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Avandia - Information

AVANDIA^®

rosiglitazone

Presentation

Film coated, pentagonal shaped Tiltab® tablets. The tablet strengths are distinguished by colour: 4.0mg (orange) and 8.0mg (red-brown).

Each strength is provided in opaque blister packs (PVC/aluminium).

Clinical Particulars

Therapeutic indications

Avandia is indicated for the treatment of Type 2 diabetes mellitus (non-insulin dependent diabetes mellitus).

It may be used as monotherapy in patients inadequately controlled by diet and exercise and in combination with sulphonylureas or metformin to improve glycaemic control in patients with Type 2 diabetes mellitus.

Posology and method of administration

Avandia therapy should be individualised for each patient.

The recommended starting dose for Avandia is 4mg/day. If patients require greater glycaemic control after 6-8 weeks of treatment, this dose can be increased to 8mg/day . Avandia may be given once or twice a day.

Avandia may be taken with or without food.

No dose adjustment is required in the elderly.

There are no data available on the use of Avandia in patients under 18 years of age, and therefore its use in this age group is not recommended.

Impaired renal function

No dose adjustment is required in patients with varying degrees of renal insufficiency, including patients with end stage renal disease on chronic haemodialysis. Limited data are available in patients with severe renal insufficiency and therefore Avandia should be used with caution in these patients.

Impaired hepatic function

In patients with mild hepatic impairment (Child-Pugh A, scores of 6 or less) no dose adjustment is required. Owing to a difference in the pharmacokinetic profile (see Pharmacokinetic properties) and limited experience, Avandia is not recommended in patients with moderate to severe hepatic impairment (Child-Pugh B/C, scores greater than 6).

Contraindications

Avandia is contraindicated in patients with a previous history of hypersensitivity to rosiglitazone or excipients.

Special warnings and special precautions for use

As a consequence of improving insulin sensitivity, Avandia treatment in premenopausal anovulatory patients with insulin resistance (eg. patients with polycystic ovary syndrome) may result in resumption of ovulation. These patients may be at risk of pregnancy.

Premenopausal women have received Avandia during clinical studies. Although hormonal imbalance has been seen in preclinical studies (see Preclinical safety data), no significant adverse experiences associated with menstrual disorders have been observed. If unexpected menstrual dysfunction occurs the benefits of continued therapy should be reviewed .

Since thiazolidinediones can cause fluid retention, which can exacerbate congestive heart failure, patients at risk for heart failure (particularly those on insulin) should be monitored for signs and symptoms of heart failure.

Patients with severe cardiac failure (NYHA Class III & IV) were not studied during clinical trials. Avandia is not indicated in these patients unless the potential benefit is believed to outweigh the potential risk.

Avandia is effective only in the presence of insulin and should not be used in type 1 diabetes mellitus.

Interaction with other medicaments and other forms of interaction

No clinically relevant drug interactions have been observed with Avandia.

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 and acarbose.

Avandia had no effects on the steady state pharmacokinetics of digoxin or warfarin nor did it affect the anti-coagulant activity of warfarin.

In vitro studies demonstrate that Avandia is predominantly metabolised by CYP 2C8, with CYP 2C9 as only a minor pathway. However, clinical data have shown that Avandia had no clinically relevant effect on the pharmacokinetics of S(-)-warfarin (a substrate for CYP 2C9).

No clinically relevant effects on nifedipine or oral contraceptives (components ethinylestradiol and norethindrone) were observed after co-administration with Avandia confirming a low probability of interaction with drugs metabolised by CYP 3A4.

Moderate ingestion of alcohol with Avandia has no effect on glycaemic control.

Pregnancy and lactation

Use in pregnancy and lactation:

Adequate data are not available for Avandia during pregnancy or lactation in humans. Avandia was not teratogenic in animal studies. There was no effect on the embryo during early pregnancy but treatment during mid-late gestation was associated with foetal death and retarded foetal development. The use of insulin is generally recommended for patients with Type 2 diabetes during pregnancy and lactation. Consequently, for patients who are pregnant or breastfeeding, the benefit/risk of treatment should be considered.

Effects on ability to drive and use machines

Avandia does not cause drowsiness or sedation. No effects on the ability to drive or operate machinery have been observed.

Undesirable effects

Adverse experiences with Avandia were generally not dose related, were mostly mild and transient in nature. In placebo-controlled studies, Avandia was well-tolerated when used as monotherapy or in combination with sulphonylureas and metformin. The most common adverse experiences with Avandia > 5% were upper respiratory tract infection, injury and headache but these are unlikely to be causally related to Avandia therapy. The need for discontinuation of therapy due to adverse experience occurred in 7.5% of patients treated with Avandia compared with 8.2% of placebo patients (in placebo controlled studies).

In a small number of patients treated with Avandia adverse experiences of oedema, anaemia (decreased haemoglobin) and hypercholesterolaemia were reported in double blind studies. The elevated total cholesterol levels were associated with increase in both LDLc and HDLc and the ratio of total cholesterol:HDLc was unchanged in long term studies. The incidence of anaemia was higher when Avandia was used in combination with metformin. Overall, these experiences were generally mild to moderate and usually did not require discontinuation of treatment.

In a large clinical programme (4327 patients treated with Avandia ) 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 experience reports relating to Liver and Biliary systems also was low and equal to placebo (0.7%).

In clinical trials, an increased incidence of heart failure has been observed when Avandia is used in combination with insulin compared to insulin alone. Patients who experienced heart failure were on average older, had a longer duration of diabetes, and were mostly on the higher 8mg daily dose of Avandia.

Dose related weight gain was seen with Avandia alone and in combination with other hypoglycaemic agents. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.

Hypolglycaemia: Patients receiving rosiglitazone in combination with other oral hypoglycaemic agents or insulin or may be at risk for hypoglycaemia, and a reduction in the dose of the concomitant agent may be necessary.

Post-marketing reports of CHF and pulmonary oedema have been received rarely. It is known that the risk of developing heart failure is increased substantially in diabetic subjects compared to non-diabetic subjects.

Post-marketing reports of hepatic dysfunction, primarily evidenced by elevated hepatic enzymes have been received rarely, although a causal relationship to rosiglitazone has not been established. Hepatic abnormalities are known to be common in patients with diabetes.

Overdose

Limited data are available with regard to overdosage in humans. In clinical studies in volunteers Avandia has been administered at single oral doses of up to 20mg and was well tolerated.

In the event of an overdose, it is recommended that appropriate supportive treatment should be initiated as dictated by the patient's clinical status. Avandia is highly protein bound and is not cleared by haemodialysis.

Pharmacological Properties

Pharmacodynamic properties

Pharmacotherapeutic group: ATC code: Antihyperglycaemic

Avandia is a selective and potent agonist at the PPARg (peroxisomal proliferator activated gamma) nuclear receptor and is a member of the thiazolidinedione class of antidiabetic agents. It improves glycaemic control by improving insulin sensitivity at key sites of insulin resistance namely adipose tissue, skeletal muscle and liver. Insulin resistance is known to play a major role in the pathogenesis of type 2 diabetes. Thus, Avandia improves metabolic control by lowering blood glucose, circulating insulin and free fatty acids.

The antihyperglycaemic activity of Avandia has been demonstrated in a number of animal models of type 2 diabetes. In addition, Avandia preserved β-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. Avandia has also been shown to significantly delay the onset of renal dysfunction and systolic hypertension. Avandia did not stimulate pancreatic insulin secretion or induce hypoglycaemia in rats and mice.

In clinical studies with Avandia given as monotherapy at doses of 4 to 8mg/day, the glucose lowering effects are gradual in onset and are not associated with hypoglycaemia. Reductions in fasting plasma glucose are observed from 1 week of initiation of therapy, although the full therapeutic effect may take 6-8 weeks to occur. Patients taking 8mg/day as monotherapy have experienced greater glycaemic control with Avandia given as a divided dose. Consistent with other anti- hyperglycaemic agents, improvement in glycaemic control with Avandia was associated with small increases in weight.

In type 2 diabetes, long term and sustained improvements in glycaemic control (FPG and HbA1c) have been demonstrated with Avandia given once or twice daily as monotherapy or in combination with other oral antidiabetic agents. In two studies, Avandia produced significantly greater reductions in fasting plasma glucose than glibenclamide after 52 weeks of treatment. Avandia treatment has been associated with clinically significant reductions in fasting and postprandial plasma glucose levels and in glycated haemoglobin.

As a consequence of different but complementary mechanisms of action, combination therapy of Avandia with a sulphonylurea or metformin resulted in synergistic improvements in glycaemic control in type 2 diabetic patients.

Consistent with the mechanism of action of Avandia, enhanced glycaemic control is accompanied by clinically significant decreases in serum insulin levels. There are also reductions in insulin precursors, which are believed to be cardiovascular risk factors. Significant decreases in free fatty acids are a key feature of Avandia treatment.

Pharmacokinetic properties

Absorption

Absolute bioavailability of Avandia following both a 4 and an 8mg oral dose is approximately 99%. Avandia plasma concentrations peak at around 1 hour after dosing. Plasma concentrations are approximately dose proportional over the therapeutic dose range.

Administration of Avandia with food resulted in no change in overall exposure (AUC), although a small decrease in Cmax (approx 20-28%) and a delay in Tmax (1.75 h) were observed compared to dosing in the fasted state. These small changes are not clinically significant and, therefore, it is not necessary to administer Avandia at any particular time in relation to meals. The absorption of Avandia is not affected by increases in gastric pH.

Distribution

The volume of distribution of Avandia is approximately 14 litres and total plasma clearance around 3 L/h in healthy volunteers. Plasma protein binding of Avandia is high (approximately 99.8%) and is not influenced by concentration or age. There is no evidence for unexpected accumulation of Avandia after once daily or twice daily dosing.

Metabolism

Metabolism of Avandia 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 metabolites of Avandia are not considered to have any clinical relevance.

In vitro studies demonstrate that Avandia 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 Avandia, there is a low probability of significant metabolism-based interactions with drugs metabolised by these P450 enzymes.

Avandia showed moderate inhibition of CYP2C8 (IC₅₀ 18 �M) and low inhibition of CYP2C9 (IC₅₀ 50 �M) in vitro. An in vivo interaction study with warfarin indicated that rosiglitazone does not interact with CYP2C9 substrates in vivo.

Elimination

Total plasma clearance of Avandia 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 a 5-fold accumulation is anticipated.

Special populations

Gender: In the pooled population pharmacokinetic analysis, there were no marked differences in the pharmacokinetics of Avandia between males and females.

Elderly: In the pooled population pharmacokinetic analysis, there were no marked differences in the pharmacokinetics of Avandia between elderly and non-elderly patients.

Hepatic Insufficiency: In patients with moderate to severe (Child-Pugh B/C) hepatic disease, unbound Cmax and AUC were 2- and 3-fold higher in patients with hepatic impairment as a result of decreased plasma protein binding and reduced clearance of Avandia (see Posology and method of administration).

Renal Insufficiency: There are no clinically significant differences in the pharmacokinetics of Avandia in patients with renal impairment or end stage renal disease on chronic dialysis.

Preclinical safety data

Consistent with other thiazolidinediones, Avandia inhibits ovarian oestradiol and progesterone synthesis and lowers plasma levels of these hormones resulting in effects on oestrous/menstrual cycles and fertility in animals. There are no additional data of clinical significance.