ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
AVANDIA
2 mg film-coated tablets
2.
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Excipient
Contains lactose (approximately 108 mg).
For a full list of excipients, see section 6.1.
3.
Film-coated tablet (tablet).
Pink film-coated tablets debossed with “GSK” on one side and "2" on the other side.
4.
Rosiglitazone is indicated in the treatment of type 2 diabetes mellitus:
as
monotherapy
–
in adults (particularly overweight adults) inadequately controlled by diet and exercise for whom
metformin is inappropriate because of contraindications or intolerance
as
dual oral therapy
in combination with
–
metformin, in adults (particularly overweight adults) with insufficient glycaemic control despite
maximal tolerated dose of monotherapy with metformin
–
a sulphonylurea, only in adults who show intolerance to metformin or for whom metformin is
contraindicated, with insufficient glycaemic control despite monotherapy with a sulphonylurea
as
triple oral therapy
in combination with
–
metformin and a sulphonylurea, in adults (particularly overweight adults) with insufficient
glycaemic control despite dual oral therapy (see section 4.4).
Posology
Rosiglitazone treatment is usually initiated at 4 mg/day. This dose can
be increased to 8 mg/day after
eight
weeks if greater glycaemic control is required. In patients administered rosiglitazone in
combination with a sulphonylurea, an increase in rosiglitazone to 8 mg/day should be undertaken
cautiously following appropriate clinical evaluation to assess the patient's risk of developing adverse
reactions relating to fluid retention (see sections 4.4 and 4.8).
Rosiglitazone may be given once or twice a day (either as one daily dose, or two divided doses).
Special populations
Elderly (
≥
65 years old) (see section 4.4 Fluid retention and cardiac failure)
No dose adjustment is required in the elderly.
2
Each tablet contains rosiglitazone maleate corresponding to 2 mg of rosiglitazone.
Renal impairment (see section 4.4 Fluid retention and cardiac failure)
No dose adjustment is required in patients with mild and moderate renal insufficiency. Limited data
are available in patients with severe renal insufficiency (creatinine clearance < 30 ml/min) and
therefore rosiglitazone should be used with caution in these patients.
Hepatic impairment
Rosiglitazone must not be used in patients with hepatic impairment (see section 4.3).
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Method of administration
The tablets should be swallowed with water and may be taken with or without food.
To improve medicine compliance, it is suggested that patients are advised to take the tablets around
the same time every day.
Use of rosiglitazone is contraindicated in patients with:
−
known hypersensitivity to rosiglitazone or to any of the excipients
−
cardiac failure or history of cardiac failure (NYHA class I to IV)
−
an Acute Coronary Syndrome (unstable angina, non-ST segment elevation myocardial
infarction (NSTEMI) and ST segment elevation myocardial infarction (STEMI)) (see section
4.4)
−
hepatic impairment
-
diabetic ketoacidosis or diabetic pre-coma.
Fluid retention and cardiac failure
Thiazolidinediones can cause fluid retention which may exacerbate or precipitate signs or symptoms
of congestive heart failure. Rosiglitazone can cause dose-dependent fluid retention. The possible
contribution of fluid retention to weight gain should be individually assessed as rapid and excessive
weight gain has been reported very rarely as a sign of fluid retention. All patients, particularly those
receiving concurrent insulin or sulphonylurea therapy, those at risk for heart failure, and those with
reduced cardiac reserve, should be monitored for signs and symptoms of adverse reactions relating to
fluid retention, including weight gain and heart failure. Increased monitoring of the patient is
recommended if rosiglitazone is used in combination with metformin and insulin. Rosiglitazone
should be discontinued if any deterioration in cardiac status occurs.
Heart failure was also reported more frequently in patients with a history of heart failure; oedema and
heart failure was also reported more frequently in elderly patients and in patients with mild or
moderate renal failure. Caution should be exercised in patients over 75 years because of the limited
experience in this patient group. Since NSAIDs and rosiglitazone are associated with fluid retention,
concomitant administration may increase the risk of oedema.
Combination with insulin
An increased incidence of cardiac failure has been observed in clinical trials when rosiglitazone is
used in combination with insulin. Insulin and rosiglitazone are both associated with fluid retention,
3
Paediatric population
There are no data available on the use of rosiglitazone in children under 10 years of age. For children
and adolescents aged 10 to 17 years, there are limited data on rosiglitazone as monotherapy (see
sections 5.1 and 5.2). The available data do not support efficacy in the paediatric population and
therefore such use is not recommended.
concomitant administration may increase the risk of oedema and could increase the risk of ischaemic
heart disease. Insulin should only be added to established rosiglitazone therapy in exceptional cases
and under close supervision.
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Acute Coronary Syndrome (ACS)
Patients experiencing an ACS have not been studied in rosiglitazone controlled clinical trials. In view
of the potential for development of heart failure in these patients, rosiglitazone should therefore not be
initiated in patients having an acute coronary event and it should be discontinued during the acute
phase (see section 4.3).
Monitoring of liver function
There have been rare reports of hepatocellular dysfunction during post-marketing experience (see
section 4.8). There is limited experience with rosiglitazone in patients with elevated liver enzymes
(ALT >2.5X upper limit of normal). Therefore, liver enzymes should be checked prior to the initiation
of therapy with rosiglitazone in all patients and periodically thereafter based on clinical judgement.
Therapy with rosiglitazone should not be initiated in patients with increased baseline liver enzyme
levels (ALT >2.5X upper limit of normal) or with any other evidence of liver disease. If ALT levels
are increased to >3X upper limit of normal during rosiglitazone therapy, liver enzyme levels should be
reassessed as soon as possible. If ALT levels remain >3X the upper limit of normal, therapy should be
discontinued. If any patient develops symptoms suggesting hepatic dysfunction, which may include
unexplained nausea, vomiting, abdominal pain, fatigue, anorexia and/or dark urine, liver enzymes
should be checked. The decision whether to continue the patient on therapy with rosiglitazone should
be guided by clinical judgement pending laboratory evaluations. If jaundice is observed, treatment
with rosiglitazone should be discontinued.
Eye disorders
Post-marketing reports of new-onset or worsening diabetic macular oedema with decreased visual
acuity have been reported with thiazolidinediones, including rosiglitazone. Many of these patients
reported concurrent peripheral oedema. It is unclear whether or not there is a direct association
between rosiglitazone and macular oedema but prescribers should be alert to the possibility of macular
oedema if patients report disturbances in visual acuity and appropriate ophthalmologic referral should
be considered.
Weight gain
In clinical trials with rosiglitazone there was evidence of dose-related weight gain, which was greater
when used in combination with insulin. Therefore weight should be closely monitored, given that it
may be attributable to fluid retention, which may be associated with cardiac failure.
Anaemia
Rosiglitazone treatment is associated with a dose-related reduction of haemoglobin levels. In patients
with low haemoglobin levels before initiating therapy, there is an increased risk of anaemia during
treatment with rosiglitazone.
Hypoglycaemia
Patients receiving rosiglitazone in combination therapy with a sulphonylurea or with insulin, may be at
risk for dose-related hypoglycaemia. Increased monitoring of the patient and a reduction in the dose of
the concomitant medicinal product may be necessary.
Triple oral therapy
4
Myocardial ischaemia
A retrospective analysis of data from 42 pooled short-term clinical studies indicated that treatment
with rosiglitazone may be associated with an increased risk of myocardial ischaemic events. However,
in their entirety the available data on the risk of cardiac ischaemia are inconclusive (see section 4.8).
There are limited clinical trial data in patients with ischaemic heart disease and/or peripheral arterial
disease. Therefore, as a precaution, the use of rosiglitazone is not recommended in these patients,
particularly those with myocardial ischaemic symptoms.
The use of rosiglitazone in triple oral therapy, in combination with metformin and a sulphonylurea,
may be associated with increased risks for fluid retention and heart failure, as well as hypoglycaemia
(see section 4.8). Increased monitoring of the patient is recommended and adjustment of the dose of
sulphonylurea may be necessary. The decision to initiate triple oral therapy should include
consideration of the alternative to switch the patient to insulin.
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Others
Premenopausal women have received rosiglitazone during clinical studies. Although hormonal
imbalance has been seen in preclinical studies (see section 5.3), no significant adverse reactions
associated with menstrual disorders have been observed. As a consequence of improving insulin
sensitivity, resumption of ovulation may occur in patients who are anovulatory due to insulin
resistance. Patients should be aware of the risk of pregnancy and if a patient wishes to become
pregnant or if pregnancy occurs the treatment should be discontinued (see section 4.6).
Rosiglitazone should be used with caution in patients with severe renal insufficiency (creatinine
clearance < 30 ml/min).
Rosiglitazone should be used with caution during concomitant administration of CYP2C8 inhibitors
(e.g. gemfibrozil) or inducers (e.g. rifampicin). Glycaemic control should be monitored closely.
Rosiglitazone dose adjustment within the recommended posology or changes in diabetic treatment
should be considered (see section 4.5).
AVANDIA tablets contain lactose and therefore should not be administered to patients with rare
hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose
malabsorption.
In vitro
studies demonstrate that rosiglitazone is predominantly metabolised by CYP2C8, with
CYP2C9 as only a minor pathway.
Co-administration of rosiglitazone with gemfibrozil (an inhibitor of CYP2C8) resulted in a twofold
increase in rosiglitazone plasma concentrations. Since there is a potential for an increase in the risk of
dose-related adverse reactions, a decrease in rosiglitazone dose may be needed. Close monitoring of
glycaemic control should be considered (see section 4.4).
Co-administration of rosiglitazone with rifampicin (an inducer of CYP2C8) resulted in a 66 %
decrease in rosiglitazone plasma concentrations. It cannot be excluded that other inducers (e.g.
phenytoin, carbamazepine, phenobarbital, St John’s wort) may also affect rosiglitazone exposure. The
rosiglitazone dose may need to be increased. Close monitoring of glycaemic control should be
considered (see section 4.4).
Clinically significant interactions with CYP2C9 substrates or inhibitors are not anticipated.
Concomitant administration with the oral anti-diabetic medicinal products metformin, glibenclamide
and acarbose did not result in any clinically relevant pharmacokinetic interactions with rosiglitazone.
Moderate ingestion of alcohol with rosiglitazone has no effect on glycaemic control.
No clinically relevant interactions with digoxin, the CYP2C9 substrate warfarin, the CYP3A4
substrates nifedipine, ethinylestradiol or norethindrone were observed after co-administration with
5
Bone disorders
Long-term studies show an increased incidence of bone fractures in patients, particularly female
patients, taking rosiglitazone (see section 4.8). The majority of the fractures have occurred in the upper
limbs and distal lower limbs. In females, this increased incidence was noted after the first year of
treatment and persisted during long-term treatment. The risk of fracture should be considered in the
care of patients, especially female patients, treated with rosiglitazone.
rosiglitazone.
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Breast-feeding
Rosiglitazone has been detected in the milk of experimental animals. It is not known whether breast-
feeding will lead to exposure of the infant to the medicinal product. Rosiglitazone should therefore not
be used in women who are breast-feeding.
Fertility
As a consequence of improving insulin sensitivity, resumption of ovulation may occur in patients who
are anovulatory due to insulin resistance (e.g. patients with polycystic ovary syndrome). Patients
should be aware of the risk of pregnancy and if a patient wishes to become pregnant or if pregnancy
occurs the treatment should be discontinued.
AVANDIA has no or negligible influence on the ability to drive and use machines.
Clinical trial data
The most commonly reported adverse reactions during treatment with rosiglitazone are dose-
dependent fluid-related reactions which include oedema and anaemia. Concurrent rosiglitazone and
sulphonylurea therapy may be associated with an increased frequency of hypoglycaemia and anaemia
compared to rosiglitazone monotherapy. It is important to monitor patients for fluid retention which
may exacerbate or precipitate signs or symptoms of congestive heart failure (see section 4.4).
Adverse reactions for each treatment regimen are presented below by system organ class and absolute
frequency. For dose-related adverse reactions the frequency category reflects the higher dose of
rosiglitazone. Frequency categories do not account for other factors including varying study duration,
pre-existing conditions and baseline patient characteristics. Adverse reaction frequency categories
assigned based on clinical trial experience may not reflect the frequency of adverse reactions occurring
during normal clinical practice. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100
to < 1/10); and uncommon (≥ 1/1000 to < 1/100).
Table 1 lists adverse reactions identified from an overview of clinical trials involving over 5,000
rosiglitazone-treated patients. Within each system organ class, adverse reactions are presented in the
table by decreasing frequency for the rosiglitazone monotherapy treatment regimen. Within each
frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1. The frequency of adverse reactions identified from clinical trial data
Adverse reaction
Frequency of adverse reaction by treatment regimen
RSG
RSG +
MET
RSG + SU
RSG +MET +SU
Blood and lymphatic system disorders
anaemia
Common
Common Common
Common
leucopaenia
Common
thrombocytopaenia
Common
6
Pregnancy
Rosiglitazone has been reported to cross the human placenta and to be detectable in foetal tissues.
There are no adequate data from the use of rosiglitazone in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Rosiglitazone
should not be used during pregnancy.
granulocytopaenia
Common
Metabolism and nutrition disorders
hypercholesterolaemia
1
Common
Common Common
Common
hypertriglyceridaemia
Common
Common
hyperlipaemia
Common Common Common
Common
weight increase
Common Common Common
Common
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Common
Uncommon
hypoglycaemia
Common Very common
Very common
Nervous system disorders
dizziness*
Common Common
headache*
Common
Cardiac disorders
cardiac failure
2
Common Common
Common
cardiac ischaemia
3*
Common Common Common
Common
Gastrointestinal disorders
constipation
Common Common Common
Common
Musculoskeletal and connective tissue disorders
bone fractures
4
Common Common Common
myalgia*
Common
General disorders and administration site conditions
oedema Common Common Very common Very common
RSG - Rosiglitazone monotherapy; RSG + MET - Rosiglitazone with metformin; RSG + SU -
Rosiglitazone with sulphonylurea; RSG + MET + SU - Rosiglitazone with metformin and
sulphonylurea
*The frequency category for the background incidence of these adverse reactions, as taken from
placebo group data from clinical trials, is 'common'.
1
Hypercholesterolaemia was reported in up to 5.3 % of patients treated with rosiglitazone
(monotherapy, dual or triple oral therapy). The elevated total cholesterol levels were associated with
increase in both LDLc and HDLc, but the ratio of total cholesterol: HDLc was unchanged or improved
in long term studies. Overall, these increases were generally mild to moderate and usually did not
require discontinuation of treatment.
2
An increased incidence of heart failure has been observed when rosiglitazone was added to treatment
regimens with a sulphonylurea (either as dual or triple therapy), and appeared higher with 8 mg
rosiglitazone compared to 4 mg rosiglitazone (total daily dose). The incidence of heart failure on triple
oral therapy was 1.4 % in the main double blind study, compared to 0.4 % for metformin plus
sulphonylurea dual therapy. The incidence of heart failure in combination with insulin (rosiglitazone
added to established insulin therapy) was 2.4 %, compared to insulin alone, 1.1 %. Moreover in
patients with congestive heart failure NYHA class I-II, a placebo-controlled one-year trial
demonstrated worsening or possible worsening of heart failure in 6.4 % of patients treated with
rosiglitazone, compared with 3.5 % on placebo.
3
In a retrospective analysis of data from 42 pooled short-term clinical studies, the overall incidence of
events typically associated with cardiac ischaemia was higher for rosiglitazone containing regimens,
2.00 % versus combined active and placebo comparators, 1.53 % [hazard ratio (HR) 1.30 (95 %
confidence interval (CI) 1.004 - 1.69)]. This risk was increased when rosiglitazone was added to
established insulin and in patients receiving nitrates for known ischaemic heart disease. In an update to
this retrospective analysis that included 10 further studies that met the criteria for inclusion, but were
7
increased appetite
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In double-blind clinical trials with rosiglitazone the incidence of elevations of ALT greater than three
times the upper limit of normal was equal to placebo (0.2 %) and less than that of the active
comparators (0.5 % metformin/sulphonylureas). The incidence of all adverse reactions relating to liver
and biliary systems was < 1.5 % in any treatment group and similar to placebo.
Post-marketing data
In addition to the adverse reactions identified from clinical trial data, the adverse reactions presented
in Table 2 have been identified in post approval use of rosiglitazone. Frequencies are defined as: rare
(≥1/10,000 to <1/1000) and very rare (<1/10,000).
Table 2. The frequency of adverse reactions identified from post-marketing data
Adverse reaction
Frequency
Immune system disorders
anaphylactic reaction
Very rare
angioedema
Very rare
skin reactions (e.g. urticaria, pruritus, rash)
Very rare
Metabolism and nutrition disorders
rapid and excessive weight gain
Very rare
Eye disorders
macular oedema
Rare
Cardiac disorders
congestive heart failure/pulmonary oedema
Rare
Hepatobiliary disorders
hepatic dysfunction, primarily evidenced by elevated hepatic enzymes
5
Rare
5
Rare cases of elevated liver enzymes and hepatocellular dysfunction have been reported. In very rare
cases a fatal outcome has been reported.
8
not available at the time of the original analysis, the overall incidence of events typically associated
with cardiac ischaemia was not statistically different for rosiglitazone containing regimens, 2.21 %
versus combined active and placebo comparators, 2.08 % [HR 1.098 (95 % CI 0.809 - 1.354)]. In a
prospective cardiovascular outcomes study (mean follow-up 5.5 years) the primary endpoint events of
cardiovascular death or hospitalisation were similar between rosiglitazone and active comparators
[HR 0.99 (95 % CI 0.85 - 1.16)]. Two other long-term prospective randomised controlled clinical trials
(9,620 patients, study duration >3 years in each study), comparing rosiglitazone to some other
approved oral antidiabetic medicinal products or placebo, have not confirmed or excluded the potential
risk of cardiac ischaemia. In their entirety, the available data on the risk of cardiac ischaemia are
inconclusive.
4
Long-term studies show an increased incidence of bone fracture in patients, particularly female
patients, taking rosiglitazone. In a monotherapy study, the incidence in females for rosiglitazone was
9.3 % (2.7 patients per 100 patient years) vs 5.1 % (1.5 patients per 100 patient years) for metformin
or 3.5 % (1.3 patients per 100 patient years) for glibenclamide. In another long-term study, there was
an increased incidence of bone fracture for subjects in the combined rosiglitazone group compared to
active control [8.3 % vs 5.3 %, Risk ratio 1.57 (95 % CI 1.26 - 1.97)]. The risk of fracture appeared to
be higher in females relative to control [11.5 % vs 6.3 %, Risk ratio 1.82 (95 % CI 1.37 - 2.41)], than
in males relative to control [5.3 % vs 4.3 %, Risk ratio 1.23 (95 % CI 0.85 - 1.77)]. Additional data are
necessary to determine whether there is an increased risk of fracture in males after a longer period of
follow-up. The majority of the fractures were reported in the upper limbs and distal lower limbs (see
section 4.4).
Limited data are available with regard to overdose in humans. In clinical studies in volunteers
rosiglitazone has been administered at single oral doses of up to 20 mg and no serious adverse
reactions were observed.
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5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in diabetes, blood glucose lowering drugs, excluding insulins,
ATC code: A10BG02
Rosiglitazone is a selective agonist at the PPARγ (peroxisomal proliferator activated receptor gamma)
nuclear receptor and is a member of the thiazolidinedione class of anti-diabetic medicinal products. It
reduces glycaemia by reducing insulin resistance at adipose tissue, skeletal muscle and liver.
Preclinical data
The antihyperglycaemic activity of rosiglitazone has been demonstrated in a number of animal models
of type 2 diabetes. In addition, rosiglitazone preserved ß-cell function as shown by increased
pancreatic islet mass and insulin content and prevented the development of overt hyperglycaemia in
animal models of type 2 diabetes. Rosiglitazone did not stimulate pancreatic insulin secretion or
induce hypoglycaemia in rats and mice. The major metabolite (para-hydroxy-sulphate) with high
affinity to the soluble human PPARγ, exhibited relatively high potency in a glucose tolerance assay in
obese mouse. The clinical relevance of this observation has not been fully elucidated.
Clinical trials data
The glucose lowering effects observed with rosiglitazone are gradual in onset with near maximal
reductions in fasting plasma glucose (FPG) evident following approximately 8 weeks of therapy. The
improved glycaemic control is associated with reductions in both fasting and post-prandial glucose.
Rosiglitazone was associated with increases in weight. In mechanistic studies, the weight increase was
predominantly shown to be due to increased subcutaneous fat with decreased visceral and intra-hepatic
fat.
Consistent with the mechanism of action, rosiglitazone reduced insulin resistance and improved
pancreatic ß-cell function. Improved glycaemic control was also associated with significant decreases
in free fatty acids. As a consequence of different but complementary mechanisms of action, dual oral
therapy of rosiglitazone
with
a sulphonylurea or metformin resulted in additive effects on glycaemic
control in type 2 diabetic patients.
In studies with a maximal duration of three years, rosiglitazone given once or twice daily produced a
sustained improvement in glycaemic control (FPG and HbA1c). A more pronounced glucose-lowering
effect was observed in obese patients. An outcome study has not been completed with rosiglitazone,
therefore the long-term benefits associated with improved glycaemic control have not been
demonstrated.
ADOPT (A Diabetes Outcome Progression Trial) was a multicentre, double-blind, controlled trial with
a treatment duration of 4-6 years (median duration of 4 years), in which rosiglitazone at doses of 4 to
8 mg/day was compared to metformin (500 mg to 2000 mg/day) and glibenclamide (2.5 to 15 mg/day)
in 4351 drug naive subjects recently diagnosed (≤3 years) with type 2 diabetes. Rosiglitazone
9
In the event of an overdose, it is recommended that appropriate supportive treatment should be
initiated, as dictated by the patient's clinical status. Rosiglitazone is highly protein bound and is not
cleared by haemodialysis.
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The RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in
Diabetes) trial was a large (4,447 subjects), open-label, prospective, controlled study (mean follow-up
5.5 years) in which patients with type 2 diabetes inadequately controlled with metformin or
sulphonylurea were randomised to add-on rosiglitazone or metformin or sulphonylurea. The mean
duration of diabetes in these patients was approximately 7 years. The adjudicated primary endpoint
was cardiovascular hospitalisation (which included hospitalisations for heart failure) or cardiovascular
death. Mean doses at the end of randomised treatment are shown in the following table:
Randomised Treatment
†
Mean (SD) dose at end of randomised treatment
Rosiglitazone (either SU or metformin) 6.7 (1.9) mg
Sulphonylurea (background metformin)
Glimepiride* 3.6 (1.8) mg
Metformin (background sulphonylurea) 1995.5 (682.6) mg
† Patients who took designated treatment as randomised in combination with the correct background
treatment and with evaluable data.
*Similar relative effective doses (i.e. approximately half maximal dose) for other sulphonylureas
(glibenclamide and glicazide).
No difference in the number of adjudicated primary endpoint events for rosiglitazone (321/2220)
versus active control (323/2227) (HR 0.99, CI 0.85-1.16) was observed, meeting the pre-defined non-
inferiority criterion of 1.20 (non-inferiority p = 0.02). HR and CI for key secondary endpoints were:
all-cause death (HR 0.86, CI 0.68-1.08), MACE (Major Adverse Cardiac Events - cardiovascular
death, acute myocardial infarction, stroke) (HR 0.93, CI 0.74-1.15), cardiovascular death (HR 0.84,
CI 0.59-1.18), acute myocardial infarction (HR 1.14, CI 0.80-1.63) and stroke (HR 0.72, CI 0.49-
1.06). In a sub-study at 18 months, add-on rosiglitazone dual therapy was non-inferior to the
combination of sulphonylurea plus metformin for lowering HbA1c. In the final analysis at 5 years, an
adjusted mean reduction from baseline in HbA1c of 0.14 % for patients on rosiglitazone added to
metformin versus an increase of 0.17 % for patients taking sulphonylurea added to metformin was
seen during treatment with randomised dual-combination therapy (p<0.0001 for treatment difference).
An adjusted mean reduction in HbA1c of 0.24 % was seen for patients taking rosiglitazone added to
sulphonylurea, versus a reduction in HbA1c of 0.10 % for patients taking metformin added to
sulphonylurea, (p=0.0083 for treatment difference). There was a significant increase in heart failure
(fatal and non-fatal) (HR 2.10, CI 1.35-3.27) and bone fractures (Risk Ratio 1.57, CI 1.26-1.97) in
rosiglitazone-containing treatments compared to active control (see sections 4.4 and 4.8). A total of
564 patients withdrew from cardiovascular follow-up, which accounted for 12.3 % of rosiglitazone
patients and 13 % of control patients; representing 7.2 % of patient-years lost for cardiovascular events
follow-up and 2.0 % of patient-years lost for all cause mortality follow-up.
Paediatric population
An active controlled clinical trial (rosiglitazone up to 8 mg daily or metformin up to 2,000 mg daily)
of 24 weeks duration was performed in 197 children and adolescents (10-17 years of age) with type 2
diabetes. Improvement in HbA1c from baseline achieved statistical significance only in the metformin
group. Rosiglitazone failed to demonstrate non-inferiority to metformin. Following rosiglitazone
treatment, there were no new safety concerns noted in children and adolescents compared to adult
patients with type 2 diabetes mellitus. No long-term efficacy and safety data are available in paediatric
10
treatment significantly reduced the risk of reaching monotherapy failure (FPG>10.0 mmol/L) by 63 %
relative to glibenclamide (HR 0.37, CI 0.30-0.45) and by 32 % relative to metformin (HR 0.68,
CI 0.55-0.85) during the course of the study (up to 72 months of treatment). This translates to a
cumulative incidence of treatment failure of 10.3 % for rosiglitazone, 14.8 % for metformin and
23.3 % for glibenclamide treated patients. Overall, 43 %, 47 % and 42 % of subjects in the
rosiglitazone, glibenclamide and metformin groups respectively withdrew due to reasons other than
monotherapy failure. The impact of these findings on disease progression or on microvascular or
macrovascular outcomes has not been determined (see section 4.8). In this study, the adverse events
observed were consistent with the known adverse event profile for each of the treatments, including
continuing weight gain with rosiglitazone. An additional observation of an increased incidence of bone
fractures was seen in women with rosiglitazone (see sections 4.4 and 4.8).
patients.
The European Medicines Agency has waived the obligation to submit the results of studies with
AVANDIA in all subsets of the paediatric population in Type II diabetes mellitus (see section 4.2 for
information on paediatric use).
5.2 Pharmacokinetic properties
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Administration of rosiglitazone with food resulted in no change in overall exposure (AUC), although a
small decrease in C
max
(approximately 20 % to 28 %) and a delay in t
max
(ca.1.75 h) were observed
compared to dosing in the fasting state. These small changes are not clinically significant and,
therefore, it is not necessary to administer rosiglitazone at any particular time in relation to meals. The
absorption of rosiglitazone is not affected by increases in gastric pH.
Distribution
The volume of distribution of rosiglitazone is approximately 14 litres in healthy volunteers. Plasma
protein binding of rosiglitazone is high (approximately 99.8 %) and is not influenced by concentration
or age. The protein binding of the major metabolite (para-hydroxy-sulphate) is very high (>99.99 %).
Biotransformation
Metabolism of rosiglitazone is extensive with no parent compound being excreted unchanged. The
major routes of metabolism are N-demethylation and hydroxylation, followed by conjugation with
sulphate and glucuronic acid. The contribution of the major metabolite (para-hydroxy-sulphate) to the
overall anti-diabetic activity of rosiglitazone has not been fully elucidated in man and it cannot be
ruled out that the metabolite may contribute to the activity. However, this raises no safety concern
regarding target or special populations as hepatic impairment is contraindicated and the phase III
clinical studies included a considerable number of elderly patients and patients with mild to moderate
renal impairment.
In vitro
studies demonstrate that rosiglitazone is predominantly metabolised by CYP2C8, with a minor
contribution by CYP2C9.
Since there is no significant
in vitro
inhibition of CYP1A2, 2A6, 2C19, 2D6, 2E1, 3A or 4A with
rosiglitazone, there is a low probability of significant metabolism-based interactions with substances
metabolised by these P450 enzymes. Rosiglitazone showed moderate inhibition of CYP2C8
(IC
50
18 µM) and low inhibition of CYP2C9 (IC
50
50 µM)
in vitro
(see section 4.5). An
in vivo
interaction study with warfarin indicated that rosiglitazone does not interact with CYP2C9 substrates
in vivo
.
Elimination
Total plasma clearance of rosiglitazone is around 3 l/h and the terminal elimination half-life of
rosiglitazone is approximately 3 to 4 hours. There is no evidence for unexpected accumulation of
rosiglitazone after once or twice daily dosing. The major route of excretion is the urine with
approximately two-thirds of the dose being eliminated by this route, whereas faecal elimination
accounts for approximately 25 % of dose. No intact drug is excreted in urine or faeces. The terminal
half-life for radioactivity was about 130 hours indicating that elimination of metabolites is very slow.
Accumulation of the metabolites in plasma is expected upon repeated dosing, especially that of the
major metabolite (para-hydroxy-sulphate) for which an 8-fold accumulation is anticipated.
Special populations
Gender: In the pooled population pharmacokinetic analysis, there were no marked differences in the
pharmacokinetics of rosiglitazone between males and females.
11
Absorption
Absolute bioavailability of rosiglitazone following both a 4 and an 8 mg oral dose is approximately
99 %. Rosiglitazone plasma concentrations peak at around 1 hour after dosing. Plasma concentrations
are approximately dose proportional over the therapeutic dose range.
Elderly: In the pooled population pharmacokinetic analysis
,
age was not found to influence the
pharmacokinetics of rosiglitazone to any significant extent
.
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Hepatic impairment: In cirrhotic patients with moderate (Child-Pugh B) hepatic impairment, unbound
C
max
and AUC were 2- and 3-fold higher than in normal subjects. The inter-subject variability was
large, with a 7-fold difference in unbound AUC between patients.
Renal impairment: There are no clinically significant differences in the pharmacokinetics of
rosiglitazone in patients with renal impairment or end stage renal disease on chronic dialysis.
5.3 Preclinical safety data
Adverse effects observed in animal studies with possible relevance to clinical use were as follows: An
increase in plasma volume accompanied by decrease in red cell parameters and increase in heart
weight. Increases in liver weight, plasma ALT (dog only) and fat tissue were also observed. Similar
effects have been seen with other thiazolidinediones.
In reproductive toxicity studies, administration of rosiglitazone to rats during mid-late gestation was
associated with foetal death and retarded foetal development. In addition, rosiglitazone inhibited
ovarian oestradiol and progesterone synthesis and lowered plasma levels of these hormones resulting
in effects on oestrus/menstrual cycles and fertility (see section 4.4).
In an animal model for familial adenomatous polyposis (FAP), treatment with rosiglitazone at
200 times the pharmacologically active dose increased tumour multiplicity in the colon. The relevance
of this finding is unknown. However, rosiglitazone promoted differentiation and reversal of mutagenic
changes in human colon cancer cells
in vitro
. In addition, rosiglitazone was not genotoxic in a battery
of
in vivo
and
in vitro
genotoxicity studies and there was no evidence of colon tumours in lifetime
studies of rosiglitazone in two rodent species.
6.
6.1 List of excipients
Tablet core
sodium starch glycolate (type A)
hypromellose
microcrystalline cellulose
lactose monohydrate
magnesium stearate
Film coating
hypromellose 6cP
titanium dioxide (E171)
macrogol 3000
lactose monohydrate
glycerol triacetate
iron oxide red (E172)
6.2 Incompatibilities
12
Children and adolescents: Population pharmacokinetic analysis including 96 paediatric patients aged
10 to 18 years and weighing 35 to 178 kg suggested similar mean CL/F in children and adolescents
compared to adults. Individual CL/F in the paediatric population was in the same range as individual
adult data. CL/F seemed to be independent of age, but increased with weight in the paediatric
population.
Not applicable.
6.3 Shelf life
2 years
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This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Opaque blister packs (PVC/ aluminium). 56, 112, 168 or 180 film-coated tablets or 56 film-coated
tablets, unit dose pack.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused medicinal product should be disposed of in accordance with local requirements.
7.
SmithKline Beecham Ltd, 980 Great West Road, Brentford, Middlesex, TW8 9GS, United Kingdom
8.
EU/1/00/137/002-004, EU/1/00/137/013, EU/1/00/137/016
9.
Date of first authorisation: 11 July 2000
Date of latest renewal: 11 July 2005
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu
13
6.4 Special precautions for storage
1.
AVANDIA
4 mg film-coated tablets
2.
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Excipient
Contains lactose (approximately 105 mg).
For a full list of excipients, see section 6.1.
3.
Film-coated tablet (tablet).
Orange film-coated tablets debossed with “GSK” on one side and "4" on the other side.
4.
Rosiglitazone is indicated in the treatment of type 2 diabetes mellitus:
as
monotherapy
–
in adults (particularly overweight adults) inadequately controlled by diet and exercise for whom
metformin is inappropriate because of contraindications or intolerance
as
dual oral therapy
in combination with
–
metformin, in adults (particularly overweight adults) with insufficient glycaemic control despite
maximal tolerated dose of monotherapy with metformin
–
a sulphonylurea, only in adults who show intolerance to metformin or for whom metformin is
contraindicated, with insufficient glycaemic control despite monotherapy with a sulphonylurea
as
triple oral therapy
in combination with
–
metformin and a sulphonylurea, in adults (particularly overweight adults) with insufficient
glycaemic control despite dual oral therapy (see section 4.4).
Posology
Rosiglitazone treatment is usually initiated at 4 mg/day. This dose can
be increased to 8 mg/day after
eight
weeks if greater glycaemic control is required. In patients administered rosiglitazone in
combination with a sulphonylurea, an increase in rosiglitazone to 8 mg/day should be undertaken
cautiously following appropriate clinical evaluation to assess the patient's risk of developing adverse
reactions relating to fluid retention (see sections 4.4 and 4.8).
Rosiglitazone may be given once or twice a day (either as one daily dose, or two divided doses).
Special populations
Elderly (
≥
65 years old) (see section 4.4 Fluid retention and cardiac failure)
No dose adjustment is required in the elderly.
14
Each tablet contains rosiglitazone maleate corresponding to 4 mg of rosiglitazone.
Renal impairment (see section 4.4 Fluid retention and cardiac failure)
No dose adjustment is required in patients with mild and moderate renal insufficiency. Limited data
are available in patients with severe renal insufficiency (creatinine clearance < 30 ml/min) and
therefore rosiglitazone should be used with caution in these patients.
Hepatic impairment
Rosiglitazone must not be used in patients with hepatic impairment (see section 4.3).
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Method of administration
The tablets should be swallowed with water and may be taken with or without food.
To improve medicine compliance, it is suggested that patients are advised to take the tablets around
the same time every day.
Use of rosiglitazone is contraindicated in patients with:
−
known hypersensitivity to rosiglitazone or to any of the excipients
−
cardiac failure or history of cardiac failure (NYHA class I to IV)
−
an Acute Coronary Syndrome (unstable angina, non-ST segment elevation myocardial
infarction (NSTEMI) and ST segment elevation myocardial infarction (STEMI)) (see section
4.4)
−
hepatic impairment
-
diabetic ketoacidosis or diabetic pre-coma.
Fluid retention and cardiac failure
Thiazolidinediones can cause fluid retention which may exacerbate or precipitate signs or symptoms
of congestive heart failure. Rosiglitazone can cause dose-dependent fluid retention. The possible
contribution of fluid retention to weight gain should be individually assessed as rapid and excessive
weight gain has been reported very rarely as a sign of fluid retention. All patients, particularly those
receiving concurrent insulin or sulphonylurea therapy, those at risk for heart failure, and those with
reduced cardiac reserve, should be monitored for signs and symptoms of adverse reactions relating to
fluid retention, including weight gain and heart failure. Increased monitoring of the patient is
recommended if rosiglitazone is used in combination with metformin and insulin. Rosiglitazone
should be discontinued if any deterioration in cardiac status occurs.
Heart failure was also reported more frequently in patients with a history of heart failure; oedema and
heart failure was also reported more frequently in elderly patients and in patients with mild or
moderate renal failure. Caution should be exercised in patients over 75 years because of the limited
experience in this patient group. Since NSAIDs and rosiglitazone are associated with fluid retention,
concomitant administration may increase the risk of oedema.
Combination with insulin
An increased incidence of cardiac failure has been observed in clinical trials when rosiglitazone is
used in combination with insulin. Insulin and rosiglitazone are both associated with fluid retention,
15
Paediatric population
There are no data available on the use of rosiglitazone in children under 10 years of age. For children
and adolescents aged 10 to 17 years, there are limited data on rosiglitazone as monotherapy (see
sections 5.1 and 5.2). The available data do not support efficacy in the paediatric population and
therefore such use is not recommended.
concomitant administration may increase the risk of oedema and could increase the risk of ischaemic
heart disease. Insulin should only be added to established rosiglitazone therapy in exceptional cases
and under close supervision.
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Acute Coronary Syndrome (ACS)
Patients experiencing an ACS have not been studied in rosiglitazone controlled clinical trials. In view
of the potential for development of heart failure in these patients, rosiglitazone should therefore not be
initiated in patients having an acute coronary event and it should be discontinued during the acute
phase (see section 4.3).
Monitoring of liver function
There have been rare reports of hepatocellular dysfunction during post-marketing experience (see
section 4.8). There is limited experience with rosiglitazone in patients with elevated liver enzymes
(ALT >2.5X upper limit of normal). Therefore, liver enzymes should be checked prior to the initiation
of therapy with rosiglitazone in all patients and periodically thereafter based on clinical judgement.
Therapy with rosiglitazone should not be initiated in patients with increased baseline liver enzyme
levels (ALT >2.5X upper limit of normal) or with any other evidence of liver disease. If ALT levels
are increased to >3X upper limit of normal during rosiglitazone therapy, liver enzyme levels should be
reassessed as soon as possible. If ALT levels remain >3X the upper limit of normal, therapy should be
discontinued. If any patient develops symptoms suggesting hepatic dysfunction, which may include
unexplained nausea, vomiting, abdominal pain, fatigue, anorexia and/or dark urine, liver enzymes
should be checked. The decision whether to continue the patient on therapy with rosiglitazone should
be guided by clinical judgement pending laboratory evaluations. If jaundice is observed, treatment
with rosiglitazone should be discontinued.
Eye disorders
Post-marketing reports of new-onset or worsening diabetic macular oedema with decreased visual
acuity have been reported with thiazolidinediones, including rosiglitazone. Many of these patients
reported concurrent peripheral oedema. It is unclear whether or not there is a direct association
between rosiglitazone and macular oedema but prescribers should be alert to the possibility of macular
oedema if patients report disturbances in visual acuity and appropriate ophthalmologic referral should
be considered.
Weight gain
In clinical trials with rosiglitazone there was evidence of dose-related weight gain, which was greater
when used in combination with insulin. Therefore weight should be closely monitored, given that it
may be attributable to fluid retention, which may be associated with cardiac failure.
Anaemia
Rosiglitazone treatment is associated with a dose-related reduction of haemoglobin levels. In patients
with low haemoglobin levels before initiating therapy, there is an increased risk of anaemia during
treatment with rosiglitazone.
Hypoglycaemia
Patients receiving rosiglitazone in combination therapy with a sulphonylurea or with insulin, may be at
risk for dose-related hypoglycaemia. Increased monitoring of the patient and a reduction in the dose of
the concomitant medicinal product may be necessary.
Triple oral therapy
16
Myocardial ischaemia
A retrospective analysis of data from 42 pooled short-term clinical studies indicated that treatment
with rosiglitazone may be associated with an increased risk of myocardial ischaemic events. However,
in their entirety the available data on the risk of cardiac ischaemia are inconclusive (see section 4.8).
There are limited clinical trial data in patients with ischaemic heart disease and/or peripheral arterial
disease. Therefore, as a precaution, the use of rosiglitazone is not recommended in these patients,
particularly those with myocardial ischaemic symptoms.
The use of rosiglitazone in triple oral therapy, in combination with metformin and a sulphonylurea,
may be associated with increased risks for fluid retention and heart failure, as well as hypoglycaemia
(see section 4.8). Increased monitoring of the patient is recommended and adjustment of the dose of
sulphonylurea may be necessary. The decision to initiate triple oral therapy should include
consideration of the alternative to switch the patient to insulin.
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Others
Premenopausal women have received rosiglitazone during clinical studies. Although hormonal
imbalance has been seen in preclinical studies (see section 5.3), no significant adverse reactions
associated with menstrual disorders have been observed. As a consequence of improving insulin
sensitivity, resumption of ovulation may occur in patients who are anovulatory due to insulin
resistance. Patients should be aware of the risk of pregnancy and if a patient wishes to become
pregnant or if pregnancy occurs the treatment should be discontinued (see section 4.6).
Rosiglitazone should be used with caution in patients with severe renal insufficiency (creatinine
clearance < 30 ml/min).
Rosiglitazone should be used with caution during concomitant administration of CYP2C8 inhibitors
(e.g. gemfibrozil) or inducers (e.g. rifampicin). Glycaemic control should be monitored closely.
Rosiglitazone dose adjustment within the recommended posology or changes in diabetic treatment
should be considered (see section 4.5).
AVANDIA tablets contain lactose and therefore should not be administered to patients with rare
hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose
malabsorption.
In vitro
studies demonstrate that rosiglitazone is predominantly metabolised by CYP2C8, with
CYP2C9 as only a minor pathway.
Co-administration of rosiglitazone with gemfibrozil (an inhibitor of CYP2C8) resulted in a twofold
increase in rosiglitazone plasma concentrations. Since there is a potential for an increase in the risk of
dose-related adverse reactions, a decrease in rosiglitazone dose may be needed. Close monitoring of
glycaemic control should be considered (see section 4.4).
Co-administration of rosiglitazone with rifampicin (an inducer of CYP2C8) resulted in a 66 %
decrease in rosiglitazone plasma concentrations. It cannot be excluded that other inducers (e.g.
phenytoin, carbamazepine, phenobarbital, St John’s wort) may also affect rosiglitazone exposure. The
rosiglitazone dose may need to be increased. Close monitoring of glycaemic control should be
considered (see section 4.4).
Clinically significant interactions with CYP2C9 substrates or inhibitors are not anticipated.
Concomitant administration with the oral anti-diabetic medicinal products metformin, glibenclamide
and acarbose did not result in any clinically relevant pharmacokinetic interactions with rosiglitazone.
Moderate ingestion of alcohol with rosiglitazone has no effect on glycaemic control.
No clinically relevant interactions with digoxin, the CYP2C9 substrate warfarin, the CYP3A4
substrates nifedipine, ethinylestradiol or norethindrone were observed after co-administration with
17
Bone disorders
Long-term studies show an increased incidence of bone fractures in patients, particularly female
patients, taking rosiglitazone (see section 4.8). The majority of the fractures have occurred in the upper
limbs and distal lower limbs. In females, this increased incidence was noted after the first year of
treatment and persisted during long-term treatment. The risk of fracture should be considered in the
care of patients, especially female patients, treated with rosiglitazone.
rosiglitazone.
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Breast-feeding
Rosiglitazone has been detected in the milk of experimental animals. It is not known whether breast-
feeding will lead to exposure of the infant to the medicinal product. Rosiglitazone should therefore not
be used in women who are breast-feeding.
Fertility
As a consequence of improving insulin sensitivity, resumption of ovulation may occur in patients who
are anovulatory due to insulin resistance (e.g. patients with polycystic ovary syndrome). Patients
should be aware of the risk of pregnancy and if a patient wishes to become pregnant or if pregnancy
occurs the treatment should be discontinued.
AVANDIA has no or negligible influence on the ability to drive and use machines.
Clinical trial data
The most commonly reported adverse reactions during treatment with rosiglitazone are dose-
dependent fluid-related reactions which include oedema and anaemia. Concurrent rosiglitazone and
sulphonylurea therapy may be associated with an increased frequency of hypoglycaemia and anaemia
compared to rosiglitazone monotherapy. It is important to monitor patients for fluid retention which
may exacerbate or precipitate signs or symptoms of congestive heart failure (see section 4.4).
Adverse reactions for each treatment regimen are presented below by system organ class and absolute
frequency. For dose-related adverse reactions the frequency category reflects the higher dose of
rosiglitazone. Frequency categories do not account for other factors including varying study duration,
pre-existing conditions and baseline patient characteristics. Adverse reaction frequency categories
assigned based on clinical trial experience may not reflect the frequency of adverse reactions occurring
during normal clinical practice. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100
to < 1/10); and uncommon (≥ 1/1000 to < 1/100).
Table 1 lists adverse reactions identified from an overview of clinical trials involving over 5,000
rosiglitazone-treated patients. Within each system organ class, adverse reactions are presented in the
table by decreasing frequency for the rosiglitazone monotherapy treatment regimen. Within each
frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1. The frequency of adverse reactions identified from clinical trial data
Adverse reaction
Frequency of adverse reaction by treatment regimen
RSG
RSG +
MET
RSG + SU
RSG +MET +SU
Blood and lymphatic system disorders
anaemia
Common
Common Common
Common
leucopaenia
Common
thrombocytopaenia
Common
18
Pregnancy
Rosiglitazone has been reported to cross the human placenta and to be detectable in foetal tissues.
There are no adequate data from the use of rosiglitazone in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Rosiglitazone
should not be used during pregnancy.
granulocytopaenia
Common
Metabolism and nutrition disorders
hypercholesterolaemia
1
Common
Common Common
Common
hypertriglyceridaemia
Common
Common
hyperlipaemia
Common Common Common
Common
weight increase
Common Common Common
Common
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Common
Uncommon
hypoglycaemia
Common Very common
Very common
Nervous system disorders
dizziness*
Common Common
headache*
Common
Cardiac disorders
cardiac failure
2
Common Common
Common
cardiac ischaemia
3*
Common Common Common
Common
Gastrointestinal disorders
constipation
Common Common Common
Common
Musculoskeletal and connective tissue disorders
bone fractures
4
Common Common Common
myalgia*
Common
General disorders and administration site conditions
oedema Common Common Very common Very common
RSG - Rosiglitazone monotherapy; RSG + MET - Rosiglitazone with metformin; RSG + SU -
Rosiglitazone with sulphonylurea; RSG + MET + SU - Rosiglitazone with metformin and
sulphonylurea
*The frequency category for the background incidence of these adverse reactions, as taken from
placebo group data from clinical trials, is 'common'.
1
Hypercholesterolaemia was reported in up to 5.3 % of patients treated with rosiglitazone
(monotherapy, dual or triple oral therapy). The elevated total cholesterol levels were associated with
increase in both LDLc and HDLc, but the ratio of total cholesterol: HDLc was unchanged or improved
in long term studies. Overall, these increases were generally mild to moderate and usually did not
require discontinuation of treatment.
2
An increased incidence of heart failure has been observed when rosiglitazone was added to treatment
regimens with a sulphonylurea (either as dual or triple therapy), and appeared higher with 8 mg
rosiglitazone compared to 4 mg rosiglitazone (total daily dose). The incidence of heart failure on triple
oral therapy was 1.4 % in the main double blind study, compared to 0.4 % for metformin plus
sulphonylurea dual therapy. The incidence of heart failure in combination with insulin (rosiglitazone
added to established insulin therapy) was 2.4 %, compared to insulin alone, 1.1 %. Moreover in
patients with congestive heart failure NYHA class I-II, a placebo-controlled one-year trial
demonstrated worsening or possible worsening of heart failure in 6.4 % of patients treated with
rosiglitazone, compared with 3.5 % on placebo.
3
In a retrospective analysis of data from 42 pooled short-term clinical studies, the overall incidence of
events typically associated with cardiac ischaemia was higher for rosiglitazone containing regimens,
2.00 % versus combined active and placebo comparators, 1.53 % [hazard ratio (HR) 1.30 (95 %
confidence interval (CI) 1.004 - 1.69)]. This risk was increased when rosiglitazone was added to
established insulin and in patients receiving nitrates for known ischaemic heart disease. In an update to
this retrospective analysis that included 10 further studies that met the criteria for inclusion, but were
19
increased appetite
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In double-blind clinical trials with rosiglitazone the incidence of elevations of ALT greater than three
times the upper limit of normal was equal to placebo (0.2 %) and less than that of the active
comparators (0.5 % metformin/sulphonylureas). The incidence of all adverse reactions relating to liver
and biliary systems was < 1.5 % in any treatment group and similar to placebo.
Post-marketing data
In addition to the adverse reactions identified from clinical trial data, the adverse reactions presented
in Table 2 have been identified in post approval use of rosiglitazone. Frequencies are defined as: rare
(≥1/10,000 to <1/1000) and very rare (<1/10,000).
Table 2. The frequency of adverse reactions identified from post-marketing data
Adverse reaction
Frequency
Immune system disorders
anaphylactic reaction
Very rare
angioedema
Very rare
skin reactions (e.g. urticaria, pruritus, rash)
Very rare
Metabolism and nutrition disorders
rapid and excessive weight gain
Very rare
Eye disorders
macular oedema
Rare
Cardiac disorders
congestive heart failure/pulmonary oedema
Rare
Hepatobiliary disorders
hepatic dysfunction, primarily evidenced by elevated hepatic enzymes
5
Rare
5
Rare cases of elevated liver enzymes and hepatocellular dysfunction have been reported. In very rare
cases a fatal outcome has been reported.
20
not available at the time of the original analysis, the overall incidence of events typically associated
with cardiac ischaemia was not statistically different for rosiglitazone containing regimens, 2.21 %
versus combined active and placebo comparators, 2.08 % [HR 1.098 (95 % CI 0.809 - 1.354)]. In a
prospective cardiovascular outcomes study (mean follow-up 5.5 years) the primary endpoint events of
cardiovascular death or hospitalisation were similar between rosiglitazone and active comparators
[HR 0.99 (95 % CI 0.85 - 1.16)]. Two other long-term prospective randomised controlled clinical trials
(9,620 patients, study duration >3 years in each study), comparing rosiglitazone to some other
approved oral antidiabetic medicinal products or placebo, have not confirmed or excluded the potential
risk of cardiac ischaemia. In their entirety, the available data on the risk of cardiac ischaemia are
inconclusive.
4
Long-term studies show an increased incidence of bone fracture in patients, particularly female
patients, taking rosiglitazone. In a monotherapy study, the incidence in females for rosiglitazone was
9.3 % (2.7 patients per 100 patient years) vs 5.1 % (1.5 patients per 100 patient years) for metformin
or 3.5 % (1.3 patients per 100 patient years) for glibenclamide. In another long-term study, there was
an increased incidence of bone fracture for subjects in the combined rosiglitazone group compared to
active control [8.3 % vs 5.3 %, Risk ratio 1.57 (95 % CI 1.26 - 1.97)]. The risk of fracture appeared to
be higher in females relative to control [11.5 % vs 6.3 %, Risk ratio 1.82 (95 % CI 1.37 - 2.41)], than
in males relative to control [5.3 % vs 4.3 %, Risk ratio 1.23 (95 % CI 0.85 - 1.77)]. Additional data are
necessary to determine whether there is an increased risk of fracture in males after a longer period of
follow-up. The majority of the fractures were reported in the upper limbs and distal lower limbs (see
section 4.4).
Limited data are available with regard to overdose in humans. In clinical studies in volunteers
rosiglitazone has been administered at single oral doses of up to 20 mg and no serious adverse
reactions were observed.
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5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in diabetes, blood glucose lowering drugs, excluding insulins,
ATC code: A10BG02
Rosiglitazone is a selective agonist at the PPARγ (peroxisomal proliferator activated receptor gamma)
nuclear receptor and is a member of the thiazolidinedione class of anti-diabetic medicinal products. It
reduces glycaemia by reducing insulin resistance at adipose tissue, skeletal muscle and liver.
Preclinical data
The antihyperglycaemic activity of rosiglitazone has been demonstrated in a number of animal models
of type 2 diabetes. In addition, rosiglitazone preserved ß-cell function as shown by increased
pancreatic islet mass and insulin content and prevented the development of overt hyperglycaemia in
animal models of type 2 diabetes. Rosiglitazone did not stimulate pancreatic insulin secretion or
induce hypoglycaemia in rats and mice. The major metabolite (para-hydroxy-sulphate) with high
affinity to the soluble human PPARγ, exhibited relatively high potency in a glucose tolerance assay in
obese mouse. The clinical relevance of this observation has not been fully elucidated.
Clinical trials data
The glucose lowering effects observed with rosiglitazone are gradual in onset with near maximal
reductions in fasting plasma glucose (FPG) evident following approximately 8 weeks of therapy. The
improved glycaemic control is associated with reductions in both fasting and post-prandial glucose.
Rosiglitazone was associated with increases in weight. In mechanistic studies, the weight increase was
predominantly shown to be due to increased subcutaneous fat with decreased visceral and intra-hepatic
fat.
Consistent with the mechanism of action, rosiglitazone reduced insulin resistance and improved
pancreatic ß-cell function. Improved glycaemic control was also associated with significant decreases
in free fatty acids. As a consequence of different but complementary mechanisms of action, dual oral
therapy of rosiglitazone
with
a sulphonylurea or metformin resulted in additive effects on glycaemic
control in type 2 diabetic patients.
In studies with a maximal duration of three years, rosiglitazone given once or twice daily produced a
sustained improvement in glycaemic control (FPG and HbA1c). A more pronounced glucose-lowering
effect was observed in obese patients. An outcome study has not been completed with rosiglitazone,
therefore the long-term benefits associated with improved glycaemic control have not been
demonstrated.
ADOPT (A Diabetes Outcome Progression Trial) was a multicentre, double-blind, controlled trial with
a treatment duration of 4-6 years (median duration of 4 years), in which rosiglitazone at doses of 4 to
8 mg/day was compared to metformin (500 mg to 2000 mg/day) and glibenclamide (2.5 to 15 mg/day)
in 4351 drug naive subjects recently diagnosed (≤3 years) with type 2 diabetes. Rosiglitazone
21
In the event of an overdose, it is recommended that appropriate supportive treatment should be
initiated, as dictated by the patient's clinical status. Rosiglitazone is highly protein bound and is not
cleared by haemodialysis.
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The RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in
Diabetes) trial was a large (4,447 subjects), open-label, prospective, controlled study (mean follow-up
5.5 years) in which patients with type 2 diabetes inadequately controlled with metformin or
sulphonylurea were randomised to add-on rosiglitazone or metformin or sulphonylurea. The mean
duration of diabetes in these patients was approximately 7 years. The adjudicated primary endpoint
was cardiovascular hospitalisation (which included hospitalisations for heart failure) or cardiovascular
death. Mean doses at the end of randomised treatment are shown in the following table:
Randomised Treatment
†
Mean (SD) dose at end of randomised treatment
Rosiglitazone (either SU or metformin) 6.7 (1.9) mg
Sulphonylurea (background metformin)
Glimepiride* 3.6 (1.8) mg
Metformin (background sulphonylurea) 1995.5 (682.6) mg
† Patients who took designated treatment as randomised in combination with the correct background
treatment and with evaluable data.
*Similar relative effective doses (i.e. approximately half maximal dose) for other sulphonylureas
(glibenclamide and glicazide).
No difference in the number of adjudicated primary endpoint events for rosiglitazone (321/2220)
versus active control (323/2227) (HR 0.99, CI 0.85-1.16) was observed, meeting the pre-defined non-
inferiority criterion of 1.20 (non-inferiority p = 0.02). HR and CI for key secondary endpoints were:
all-cause death (HR 0.86, CI 0.68-1.08), MACE (Major Adverse Cardiac Events - cardiovascular
death, acute myocardial infarction, stroke) (HR 0.93, CI 0.74-1.15), cardiovascular death (HR 0.84,
CI 0.59-1.18), acute myocardial infarction (HR 1.14, CI 0.80-1.63) and stroke (HR 0.72, CI 0.49-
1.06). In a sub-study at 18 months, add-on rosiglitazone dual therapy was non-inferior to the
combination of sulphonylurea plus metformin for lowering HbA1c. In the final analysis at 5 years, an
adjusted mean reduction from baseline in HbA1c of 0.14 % for patients on rosiglitazone added to
metformin versus an increase of 0.17 % for patients taking sulphonylurea added to metformin was
seen during treatment with randomised dual-combination therapy (p<0.0001 for treatment difference).
An adjusted mean reduction in HbA1c of 0.24 % was seen for patients taking rosiglitazone added to
sulphonylurea, versus a reduction in HbA1c of 0.10 % for patients taking metformin added to
sulphonylurea, (p=0.0083 for treatment difference). There was a significant increase in heart failure
(fatal and non-fatal) (HR 2.10, CI 1.35-3.27) and bone fractures (Risk Ratio 1.57, CI 1.26-1.97) in
rosiglitazone-containing treatments compared to active control (see sections 4.4 and 4.8). A total of
564 patients withdrew from cardiovascular follow-up, which accounted for 12.3 % of rosiglitazone
patients and 13 % of control patients; representing 7.2 % of patient-years lost for cardiovascular events
follow-up and 2.0 % of patient-years lost for all cause mortality follow-up.
Paediatric population
An active controlled clinical trial (rosiglitazone up to 8 mg daily or metformin up to 2,000 mg daily)
of 24 weeks duration was performed in 197 children and adolescents (10-17 years of age) with type 2
diabetes. Improvement in HbA1c from baseline achieved statistical significance only in the metformin
group. Rosiglitazone failed to demonstrate non-inferiority to metformin. Following rosiglitazone
treatment, there were no new safety concerns noted in children and adolescents compared to adult
patients with type 2 diabetes mellitus. No long-term efficacy and safety data are available in paediatric
22
treatment significantly reduced the risk of reaching monotherapy failure (FPG>10.0 mmol/L) by 63 %
relative to glibenclamide (HR 0.37, CI 0.30-0.45) and by 32 % relative to metformin (HR 0.68,
CI 0.55-0.85) during the course of the study (up to 72 months of treatment). This translates to a
cumulative incidence of treatment failure of 10.3 % for rosiglitazone, 14.8 % for metformin and
23.3 % for glibenclamide treated patients. Overall, 43 %, 47 % and 42 % of subjects in the
rosiglitazone, glibenclamide and metformin groups respectively withdrew due to reasons other than
monotherapy failure. The impact of these findings on disease progression or on microvascular or
macrovascular outcomes has not been determined (see section 4.8). In this study, the adverse events
observed were consistent with the known adverse event profile for each of the treatments, including
continuing weight gain with rosiglitazone. An additional observation of an increased incidence of bone
fractures was seen in women with rosiglitazone (see sections 4.4 and 4.8).
patients.
The European Medicines Agency has waived the obligation to submit the results of studies with
AVANDIA in all subsets of the paediatric population in Type II diabetes mellitus (see section 4.2 for
information on paediatric use).
5.2 Pharmacokinetic properties
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Administration of rosiglitazone with food resulted in no change in overall exposure (AUC), although a
small decrease in C
max
(approximately 20 % to 28 %) and a delay in t
max
(ca.1.75 h) were observed
compared to dosing in the fasting state. These small changes are not clinically significant and,
therefore, it is not necessary to administer rosiglitazone at any particular time in relation to meals. The
absorption of rosiglitazone is not affected by increases in gastric pH.
Distribution
The volume of distribution of rosiglitazone is approximately 14 litres in healthy volunteers. Plasma
protein binding of rosiglitazone is high (approximately 99.8 %) and is not influenced by concentration
or age. The protein binding of the major metabolite (para-hydroxy-sulphate) is very high (>99.99 %).
Biotransformation
Metabolism of rosiglitazone is extensive with no parent compound being excreted unchanged. The
major routes of metabolism are N-demethylation and hydroxylation, followed by conjugation with
sulphate and glucuronic acid. The contribution of the major metabolite (para-hydroxy-sulphate) to the
overall anti-diabetic activity of rosiglitazone has not been fully elucidated in man and it cannot be
ruled out that the metabolite may contribute to the activity. However, this raises no safety concern
regarding target or special populations as hepatic impairment is contraindicated and the phase III
clinical studies included a considerable number of elderly patients and patients with mild to moderate
renal impairment.
In vitro
studies demonstrate that rosiglitazone is predominantly metabolised by CYP2C8, with a minor
contribution by CYP2C9.
Since there is no significant
in vitro
inhibition of CYP1A2, 2A6, 2C19, 2D6, 2E1, 3A or 4A with
rosiglitazone, there is a low probability of significant metabolism-based interactions with substances
metabolised by these P450 enzymes. Rosiglitazone showed moderate inhibition of CYP2C8
(IC
50
18 µM) and low inhibition of CYP2C9 (IC
50
50 µM)
in vitro
(see section 4.5). An
in vivo
interaction study with warfarin indicated that rosiglitazone does not interact with CYP2C9 substrates
in vivo
.
Elimination
Total plasma clearance of rosiglitazone is around 3 l/h and the terminal elimination half-life of
rosiglitazone is approximately 3 to 4 hours. There is no evidence for unexpected accumulation of
rosiglitazone after once or twice daily dosing. The major route of excretion is the urine with
approximately two-thirds of the dose being eliminated by this route, whereas faecal elimination
accounts for approximately 25 % of dose. No intact drug is excreted in urine or faeces. The terminal
half-life for radioactivity was about 130 hours indicating that elimination of metabolites is very slow.
Accumulation of the metabolites in plasma is expected upon repeated dosing, especially that of the
major metabolite (para-hydroxy-sulphate) for which an 8-fold accumulation is anticipated.
Special populations
Gender: In the pooled population pharmacokinetic analysis, there were no marked differences in the
pharmacokinetics of rosiglitazone between males and females.
23
Absorption
Absolute bioavailability of rosiglitazone following both a 4 and an 8 mg oral dose is approximately
99 %. Rosiglitazone plasma concentrations peak at around 1 hour after dosing. Plasma concentrations
are approximately dose proportional over the therapeutic dose range.
Elderly: In the pooled population pharmacokinetic analysis
,
age was not found to influence the
pharmacokinetics of rosiglitazone to any significant extent
.
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Hepatic impairment: In cirrhotic patients with moderate (Child-Pugh B) hepatic impairment, unbound
C
max
and AUC were 2- and 3-fold higher than in normal subjects. The inter-subject variability was
large, with a 7-fold difference in unbound AUC between patients.
Renal impairment: There are no clinically significant differences in the pharmacokinetics of
rosiglitazone in patients with renal impairment or end stage renal disease on chronic dialysis.
5.3 Preclinical safety data
Adverse effects observed in animal studies with possible relevance to clinical use were as follows: An
increase in plasma volume accompanied by decrease in red cell parameters and increase in heart
weight. Increases in liver weight, plasma ALT (dog only) and fat tissue were also observed. Similar
effects have been seen with other thiazolidinediones.
In reproductive toxicity studies, administration of rosiglitazone to rats during mid-late gestation was
associated with foetal death and retarded foetal development. In addition, rosiglitazone inhibited
ovarian oestradiol and progesterone synthesis and lowered plasma levels of these hormones resulting
in effects on oestrus/menstrual cycles and fertility (see section 4.4).
In an animal model for familial adenomatous polyposis (FAP), treatment with rosiglitazone at
200 times the pharmacologically active dose increased tumour multiplicity in the colon. The relevance
of this finding is unknown. However, rosiglitazone promoted differentiation and reversal of mutagenic
changes in human colon cancer cells
in vitro
. In addition, rosiglitazone was not genotoxic in a battery
of
in vivo
and
in vitro
genotoxicity studies and there was no evidence of colon tumours in lifetime
studies of rosiglitazone in two rodent species.
6.
6.1 List of excipients
Tablet core
sodium starch glycolate (type A)
hypromellose
microcrystalline cellulose
lactose monohydrate
magnesium stearate
Film coating
hypromellose 6cP
titanium dioxide (E171)
macrogol 3000
purified talc
lactose monohydrate
glycerol triacetate
iron oxide red (E172)
iron oxide yellow (E172)
24
Children and adolescents: Population pharmacokinetic analysis including 96 paediatric patients aged
10 to 18 years and weighing 35 to 178 kg suggested similar mean CL/F in children and adolescents
compared to adults. Individual CL/F in the paediatric population was in the same range as individual
adult data. CL/F seemed to be independent of age, but increased with weight in the paediatric
population.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
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6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Opaque blister packs (PVC/ aluminium). 7, 28, 56, 84, 90 or 112 film-coated tablets or 56 film-coated
tablets, unit dose pack.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused medicinal product should be disposed of in accordance with local requirements.
7.
SmithKline Beecham Ltd, 980 Great West Road, Brentford, Middlesex, TW8 9GS, United Kingdom
8.
EU/1/00/137/005-009, EU/1/00/137/014, EU/1/00/137/017
9.
Date of first authorisation: 11 July 2000
Date of latest renewal: 11 July 2005
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu
25
2 years
1.
AVANDIA
8 mg film-coated tablets
2.
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Excipient
Contains lactose (approximately 209 mg).
For a full list of excipients, see section 6.1.
3.
Film-coated tablet (tablet).
Red-brown film-coated tablets debossed with “GSK” on one side and "8" on the other side.
4.
Rosiglitazone is indicated in the treatment of type 2 diabetes mellitus:
as
monotherapy
–
in adults (particularly overweight adults) inadequately controlled by diet and exercise for whom
metformin is inappropriate because of contraindications or intolerance
as
dual oral therapy
in combination with
–
metformin, in adults (particularly overweight adults) with insufficient glycaemic control despite
maximal tolerated dose of monotherapy with metformin
–
a sulphonylurea, only in adults who show intolerance to metformin or for whom metformin is
contraindicated, with insufficient glycaemic control despite monotherapy with a sulphonylurea
as
triple oral therapy
in combination with
–
metformin and a sulphonylurea, in adults (particularly overweight adults) with insufficient
glycaemic control despite dual oral therapy (see section 4.4).
Posology
Rosiglitazone treatment is usually initiated at 4 mg/day. This dose can
be increased to 8 mg/day after
eight
weeks if greater glycaemic control is required. In patients administered rosiglitazone in
combination with a sulphonylurea, an increase in rosiglitazone to 8 mg/day should be undertaken
cautiously following appropriate clinical evaluation to assess the patient's risk of developing adverse
reactions relating to fluid retention (see sections 4.4 and 4.8).
Rosiglitazone may be given once or twice a day (either as one daily dose, or two divided doses).
Special populations
Elderly (
≥
65 years old) (see section 4.4 Fluid retention and cardiac failure)
No dose adjustment is required in the elderly.
26
Each tablet contains rosiglitazone maleate corresponding to 8 mg of rosiglitazone.
Renal impairment (see section 4.4 Fluid retention and cardiac failure)
No dose adjustment is required in patients with mild and moderate renal insufficiency. Limited data
are available in patients with severe renal insufficiency (creatinine clearance < 30 ml/min) and
therefore rosiglitazone should be used with caution in these patients.
Hepatic impairment
Rosiglitazone must not be used in patients with hepatic impairment (see section 4.3).
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Method of administration
The tablets should be swallowed with water and may be taken with or without food.
To improve medicine compliance, it is suggested that patients are advised to take the tablets around
the same time every day.
Use of rosiglitazone is contraindicated in patients with:
−
known hypersensitivity to rosiglitazone or to any of the excipients
−
cardiac failure or history of cardiac failure (NYHA class I to IV)
−
an Acute Coronary Syndrome (unstable angina, non-ST segment elevation myocardial
infarction (NSTEMI) and ST segment elevation myocardial infarction (STEMI)) (see section
4.4)
−
hepatic impairment
-
diabetic ketoacidosis or diabetic pre-coma.
Fluid retention and cardiac failure
Thiazolidinediones can cause fluid retention which may exacerbate or precipitate signs or symptoms
of congestive heart failure. Rosiglitazone can cause dose-dependent fluid retention. The possible
contribution of fluid retention to weight gain should be individually assessed as rapid and excessive
weight gain has been reported very rarely as a sign of fluid retention. All patients, particularly those
receiving concurrent insulin or sulphonylurea therapy, those at risk for heart failure, and those with
reduced cardiac reserve, should be monitored for signs and symptoms of adverse reactions relating to
fluid retention, including weight gain and heart failure. Increased monitoring of the patient is
recommended if rosiglitazone is used in combination with metformin and insulin. Rosiglitazone
should be discontinued if any deterioration in cardiac status occurs.
Heart failure was also reported more frequently in patients with a history of heart failure; oedema and
heart failure was also reported more frequently in elderly patients and in patients with mild or
moderate renal failure. Caution should be exercised in patients over 75 years because of the limited
experience in this patient group. Since NSAIDs and rosiglitazone are associated with fluid retention,
concomitant administration may increase the risk of oedema.
Combination with insulin
An increased incidence of cardiac failure has been observed in clinical trials when rosiglitazone is
used in combination with insulin. Insulin and rosiglitazone are both associated with fluid retention,
27
Paediatric population
There are no data available on the use of rosiglitazone in children under 10 years of age. For children
and adolescents aged 10 to 17 years, there are limited data on rosiglitazone as monotherapy (see
sections 5.1 and 5.2). The available data do not support efficacy in the paediatric population and
therefore such use is not recommended.
concomitant administration may increase the risk of oedema and could increase the risk of ischaemic
heart disease. Insulin should only be added to established rosiglitazone therapy in exceptional cases
and under close supervision.
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Acute Coronary Syndrome (ACS)
Patients experiencing an ACS have not been studied in rosiglitazone controlled clinical trials. In view
of the potential for development of heart failure in these patients, rosiglitazone should therefore not be
initiated in patients having an acute coronary event and it should be discontinued during the acute
phase (see section 4.3).
Monitoring of liver function
There have been rare reports of hepatocellular dysfunction during post-marketing experience (see
section 4.8). There is limited experience with rosiglitazone in patients with elevated liver enzymes
(ALT >2.5X upper limit of normal). Therefore, liver enzymes should be checked prior to the initiation
of therapy with rosiglitazone in all patients and periodically thereafter based on clinical judgement.
Therapy with rosiglitazone should not be initiated in patients with increased baseline liver enzyme
levels (ALT >2.5X upper limit of normal) or with any other evidence of liver disease. If ALT levels
are increased to >3X upper limit of normal during rosiglitazone therapy, liver enzyme levels should be
reassessed as soon as possible. If ALT levels remain >3X the upper limit of normal, therapy should be
discontinued. If any patient develops symptoms suggesting hepatic dysfunction, which may include
unexplained nausea, vomiting, abdominal pain, fatigue, anorexia and/or dark urine, liver enzymes
should be checked. The decision whether to continue the patient on therapy with rosiglitazone should
be guided by clinical judgement pending laboratory evaluations. If jaundice is observed, treatment
with rosiglitazone should be discontinued.
Eye disorders
Post-marketing reports of new-onset or worsening diabetic macular oedema with decreased visual
acuity have been reported with thiazolidinediones, including rosiglitazone. Many of these patients
reported concurrent peripheral oedema. It is unclear whether or not there is a direct association
between rosiglitazone and macular oedema but prescribers should be alert to the possibility of macular
oedema if patients report disturbances in visual acuity and appropriate ophthalmologic referral should
be considered.
Weight gain
In clinical trials with rosiglitazone there was evidence of dose-related weight gain, which was greater
when used in combination with insulin. Therefore weight should be closely monitored, given that it
may be attributable to fluid retention, which may be associated with cardiac failure.
Anaemia
Rosiglitazone treatment is associated with a dose-related reduction of haemoglobin levels. In patients
with low haemoglobin levels before initiating therapy, there is an increased risk of anaemia during
treatment with rosiglitazone.
Hypoglycaemia
Patients receiving rosiglitazone in combination therapy with a sulphonylurea or with insulin, may be at
risk for dose-related hypoglycaemia. Increased monitoring of the patient and a reduction in the dose of
the concomitant medicinal product may be necessary.
Triple oral therapy
28
Myocardial ischaemia
A retrospective analysis of data from 42 pooled short-term clinical studies indicated that treatment
with rosiglitazone may be associated with an increased risk of myocardial ischaemic events. However,
in their entirety the available data on the risk of cardiac ischaemia are inconclusive (see section 4.8).
There are limited clinical trial data in patients with ischaemic heart disease and/or peripheral arterial
disease. Therefore, as a precaution, the use of rosiglitazone is not recommended in these patients,
particularly those with myocardial ischaemic symptoms.
The use of rosiglitazone in triple oral therapy, in combination with metformin and a sulphonylurea,
may be associated with increased risks for fluid retention and heart failure, as well as hypoglycaemia
(see section 4.8). Increased monitoring of the patient is recommended and adjustment of the dose of
sulphonylurea may be necessary. The decision to initiate triple oral therapy should include
consideration of the alternative to switch the patient to insulin.
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Others
Premenopausal women have received rosiglitazone during clinical studies. Although hormonal
imbalance has been seen in preclinical studies (see section 5.3), no significant adverse reactions
associated with menstrual disorders have been observed. As a consequence of improving insulin
sensitivity, resumption of ovulation may occur in patients who are anovulatory due to insulin
resistance. Patients should be aware of the risk of pregnancy and if a patient wishes to become
pregnant or if pregnancy occurs the treatment should be discontinued (see section 4.6).
Rosiglitazone should be used with caution in patients with severe renal insufficiency (creatinine
clearance < 30 ml/min).
Rosiglitazone should be used with caution during concomitant administration of CYP2C8 inhibitors
(e.g. gemfibrozil) or inducers (e.g. rifampicin). Glycaemic control should be monitored closely.
Rosiglitazone dose adjustment within the recommended posology or changes in diabetic treatment
should be considered (see section 4.5).
AVANDIA tablets contain lactose and therefore should not be administered to patients with rare
hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose
malabsorption.
In vitro
studies demonstrate that rosiglitazone is predominantly metabolised by CYP2C8, with
CYP2C9 as only a minor pathway.
Co-administration of rosiglitazone with gemfibrozil (an inhibitor of CYP2C8) resulted in a twofold
increase in rosiglitazone plasma concentrations. Since there is a potential for an increase in the risk of
dose-related adverse reactions, a decrease in rosiglitazone dose may be needed. Close monitoring of
glycaemic control should be considered (see section 4.4).
Co-administration of rosiglitazone with rifampicin (an inducer of CYP2C8) resulted in a 66 %
decrease in rosiglitazone plasma concentrations. It cannot be excluded that other inducers (e.g.
phenytoin, carbamazepine, phenobarbital, St John’s wort) may also affect rosiglitazone exposure. The
rosiglitazone dose may need to be increased. Close monitoring of glycaemic control should be
considered (see section 4.4).
Clinically significant interactions with CYP2C9 substrates or inhibitors are not anticipated.
Concomitant administration with the oral anti-diabetic medicinal products metformin, glibenclamide
and acarbose did not result in any clinically relevant pharmacokinetic interactions with rosiglitazone.
Moderate ingestion of alcohol with rosiglitazone has no effect on glycaemic control.
No clinically relevant interactions with digoxin, the CYP2C9 substrate warfarin, the CYP3A4
substrates nifedipine, ethinylestradiol or norethindrone were observed after co-administration with
29
Bone disorders
Long-term studies show an increased incidence of bone fractures in patients, particularly female
patients, taking rosiglitazone (see section 4.8). The majority of the fractures have occurred in the upper
limbs and distal lower limbs. In females, this increased incidence was noted after the first year of
treatment and persisted during long-term treatment. The risk of fracture should be considered in the
care of patients, especially female patients, treated with rosiglitazone.
rosiglitazone.
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Breast-feeding
Rosiglitazone has been detected in the milk of experimental animals. It is not known whether breast-
feeding will lead to exposure of the infant to the medicinal product. Rosiglitazone should therefore not
be used in women who are breast-feeding.
Fertility
As a consequence of improving insulin sensitivity, resumption of ovulation may occur in patients who
are anovulatory due to insulin resistance (e.g. patients with polycystic ovary syndrome). Patients
should be aware of the risk of pregnancy and if a patient wishes to become pregnant or if pregnancy
occurs the treatment should be discontinued.
AVANDIA has no or negligible influence on the ability to drive and use machines.
Clinical trial data
The most commonly reported adverse reactions during treatment with rosiglitazone are dose-
dependent fluid-related reactions which include oedema and anaemia. Concurrent rosiglitazone and
sulphonylurea therapy may be associated with an increased frequency of hypoglycaemia and anaemia
compared to rosiglitazone monotherapy. It is important to monitor patients for fluid retention which
may exacerbate or precipitate signs or symptoms of congestive heart failure (see section 4.4).
Adverse reactions for each treatment regimen are presented below by system organ class and absolute
frequency. For dose-related adverse reactions the frequency category reflects the higher dose of
rosiglitazone. Frequency categories do not account for other factors including varying study duration,
pre-existing conditions and baseline patient characteristics. Adverse reaction frequency categories
assigned based on clinical trial experience may not reflect the frequency of adverse reactions occurring
during normal clinical practice. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100
to < 1/10); and uncommon (≥ 1/1000 to < 1/100).
Table 1 lists adverse reactions identified from an overview of clinical trials involving over 5,000
rosiglitazone-treated patients. Within each system organ class, adverse reactions are presented in the
table by decreasing frequency for the rosiglitazone monotherapy treatment regimen. Within each
frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1. The frequency of adverse reactions identified from clinical trial data
Adverse reaction
Frequency of adverse reaction by treatment regimen
RSG
RSG +
MET
RSG + SU
RSG +MET +SU
Blood and lymphatic system disorders
anaemia
Common
Common Common
Common
leucopaenia
Common
thrombocytopaenia
Common
30
Pregnancy
Rosiglitazone has been reported to cross the human placenta and to be detectable in foetal tissues.
There are no adequate data from the use of rosiglitazone in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Rosiglitazone
should not be used during pregnancy.
granulocytopaenia
Common
Metabolism and nutrition disorders
hypercholesterolaemia
1
Common
Common Common
Common
hypertriglyceridaemia
Common
Common
hyperlipaemia
Common Common Common
Common
weight increase
Common Common Common
Common
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Common
Uncommon
hypoglycaemia
Common Very common
Very common
Nervous system disorders
dizziness*
Common Common
headache*
Common
Cardiac disorders
cardiac failure
2
Common Common
Common
cardiac ischaemia
3*
Common Common Common
Common
Gastrointestinal disorders
constipation
Common Common Common
Common
Musculoskeletal and connective tissue disorders
bone fractures
4
Common Common Common
myalgia*
Common
General disorders and administration site conditions
oedema Common Common Very common Very common
RSG - Rosiglitazone monotherapy; RSG + MET - Rosiglitazone with metformin; RSG + SU -
Rosiglitazone with sulphonylurea; RSG + MET + SU - Rosiglitazone with metformin and
sulphonylurea
*The frequency category for the background incidence of these adverse reactions, as taken from
placebo group data from clinical trials, is 'common'.
1
Hypercholesterolaemia was reported in up to 5.3 % of patients treated with rosiglitazone
(monotherapy, dual or triple oral therapy). The elevated total cholesterol levels were associated with
increase in both LDLc and HDLc, but the ratio of total cholesterol: HDLc was unchanged or improved
in long term studies. Overall, these increases were generally mild to moderate and usually did not
require discontinuation of treatment.
2
An increased incidence of heart failure has been observed when rosiglitazone was added to treatment
regimens with a sulphonylurea (either as dual or triple therapy), and appeared higher with 8 mg
rosiglitazone compared to 4 mg rosiglitazone (total daily dose). The incidence of heart failure on triple
oral therapy was 1.4 % in the main double blind study, compared to 0.4 % for metformin plus
sulphonylurea dual therapy. The incidence of heart failure in combination with insulin (rosiglitazone
added to established insulin therapy) was 2.4 %, compared to insulin alone, 1.1 %. Moreover in
patients with congestive heart failure NYHA class I-II, a placebo-controlled one-year trial
demonstrated worsening or possible worsening of heart failure in 6.4 % of patients treated with
rosiglitazone, compared with 3.5 % on placebo.
3
In a retrospective analysis of data from 42 pooled short-term clinical studies, the overall incidence of
events typically associated with cardiac ischaemia was higher for rosiglitazone containing regimens,
2.00 % versus combined active and placebo comparators, 1.53 % [hazard ratio (HR) 1.30 (95 %
confidence interval (CI) 1.004 - 1.69)]. This risk was increased when rosiglitazone was added to
established insulin and in patients receiving nitrates for known ischaemic heart disease. In an update to
this retrospective analysis that included 10 further studies that met the criteria for inclusion, but were
31
increased appetite
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In double-blind clinical trials with rosiglitazone the incidence of elevations of ALT greater than three
times the upper limit of normal was equal to placebo (0.2 %) and less than that of the active
comparators (0.5 % metformin/sulphonylureas). The incidence of all adverse reactions relating to liver
and biliary systems was < 1.5 % in any treatment group and similar to placebo.
Post-marketing data
In addition to the adverse reactions identified from clinical trial data, the adverse reactions presented
in Table 2 have been identified in post approval use of rosiglitazone. Frequencies are defined as: rare
(≥1/10,000 to <1/1000) and very rare (<1/10,000).
Table 2. The frequency of adverse reactions identified from post-marketing data
Adverse reaction
Frequency
Immune system disorders
anaphylactic reaction
Very rare
angioedema
Very rare
skin reactions (e.g. urticaria, pruritus, rash)
Very rare
Metabolism and nutrition disorders
rapid and excessive weight gain
Very rare
Eye disorders
macular oedema
Rare
Cardiac disorders
congestive heart failure/pulmonary oedema
Rare
Hepatobiliary disorders
hepatic dysfunction, primarily evidenced by elevated hepatic enzymes
5
Rare
5
Rare cases of elevated liver enzymes and hepatocellular dysfunction have been reported. In very rare
cases a fatal outcome has been reported.
32
not available at the time of the original analysis, the overall incidence of events typically associated
with cardiac ischaemia was not statistically different for rosiglitazone containing regimens, 2.21 %
versus combined active and placebo comparators, 2.08 % [HR 1.098 (95 % CI 0.809 - 1.354)]. In a
prospective cardiovascular outcomes study (mean follow-up 5.5 years) the primary endpoint events of
cardiovascular death or hospitalisation were similar between rosiglitazone and active comparators
[HR 0.99 (95 % CI 0.85 - 1.16)]. Two other long-term prospective randomised controlled clinical trials
(9,620 patients, study duration >3 years in each study), comparing rosiglitazone to some other
approved oral antidiabetic medicinal products or placebo, have not confirmed or excluded the potential
risk of cardiac ischaemia. In their entirety, the available data on the risk of cardiac ischaemia are
inconclusive.
4
Long-term studies show an increased incidence of bone fracture in patients, particularly female
patients, taking rosiglitazone. In a monotherapy study, the incidence in females for rosiglitazone was
9.3 % (2.7 patients per 100 patient years) vs 5.1 % (1.5 patients per 100 patient years) for metformin
or 3.5 % (1.3 patients per 100 patient years) for glibenclamide. In another long-term study, there was
an increased incidence of bone fracture for subjects in the combined rosiglitazone group compared to
active control [8.3 % vs 5.3 %, Risk ratio 1.57 (95 % CI 1.26 - 1.97)]. The risk of fracture appeared to
be higher in females relative to control [11.5 % vs 6.3 %, Risk ratio 1.82 (95 % CI 1.37 - 2.41)], than
in males relative to control [5.3 % vs 4.3 %, Risk ratio 1.23 (95 % CI 0.85 - 1.77)]. Additional data are
necessary to determine whether there is an increased risk of fracture in males after a longer period of
follow-up. The majority of the fractures were reported in the upper limbs and distal lower limbs (see
section 4.4).
Limited data are available with regard to overdose in humans. In clinical studies in volunteers
rosiglitazone has been administered at single oral doses of up to 20 mg and no serious adverse
reactions were observed.
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5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in diabetes, blood glucose lowering drugs, excluding insulins,
ATC code: A10BG02
Rosiglitazone is a selective agonist at the PPARγ (peroxisomal proliferator activated receptor gamma)
nuclear receptor and is a member of the thiazolidinedione class of anti-diabetic medicinal products. It
reduces glycaemia by reducing insulin resistance at adipose tissue, skeletal muscle and liver.
Preclinical data
The antihyperglycaemic activity of rosiglitazone has been demonstrated in a number of animal models
of type 2 diabetes. In addition, rosiglitazone preserved ß-cell function as shown by increased
pancreatic islet mass and insulin content and prevented the development of overt hyperglycaemia in
animal models of type 2 diabetes. Rosiglitazone did not stimulate pancreatic insulin secretion or
induce hypoglycaemia in rats and mice. The major metabolite (para-hydroxy-sulphate) with high
affinity to the soluble human PPARγ, exhibited relatively high potency in a glucose tolerance assay in
obese mouse. The clinical relevance of this observation has not been fully elucidated.
Clinical trials data
The glucose lowering effects observed with rosiglitazone are gradual in onset with near maximal
reductions in fasting plasma glucose (FPG) evident following approximately 8 weeks of therapy. The
improved glycaemic control is associated with reductions in both fasting and post-prandial glucose.
Rosiglitazone was associated with increases in weight. In mechanistic studies, the weight increase was
predominantly shown to be due to increased subcutaneous fat with decreased visceral and intra-hepatic
fat.
Consistent with the mechanism of action, rosiglitazone reduced insulin resistance and improved
pancreatic ß-cell function. Improved glycaemic control was also associated with significant decreases
in free fatty acids. As a consequence of different but complementary mechanisms of action, dual oral
therapy of rosiglitazone
with
a sulphonylurea or metformin resulted in additive effects on glycaemic
control in type 2 diabetic patients.
In studies with a maximal duration of three years, rosiglitazone given once or twice daily produced a
sustained improvement in glycaemic control (FPG and HbA1c). A more pronounced glucose-lowering
effect was observed in obese patients. An outcome study has not been completed with rosiglitazone,
therefore the long-term benefits associated with improved glycaemic control have not been
demonstrated.
ADOPT (A Diabetes Outcome Progression Trial) was a multicentre, double-blind, controlled trial with
a treatment duration of 4-6 years (median duration of 4 years), in which rosiglitazone at doses of 4 to
8 mg/day was compared to metformin (500 mg to 2000 mg/day) and glibenclamide (2.5 to 15 mg/day)
in 4351 drug naive subjects recently diagnosed (≤3 years) with type 2 diabetes. Rosiglitazone
treatment significantly reduced the risk of reaching monotherapy failure (FPG>10.0 mmol/L) by 63 %
33
In the event of an overdose, it is recommended that appropriate supportive treatment should be
initiated, as dictated by the patient's clinical status. Rosiglitazone is highly protein bound and is not
cleared by haemodialysis.
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The RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in
Diabetes) trial was a large (4,447 subjects), open-label, prospective, controlled study (mean follow-up
5.5 years) in which patients with type 2 diabetes inadequately controlled with metformin or
sulphonylurea were randomised to add-on rosiglitazone or metformin or sulphonylurea. The mean
duration of diabetes in these patients was approximately 7 years. The adjudicated primary endpoint
was cardiovascular hospitalisation (which included hospitalisations for heart failure) or cardiovascular
death. Mean doses at the end of randomised treatment are shown in the following table:
Randomised Treatment
†
Mean (SD) dose at end of randomised treatment
Rosiglitazone (either SU or metformin) 6.7 (1.9) mg
Sulphonylurea (background metformin)
Glimepiride* 3.6 (1.8) mg
Metformin (background sulphonylurea) 1995.5 (682.6) mg
† Patients who took designated treatment as randomised in combination with the correct background
treatment and with evaluable data.
*Similar relative effective doses (i.e. approximately half maximal dose) for other sulphonylureas
(glibenclamide and glicazide).
No difference in the number of adjudicated primary endpoint events for rosiglitazone (321/2220)
versus active control (323/2227) (HR 0.99, CI 0.85-1.16) was observed, meeting the pre-defined non-
inferiority criterion of 1.20 (non-inferiority p = 0.02). HR and CI for key secondary endpoints were:
all-cause death (HR 0.86, CI 0.68-1.08), MACE (Major Adverse Cardiac Events - cardiovascular
death, acute myocardial infarction, stroke) (HR 0.93, CI 0.74-1.15), cardiovascular death (HR 0.84,
CI 0.59-1.18), acute myocardial infarction (HR 1.14, CI 0.80-1.63) and stroke (HR 0.72, CI 0.49-
1.06). In a sub-study at 18 months, add-on rosiglitazone dual therapy was non-inferior to the
combination of sulphonylurea plus metformin for lowering HbA1c. In the final analysis at 5 years, an
adjusted mean reduction from baseline in HbA1c of 0.14 % for patients on rosiglitazone added to
metformin versus an increase of 0.17 % for patients taking sulphonylurea added to metformin was
seen during treatment with randomised dual-combination therapy (p<0.0001 for treatment difference).
An adjusted mean reduction in HbA1c of 0.24 % was seen for patients taking rosiglitazone added to
sulphonylurea, versus a reduction in HbA1c of 0.10 % for patients taking metformin added to
sulphonylurea, (p=0.0083 for treatment difference). There was a significant increase in heart failure
(fatal and non-fatal) (HR 2.10, CI 1.35-3.27) and bone fractures (Risk Ratio 1.57, CI 1.26-1.97) in
rosiglitazone-containing treatments compared to active control (see sections 4.4 and 4.8). A total of
564 patients withdrew from cardiovascular follow-up, which accounted for 12.3 % of rosiglitazone
patients and 13 % of control patients; representing 7.2 % of patient-years lost for cardiovascular events
follow-up and 2.0 % of patient-years lost for all cause mortality follow-up.
Paediatric population
An active controlled clinical trial (rosiglitazone up to 8 mg daily or metformin up to 2,000 mg daily)
of 24 weeks duration was performed in 197 children and adolescents (10-17 years of age) with type 2
diabetes. Improvement in HbA1c from baseline achieved statistical significance only in the metformin
group. Rosiglitazone failed to demonstrate non-inferiority to metformin. Following rosiglitazone
treatment, there were no new safety concerns noted in children and adolescents compared to adult
patients with type 2 diabetes mellitus. No long-term efficacy and safety data are available in paediatric
patients.
34
relative to glibenclamide (HR 0.37, CI 0.30-0.45) and by 32 % relative to metformin (HR 0.68,
CI 0.55-0.85) during the course of the study (up to 72 months of treatment). This translates to a
cumulative incidence of treatment failure of 10.3 % for rosiglitazone, 14.8 % for metformin and
23.3 % for glibenclamide treated patients. Overall, 43 %, 47 % and 42 % of subjects in the
rosiglitazone, glibenclamide and metformin groups respectively withdrew due to reasons other than
monotherapy failure. The impact of these findings on disease progression or on microvascular or
macrovascular outcomes has not been determined (see section 4.8). In this study, the adverse events
observed were consistent with the known adverse event profile for each of the treatments, including
continuing weight gain with rosiglitazone. An additional observation of an increased incidence of bone
fractures was seen in women with rosiglitazone (see sections 4.4 and 4.8).
The European Medicines Agency has waived the obligation to submit the results of studies with
AVANDIA in all subsets of the paediatric population in Type II diabetes mellitus (see section 4.2 for
information on paediatric use).
5.2 Pharmacokinetic properties
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Administration of rosiglitazone with food resulted in no change in overall exposure (AUC), although a
small decrease in C
max
(approximately 20 % to 28 %) and a delay in t
max
(ca.1.75 h) were observed
compared to dosing in the fasting state. These small changes are not clinically significant and,
therefore, it is not necessary to administer rosiglitazone at any particular time in relation to meals. The
absorption of rosiglitazone is not affected by increases in gastric pH.
Distribution
The volume of distribution of rosiglitazone is approximately 14 litres in healthy volunteers. Plasma
protein binding of rosiglitazone is high (approximately 99.8 %) and is not influenced by concentration
or age. The protein binding of the major metabolite (para-hydroxy-sulphate) is very high (>99.99 %).
Biotransformation
Metabolism of rosiglitazone is extensive with no parent compound being excreted unchanged. The
major routes of metabolism are N-demethylation and hydroxylation, followed by conjugation with
sulphate and glucuronic acid. The contribution of the major metabolite (para-hydroxy-sulphate) to the
overall anti-diabetic activity of rosiglitazone has not been fully elucidated in man and it cannot be
ruled out that the metabolite may contribute to the activity. However, this raises no safety concern
regarding target or special populations as hepatic impairment is contraindicated and the phase III
clinical studies included a considerable number of elderly patients and patients with mild to moderate
renal impairment.
In vitro
studies demonstrate that rosiglitazone is predominantly metabolised by CYP2C8, with a minor
contribution by CYP2C9.
Since there is no significant
in vitro
inhibition of CYP1A2, 2A6, 2C19, 2D6, 2E1, 3A or 4A with
rosiglitazone, there is a low probability of significant metabolism-based interactions with substances
metabolised by these P450 enzymes. Rosiglitazone showed moderate inhibition of CYP2C8
(IC
50
18 µM) and low inhibition of CYP2C9 (IC
50
50 µM)
in vitro
(see section 4.5). An
in vivo
interaction study with warfarin indicated that rosiglitazone does not interact with CYP2C9 substrates
in vivo
.
Elimination
Total plasma clearance of rosiglitazone is around 3 l/h and the terminal elimination half-life of
rosiglitazone is approximately 3 to 4 hours. There is no evidence for unexpected accumulation of
rosiglitazone after once or twice daily dosing. The major route of excretion is the urine with
approximately two-thirds of the dose being eliminated by this route, whereas faecal elimination
accounts for approximately 25 % of dose. No intact drug is excreted in urine or faeces. The terminal
half-life for radioactivity was about 130 hours indicating that elimination of metabolites is very slow.
Accumulation of the metabolites in plasma is expected upon repeated dosing, especially that of the
major metabolite (para-hydroxy-sulphate) for which an 8-fold accumulation is anticipated.
Special populations
Gender: In the pooled population pharmacokinetic analysis, there were no marked differences in the
pharmacokinetics of rosiglitazone between males and females.
35
Absorption
Absolute bioavailability of rosiglitazone following both a 4 and an 8 mg oral dose is approximately
99 %. Rosiglitazone plasma concentrations peak at around 1 hour after dosing. Plasma concentrations
are approximately dose proportional over the therapeutic dose range.
Elderly: In the pooled population pharmacokinetic analysis
,
age was not found to influence the
pharmacokinetics of rosiglitazone to any significant extent
.
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Hepatic impairment: In cirrhotic patients with moderate (Child-Pugh B) hepatic impairment, unbound
C
max
and AUC were 2- and 3-fold higher than in normal subjects. The inter-subject variability was
large, with a 7-fold difference in unbound AUC between patients.
Renal impairment: There are no clinically significant differences in the pharmacokinetics of
rosiglitazone in patients with renal impairment or end stage renal disease on chronic dialysis.
5.3 Preclinical safety data
Adverse effects observed in animal studies with possible relevance to clinical use were as follows: An
increase in plasma volume accompanied by decrease in red cell parameters and increase in heart
weight. Increases in liver weight, plasma ALT (dog only) and fat tissue were also observed. Similar
effects have been seen with other thiazolidinediones.
In reproductive toxicity studies, administration of rosiglitazone to rats during mid-late gestation was
associated with foetal death and retarded foetal development. In addition, rosiglitazone inhibited
ovarian oestradiol and progesterone synthesis and lowered plasma levels of these hormones resulting
in effects on oestrus/menstrual cycles and fertility (see section 4.4).
In an animal model for familial adenomatous polyposis (FAP), treatment with rosiglitazone at
200 times the pharmacologically active dose increased tumour multiplicity in the colon. The relevance
of this finding is unknown. However, rosiglitazone promoted differentiation and reversal of mutagenic
changes in human colon cancer cells
in vitro
. In addition, rosiglitazone was not genotoxic in a battery
of
in vivo
and
in vitro
genotoxicity studies and there was no evidence of colon tumours in lifetime
studies of rosiglitazone in two rodent species.
6.
6.1 List of excipients
Tablet core
sodium starch glycolate (type A)
hypromellose
microcrystalline cellulose
lactose monohydrate
magnesium stearate
Film coating
hypromellose 6cP
titanium dioxide (E171)
macrogol 3000
lactose monohydrate
glycerol triacetate
iron oxide red (E172)
6.2 Incompatibilities
36
Children and adolescents: Population pharmacokinetic analysis including 96 paediatric patients aged
10 to 18 years and weighing 35 to 178 kg suggested similar mean CL/F in children and adolescents
compared to adults. Individual CL/F in the paediatric population was in the same range as individual
adult data. CL/F seemed to be independent of age, but increased with weight in the paediatric
population.
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
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6.5 Nature and contents of container
Opaque blister packs (PVC/ aluminium). 7, 28, 84, 90 or 112 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused medicinal product should be disposed of in accordance with local requirements.
7.
SmithKline Beecham Ltd, 980 Great West Road, Brentford, Middlesex, TW8 9GS, United Kingdom
8.
EU/1/00/137/010-012, EU/1/00/137/015, EU/1/00/137/018
9.
Date of first authorisation: 11 July 2000
Date of latest renewal: 11 July 2005
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu
37
This medicinal product does not require any special storage conditions.
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A.
MANUFACTURING AUTHORISATION HOLDER(S)
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
38
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer(s) responsible for batch release
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or
Glaxo Wellcome S.A.
Avenida de Extremadura 3
09400 Aranda de Duero
Burgos
Spain
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.
B.
CONDITIONS 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 Marketing Authorisation Holder (MAH) must ensure that the system of pharmacovigilance, as
described in version 7.2 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 4 of the Risk Management Plan (RMP) presented in
Module 1.8.2. of the Marketing Authorisation and any subsequent updates of the RMP agreed by the
CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any
updated RMP should be submitted at the same time as the following Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted:
−
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
−
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being reached
39
Glaxo Wellcome Production
Z.I. Du Terras
53100 Mayenne
France
−
At the request of the EMEA.
PSURs
Following the renewal of the Marketing Authorisation, the Marketing Authorisation Holder will
submit yearly PSURs unless otherwise decided by the CHMP.
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40
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41
ANNEX III
LABELLING AND PACKAGE LEAFLET
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42
A. LABELLING
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
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2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains rosiglitazone maleate corresponding to 2 mg of rosiglitazone.
3.
LIST OF EXCIPIENTS
Contains lactose, see leaflet for further information.
4.
56 film-coated tablets
112 film-coated tablets
168 film-coated tablets
180 film-coated tablets
56 film-coated tablets, unit dose pack
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Use only as directed by your doctor.
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
43
AVANDIA 2 mg film-coated tablets
rosiglitazone
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
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SmithKline Beecham Ltd
980 Great West Road
Brentford, Middlesex TW8 9GS
United Kingdom
EU/1/00/137/002 56 tablets
EU/1/00/137/003 112 tablets
EU/1/00/137/013 168 tablets
EU/1/00/137/016 180 tablets
EU/1/00/137/004 56 tablet unit dose pack
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
avandia 2 mg
44
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTERS
1.
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2.
SmithKline Beecham Ltd
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
45
AVANDIA 2 mg tablets
rosiglitazone
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
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2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains rosiglitazone maleate corresponding to 4 mg of rosiglitazone.
3.
LIST OF EXCIPIENTS
Contains lactose, see leaflet for further information.
4.
7 film-coated tablets
28 film-coated tablets
56 film-coated tablets
84 film-coated tablets
90 film-coated tablets
112 film-coated tablets
56 film-coated tablets, unit dose pack
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Use only as directed by your doctor.
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
46
AVANDIA 4 mg film-coated tablets
rosiglitazone
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
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EU/1/00/137/005 7 tablets
EU/1/00/137/006 28 tablets
EU/1/00/137/007 56 tablets
EU/1/00/137/014 84 tablets
EU/1/00/137/017 90 tablets
EU/1/00/137/008 112 tablets
EU/1/00/137/009 56 tablet unit dose pack
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
avandia 4 mg
47
SmithKline Beecham Ltd
980 Great West Road
Brentford, Middlesex TW8 9GS
United Kingdom
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTERS
1.
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2.
SmithKline Beecham Ltd
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
48
AVANDIA 4 mg tablets
rosiglitazone
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
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2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains rosiglitazone maleate corresponding to 8 mg of rosiglitazone.
3.
LIST OF EXCIPIENTS
Contains lactose, see leaflet for further information.
4.
7 film-coated tablets
28 film-coated tablets
84 film-coated tablets
90 film-coated tablets
112 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Use only as directed by your doctor.
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
49
AVANDIA 8 mg film-coated tablets
rosiglitazone
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
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SmithKline Beecham Ltd
980 Great West Road
Brentford, Middlesex TW8 9GS
United Kingdom
EU/1/00/137/010 7 tablets
EU/1/00/137/011 28 tablets
EU/1/00/137/015 84 tablets
EU/1/00/137/018 90 tablets
EU/1/00/137/012 112 tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
avandia 8 mg
50
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTERS
1.
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2.
SmithKline Beecham Ltd
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
51
AVANDIA 8 mg tablets
rosiglitazone
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52
B. PACKAGE LEAFLET
PACKAGE LEAFLET: INFORMATION FOR THE USER
AVANDIA 2 mg film-coated tablets
AVANDIA 4 mg film-coated tablets
AVANDIA 8 mg film-coated tablets
rosiglitazone
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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, tell your doctor or pharmacist.
In this leaflet:
1.
What AVANDIA is and what it is used for
2.
Before you take AVANDIA
4.
Possible side effects
5
How to store AVANDIA
6.
Further information
1.
WHAT AVANDIA IS AND WHAT IT IS USED FOR
AVANDIA
contains
rosiglitazone
, which is
used to treat type 2 diabetes
in adults
.
People with type
2 diabetes either don’t make enough insulin (a hormone that controls blood sugar levels), or don’t
respond normally to the insulin their body makes. AVANDIA helps to reduce your blood sugar
towards a normal level, by helping your body make better use of the insulin it produces.
AVANDIA can be used alone or in combination with other medicines to treat diabetes (such as
metformin or a sulphonylurea).
2.
BEFORE YOU TAKE AVANDIA
To help manage your diabetes, it is important that you follow any diet and lifestyle advice from your
doctor, pharmacist or nurse as well as taking AVANDIA.
Don’t take AVANDIA:
•
if you are allergic
(hypersensitive) to rosiglitazone or any of the other ingredients of
AVANDIA (listed in section 6)
•
if you have had a heart attack or severe angina,
that’s being treated in hospital
•
if you have heart failure,
or have had heart failure in the past
•
if you have liver disease
•
if you have diabetic ketoacidosis
(a complication of diabetes causing rapid weight loss,
nausea or vomiting, which can lead to diabetic pre-coma)
Check with your doctor
if you think any of these apply to you.
Don’t take AVANDIA.
Take special care with AVANDIA
Children
AVANDIA is not recommended for children aged under 18
, as the effectiveness in children has not
been shown.
53
Read all of this leaflet carefully before you start taking this medicine.
-
-
If you have any further questions, ask your doctor or pharmacist.
3.
How to take AVANDIA
Check with your doctor:
•
if you have been diagnosed with angina
(chest pain) or peripheral arterial disease (reduced blood
flow to the legs)
•
if you have
severe kidney problems
Check with your doctor
if you think either of these applies to you
,
as
AVANDIA may not be
suitable for you.
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Ovulation may restart
Women who are infertile due to a condition affecting their ovaries (such as Polycystic Ovarian
Syndrome), may start ovulating again when they start taking AVANDIA. If this applies to you, use
appropriate contraception to avoid the possibility of an unplanned pregnancy (see ‘Pregnancy and
breast-feeding’ later in section 2).
Taking other medicines
Tell your doctor or pharmacist if you are taking any other medicines, if you have taken any recently,
or if you start taking new ones. This includes herbal medicines and other medicines you bought
without a prescription.
Certain medicines are especially likely to affect the amount of sugar in your blood:
•
gemfibrozil (used to
lower cholesterol
)
•
rifampicin (used to treat
tuberculosis
and other infections)
Tell a doctor or pharmacist if you are taking any of these.
Your blood sugar will be checked,
and your dose of AVANDIA may need to be changed.
Pregnancy and breast-feeding
•
AVANDIA is not recommended during pregnancy.
If you are pregnant or could be pregnant,
tell your doctor.
•
Don’t breast-feed
while you are taking AVANDIA. The ingredients may pass into breast milk
and so may harm your baby.
Driving and using machines
This medicine should not affect your ability to drive or use machines.
AVANDIA contains lactose
AVANDIA tablets contain lactose. Patients who are intolerant to lactose or have a rare hereditary
problem of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption
should not take this medicine.
3.
HOW TO TAKE AVANDIA
Always take AVANDIA exactly as your doctor has told you. Do not take more than the recommended
dose. Check with your doctor or pharmacist if you are not sure.
How much to take
The usual starting dose
is 4 mg a day. This can be taken as one 4 mg tablet once a day, or as one
2 mg tablet taken twice a day.
After about 8 weeks your doctor may need to increase your dose. The maximum dose is 8 mg of
AVANDIA a day.
54
Conditions to look out for
AVANDIA and other medicines for diabetes can make some existing conditions worse or cause
serious side effects. You must look out for certain symptoms while you are taking AVANDIA, to
reduce the risk of any problems. See ‘Conditions you need to look out for’
in section 4.
How to take
Swallow the tablets with some water.
You can take AVANDIA with or without food.
Take your tablets around the same time every day and follow any dietary advice that your doctor has
given you.
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If you forget to take AVANDIA
Don’t take extra tablets to make up for a missed dose. Just take your next dose at the usual time.
If you stop taking AVANDIA
Take AVANDIA for as long as your doctor recommends. If you stop taking AVANDIA, your blood
sugar will not be controlled, and you may become unwell. Talk to your doctor if you want to stop.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, AVANDIA can cause side effects, but not everybody gets them.
Conditions you need to look out for
Allergic reactions:
These are very rare in people taking AVANDIA. Signs include:
•
raised and itchy rash (hives)
•
swelling, sometimes of the face or mouth (angioedema), causing difficulty in breathing
•
collapse.
Contact a doctor immediately
if you get any of these symptoms.
Stop taking
AVANDIA.
Fluid retention and heart failure:
AVANDIA can cause you to retain water (fluid retention) which
leads to swelling and weight gain. Extra body fluid can make some existing heart problems worse or
lead to heart failure. This is more likely if you are also taking other medicines for your diabetes (like
insulin or sulphonylureas), if you have kidney problems, or if you are over 65.
Check your weight
regularly; if it goes up rapidly, tell your doctor.
Symptoms of heart failure include:
•
shortness of breath, waking up short of breath at night
•
getting tired easily after light physical activity such as walking
•
rapid increase in your weight
•
swollen ankles or feet.
Tell your doctor as soon as possible
if you get any of these symptoms - either for the first time or
if they get worse.
Low blood sugar
(hypoglycaemia): If you are taking AVANDIA with other medicines for diabetes, it
is more likely that your blood sugar could fall below the normal level. Early symptoms of low blood
sugar are:
shaking, sweating, faintness
nervousness, palpitations
hunger.
The severity can increase, leading to confusion and loss of consciousness.
Tell your doctor as soon as possible
if you get any of these symptoms. The dose of your
medicines may need to be reduced.
Liver problems:
Before you start taking AVANDIA you will have a blood sample taken to check
your liver function. This check may be repeated at intervals. These may be signs of liver problems:
•
nausea and vomiting
55
If you take more AVANDIA than you should
If you accidentally take too many tablets, contact your doctor or pharmacist for advice.
•
stomach (abdominal) pain
•
loss of appetite
•
dark-coloured urine.
Tell your doctor as soon as possible
if you get these symptoms.
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Broken bones:
Bone fractures can occur in people with diabetes. The chances of this happening may
be higher in people, particularly women, taking AVANDIA for more than one year. The most
common are breaks in feet, hands and arms.
Common side effects
These may affect
up to 1 in 10
people:
•
chest pain (angina)
•
broken bones
•
reduction in blood count (anaemia)
•
small increases in blood cholesterol, increased amount of fats in the blood
•
increased weight, increased appetite
•
constipation
•
swelling (oedema) due to water retention.
Rare side effects
These may affect
up to 1 in 1,000
people:
•
fluid in the lungs (pulmonary oedema) causing breathlessness
•
heart failure
•
swelling of the retina at the back of the eye (macular oedema)
•
liver doesn’t function as well as it should (increase in liver enzymes).
Very rare side effects
These may affect
up to 1 in 10,000
people:
•
allergic reactions
•
rapid and excessive weight gain caused by fluid retention.
If you get side effects
Tell your doctor or pharmacist
if any of the side effects listed gets severe or troublesome, or if
you notice any side effects not listed in this leaflet.
5.
HOW TO STORE AVANDIA
Keep out of the reach and sight of children.
Do not use AVANDIA after the expiry date which is stated on the carton and blister after “EXP”. The
expiry date refers to the last date of that month.
This medicine does not require any special storage conditions.
If you have any unwanted tablets, don’t put them in waste water or household waste. Ask your
pharmacist how to dispose of medicines no longer required. These measures will help to protect the
environment.
56
Eye problems:
Swelling of the retina at the back of the eye which can cause blurred vision (
macular
oedema
) can be a problem for people with diabetes. New or worse cases of macular oedema have
occurred on rare occasions in people taking AVANDIA and similar medicines.
Discuss with your doctor
any concerns about your eyesight.
6.
FURTHER INFORMATION
What AVANDIA contains
The active substance is rosiglitazone. AVANDIA film-coated tablets (tablets) come in different
strengths. Each tablet contains either: 2 mg, 4 mg or 8 mg of rosiglitazone.
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What AVANDIA looks like and contents of the pack
AVANDIA
2 mg
tablets are pink and marked "GSK" on one side and "2" on the other. The tablets are
provided in blister packs containing 56, 112, 168 or 180 film-coated tablets or 56 film-coated tablets in
a unit dose pack.
AVANDIA 4 mg
tablets are orange, marked "GSK" on one side and "4" on the other. The tablets are
provided in blister packs containing 7, 28, 56, 84, 90 or 112 film-coated tablets or 56 film-coated
tablets in a unit dose pack.
AVANDIA 8 mg
tablets are red-brown, marked "GSK" on one side and "8" on the other. The tablets
are provided in blister packs containing 7, 28, 84, 90 or 112 film-coated tablets.
Not all pack sizes or tablet strengths may be available in your country.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
: SmithKline Beecham Ltd, 980 Great West Road, Brentford,
Middlesex, TW8 9GS, United Kingdom.
Manufacturer:
Glaxo Wellcome Production, ZI du Terras, 53100 Mayenne, France.
Glaxo Wellcome S.A., Avenida de Extremadura 3, 09400 Aranda de Duero, Burgos, Spain.
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België/Belgique/Belgien
GlaxoSmithKline s.a./n.v.
Tél/Tel: + 32 (0)2 656 21 11
Luxembourg/Luxemburg
GlaxoSmithKline s.a./n.v.
Belgique/Belgien
Tél/Tel: + 32 (0)2 656 21 11
България
ГлаксоСмитКлайн ЕООД
Teл.: + 359 2 953 10 34
Magyarország
GlaxoSmithKline Kft.
Tel.: + 36 1 225 5300
Česká republika
GlaxoSmithKline s.r.o.
Tel: + 420 222 001 111
gsk.czmail@gsk.com
Malta
GlaxoSmithKline Malta
Tel: + 356 21 238131
Danmark
GlaxoSmithKline Pharma A/S
Tlf: + 45 36 35 91 00
dk-info@gsk.com
Nederland
GlaxoSmithKline BV
Tel: + 31 (0)30 6938100
nlinfo@gsk.com
Deutschland
GlaxoSmithKline GmbH & Co. KG
Tel.: + 49 (0)89 36044 8701
produkt.info@gsk.com
Norge
GlaxoSmithKline AS
Tlf: + 47 22 70 20 00
firmapost@gsk.no
57
The other ingredients are: sodium starch glycolate (type A), hypromellose, hypromellose 6cP,
microcrystalline cellulose, lactose monohydrate, magnesium stearate, titanium dioxide (E171),
macrogol 3000, glycerol triacetate and iron oxide red (E172). The 4 mg tablet also contains purified
talc and iron oxide yellow (E172).
Eesti
GlaxoSmithKline Eesti OÜ
Tel: + 372 6676 900
estonia@gsk.com
Österreich
GlaxoSmithKline Pharma GmbH
Tel: + 43 (0)1 97075 0
at.info@gsk.com
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Polska
GSK Commercial Sp. z o.o.
Tel.: + 48 (0)22 576 9000
España
GlaxoSmithKline, S.A.
Tel: + 34 902 202 700
es-ci@gsk.com
Portugal
GlaxoSmithKline – Produtos Farmacêuticos, Lda
Tel: + 351 21 412 95 00
FI.PT@gsk.com
France
Laboratoire GlaxoSmithKline
Tél.: + 33 (0)1 39 17 84 44
diam@gsk.com
România
GlaxoSmithKline (GSK) S.R.L.
Tel: + 4021 3028 208
Ireland
GlaxoSmithKline (Ireland) Limited
Tel: + 353 (0)1 4955000
Slovenija
GlaxoSmithKline d.o.o.
Tel: + 386 (0)1 280 25 00
medical.x.si@gsk.com
Ísland
GlaxoSmithKline ehf.
Sími: + 354 530 3700
Slovenská republika
GlaxoSmithKline Slovakia s. r. o.
Tel: + 421 (0)2 48 26 11 11
recepcia.sk@gsk.com
Italia
GlaxoSmithKline S.p.A.
Tel: + 39 (0)45 9218 111
Suomi/Finland
GlaxoSmithKline Oy
Puh/Tel: + 358 (0)10 30 30 30
Finland.tuoteinfo@gsk.com
Κύπρος
GlaxoSmithKline Cyprus Ltd
Τηλ: + 357 22 39 70 00
Sverige
GlaxoSmithKline AB
Tel: + 46 (0)8 638 93 00
info.produkt@gsk.com
Latvija
GlaxoSmithKline Latvia SIA
Tel: + 371 67312687
lv-epasts@gsk.com
United Kingdom
GlaxoSmithKline UK
Tel: + 44 (0)800 221441
customercontactuk@gsk.com
Lietuva
GlaxoSmithKline Lietuva UAB
Tel: + 370 5 264 90 00
info.lt@gsk.com
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
58
Ελλάδα
GlaxoSmithKline A.E.B.E.
Τηλ: + 30 210 68 82 100
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59
ANNEX IV
GROUNDS FOR ONE ADDITIONAL RENEWAL
GROUNDS FOR ONE ADDITIONAL RENEWAL
Based on the review of the available information, the CHMP is of the opinion that the quality, the
safety and the efficacy of AVANDIA continues to be adequately and sufficiently demonstrated and
therefore considers that the benefit/risk profile of this medicinal product continues to be favourable but
considers that its safety profile is to be closely monitored for the following reasons:
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Results from several studies are also awaited to provide further answers on the risk of bone fractures
and cardiovascular safety.
Therefore, based upon the safety profile of AVANDIA, which requires the submission of yearly
PSURs, the CHMP concluded that the MAH should, on the basis of pharmacovigilance grounds,
submit one additional renewal application in 5 years time.
60
The use of rosiglitazone is associated with a number of identified adverse events (PPARγ fluid
retention including heart failure, weight gain, anaemia, macular oedema, and bone fractures) as well as
potential risks (hepatic events, cardiac ischemia in short-term treatment, long-term cardiovascular
outcomes, clinical effect of lipid changes, and carcinogenicity) to be closely monitored and to be
reported in yearly PSURs and included in the Risk Management Plan.
Source: European Medicines Agency
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