Medicinal Products

AVANDAMET 4 mg / 1000 mg

Generic drug of the therapeutic class: Metabolism and nutrition
Active ingredients: Rosiglitazone, Metformin
laboratory: Smithkline Beecham Plc

Coated tablet
Box of 168
All forms

Indication

AVANDAMET is indicated for the treatment of patients with type 2 diabetes, particularly overweight:
- which is insufficiently balanced by its maximum tolerated dose of metformin alone.
- in triple oral therapy with a sulphonylurea in patients who are inadequately controlled by oral dual therapy combining metformin and a sulphonylurea at their maximum tolerated dose (see section on warnings and precautions for use).

Dosage AVANDAMET 4 mg / 1000 mg Film-coated tablet Box of 168

- AVANDAMET is available in dosages adapted to different dosages.
- Treatment with AVANDAMET may be initiated at a dose of 4 mg rosiglitazone daily plus 2000 mg metformin hydrochloride.
- The dose of rosiglitazone may be increased to 8 mg daily after 8 weeks if better glycemic control is needed. The maximum recommended dose of AVANDAMET is 8 mg rosiglitazone plus 2000 mg metformin hydrochloride per day.
- The total daily dose of AVANDAMET should be administered in two divided doses.
- An adjustment of the dose of rosiglitazone (in combination with the optimal dose of metformin) may be considered before switching to AVANDAMET.
- Direct substitution of metformin monotherapy with AVANDAMET may be considered depending on the clinical situation.
- Taking AVANDAMET during or at the end of a meal may reduce the gastrointestinal symptoms associated with taking metformin.
- Oral triple therapy (rosiglitazone, metformin and a sulphonylurea hypoglycemic agent) (see section on warnings and precautions for use):
. Patients on metformin and sulphonylurea: when appropriate AVANDAMET can be initiated at 4 mg / day of rosiglitazone with the corresponding dose of metformin already taken.
. Patients taking oral triple therapy: when appropriate, AVANDAMET may replace doses of rosiglitazone and metformin already taken.
When appropriate, AVANDAMET may replace the concomitant use of rosiglitazone and metformin in an existing bi or triple oral therapy to simplify treatment.
- Elderly:
Since metformin is eliminated by the kidney and in view of the possible decrease in renal function in the elderly, regular monitoring of renal function is necessary in elderly patients treated with AVANDAMET (see sections contraindications and warnings and precautions for use).
- Inadequate renal:
AVANDAMET should not be used in patients with renal impairment or renal impairment, eg creatinine> 135 μmol / L in men and> 110 μmol / L in women and / or clearance of creatinine <70 ml / min (see sections contraindications and warnings and precautions for use).
- Child and teenager:
In the absence of available efficacy and safety data in children and adolescents under 18 years, the use of AVANDAMET is not recommended in this age group (see sections on pharmacodynamic properties and pharmacokinetic properties). ).

Against indications

CONTRAINDICATED:
AVANDAMET is contraindicated in patients with:
- known hypersensitivity to rosiglitazone, metformin hydrochloride or any of the excipients of the tablet,
- heart failure or a history of heart failure [New York Heart Association (NYHA) class I to IV],
- acute coronary syndrome (unstable angina, myocardial infarction with or without ST segment elevation (see section warnings and precautions for use),
- an acute or chronic disease that can lead to tissue hypoxia, such as:
. heart or respiratory failure,
. recent myocardial infarction,
. shock,
- hepatic insufficiency,
- acute alcohol intoxication, alcoholism (see section on warnings and precautions for use),
diabetic ketoacidosis or a diabetic precoma,
- renal impairment or impairment of renal function, eg creatinine> 135 μmol / L in humans and> 110 μmol / L in women and / or creatinine clearance <70 ml / min (see section guard and precautions for use),
- an acute condition likely to impair renal function, such as:
. dehydration,
. serious infection,
. shock,
. intravascular administration of iodinated contrast media (see section on warnings and precautions for use),
- when breastfeeding: There are no preclinical or clinical data available on the use of AVANDAMET in breastfeeding women. In animals, rosiglitazone and metformin have been detected in milk. It is not known if breastfeeding exposes the child to the product. AVANDAMET should not be used in women who are breastfeeding.
- Pregnancy: There are no preclinical or clinical data available on the use of AVANDAMET in pregnant women. It has been observed that rosiglitazone crosses the placental barrier in women and is detected in fetal tissue. There are no sufficiently relevant data concerning the administration of rosiglitazone in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk in clinic is not known. Therefore, AVANDAMET should not be used during pregnancy. If a patient is planning pregnancy or pregnancy, treatment with AVANDAMET should be discontinued unless the benefit to the mother is greater than the potential risk to the fetus.
- AVANDAMET tablets contain lactose . Therefore, they should not be administered in patients with congenital galactosemia, Lapp lactase deficiency, or glucose-galactose malabsorption.
NOT RECOMMENDED :
- Child and adolescent: In the absence of available data on efficacy and safety in children and adolescents under 18 years of age, the use of AVANDAMET is not recommended in this age group.
- Avoid taking alcoholic drinks and drugs containing alcohol.

Avandamet side effects

- Adverse effects are presented below for each component of AVANDAMET. An adverse event is reported for the fixed combination only if it has not been observed with any of AVANDAMET's components or if it has occurred at a higher frequency than that reported for any of the components.
- Adverse effects for each treatment are presented below, by organ system and absolute frequency. For dose-related adverse events, the indicated frequency category corresponds to that of the highest dose of rosiglitazone. The different frequency categories do not take into account other factors such as different study durations, patient history and their characteristics at entry into clinical studies. Frequency categories are those observed in clinical studies; they may not reflect the frequency of adverse events occurring in daily clinical practice. Frequencies are defined as follows: very common (> = 1/10), frequent (> = 1/100 to = 1/1000 to = 1/10000 to <1/1000) and very rare (<1/10000 including isolated notifications).
AVANDAMET :
- The results of double-blind clinical studies confirm that the concomitant safety profile of rosiglitazone and metformin is similar to the cumulative adverse effects of both drugs. The data with AVANDAMET are also consistent with this combined profile of adverse effects.
- Data from clinical studies (addition of insulin to treatment with AVANDAMET):
In a single study (n = 322) where insulin was added to patients on AVANDAMET, no new adverse events were observed in addition to those already defined for both AVANDAMET and rosiglitazone-associated therapies. .
- However, the risk of adverse events related to fluid retention and hypoglycemia is increased when AVANDAMET is used in combination with insulin.
ROSIGLITAZONE :
DATA FROM CLINICAL STUDIES:
- The undesirable effects for each treatment are presented below by organ system and by absolute frequency. For dose-related adverse events, the indicated frequency category corresponds to that of the highest dose of rosiglitazone. The different frequency categories do not take into account other factors such as the various study durations, patient history and their characteristics at entry into clinical studies.
- Table 1 presents the adverse effects identified in all clinical trial populations of more than 5000 patients treated with rosiglitazone. For each organ system, the adverse effects are presented in the table in order of decreasing frequency for rosiglitazone monotherapy. For each frequency, adverse effects are presented in order of decreasing severity.
TABLE 1: Frequencies of adverse events identified in clinical studies with rosiglitazone .
ROSIGLITAZONE IN MONOTHERAPY:
- Hematological and lymphatic system disorders:
Frequent : anemia.
- Metabolism and nutrition disorders:
Frequent : hypercholesterolemia (1), hypertriglyceridaemia, hyperlipemia, weight gain, increased appetite.
- Cardiac disorders:
Common : cardiac ischemia (3).
- Gastrointestinal disorders:
Common : constipation
- Musculoskeletal and systemic disorders:
Frequent : bone fractures (4).
- General disorders and anomalies at the site of administration:
Frequent : edema.
ROSIGLITAZONE ASSOCIATED WITH METFORMIN:
- Hematological and lymphatic system disorders:
Frequent : anemia.
- Metabolism and nutrition disorders:
Frequent : hypercholesterolemia (1), hyperlipemia, weight gain, hypoglycemia.
- disorders of the nervous system:
Frequent : dizzying sensations *.
- Cardiac disorders:
Common : cardiac ischemia (3).
- Gastrointestinal disorders:
Common : constipation
- General disorders and anomalies at the site of administration:
Frequent : edema.
ROSIGLITAZONE ASSOCIATED WITH METFORMIN AND A HYPOGLYCEMIC SULFAMIDE:
- Hematological and lymphatic system disorders:
Common : anemia, granulocytopenia.
- Metabolism and nutrition disorders:
. Frequent : hypercholesterolemia (1), hyperlipemia, weight gain.
. Very common : hypoglycaemia.
- disorders of the nervous system:
Frequent : headache *.
- Cardiac disorders:
Common : heart failure (2), cardiac ischemia (3).
- Gastrointestinal disorders:
Common : constipation
- Musculoskeletal and systemic disorders:
Frequent : myalgia *.
- General disorders and anomalies at the site of administration:
Very common : edema.
* These adverse effects were noted as "common" in the placebo group of clinical studies.
(1) Hypercholesterolemia has been reported up to 5.3% of patients treated with rosiglitazone (monotherapy, dual therapy or oral triple therapy). The increase in total cholesterol involved an increase in the LDLc and HDLc fractions, but the total cholesterol / HDLc ratio remained stable or improved in the long-term studies. Overall, these effects were generally mild to moderate and usually did not necessitate discontinuation of treatment.
(2) An increase in the incidence of heart failure was observed when rosiglitazone was associated with treatment with a sulphonylurea (whether dual therapy or triple therapy); this increase is higher with a dose of 8 mg rosiglitazone than with a dose of 4 mg rosiglitazone (total daily dose). The incidence of heart failure in triple oral therapy was 1.4% in the main double-blind study, compared to 0.4% for the metformin and sulphonylurea combination. The incidence of heart failure in combination with insulin (rosiglitazone being added to insulin treatment already in progress) was 2.4%, compared with insulin alone, 1.1%.
In patients with congestive heart failure class I-II, a one-year randomized placebo-controlled study showed worsening or possible worsening of heart failure in 6.4% of rosiglitazone-treated patients compared to 3, 5% under placebo.
(3) A retrospective analysis of data from 42 short-term pooled clinical studies found that the overall incidence of events specifically associated with cardiac ischemia was higher in therapeutic strategies including rosiglitazone, which was 1.99% versus 1%., 51% [Hazard ratio 1.31 (95% confidence interval 1.01-1.70)] with active comparators and placebo. This risk was increased when rosiglitazone was combined with insulin therapy and in patients receiving nitrate derivatives for known ischemic heart disease.
A wide observational study in which the patient population was well distributed at entry to the study showed that the incidence of composite myocardial infarction and coronary revascularization was 17.46 events per 1000 person-years for drug treatments including rosiglitazone and 17.57 events per 1000 person-years for other antidiabetic agents [Hazard ratio 0.93 (95% confidence interval 0.8 - 1.10)]. Three large, prospective, randomized controlled long-term (average duration of 41 months; 14067 patients) clinical trials comparing rosiglitazone with other oral antidiabetic drugs or placebo did not confirm or rule out this risk. Overall, the available data on the risk of myocardial ischemia are inconclusive.
(4) In a long-term (4 to 6 years) randomized monotherapy study in patients with newly diagnosed type 2 diabetes, an increase in the incidence of bone fractures was observed after the first year of treatment in female patients receiving rosiglitazone (9.3%, 2.7 patients per 100 patients-year) vs metformin (5.1%, 1.5 patients per 100 patients-year) or glyburide / glibenclamide (3.5 %, 1.3 patients per 100 patient-years). This increased risk of fracture was found throughout the study. The majority of fractures in women treated with rosiglitazone were seen in the foot, hand and arm.
- In clinical double-blind studies with rosiglitazone, the incidence of elevation of ALT 3-fold greater than the upper limit of normal was similar to placebo (0.2%) and lower than that observed with comparators ( 0.5% metformin / sulphonylureas). The incidence of all adverse reactions in the hepatic and biliary systems was <1.5% in all treatment groups and similar to placebo.
POST-MARKETING DATA:
In addition to the adverse effects identified in the clinical studies, the adverse reactions presented in Table 2 were identified after the marketing of rosiglitazone.
TABLE 2: Frequencies of post-marketing adverse effects of rosiglitazone .
- Metabolism and nutrition disorders:
Very rare : rapid and excessive weight gain.
- Immune system disorders (see skin and subcutaneous tissue disorders):
Very rare : anaphylactic reaction.
- Eye disorders:
Rare : macular edema.
- Cardiac disorders:
Rare : congestive heart failure / pulmonary edema.
- Hepatobiliary disorders:
Rare : impaired liver function, mainly evidenced by elevated liver enzymes (5).
- Skin and subcutaneous tissue disorders (see Immune system disorders):
Very rare : angioedema, skin reactions (eg urticaria, pruritus, rash).
(5) Rare cases of elevated liver enzymes and hepatocellular dysfunction have been reported. In very rare cases, a fatal evolution has been reported.
METFORMIN :
DATA FROM CLINICAL STUDIES AND POST-MARKETING:
Table 3 presents the adverse effects by organ system and by frequency category. The frequency categories are based on the information available in the summary of product characteristics of metformin available in Europe.
TABLE 3: Frequencies of adverse effects of metformin identified in clinical trials and post-marketing .
- Gastrointestinal disorders:
Very common : gastrointestinal symptoms (6).
- Metabolism and nutrition disorders:
Very rare : lactic acidosis, vitamin B12 deficiency (7).
- disorders of the nervous system:
Frequent : metallic taste.
- Hepatobiliary disorders:
Very rare : impaired hepatic function, hepatitis.
- Skin and subcutaneous tissue disorders:
Very rare : urticaria, erythema, pruritus.
(6) Gastrointestinal symptoms, such as nausea, vomiting, diarrhea, abdominal pain, and loss of appetite, occur most often during the initiation of treatment and regress spontaneously in most cases.
(7) Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption that very rarely leads to clinically significant vitamin B12 deficiency (eg megaloblastic anemia).

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