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Brand Name: Avandia
Generic Name: Rosiglitazone maleate
QUALITATIVE AND QUANTITATIVE COMPOSITION
Avandia – (Rosiglitazone maleate) is an oral antidiabetic agent which acts primarily by increasing insulin sensitivity. Avandia is used In the management of type 2 diabetes mellitus (also known as non-insulin dependent diabetes mellitus (NIDDM) or adult -onset diabetes).
Avandia improves glycaemic control while reducing circulating insulin levels. Pharmacological studies in animal models indicate that Rosiglitazone improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluco-neogenesis. Rosiglitazone is not chemically or functionally related to the sulphonylureas, the biguandies, or the alpha-glucosidase inhibitors.
Rosiglitazione is a white to off-white solid with a melting point range from 122° to 123°C. The pKa, values of rosiglitazone are 6.8 and 6.1. It is readily soluble in ethanol and a buffered aqueous solution with pH of 2.3; solubility decreases with increasing pH in the physiological range.
Each pentagonal film-coated Tiltab tablet contains rosiglitazone maleate equivalent to rosiglitazone 2 mg. 4 mg or 8 mg, for oral administration.
AVANDIA is indicated as monotherapy as an adjunct to diet and exercise for glycaemic control in patients with type 2 diabetes mellitus.
AVANDIA is indicated for use in combination with metformin when diet. exercise, and AVANDIA alone or diet, exercise, and metformin alone do not result in adequate glycaemic control in patients with type 2 diabetes. For patients inadequately controlled with a maximum dose of metformin, AVANDIA should be added to, rather than substituted for, metformin.
AVANDIA is also indicated for use in combination with sulphonylurea when diet, exercise, and AVANDIA alone or diet, exercise, and sulphonylurea alone do not result in adequate glycaemic control in patients with type 2 diabetes. AVANDIA is also indicated for use in combination with insulin when diet, exercise, and AVANDIA alone or diet, exercise, and insulin alone do not result in adequate glycaemic control in patients with type 2 diabetes. AVANDIA is also indicated for use in combination with both metformin and a sulphonylurea (oral triple combination therapy) when diet, exercise, and dual combination therapy with AVANDIA metformin or sulphonylurea do not result in adequate glycaemic control in patients with type 2 diabetes. Management of type 2 diabetes should include diet control. Caloric restriction, weight loss, and exercise are essential for the proper treatment of the diabetic patient because they help improve insulin sensitivity. This is important not only in the primary treatment of type 2 diabetes, but also in maintaining the efficacy of drug therapy. Prior to initiation of therapy with AVANDIA, secondary causes of poor glycaemic control, e.g., infection, should be investigated and treated.
Dosage and Administration
The management of antidiabetic therapy should be individualised Periodic fasting blood glucose measurements should be performed to monitor therapeutic response prior to up-titrating dose.
AVANDIA may be taken with or without food.
AVANDIA dose adjustment may be needed when AVANDIA is co-administered with certain other drugs (see Warnings and Precautions, Interactions, Pharmacokinetics).
The usual starting dose of AVANDIA is 4 mg administered either as a single dose once daily or in divided doses twice daily For patients who respond inadequately following 12 weeks of treatment as determined by reduction in FPG, the dose may be increased to 8 mg administered as a single dose once daily or in divided doses twice daily. Reductions in glycaemic parameters by dose and regimen are described under Pharmacodynamics and Clinical Effects. In clinical trials, the 4 mg twice daily regimen resulted in the greatest reduction in FPG and HbA1c.
Combination Therapy with Metformin
The usual starting dose of AVANDIA in combination with metformin is 4 mg, administered as either a single dose once daily, or in divided doses twice daily. The dose of AVANDIA may be increased to 8 mg/day following 8 week of therapy if there is insufficient reduction in FPG. AVANDIA may be administered as a single dose in the morning, or divided and administered in the morning and evening.
Combination Therapy with Sutphonyturea
The recommended starting dose of AVANDIA when used combination with sulphonylurea is 4 mg administered as either a single dose once daily or in divided doses two daily. The dose of AVANDIA may be increased to 8 mg per day, following 8 weeks of therapy if there is insufficient reduction in FPG. Increases in AVANDIA to 8mg/day should be undertaken cautiously following appropriate clinical evaluation to assess the patient's risk of developing adverse reactions relating to fluid retention (see Warnings and Precautions and Adverse Reactionas). AVANDIA may be administered as a single daily dose in the morning, or divided and administered in the morning and evening. The dose of sulphonylurea may require adjustment to optimise therapy.
Combination Therapy with Insulin
For patients stabilised on insulin, the insulin dose should be continued upon initiation of therapy with AVANIDIA. AVANDIA should be dosed at 4 mg as the total daily dose, administered either once daily or in two divided doses. It is recommended that the insulin dose be decreased by 10% to 25% if the patient reports hypoglycaemia or if FPG concentrations decrease to less than 100 mg/dl. Further adjusments should be individualised based on glucouse-lowering response.
Oral Triple Combination Therapy with Metformin and a Sulphonylurea.
The recommended starting dose of AVANDIA when used in oral triple combination therapy with metformin and a sulphonylurea is 4 mg, administered as either a single dose once daily or in divided doses twice daily. Only limited data are available on doses of AVANDIA greater than 4 mg daily in combination with both metformin and a sulphonylurea. Patients who are inadequately controlled on 4 mg/day of AVANDIA in oral triple combination therapy may benefit by adjustment of their dose to 8 mg/day, 8 weeks after initiation of therapy. Increases in AVANDIA 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 Warnings and Precautions and Adverse Reactions).
Special Patient Populations
No dosage adjustments are required for the elderly. No dosage adjustment is necessary when AVANDIA is used as monotherapy in patients with renal impairment. Since metformin is contraindicated in such patients, concomitant administration of metformin and AVANDIA is also contra-indicated in patients with renal impairment. Therapy with AVANDIA should not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (ALT > 2.5 times the upper limit of normal at start of therapy (see Pharmacokinetics, Hepatic Impairment). Liver enzyme monitoring is recommended in all patients prior to initiation of therapy with AVANDIA and periodically thereafter (See Warnings and Precautions, Hepatic Effects). There are no data on the use of AVANDIA in patients under 18 years of age; therefore, use of AVANDIA in paediatric patients is not recommended.
AVANDIA in patients with mild to moderate heart failure
In patients with mild to moderate heart failure (NYHA class I or II, the dose of AVANDIA should be initiated at 4 mg/day. Increases in AVANDIA 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 Warnings and Precautions, Adverse Reactions, Clinical Studies).
-AVANDIA is contraindicated in patients with previous history of hypersensitivity to rosiglitazone or any other ingredient of the preparation (see List of Excipients).
Warnings and Precautions
Type 1 diabetes mellitus
Due to its mechanism of action, AVANDIA is active only in the presence of insulin. Therefore, AVANDIA should not be used in the treatment of type 1 diabetes. Patients receiving AVANDIA in combination with other hypoglycaemic agents may be at risk of hypoglycaemia, and a reduction in the dose of the concomitant agent may benecessary.
Premenopausal anovolutary women
AVANDIA, like other thiazolidinediones, may result in resumption of ovulation in premenopausal, anovulatory women with insulin resistance. As a consequence of their improved insulin sensitivity, these patients may be at risk for pregnancy if adequate contraception is not used. Although hormonal imbalance has been seen in preclinical studies (see Carcinogenesis, Mutagenesis, Impairment of Fertility) the clinical significance of this finding is not known. If unexpected menstrual dysfunction occurs, the benefits of continued therapy with AVANDIA should be reviewed.
Heart Failure / Oedema
In preclinical studies, thiazolidinediones, including rosiglitazone, caused plasma volume expansion and preload-induced cardiac hypertrophy. In two echocardiography studies in patients with type 2 diabetes designed to detect a change in left ventricular mass of 10% or more, no deleterious alteration in cardiac structure or function was observed following 148 weeks of treatment with 8 mg rosiglitazone. Patients with severe cardiac failure [New York Heart Association (NYHA) Class III and IV and acute heart failure] were not studied during the rosiglitazone clinical trials. AVANDIA is not recommended in these patients unless the expected potential benefit is believed to outweigh the potential risk.
In post-marketing experience with AVANDIA, adverse events potentially related to volume expansion (e.g. congestive heart failure and pulmonary oedema) have been reported. AVANDIA, like other thiazolidinediones, can cause fluid retention, which can exacerbate or lead to signs or symptoms of congestive heart failure. The fluid retention may very rarely present as rapid and excessive weight gain. All patients, particularly those receiving concurrent sulphonylurea or insulin therapy, those with mild to moderate heart failure (NYHA class I and II), and those at risk for heart failure, should be monitored for signs and symptoms of adverse reactions relating to fluid retention, including heart failure.
Very rare postmarketing reports of new-onset or worsening diabetic macular oedema with decreased visual acuity have been reported with AVANDIA. Many of these patients reported concurrent peripheral oedema. In some cases the visual events resolved or improved following discontinuation of the drug. Prescribes should be alert to the possibility of macular oedema if patients report disturbances in visual acuity.
Administration with other drugs
Close monitoring of glyeaemie control and rosiglitazone dose adjustment may be needed when AVANDIA is coadministered with CYP2C8 inhibitors or inducers (see Dosage and Administration, Interactions, Pharmacokinetics).
Another drug of the thiazolidinedione class, troglitazone, has been associated with idiosyncratic hepatotoxicity, and very rare cases of liver failure, liver transplants, and death have been reported during postmarketing clinical use. In pre-approval controlled clinical trials in patients with type
2 diabetes, troglitazone was more frequently associated with clinically significant elevations of hepatic enzymes (ALT > 3X upper limit of normal) compared to placebo, and very rare cases of reversible jaundice were reported.
In clinical studies in 4598 patients treated with rosiglitazone, encompassing approximately 3600 patient years of exposure, there was no evidence of drug-induced hepatotoxicity or elevation of ALT levels. In early post-marketing experience with rosiglitazone, rare reports or hepatocellular dysfunction, primarily evidenced by elevated liver enzymes, have been received. Causality has not been established. In controlled trials, 0.2% of patients treated with rosiglitazone had elevations in ALT > 3X the upper limit of normal compared to 0.2% on placebo and 0.5% on active comparators. The ALT elevations in patients treated with rosiglitazone were reversible and were not clearly causally related to therapy with rosiglitazone. Although available clinical data show no evidence of rosiglitazone induced hepatotoxicity or ALT elevations, rosiglitazone is structurally very similar to troglitazone, which has been associated with idiosyncratic hepatotoxicity and rare eases of liver failure, liver transplants, and death. Pending the availability of the results of additional large, long-term controlled clinical trials and postmarketing safety data following wide clinical use of rosiglitazone to more fully define its hepatic safety profile, it is recommended that patients treated with rosiglitazone undergo periodic monitoring of liver enzymes. Liver enzymes should be checked prior to the initiation of therapy with rosiglitazone in all patients. Therapy with rosiglitazone should not be initiated in patients with increased baseline liver enzyme levels (ALT > 2.5X uper limit of normal). Liver enzymes should be checked prior to the initiation of therapy with AVANDIA in all patients and periodically thereafter per the clinical judgement of the healthcare professional. Patients with mildly elevated liver enzymes (ALT levels one to 2.5X upper limit of normal) at baseline or during therapy with rosiglitazone should be evaluated to determine the cause of the liver enzyme elevation. Initiation of, or continuation of, therapy with rosiglitazone in patients with mild liver enzyme elevations should proceed with caution and include appropriate close clinical follow-up, including more frequent liver enzyme monitoring, to determine if the liver enzyme elevations resolve or worsen. If at any time ALT levels increase to >3X upper limit of normal in patients on therapy with rosiglitazone, liver enzyme levels should be rechecked as soon as possible. If ALT levels remain >3X the upper limit of normal , therapy with rosiglitazone should be continued.
There are no data available to evaluate the safety of rosiglitazone alone in patients who experience abnormalities, hepatic dysfunction or jaundice while on troglitazone. Rosiglitazone should not he used in patients who experienced jaundice while taking troglitazone. For patients with normal hepatic enzymes who are switched from troglitazone to rosiglitazone a one week washout is recommended before starting therapy with rosiglitazone. 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 judgment pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued.
Periodic fasting blood glucose and HbA1c measurements should be performed to monitor therapeutic response. Liver enzyme monitoring is recommended prior to initiation of therapy with rosiglitazone in all patients and periodcally thereafter (See Warnings and Precautions for use, Hepatic Effects. Adverse Reactions, Serum Transaminase Levels).
Information for Patients
Patients should be informed of the following: Management of type 2 diabetes should include diet control. Caloric restriction, weight loss and exercise are essential for the proper treatment of the diabetic patient because they help improve insulin sensitivity. This is important not only in the primary treatment of type 2 diabetes, but in maintaining the efficacy of drug therapy.
AVANDIA can be taken with or without meals. When using AVANDIA in combination with other hypoglycaemic agents, the risk of hypoglycaemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members.
Use of AVANDIA may cause resumption of ovulation in premenopausal, anovulatory women with insulin resistance. Therefore, contraceptive measures need to be considered. Patients who experience an unusually rapid increase in weight or oedema or who develop shortness of breath or other symptoms of heart failure while on AVANDIA should immediately report these symptoms to their physician.
Drugs Metabolised by Cytochrome P450
In vitro drug metabolism studies suggest that rosiglitazone does not inhibit any of the major P450 enzymes at clinically relevant concentrations. In vitro data demonstrate that rosiglitazone is predominantly metabolised by CYP2C8, and to a lesser extent, CYP2C9.
Co-administration of AVANDIA with CYP2C8 inhibitors (e.g. gemfibrozil) resulted in increased rosiglitazone plasma concentrations (see Pharmacokinetics). Since there is a potential for an increase in the risk of dose-related adverse reactions, a decrease in AVANDIA dose may be needed when CYP2C8 inhibitors are co-administered. Co-administration of AVANDIA with a CYP2C8 inducer (e.g. rifampicin) resulted in decreased rosiglitazone plasma concentrations (see Pharmacokinetics). Therefore, close monitoring of glycaemic control and changes in diabetic treatment should be considered when CYP2C8 inducers are co-administered.
AVANDIA (4 mg twice daily) was shown to have no clinically relevant effect on the pharmacokinetics of nifedipine and oral contraceptives (ethinylestradiol and norethindrone) which are predominantly metabolised by CYP3A4. Co-administration of therapeutic doses of AVANDIA had no clinically significant effects on the steady state pharmacokinetics or pharmacodynamics of other oral antidiabetic agents including metformin, glibenclamide, glimepiride and acarbose.
Digoxin: Repeat oral dosing of AVANDIA (8 mg once daily) for 14 days did not alter the steady-state pharmacokinetics of digoxin (0.375 mg once daily) in healthy volunteers.
Warfarin: Repeat dosing with AVANDIA had no clinically relevant effect on the steady-state pharmacokinetics of warfarin enantiomers.
Ethanol: A single administration of a moderate amount of alcohol did not increase the risk of acute hypoglycaemia in type 2 diabetes mellitus patients treated with AVANDIA.
Ranitidine: Pre-treatment with ranitidine (150 mg twice daily for 4 days) did not alter the pharmacokinetics of either single oral or intravenous doses of rosiglitazone in healthy volunteers. These results suggest that the absorption of oral rosiglitazone is not altered in conditions accompanied by increases in gastrointestinal pH.
Pregnancy and Lactation
AVANDIA, like other thiazolidinediones, may result in resumption of ovulation in premenopausal, anovulatory women with insulin resistance. As a consequence of their improved insulin sensitivity, these patients may be at risk for pregnancy if adequate contraception is not used. Although hormonal imbalance has been seen in preclinical studies (see Carcinogenesis, Mutagenesis, Impairment of Fertility) the clinical significance of this finding is not known If unexpected menstrual dysfunction occurs, the benefits of continued therapy with AVANDIA should be reviewed.
Pregnancy Category C
AVANDIA has been reported to cross the human placenta and to be detectable in foetal tissues. There are no adequate data to support the use of AVANDIA during pregnancy in humans. The use of insulin is generally recommended for patients with diabetes during pregnancy. AVANDIA should not be used during pregnancy unless the potential benefit justifies the potential risk to the foetus (see Pre-Clinical Safety Data).
Labour and Delivery
The effect of AVANDIA on labour and delivery in humans is not known.
There are no adequate data to support the use of AVANDIA during lactation in humans. It is not known if AVANDIA is secreted into human milk during lactation. The use of insulin is generally recommended for patients with diabetes during lactation. AVANDIA should not be used during lactation unless the potential benefit justifies the potential risk to the infant (see Pre Clinical Safety Data).
Effects on Ability to Drive and Use Machines
AVANDIA does not cause drowsiness or sedation. It should not impair the ability to drive or operate machinery.
Adverse drug reactions (ADRs) are listed below bys system organ class and frequency. Frequencies are defined as: very common (>1/10), common (>1/100 and <1/10), uncommon (>1/1000 and <1/100), rare (>1/10 000 and <1/1000) and very rare (<1/10 000) including isolated reports. The frequencies of very common, common and uncommon events were determined from pooled safety data from a clinical trial population of >5000 AVANDIA treated patients.
Frequency categories have been assigned based on the differences in frequency between treatment and placebo or comparator groups rather than the absolute frequency, in order to estimate the portion of ADRs which may be attributable to AVANDIA. For dose related ADRs, the frequency category reflects the higher dose of AVANDIA.
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