxagliptin (as hydrochloride).
• The other ingredients are
Tablet core: lactose monohydrate, cellulose microcrystalline (E460i), croscarmellose
sodium (E468),
magnesium stearate.
Film-coating: polyvinyl alcohol, macrogol/3350, titanium dioxide (E171) and talc (E553b).
Onglyza 2.5 mg tablets also contain iron oxide yellow (E172).
Printing ink: shellac, indigo carmine aluminium lake (E132).
What Onglyza looks like and contents of the pack
• Onglyza 2.5 mg film-coated tablets are pale yellow to light yellow, biconvex, round. They have
“2.5” printed on one side and “4214” printed on the other side, in blue ink.
• Onglyza is available in aluminum foil blisters.
• Onglyza 2.5 mg tablets are available in pack sizes of 14, 28, or 98 film-coated tablets in non-
perforated calendar blisters and 30x1 or 90x1 film-coated tablets in perforated unit dose blisters.
Not all pack sizes may be marketed in your country.
Marketing Authorisation Holder and Manufacturer
Marketing authorisation holder
Bristol-Myers Squibb/AstraZeneca EEIG
Bristol-Myers Squibb House
Uxbridge Business Park
42
Sanderson Road
Uxbridge
Middlesex
UB8 1DH
United Kingdom
Manufacturer
Bristol-Myers Squibb Company
Contrada Fontana del Ceraso
IT-03012 Anagni (FR)
Italy
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
BRISTOL-MYERS SQUIBB BELGIUM
S.A./N.V.
Tél/Tel: + 32 2 352 76 11
Luxembourg/Luxemburg
BRISTOL-MYERS SQUIBB BELGIUM
S.A./N.V.
Tél/Tel: + 32 2 352 76 11
България
BRISTOL-MYERS SQUIBB
GYÓGYSZERKERESKEDELMI KFT.
Teл.: + 359 800 12 400
Magyarország
BRISTOL-MYERS SQUIBB
GYÓGYSZERKERESKEDELMI KFT.
Tel.: + 36 1 301 9700
Česká republika
BRISTOL-MYERS SQUIBB SPOL. S R.O.
Tel: + 420 221 016 111
Malta
BRISTOL-MYERS SQUIBB S.R.L.
Tel: + 39 06 50 39 61
Danmark
BRISTOL-MYERS SQUIBB
Tlf: + 45 45 93 05 06
Nederland
BRISTOL-MYERS SQUIBB BV
Tel: + 31 34 857 42 22
Deutschland
BRISTOL-MYERS SQUIBB GMBH & CO.
KGAA
Tel: + 49 89 121 42 0
Norge
BRISTOL-MYERS SQUIBB NORWAY LTD
Tlf: + 47 67 55 53 50
Eesti
BRISTOL-MYERS SQUIBB
GYÓGYSZERKERESKEDELMI KFT.
Tel: + 372 6827 400
Österreich
BRISTOL-MYERS SQUIBB GESMBH
Tel: + 43 1 60 14 30
Ελλάδα
BRISTOL-MYERS SQUIBB A.E.
Τηλ: + 30 210 6074300
Polska
BRISTOL-MYERS SQUIBB POLSKA SP. Z
O.O.
Tel.: + 48 22 5796666
España
BRISTOL-MYERS SQUIBB, S.A.
Tel: + 34 91 456 53 00
Portugal
BRISTOL-MYERS SQUIBB FARMACÊUTICA
PORTUGUESA, S.A.
Tel: + 351 21 440 70 00
France
BRISTOL-MYERS SQUIBB SARL
Tél: + 33 (0)810 410 500
România
BRISTOL-MYERS SQUIBB
GYÓGYSZERKERESKEDELMI KFT.
43
Tel: + 40 (0)21 272 16 00
Ireland
BRISTOL-MYERS SQUIBB
PHARMACEUTICALS LTD
Tel: + 353 (1 800) 749 749
Slovenija
BRISTOL-MYERS SQUIBB SPOL. S R.O.
Tel: + 386 1 236 47 00
Ísland
VISTOR HFSími:
+ 354 535 7000
Slovenská republika
BRISTOL-MYERS SQUIBB SPOL. S R.O.
Tel: + 421 2 59298411
Italia
BRISTOL-MYERS SQUIBB S.R.L.
Tel: + 39 06 50 39 61
Suomi/Finland
OY BRISTOL-MYERS SQUIBB (FINLAND)
ABPuh/
Tel: + 358 9 251 21 230
Κύπρος
BRISTOL-MYERS SQUIBB A.E.
Τηλ: + 357 800 92666
Sverige
BRISTOL-MYERS SQUIBB AB
Tel: + 46 8 704 71 00
Latvija
BRISTOL-MYERS SQUIBB
GYÓGYSZERKERESKEDELMI KFT.
Tel: + 371 750 21 85
United Kingdom
BRISTOL-MYERS SQUIBB
PHARMACEUTICALS LTD
Tel: + 44 (0800) 731 1736
Lietuva
BRISTOL-MYERS SQUIBB
GYÓGYSZERKERESKEDELMI KFT.
Tel: + 370 5 2790 762
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
www.ema.europa.eu.
---------------------------------------------------------------------------------------------------------------------------
44
PACKAGE LEAFLET: INFORMATION FOR THE USER
Onglyza 5 mg film-coated tablets
Saxagliptin
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
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 Onglyza is and what it is used for
2.
Before you take Onglyza
4.
Possible side effects
6.
How to store Onglyza
6.
Further information
1. WHAT ONGLYZA IS AND WHAT IT IS USED FOR
Onglyza contains the active substance saxagliptin, which belongs to a group of medicines called ‘oral
anti-diabetics’. They work by helping to control the level of sugar in your blood.
Onglyza is used for adult patients aged 18 years and older with ‘type 2 diabetes’, if the disease cannot
be adequately controlled with one oral anti-diabetic medicine, diet and exercise. Onglyza is used
together with another oral anti-diabetic medicine.
It is important to keep following the advice about diet and exercise that you have been given by your
doctor or nurse.
2. BEFORE YOU TAKE ONGLYZA
Do not take Onglyza
-
if you are allergic (hypersensitive) to saxagliptin or any of the other ingredients of Onglyza
(listed in section 6, ‘What Onglyza contains’).
Take special care with Onglyza
Check with your doctor or pharmacist before taking Onglyza if you:
• have type 1 diabetes (your body does not produce any insulin) or diabetic ketoacidos (a
complication of diabetes with high blood sugar, rapid weight loss, nausea or vomiting). Onglyza
should not be used to treat these conditions;
• are taking an anti-diabetic medicine known as ‘sulphonylurea’, your doctor may want to reduce
your dose of sulphonylurea when you take it together with Onglyza in order to avoid low blood
sugar;
• have had allergic reactions to any other medicines that you take to control the amount of sugar
in your blood;
• have a condition that reduces your defense against infections, such as a disease like AIDS or
from medicines that you might take after an organ transplant;
• suffer from heart failure;
45
-
If you have any further questions, ask your doctor, nurse, or pharmacist.
3.
How to take Onglyza
• have moderate to severe kidney problems, you will need to take a lower dose of Onglyza;
• have moderate or severe liver problems. If you have severe liver problems, then Onglyza is not
recommended for you
Diabetic skin lesions are a common complication of diabetes. Rash has been seen with Onglyza and
with certain anti-diabetic medicines in the same class as Onglyza. You are advised to follow the
recommendations for skin and foot care that you are given by your doctor or nurse.
Onglyza is not recommended for children and adolescents under 18 years.
Using other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This
includes medicines that you buy without a prescription.
In particular, you should tell your doctor if you are using medicines containing any of the following
active substances:
• Carbamazepine, phenobarbital or phenytoin. These may be used to control fits (seizures) or
chronic pain.
• Dexamethasone – a steroid medicine. This may be used to treat inflammation in different body
parts and organs.
• Rifampicin. This is an antibiotic used to treat infections such as tuberculosis
• Ketoconazole. This may be used to treat fungal infections.
• Diltiazem. This is a medicine used to lower blood pressure.
Taking Onglyza with food and drink
You can take Onglyza with or without food.
Pregnancy and breast-feeding
Talk to your doctor before you take Onglyza if you are pregnant or plan to become pregnant. You
should not use Onglyza if you are pregnant.
Talk to your doctor if you want to breast-feed while taking this medicine. It is not known if Onglyza
passes into human breast milk.
Driving and using machines
If you feel dizzy while taking Onglyza, do not drive or use any tools or machines.
Important information about some of the ingredients of Onglyza
Onglyza contains lactose (milk sugar). If you have been told by your doctor that you have an
intolerance to some sugars, contact your doctor before taking this medicine.
3. HOW TO TAKE ONGLYZA
Always take Onglyza exactly as your doctor has told you. Check with your doctor or pharmacist if you
are not sure.
The usual dose of Onglyza is one 5 mg tablet once a day.
If you have kidney problems, your doctor may prescribe a lower dose. This is one 2.5 mg tablet once a
day.
Your doctor will prescribe Onglyza together with another oral anti-diabetic medicine. Remember to
take this other medicine as directed by your doctor to achieve the best results for your health.
How to take Onglyza
46
Swallow the tablet whole with some water. You can take the tablet with or without food. The tablet
can be taken at any time of the day, however try to take your tablet at the same time each day. This
will help you to remember to take it.
If you take more Onglyza than you should
If you take more Onglyza tablets than you should, talk to a doctor straight away.
If you forget to take Onglyza
• If you forget to take a dose of Onglyza, take it as soon as you remember it. However, if it is
nearly time for the next dose, skip the missed dose.
• Do not take a double dose to make up for a forgotten dose. Never take two doses on the same
day.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Onglyza can cause side effects, although not everybody gets them.
Some symptoms need immediate medical attention:
You should stop taking Onglyza and see your doctor immediately if you experience the following
symptoms of low blood sugar: trembling, sweating, anxiety, blurred vision, tingling lips, paleness,
mood change, vagueness or confusion (hypoglycaemia).
Side effects below may occur with certain frequencies, which are defined as follows:
• Very common: affects more than 1 user in 10
• Common: affects 1 to 10 users in 100
• Uncommon: affects 1 to 10 users in 1,000
• Rare: affects 1 to 10 users in 10,000
• Very rare: affects less than 1 user in 10,000
• Not known: frequency cannot be estimated from the available data
Some patients have had the following side effects while taking Onglyza and metformin:
• Common: infection of the upper airways, infection of the urinary tract, inflamed stomach or gut
usually caused by an infection (gastroenteritis), infection of the upper airways with a feeling of
pain and fullness behind your cheeks and eyes (sinusitis), inflamed nose or throat
(nasopharyngitis) (signs of this may include a cold or a sore throat), headache, muscle pain
(myalgia), vomiting, inflammation of the stomach (gastritis) and indigestion (dyspepsia).
• Uncommon: joint pain (arthralgia) and difficulties in getting or maintaining an erection (erectile
dysfunction).
Some patients have had the following side effects while taking Onglyza and a sulphonylurea:
• Very common: low blood sugar (hypoglycaemia)
• Common: infection of the upper airways, infection of the urinary tract, inflamed stomach or gut
usually caused by an infection (gastroenteritis), infection of the upper airways with a feeling of
pain and fullness behind your cheeks and eyes (sinusitis), headache and vomiting.
• Uncommon: fatigue, abnormal lipid (fatty acids) levels (dyslipidemia, hypertriglyceridemia).
Some patients have had the following side effects while taking Onglyza and a thiazolidinedione:
• Common: infection of the upper airways, infection of the urinary tract, inflamed stomach or gut
usually caused by an infection (gastroenteritis), infection of the upper airways with a feeling of
pain and fullness behind your cheeks and eyes (sinusitis), headache, vomiting, swelling of the
hands, ankles or feet (peripheral oedema).
47
Some patients have had the following additional side effect while taking Onglyza alone: Common:
dizziness.
Some patients have had a small reduction in the number of one type of white blood cells (lymphocytes)
shown in a blood test. In addition, some patients have reported rash and skin reactions
(hypersensitivity) while taking Onglyza.
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 ONGLYZA
Keep out of the reach and sight of children.
Do not use Onglyza after the expiry date which is stated on the blister and the carton after EXP. The
expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Do not use Onglyza if the package is damaged or shows signs of tampering.
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 Onglyza contains
• The active substance is saxagliptin.
Each Onglyza 5 mg film-coated tablet contains 5 mg saxagliptin (as hydrochloride).
• The other ingredients are
Tablet core: lactose monohydrate, cellulose microcrystalline (E460i), croscarmellose
sodium (E468),
magnesium stearate.
Film-coating: polyvinyl alcohol, macrogol/3350, titanium dioxide (E171) and talc (E553b).
Onglyza 5 mg tablets also contain iron oxide red (E172).
Printing ink: shellac, indigo carmine aluminium lake (E132).
What Onglyza looks like and contents of the pack
• Onglyza 5 mg film-coated tablets are pink, biconvex, round. They have “5” printed on one side
and “4215” printed on the other side, in blue ink.
• Onglyza is available in aluminum foil blisters.
• Onglyza 5 mg tablets are available in pack sizes of 14, 28, 56, or 98 film-coated tablets in
non-perforated blisters, 14, 28, 56, or 98 film-coated tablets in non-perforated calendar blisters
and 30x1 or 90x1 film-coated tablets in perforated unit dose blisters.
Not all pack sizes may be marketed in your country.
Marketing Authorisation Holder and Manufacturer
Marketing authorisation holder
Bristol-Myers Squibb/AstraZeneca EEIG
Bristol-Myers Squibb House
48
Uxbridge Business Park
Sanderson Road
Uxbridge
Middlesex
UB8 1DH
United Kingdom
Manufacturer
Bristol-Myers Squibb Company
Contrada Fontana del Ceraso
IT-03012 Anagni (FR)
Italy
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
BRISTOL-MYERS SQUIBB BELGIUM
S.A./N.V.
Tél/Tel: + 32 2 352 76 11
Luxembourg/Luxemburg
BRISTOL-MYERS SQUIBB BELGIUM
S.A./N.V.
Tél/Tel: + 32 2 352 76 11
България
BRISTOL-MYERS SQUIBB
GYÓGYSZERKERESKEDELMI KFT.
Teл.: + 359 800 12 400
Magyarország
BRISTOL-MYERS SQUIBB
GYÓGYSZERKERESKEDELMI KFT.
Tel.: + 36 1 301 9700
Česká republika
BRISTOL-MYERS SQUIBB SPOL. S R.O.
Tel: + 420 221 016 111
Malta
BRISTOL-MYERS SQUIBB S.R.L.
Tel: + 39 06 50 39 61
Danmark
BRISTOL-MYERS SQUIBB
Tlf: + 45 45 93 05 06
Nederland
BRISTOL-MYERS SQUIBB BV
Tel: + 31 34 857 42 22
Deutschland
BRISTOL-MYERS SQUIBB GMBH & CO.
KGAA
Tel: + 49 89 121 42 0
Norge
BRISTOL-MYERS SQUIBB NORWAY LTD
Tlf: + 47 67 55 53 50
Eesti
BRISTOL-MYERS SQUIBB
GYÓGYSZERKERESKEDELMI KFT.
Tel: + 372 6827 400
Österreich
BRISTOL-MYERS SQUIBB GESMBH
Tel: + 43 1 60 14 30
Ελλάδα
BRISTOL-MYERS SQUIBB A.E.
Τηλ: + 30 210 6074300
Polska
BRISTOL-MYERS SQUIBB POLSKA SP. Z
O.O.
Tel.: + 48 22 5796666
España
BRISTOL-MYERS SQUIBB, S.A.
Tel: + 34 91 456 53 00
Portugal
BRISTOL-MYERS SQUIBB FARMACÊUTICA
PORTUGUESA, S.A.
Tel: + 351 21 440 70 00
France
BRISTOL-MYERS SQUIBB SARL
România
BRISTOL-MYERS SQUIBB
49
Tél: + 33 (0)810 410 500
GYÓGYSZERKERESKEDELMI KFT.
Tel: + 40 (0)21 272 16 00
Ireland
BRISTOL-MYERS SQUIBB
PHARMACEUTICALS LTD
Tel: + 353 (1 800) 749 749
Slovenija
BRISTOL-MYERS SQUIBB SPOL. S R.O.
Tel: + 386 1 236 47 00
Ísland
VISTOR HFSími:
+ 354 535 7000
Slovenská republika
BRISTOL-MYERS SQUIBB SPOL. S R.O.
Tel: + 421 2 59298411
Italia
BRISTOL-MYERS SQUIBB S.R.L.
Tel: + 39 06 50 39 61
Suomi/Finland
OY BRISTOL-MYERS SQUIBB (FINLAND)
ABPuh/
Tel: + 358 9 251 21 230
Κύπρος
BRISTOL-MYERS SQUIBB A.E.
Τηλ: + 357 800 92666
Sverige
BRISTOL-MYERS SQUIBB AB
Tel: + 46 8 704 71 00
Latvija
BRISTOL-MYERS SQUIBB
GYÓGYSZERKERESKEDELMI KFT.
Tel: + 371 750 21 85
United Kingdom
BRISTOL-MYERS SQUIBB
PHARMACEUTICALS LTD
Tel: + 44 (0800) 731 1736
Lietuva
BRISTOL-MYERS SQUIBB
GYÓGYSZERKERESKEDELMI KFT.
Tel: + 370 5 2790 762
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
www.ema.europa.eu.
---------------------------------------------------------------------------------------------------------------------------
50
Source: European Medicines Agency
- Please bookmark this page (add it to your favorites).
- If you wish to link to this page, you can do so by referring to the URL address below this line.
https://theodora.com/drugs/eu/onglyza.html
Copyright © 1995-2021 ITA all rights reserved.