Avandaryl

A study conducted in normal healthy volunteers showed that gemfibrozil (an inhibitor of CYP2C8) administered as 600 mg twice daily, increased rosiglitazone systemic exposure two-fold at steady state (see Warnings and Precautions, General).

Interactions with food have not been established.

In 32 healthy women, rosiglitazone maleate (8 mg once daily) was shown to have no statistically significant effect on the pharmacokinetics of oral contraceptives (ethinylestradiol and norethindrone). Breakthrough bleeding occurred in 5 individuals when rosiglitazone maleate was coadministered with an oral contraceptive. In one of these subjects a 40% decrease in ethinylestradiol exposure (AUC) was recorded. This was not correlated with a reduction in exposure to norethindrone, nor was there a consistent relationship between the occurrence of breakthrough bleeding and the pharmacokinetics of either ethinylestradiol or norethindrone in individual subjects.

It has been shown in vitro that rosiglitazone does not inhibit any of the major P450 enzymes at clinically relevant concentrations. In vitro studies demonstrate that rosiglitazone is predominantly metabolized by CYP2C8, with CYP2C9 as only a minor pathway. In vitro studies have shown that montelukast is an inhibitor of CYP 2C8 and may inhibit the metabolism of drugs primarily metabolized by CYP 2C8 (e.g. paclitaxel, rosiglitazone, repaglinide). No in vivo interaction studies have been performed with the CYP2C8 substrates cerivastatin and paclitaxel. The potential for a clinically relevant interaction with cerivastatin is considered to be low. Although rosiglitazone is not anticipated to affect the pharmacokinetics of paclitaxel, concomitant use is likely to result in inhibition of the metabolism of rosiglitazone.

Coadministration of rosiglitazone maleate with CYP2C8 inhibitors (e.g. gemfibrozil) resulted in increased rosiglitazone plasma concentrations. Since there is a potential for an increase in the risk of dose-related adverse reactions, a decrease in rosiglitazone maleate may be needed when CYP2C8 inhibitors are coadministered.

Coadministration of rosiglitazone maleate with a CYP2C8 inducer (e.g. rifampin) resulted in decreased rosiglitazone plasma concentrations. Therefore, close monitoring of glycemic control and changes in diabetic treatment should be considered when CYP2C8 inducers are coadministered.

Clinically significant interactions with CYP2C9 substrates or inhibitors are not anticipated.

Interactions with laboratory tests have not been established.

Interactions with herbal products have not been established.

Rosiglitazone maleate (8 mg once daily) was shown to have no clinically relevant effect on the pharmacokinetics of nifedipine and oral contraceptives (ethinylestradiol and norethindrone), which are predominantly metabolized by CYP3A4. The results of these two drug interaction studies suggest that rosiglitazone is unlikely to cause clinically important drug interactions with other drugs metabolized via CYP3A4.

A study conducted in normal healthy volunteers showed that rifampin (an inducer of CYP2C8) administered as 600 mg daily, decreased the rosiglitazone systemic exposure three-fold (see Warnings and Precautions, General). Additional pharmacokinetic studies demonstrated no clinically relevant effect of acarbose, ranitidine, or metformin on the pharmacokinetics of rosiglitazone.

Single oral doses of glimepiride in 14 healthy adult subjects had no clinically significant effect on the steady-state pharmacokinetics of rosiglitazone. No clinically significant reductions in glimepiride AUC and C_max were observed after repeat doses of rosiglitazone maleate for 8 days in healthy adult subjects.

Coadministration of rosiglitazone maleate (4 mg twice daily for 7 days) did not alter the anticoagulant response of steady-state warfarin in healthy volunteers with baseline values of INR of <2.75. Repeat dosing with rosiglitazone maleate had no clinically relevant effect on the steady-state pharmacokinetics of warfarin.

An interaction study of 22 adult patients with psoriasis examined the effect of repeat doses of rosiglitazone maleate (8 mg daily as a single dose for 8 days) on the pharmacokinetics of oral methotrexate administered as single oral doses of 5 to 25 mg weekly. Following 8 days of rosiglitazone maleate administration, the C_max and AUC_(0-inf) of methotrexate increased by 18% (90% CI: 11% to 26%) and 15% (90% CI: 8% to 23%), respectively, when compared to the same doses of methotrexate administered in the absence of rosiglitazone maleate.

Repeat oral dosing of rosiglitazone maleate (8 mg once daily) for 14 days did not alter the steady-state pharmacokinetics of digoxin (0.375 mg once daily) in healthy volunteers.

Coadministration of acetylsalicylic acid (1 g three times daily) and glimepiride led to a 34% decrease in the mean glimepiride AUC and, therefore, a 34% increase in the mean CL/f. The mean C_max had a decrease of 4%. Blood glucose and serum C-peptide concentrations were unaffected and no hypoglycemic symptoms were reported.

Coadministration of either cimetidine (800 mg once daily) or ranitidine (150 mg twice daily) with a single 4-mg oral dose of glimepiride did not significantly alter the absorption and disposition of glimepiride, and no differences were seen in hypoglycemic symptomatology.

Concomitant administration of propranolol (40 mg three times daily) and glimepiride significantly increased C_max, AUC, and T_½ of glimepiride by 23%, 22%, and 15%, respectively, and it decreased CL/f by 18%. The recovery of the major metabolites, cyclohexyl hydroxy methyl derivative (M1) and the carboxyl derivative (M2), from urine, however, did not change. The pharmacodynamic responses to glimepiride were nearly identical in normal subjects receiving propranolol and placebo. Pooled data from clinical trials in patients with type 2 diabetes showed no evidence of clinically significant adverse interactions with uncontrolled concurrent administration of beta-blockers. However, if beta-blockers are used, caution should be exercised and patients should be warned about the potential for hypoglycemia.

Concomitant administration of glimepiride tablets (4 mg once daily) did not alter the pharmacokinetic characteristics of R- and S-warfarin enantiomers following administration of a single dose (25 mg) of racemic warfarin to healthy subjects. No changes were observed in warfarin plasma protein binding. Glimepiride treatment did result in a slight, but statistically significant, decrease in the pharmacodynamic response to warfarin. The reductions in mean area under the prothrombin time (PT) curve and maximum PT values during glimepiride treatment were very small (3.3% and 9.9%, respectively) and are unlikely to be clinically important.

The responses of serum glucose, insulin, C-peptide, and plasma glucagon to 2 mg glimepiride were unaffected by coadministration of ramipril (an ACE inhibitor) 5 mg once daily in normal subjects. No hypoglycemic symptoms were reported.

A study conducted in twelve normal healthy volunteers showed that fluconazole (an inhibitor of CYP2C9) administered as 200 mg once daily, increased glimepiride systemic exposure approximately two and a half-fold (see Warnings and Precautions, General).

A study conducted in ten normal healthy volunteers showed that rifampin (an inducer of CYP2C9) administered as 600 mg once daily, decreased glimepiride systemic exposure by 34% (see Warnings and Precautions, General).

Potential interactions of glimepiride with other drugs metabolized by cytochrome P450 2C9 also include phenytoin, diclofenac, ibuprofen, naproxen, and mefenamic acid. Although no specific interaction studies were performed, pooled data from clinical trials showed no evidence of clinically significant adverse interactions with uncontrolled concurrent administration of calcium-channel blockers, estrogens, fibrates, NSAIDs, HMG-CoA reductase inhibitors, sulfonamides, or thyroid hormone.

The hypoglycemic action of sulfonylureas may be potentiated by certain drugs, including anabolic steroids and male sex hormones, ACE inhibitors, insulin and other oral antidiabetics nonsteroidal anti-inflammatory drugs and other drugs that are highly protein bound, such as azapropazone, sulfonamides (e.g. sulphaphenazole), chloramphenicol, clarithromycin, coumarins, cyclophosphamine, disopyramide, fenyramidol, fenfluramine, fibrates, fluconazole, fluoxetine, guanethidine, ifosfamide, miconazole, monoamine oxidase inhibitors, oxyphenbutazone, para-aminosalicylic acid, pentoxifylline (high dose parenteral), phenylbutazone, probenecid, propranolol, quinolones, salicylates, sulfonamide antibiotics, sulfinpyrazone and tetracyclines. When these drugs are administered to a patient receiving glimepiride, the patient should be observed closely for hypoglycemia. When these drugs are withdrawn from a patient receiving glimepiride, the patient should be observed closely for loss of glycemic control.

Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, acetazolamide, barbiturates, corticosteroids, diazoxide, epinephrine and other sympathomimetic agents, glucagon, isoniazid, laxatives (after protracted use), nicotinic acid (in high dose), estrogens and progestogens, phenothiazines, phenytoin, rifampin and thyroid products. When these drugs are administered to a patient receiving glimepiride, the patient should be closely observed for loss of glycemic control. When these drugs are withdrawn from a patient receiving glimepiride, the patient should be observed closely for hypoglycemia.

H₂ receptor antagonists, beta-blockers, clonidine and reserpine may lead to either potentiation or weakening of the blood-glucose-lowering effect.

AVANDARYL should be given once daily with a meal. The dosage of antidiabetic therapy with AVANDARYL should be individualized on the basis of effectiveness and tolerability. No exact dosage relationship exists between AVANDARYL and other antidiabetic agents.

The safety and efficacy of AVANDARYL as initial therapy for patients with type 2 diabetes have not been established. No studies have been performed specifically examining the safety and efficacy of AVANDARYL in patients previously treated with other oral hypoglycemic agents and switched to AVANDARYL. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

AVANDARYL is available for oral administration as tablets containing a fixed dose of 4 mg rosiglitazone maleate with variable doses of glimepiride (1, 2, or 4 mg) in a single tablet formulation.

For patients inadequately controlled on rosiglitazone or sulfonylurea monotherapy, the usual starting dose of AVANDARYL is 4 mg/1 mg or 4 mg/2 mg once daily. When switching from combination therapy of rosiglitazone maleate plus glimepiride as separate tablets, the usual starting dose of AVANDARYL is the dose of rosiglitazone maleate and glimepiride already being taken. The maximum recommended daily dose of AVANDARYL is 4 mg of rosiglitazone maleate and 4 mg of glimepiride.

Sufficient time should be given to assess adequacy of therapeutic response. Fasting glucose should be used to determine the therapeutic response to AVANDARYL:

• For patients previously treated with rosiglitazone monotherapy switched to AVANDARYL, dose titration is recommended if patients are not adequately controlled after 1 to 2 weeks. If additional glycemic control is needed, the daily dose of AVANDARYL may be increased by increasing the glimepiride component in no more than 2 mg increments at 1 to 2 week intervals up to the maximum recommended total daily dose of 4 mg rosiglitazone maleate/4 mg glimepiride.

  
  

• For patients previously treated with sulfonylurea monotherapy switched to AVANDARYL, it may take 2 weeks to see a reduction in blood glucose and 2 to 3 months to see the full effect of the rosiglitazone component. If additional glycemic control is needed, the dose of the glimepiride component may be increased. The dose of the rosiglitazone component should not exceed 4 mg. As with other sulfonylurea-containing antidiabetic agents, no transition period is necessary when transferring patients to AVANDARYL. Patients should be observed carefully (1 to 2 weeks) for hypoglycemia when being transferred from longer half-life sulfonylureas (e.g., chlorpropamide) to glimepiride due to potential overlapping of drug effect.

  
  

• If hypoglycemia occurs during up-titration of the dose or while maintained on therapy, a dosage reduction of the sulfonylurea component of AVANDARYL may be considered.

AVANDARYL should not be used in pregnancy or in nursing mothers. There are no data on the use of AVANDARYL in patients younger than 18 years; therefore, the use of AVANDARYL in pediatric patients is not recommended.

In elderly, debilitated, or malnourished patients, or in patients with renal insufficiency, the initial dosing, dose increments, and maintenance dosage of AVANDARYL should be conservative to avoid hypoglycemic reactions. (See Action and Clinical Pharmacology, Special Populations and Conditions and Warnings and Precautions, Hypoglycemia.)

Therapy with AVANDARYL 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 Warnings and Precautions, Hepatic and Action and Clinical Pharmacology, Hepatic Insufficiency). Liver enzyme monitoring is recommended in all patients prior to initiation of therapy with AVANDARYL and periodically thereafter. AVANDARYL is contraindicated in patients with serious hepatic impairment (see Contraindications, Warnings and Precautions, Hepatic).

If a dose of AVANDARYL is missed, the patient should be advised to take the dosage as soon as they remember anytime during the day. If a whole day is missed, the usual dose should be taken the next day. The patient should be advised not to take a double dose.

Gastrointestinal (GI) disturbances e.g. nausea, GI fullness, occur occasionally. Vomiting, gastrointestinal pain, and diarrhea have been reported, but the incidence in placebo-controlled trials was similar to that of placebo. In rare cases, there may be elevation of liver enzyme levels. Sulfonylureas, including glimepiride, may also, in isolated instances, cause impairment of liver function (e.g. with cholestasis and jaundice), as well as hepatitis which may also lead to liver failure.

In postmarketing experience with rosiglitazone maleate as monotherapy and in combination with other oral antidiabetic agents, adverse events potentially related to volume expansion (e.g., congestive heart failure, pulmonary edema, and pleural effusions) have been reported. See Warnings and Precautions, Cardiovascular.

Reports of events related to cardiovascular ischemia including myocardial infarction, and hypertension or hypertension accelerated have been received.

Reports of new onset and/or worsening macular edema with decreased visual acuity occurring with the use of rosiglitazone maleate have been received rarely. These patients frequently reported concurrent peripheral edema. In some cases, symptoms improved following discontinuation of rosiglitazone maleate (see Warnings and Precautions, Ophthalmologic).

Reports of anaphylactic reaction, rash and pruritus have been received very rarely.

Reports of hepatitis and of hepatic enzyme elevations to three or more times the upper limit of normal have been received. Very rarely, these reports have involved hepatic failure with and without fatal outcome, although causality has not been established.

Postmarketing reports of parotid gland enlargement have been associated with rosiglitazone and approximately one third of the reports resolved or improved following discontinuation of rosiglitazone.

Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occur in less than 1% of treated patients. These may be transient and may disappear despite continued use of glimepiride. If those hypersensitivity reactions persist or worsen, the drug should be discontinued. Porphyria cutanea tarda, photosensitivity reactions, and allergic vasculitis, in some cases, progressing from mild to serious reactions (including anaphylactic shock) have been reported with sulfonylureas, including glimepiride.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Ophthalmic examinations were carried out in over 500 subjects during long-term studies of glimepiride using the methodology of Taylor and West and Laties et al. No significant differences were seen between glimepiride and glyburide in the number of subjects with clinically important changes in visual acuity, intra-ocular tension, or in any of the five lens-related variables examined. Ophthalmic examinations were carried out during long-term studies using the method of Chylack et al. No significant or clinically meaningful differences were seen between glimepiride and glipizide with respect to cataract progression by subjective LOCS II grading and objective image analysis systems, visual acuity, intraocular pressure, and general ophthalmic examination.

In clinical studies in 4598 patients treated with rosiglitazone maleate encompassing approximately 3600 patient years of exposure, there was no evidence of drug-induced hepatotoxicity or elevated ALT levels.

In the controlled trials (including patients with ALT/AST of up to 2.5 times the upper limit of the reference range at study entry), 0.2% of patients treated with rosiglitazone maleate had reversible elevations in ALT >3 times the upper limit of the reference range compared to 0.2% on placebo and 0.5% on active comparators. Hyperbilirubinemia was found in 0.3% of patients treated with rosiglitazone maleate compared with 0.9% treated with placebo and 1% in patients treated with active comparators. Overall, there was a decrease in mean values for ALT, AST, alkaline phosphatase and bilirubin over time in patients treated with rosiglitazone maleate (see Warnings and Precautions, Hepatic).

In the clinical program including long-term, open-label experience, the rate per 100 patient years exposure of ALT increase to >3 times the upper limit of normal was 0.35 for patients treated with rosiglitazone maleate, 0.59 for placebo-treated patients, and 0.78 for patients treated with active comparator agents.

In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure.

Changes in accommodation and/or blurred vision may occur with the use of glimepiride. This is thought to be due to changes in blood glucose, and may be more pronounced when treatment is initiated. This condition is also seen in untreated diabetic patients, and may actually be reduced by treatment. In placebo-controlled trials of glimepiride, the incidence of blurred vision was placebo, 3.4%, and glimepiride, 1.7%.

Overall, the types of adverse experiences reported when rosiglitazone maleate was used in combination with a sulfonylurea were similar to those during monotherapy with rosiglitazone maleate.

Small increases in total cholesterol and LDL have been observed following treatment with rosiglitazone maleate (see Table 3, Action and Clinical Pharmacology, Pharmacodynamics and Clinical Effects).

In clinical trials, reports of hypoglycemia in patients treated with rosiglitazone maleate and sulfonylurea combination therapy were similar to reports in patients treated with sulfonylurea monotherapies. In double-blind studies, hypoglycemia was reported by 5.2% of patients receiving rosiglitazone maleate in combination with a sulfonylurea, by 5.9% receiving sulfonylurea monotherapy, by 0.6% receiving rosiglitazone maleate monotherapy, and by 0.2% receiving placebo.

Hypoglycemia was generally mild to moderate in nature and was dose-related when rosiglitazone maleate was used in combination with a sulfonylurea. Patients receiving rosiglitazone maleate in combination with oral hypoglycemic agents may be at risk for hypoglycemia, and a reduction in the dose of either agent may be necessary.

The overall incidence of hypoglycemia with glimepiride in placebo controlled trials was approximately 14%. In two long-term (2-2.5 years) and well-controlled studies, the incidence of hypoglycemic reaction ranged from 2.1 to 3.1%.

Leukopenia, agranulocytosis, hemolytic anemia, thrombocytopenia, aplastic anemia, erythrocytopenia, granulocytopenia, and pancytopenia have been reported with sulfonylureas, including glimepiride.

Hepatic porphyria reactions and disulfiram-like reactions have been reported with sulfonylureas; however, no cases have yet been reported with glimepiride. Cases of hyponatremia have been reported with glimepiride and all other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone. Although there have been no reports for glimepiride, the syndrome of inappropriate antidiuretic hormone (SIADH) secretion has been reported with certain other sulfonylureas, and it has been suggested that these sulfonylureas may augment the peripheral (antidiuretic) action of ADH and/or increase release of ADH.

Small decreases in hematological parameters were more common in the patients treated with rosiglitazone maleate than in placebo-treated patients. Leukopenia was reported in 0.4% of rosiglitazone maleate patients compared to 0.2% of patients on placebo, 0.6% on sulfonylureas and 1.1% on rosiglitazone maleate in combination with sulfonylureas. Decreases may be related to increased plasma volume observed with treatment with rosiglitazone maleate. The mean decrease in hemoglobin was approximately 10 to 12 g/L; the decrease in hematocrit was 0.03 to 0.04.

There are no data on the use of AVANDARYL in patients younger than 18 years; therefore, the use of AVANDARYL in pediatric patients is not recommended.

Results of the population pharmacokinetic analysis (n=716 <65 years; n=331 ≥65 years) showed that age does not significantly affect the pharmacokinetics of rosiglitazone.

Comparison of glimepiride pharmacokinetics in type 2 diabetic patients ≤65 years and those ≥65 years was performed in a study using a dosing regimen of 6 mg daily. There were no significant differences in glimepiride pharmacokinetics between the two age groups. The mean AUC at steady state for the older patients was about 13% lower than that for the younger patients; the mean weight adjusted clearance for the older patients was about 11% higher than that for the younger patients (see Warnings and Precautions, Special Populations, Geriatrics (≥65 years of age)).

Each yellow, rounded triangular tablet, debossed with gsk on one side and 4/1 on the other, contains: rosiglitazone maleate 4 mg and glimepiride 1 mg. Nonmedicinal ingredients: hypromellose 2910, lactose monohydrate, macrogol (polyethylene glycol), magnesium stearate, microcrystalline cellulose, sodium starch glycolate, titanium dioxide and one or more of the following: black, red or yellow iron oxides. Bottles of 100.

Each pink, rounded triangular tablet, debossed with gsk on one side and 4/4 on the other, contains: rosiglitazone maleate 4 mg and glimepiride 4 mg. Nonmedicinal ingredients: hypromellose 2910, lactose monohydrate, macrogol (polyethylene glycol), magnesium stearate, microcrystalline cellulose, sodium starch glycolate, titanium dioxide and one or more of the following: black, red or yellow iron oxides. Bottles of 100.

Each orange, rounded triangular tablet, debossed with gsk on one side and 4/2 on the other, contains: rosiglitazone maleate 4 mg and glimepiride 2 mg. Nonmedicinal ingredients: hypromellose 2910, lactose monohydrate, macrogol (polyethylene glycol), magnesium stearate, microcrystalline cellulose, sodium starch glycolate, titanium dioxide and one or more of the following: black, red or yellow iron oxides. Bottles of 100.

When a patient stabilized on any antidiabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold AVANDARYL and temporarily administer insulin. AVANDARYL may be reinstituted after the acute episode is resolved.

If risk factors for hypoglycemia are present, including renal insufficiency, low body weight, malnourishment or coadministration of certain other drugs (see Warnings and Precautions, Hypoglycemia; Drug Interactions and Dosage and Administration), it may be necessary to adjust the dosage of glimepiride or the entire therapy during such situations. This also applies whenever illness occurs during therapy or the patient's life-style changes.

As with other thiazolidinediones, rosiglitazone maleate may result in resumption of ovulation in premenopausal, anovulatory women with insulin resistance (e.g., patients with polycystic ovary syndrome). As a consequence of their improved insulin sensitivity, these patients may be at risk of pregnancy if adequate contraception is not used.

Although hormonal imbalance has been seen in preclinical studies, no significant adverse experiences associated with menstrual disorders have been reported in clinical trial participants, including premenopausal women. If unexpected menstrual dysfunction occurs, the benefits of continued therapy should be reviewed.

In some studies in rats, offspring of dams exposed to high levels of glimepiride during pregnancy and lactation developed skeletal deformations consisting of shortening, thickening and bending of the humerus during the postnatal period. Significant concentrations of glimepiride were observed in the serum and breast milk of the dams as well as in the serum of the pups. These skeletal deformations were determined to be the result of nursing from mothers exposed to glimepiride.

Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug. at the time of delivery. Patients who are planning a pregnancy should consult their physician.

In a retrospective analysis of data from pooled clinical studies, which included patients on combination therapy with insulin as well as patients with NYHA Class I and II heart failure, the overall incidence of events typically associated with cardiac ischemia was higher for rosiglitazone containing regimens, 2.00% versus comparators, 1.53% [hazard ratio 1.30 (95% confidence interval 1.004-1.69)]. In a subgroup analysis of this data, this risk was further increased in patients receiving nitrates with approximately twice as many events in patients receiving rosiglitazone versus comparators. The use of AVANDARYL is therefore not recommended for patients being treated with nitrates.

The completion of an adequately-designed cardiovascular outcome study is needed to further evaluate the risk of myocardial ischemic events associated with rosiglitazone.

In a large observational study where patients were well matched at baseline, the incidence of the composite endpoint of myocardial infarction and coronary revascularization was 1.75 events per 100 person years for rosiglitazone containing regimens and 1.76 events per 100 person years for other anti-diabetic agents [hazard ratio 0.93 (95% confidence interval 0.80-1.10)].

Glimepiride is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Elderly patients are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Therefore, the initial dosing, dose increments, and maintenance dosage should be conservative based upon blood glucose levels prior to and after initiation of treatment to avoid hypoglycemic reactions (see Warnings and Precautions, Hypoglycemia and Dosage and Administration, Specific Patient Populations).

The effect of AVANDARYL or its components on labour and delivery in humans is not known.

There are no controlled trials of AVANDARYL in pregnant women. Rosiglitazone has been reported to cross the human placenta and to be detectable in fetal tissues. AVANDARYL is contraindicated for use in pregnant women. Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies as well as increased neonatal morbidity and mortality, most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.

In animal studies rosiglitazone maleate was not teratogenic but treatment during mid-late gestation caused fetal death and growth retardation in both rats and rabbits at 19- and 73-fold clinical systemic exposure, respectively. In animal studies, glimepiride did not produce teratogenic effects but has been shown to be associated with intrauterine fetal death in rats when given in doses as low as 50 times the human dose based on surface area and in rabbits when given in doses as low as 0.1 times the human dose based on surface area. This fetotoxicity, observed only at doses inducing maternal hypoglycaemia, has been similarly noted with other sulfonylureas, and is believed to be directly related to the pharmacologic (hypoglycemic) action of glimepiride.

Dose-related weight gain was seen with rosiglitazone maleate alone and in combination with other hypoglycemic agents. Treatment should be re-evaluated in patients with excessive weight gain (see Action and Clinical Pharmacology and Adverse Reactions).

In a 4 to 6 year comparative study (ADOPT) of glycemic control with monotherapy in recently diagnosed patients with Type 2 diabetes mellitus, an increased incidence of bone fracture was noted in female patients taking rosiglitazone (9.3%, 2.7 patients per 100 patient-years) versus glyburide (3.5%, 1.3 patients per 100 patient-years) or metformin (5.1%, 1.5 patients per 100 patient-years). The majority of the fractures in the females who received rosiglitazone were reported in the upper arm, hand, and foot (see Adverse Reactions). The risk of fracture should be considered in the care of patients, especially female patients, treated with rosiglitazone, and attention should be given to assessing and maintaining bone health according to current standards of care.

Periodic fasting blood glucose and A1C measurements should be performed to monitor therapeutic response.

Liver enzyme monitoring is recommended prior to initiation of therapy with AVANDARYL in all patients and periodically thereafter (see Warnings and Precautions, Hepatic).

Thiazolidinediones, like rosiglitazone maleate, alone or in combination with other antidiabetic agents, can cause fluid retention, which can exacerbate or lead to congestive heart failure. The fluid retention may very rarely present as rapid and excessive weight gain. All patients should be monitored for signs and symptoms of adverse reactions relating to fluid retention and heart failure. In particular, patients who are at risk for heart failure including those receiving concurrent therapy which increases insulin levels (i.e. sulfonylureas) should be closely monitored (see Adverse Reactions). An increase in reporting of fluid retention related events including congestive heart failure has been seen in patients receiving rosiglitazone in combination with metformin and a sulfonylurea. This triple therapy regimen is not an approved indication.

Treatment with thiazolidinediones has been associated with cases of congestive heart failure, some of which were difficult to treat unless the medication was discontinued. AVANDARYL should be discontinued if any deterioration in cardiac status occurs.

AVANDARYL is contraindicated in patients with NYHA Class I, II, III and IV heart failure. Patients with severe heart failure (including NYHA Class III and IV cardiac status) were not studied during the clinical trials.

Patients experiencing acute coronary syndromes (ACS) have not been studied in rosiglitazone controlled clinical trials. Since patients experiencing ACS are at an increased risk of developing heart failure, and in view of the potential for rosiglitazone to cause or exacerbate heart failure, initiation of AVANDARYL in patients experiencing an acute coronary event is not recommended. Furthermore, discontinuation of AVANDARYL during the acute phase should be considered.

There are no data on the use of AVANDARYL in patients under 18 years of age; therefore, AVANDARYL is not indicated for use in patients under 18 years of age.

AVANDARYL should be used with caution in patients with edema. The maximum approved dose of rosiglitazone to be used in combination with a sulfonylurea is 4 mg. In healthy volunteers who received rosiglitazone maleate 8 mg once daily as monotherapy for 8 weeks, there was a statistically significant increase in median plasma volume (1.8 mL/kg) compared to placebo. In controlled clinical trials of patients with type 2 diabetes, mild to moderate edema was observed at a greater frequency in patients treated with rosiglitazone maleate and may be dose related (see Adverse Reactions). For information on macular edema, see Warnings and Precautions, Ophthalmologic.

AVANDARYL is a combination tablet containing rosiglitazone maleate and glimepiride, a sulfonylurea. All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Elderly, debilitated or malnourished patients, and those with adrenal, pituitary, or hepatic insufficiency are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Patients with impaired renal function may be more sensitive to the glucose-lowering effect of glimepiride. A starting dose of 1 mg glimepiride, as contained in AVANDARYL 4 mg/1 mg, followed by appropriate dose titration is also recommended in these patients (see Action and Clinical Pharmacology, Special Populations and Conditions, Renal Insufficiency).

Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs or other sympatholytic agents. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when other drugs with blood-glucose lowering potential are used.

Patients receiving rosiglitazone maleate in combination with a sulfonylurea may be at risk for hypoglycemia, and a reduction in the dose of either agent may be necessary (see Dosage and Administration, Specific Patient Populations).

For safety reasons, the use of AVANDARYL in combination with insulin is not indicated.

The use of AVANDARYL in combination with metformin (triple therapy) is not indicated. An increase in reporting of fluid retention related events (including congestive heart failure) has been seen in patients receiving rosiglitazone in combination with metformin and a sulfonylurea.

Close monitoring of glycemic control and dose adjustment of the rosiglitazone maleate or glimepiride components may be needed when AVANDARYL is coadministered with CYP2C8 or CYP2C9 inhibitors or inducers (see Drug Interactions).

No studies have been conducted with AVANDARYL. Rosiglitazone and/or its metabolites have been detected in the milk of lactating rats. In rat reproduction studies, significant concentrations of glimepiride were observed in the serum and breast milk of the dame, as well as in the serum of the pups. Although it is not known whether rosiglitazone and/or glimepiride are excreted in human milk, many drugs, including other sulfonylureas, are excreted in human milk. Since the potential for hypoglycemia in nursing infants exist, and because of the effects on nursing animals (see Pregnant Women, Nonteratogenic Effects), AVANDARYL should not be administered to a nursing woman. If AVANDARYL is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered (see Pregnant Women).

In patients with renal insufficiency, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemic reactions (see Dosage and Administration).

There are no data from the use of glimepiride in patients on renal dialysis (see Action and Clinical Pharmacology).

No pharmacokinetic data are available for AVANDARYL in the following special populations. Information is provided for the individual components of AVANDARYL.

Results of the population pharmacokinetic analysis showed that the mean oral clearance of rosiglitazone in female patients (n=405) was 15% lower compared to male patients (n=642), primarily related to lower body weight in females. Combination therapy with rosiglitazone maleate and sulfonylureas improved glycemic control in both males and females. In rosiglitazone maleate and sulfonylurea combination studies, a greater therapeutic response was observed in females. For a given body mass index (BMI), females tend to have a greater fat mass than males. Since the molecular target of rosiglitazone, PPARγ, is expressed in adipose tissues, this differentiating characteristic may account, at least in part, for the greater response to rosiglitazone maleate in combination with sulfonylureas in females. Since therapy should be individualized, no dose adjustments are necessary based on gender alone.

There were no differences between males and females in the pharmacokinetics of glimepiride when adjusted for differences in body weight.

The AUC and C_max of glimepiride increased in a dose-proportional manner following administration of AVANDARYL 4 mg/1 mg, 4 mg/2 mg, and 4 mg/4 mg. Administration of AVANDARYL with food decreased the rate, but not extent, of rosiglitazone absorption and increased both the rate and extent of absorption of glimepiride compared to the fasted state.

No pharmacokinetic data from studies in pediatric subjects are available for either rosiglitazone or glimepiride.

Unbound oral clearance of rosiglitazone was significantly lower in patients with moderate to severe liver disease (Child-Pugh Class B/C) compared to healthy subjects. As a result, unbound C_max and AUC_0-inf were increased 2- and 3-fold, respectively. Elimination half-life for rosiglitazone was about 2 hours longer in patients with liver disease, compared to healthy subjects. Therapy with AVANDARYL 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 Warnings and Precautions, Hepatic and Action and Clinical Pharmacology, Special Populations and Conditions, Hepatic Insufficiency.

No pharmacokinetic studies of glimepiride have been conducted in subjects with hepatic insufficiency.

Following oral or intravenous administration of [¹⁴C] rosiglitazone maleate, approximately 64% and 23% of the dose was eliminated in the urine and feces, respectively. The plasma half-life of [¹⁴C] related material ranged from 103 to 158 hours. The elimination half-life of rosiglitazone is 3 to 4 hours and is independent of dose.

Results of the population pharmacokinetic analysis (n=716 ≤65 years; n=331 ≥65 years) showed that age does not significantly affect the pharmacokinetics of rosiglitazone.

Comparison of glimepiride pharmacokinetics in type 2 diabetic patients ≤65 years and those >65 years was performed in a study using a dosing regimen of 6 mg daily. There were no significant differences in glimepiride pharmacokinetics between the two age groups. The mean AUC at steady state for the older patients was about 13% lower than that for the younger patients; the mean weight adjusted clearance for the older patients was about 11% higher than that for the younger patients (see Warnings and Precautions, Special Populations, Geriatrics (≥65 years of age)).

AVANDARYL tablets combines 2 antidiabetic agents with complementary mechanisms of action to improve glycemic control while reducing circulating insulin levels in patients with type 2 diabetes: Rosiglitazone, a member of the thiazolidinedione class, and glimepiride, a member of the sulfonylurea class. Thiazolidinediones are insulin sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas sulfonylureas act primarily by stimulating release of insulin from functioning pancreatic beta cells.

Rosiglitazone maleate is an oral antidiabetic agent which acts primarily by increasing insulin sensitivity in type 2 diabetes. Rosiglitazone, a member of the thiazolidinedione class of antidiabetic agents, improves glycemic control while reducing circulating insulin levels. It improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. Rosiglitazone is not chemically or functionally related to the sulfonylureas, the biguanides or the alpha-glucosidase inhibitors. Rosiglitazone is a highly selective and potent agonist for the peroxisome proliferator-activated receptor-gamma (PPARγ). In humans, PPAR receptors are found in key target tissues for insulin action such as adipose tissue, skeletal muscle and liver. Activation of PPARγ nuclear receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In addition, PPARγ-responsive genes also participate in the regulation of fatty acid metabolism and in the maturation of preadipocytes, predominantly of subcutaneous origin.

Insulin resistance is a primary feature characterizing the pathogenesis of type 2 diabetes. The use of rosiglitazone maleate results in increased responsiveness of insulin-dependent tissues and significantly improves hepatic and peripheral (muscle) tissue sensitivity to insulin in patients with type 2 diabetes. Clinical studies in patients with type 2 diabetes treated with rosiglitazone maleate either as monotherapy or in combination with sulfonylureas showed improved beta-cell function and decreased fasting plasma glucose, insulin and C-peptide values following 26 weeks of treatment. A homeostasis model assessment (HOMA) was conducted using fasting plasma glucose and insulin or C-peptide levels as a measure of insulin sensitivity and beta-cell function. In these studies, reductions in mean plasma pro-insulin and pro-insulin split product concentrations were also observed.

Rosiglitazone maleate significantly reduced hemoglobin A1C (A1C, a marker for long term glycemic control), and fasting blood glucose (FBG) in patients with type 2 diabetes. Inadequately controlled hyperglycemia is associated with an increased risk of diabetic complications, including cardiovascular disorders and diabetic nephropathy, retinopathy and neuropathy.

Studies between 8 and 26 weeks with rosiglitazone maleate have shown a statistically significant reduction in markers of inflammation, C-reactive protein (CRP) and matrix metalloproteinase-9 (MMP-9). The clinical significance of these effects are still unknown. Further long term clinical trials are needed.

Estimates of LDL particle size can be determined by the LDL cholesterol (LDL) to apolipoprotein B (Apo B) ratio. In controlled clinical trials, rosiglitazone maleate has been shown to increase the LDL cholesterol to Apo B ratio consistent with a beneficial change in LDL particle size from small dense LDL particles to larger more buoyant particles. This change has been confirmed by measuring LDL particle buoyancy (Rf) following 8 weeks treatment with rosiglitazone maleate in an open-label study.

The primary mechanism of action of glimepiride in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. In addition, extrapancreatic effects may also play a role in the activity of glimepiride. This is supported by both preclinical and clinical studies demonstrating that glimepiride administration can lead to increased sensitivity of peripheral tissues to insulin. These findings are consistent with the results of a long-term, randomized, placebo-controlled trial in which glimepiride therapy improved postprandial insulin/C-peptide responses and overall glycemic control without producing clinically meaningful increases in fasting insulin/C-peptide levels. However, the mechanism by which glimepiride lowers blood glucose during long-term administration has not been clearly established.

Results of a population pharmacokinetic analysis including subjects of Caucasian, black and other ethnic origins indicate that race has no influence on the pharmacokinetics of rosiglitazone.

No pharmacokinetic studies to assess the effects of race have been performed, but in placebo-controlled studies of glimepiride in patients with type 2 diabetes, the hypoglycemic effect was comparable in whites (n=536), blacks (n=63), and Hispanics (n=63).

There are no clinically relevant differences in the pharmacokinetics of rosiglitazone in patients with mild to severe renal impairment or in hemodialysis-dependent patients, compared to subjects with normal renal function.

There are no data from the use of glimepiride in patients on renal dialysis (see Warnings and Precautions).

A single-dose glimepiride, open-label study was conducted in 15 patients with renal impairment. Glimepiride (3 mg) was administered to 3 groups of patients with different levels of mean creatinine clearance (Clcr): Group I, Clcr=77.7 mL/min (1.30 mL/sec), n=5; Group II, Clcr=27.7 mL/min (0.462 mL/sec), n=3; and Group III, Clcr=9.4 mL/min (0.16 mL/sec), n=7. Glimepiride was found to be well tolerated in all 3 groups. The results showed that M1 and M2 serum levels (mean AUC values) increased 2.2 and 6.1 times from Group I to Group III as renal function decreased. The apparent terminal half life (T_½) for glimepiride did not change, while the half-lives for M1 and M2 increased as renal function decreased. Mean urinary excretion of M1 plus M2 as percent of dose, however, decreased (44.4%, 21.9%, and 9.3% for Groups I to III).

A multiple-dose glimepiride titration study was also conducted in 16 type 2 diabetic patients with renal impairment using doses ranging from 1-8 mg daily for 3 months. The results were consistent with those observed after single doses. All patients with a Clcr less than 22 mL/min (0.37 mL/sec) had adequate control of their glucose levels with a dosage regimen of only 1 mg daily. The results from this study suggested that a starting dose of 1 mg glimepiride, as in AVANDARYL 4 mg/1 mg, may be given to type 2 diabetic patients with kidney disease, and the dose may be titrated based on fasting blood glucose levels.

When ¹⁴C-glimepiride was given as a single dose orally, approximately 60% of the total radioactivity was recovered in the urine in 7days and M1 (predominant) and M2 accounted for 80-90% of that recovered in the urine. Approximately 40% of the total radioactivity was recovered in feces and M1 and M2 (predominant) accounted for about 70% of that recovered in feces. After IV dosing in patients, no significant biliary excretion of glimepiride or its M1 metabolite has been observed.

The long term significance of the lipid changes is not known.