Rosiglitazone and glimepiride

Uses

Combination of Glimepiride and Rosiglitazone is used for an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes who are already treated with a combination of Rosiglitazone and sulfonylurea as separate tablet or who are not adequately controlled on a sulfonylurea alone or for those patients who have initially responded to Rosiglitazone alone and require additional glycemic control.

Rosiglitazone and glimepiride is also used to associated treatment for these conditions: Type 2 Diabetes MellitusType 2 Diabetes Mellitus

How Rosiglitazone and glimepiride works

ATP-sensitive potassium channels on pancreatic beta cells that are gated by intracellular ATP and ADP. The hetero-octomeric complex of the channel is composed of four pore-forming Kir6.2 subunits and four regulatory sulfonylurea receptor (SUR) subunits. Alternative splicing allows the formation of channels composed of varying subunit isoforms expressed at different concentrations in different tissues. In pancreatic beta cells, ATP-sensitive potassium channels play a role as essential metabolic sensors and regulators that couple membrane excitability with glucose-stimulated insulin secretion (GSIS). When there is a decrease in the ATP:ADP ratio, the channels are activated and open, leading to K+ efflux from the cell, membrane hyperpolarization, and suppression of insulin secretion. In contrast, increased uptake of glucose into the cell leads to elevated intracellular ATP:ADP ratio, leading to the closure of channels and membrane depolarization. Depolarization leads to activation and opening of the voltage-dependent Ca2+ channels and consequently an influx of calcium ions into the cell. Elevated intracellular calcium levels causes the contraction of the filaments of actomyosin responsible for the exocytosis of insulin granules stored in vesicles. Glimepiride blocks the ATP-sensitive potassium channel by binding non-specifically to the B sites of both sulfonylurea receptor-1 (SUR1) and sulfonylurea receptor-2A (SUR2A) subunits as well as the A site of SUR1 subunit of the channel to promote insulin secretion from the beta cell.

Rosiglitazone acts as a highly selective and potent agonist at peroxisome proliferator activated receptors (PPAR) in target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPAR-gamma receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In this way, rosiglitazone enhances tissue sensitivity to insulin.

Dosage

Rosiglitazone and glimepiride dosage

Glimepiride plus Rosiglitazone should be given once daily with the first meal of the day. The dosage of antidiabetic therapy with Glimepiride plus Rosiglitazone should be individualized on the basis of effectiveness and tolerability. No exact dosage relationship exists between Glimepiride plus Rosiglitazone and other antidiabetic agents. For patients inadequately controlled on sulfonylurea monotherapy or who have initially responded to Rosiglitazone alone and require additional glycemic control, the usual starting dose of Glimepiride plus Rosiglitazone is 1 mg/4 mg or 2 mg/4 mg once daily.

When switching from combination therapy of Glimepiride plus Rosiglitazone as separate tablets, the usual starting dose of Glimepiride plus Rosiglitazone is the dose of Glimepiride and Rosiglitazone already being taken. The maximum recommended daily dose of Glimepiride plus Rosiglitazone is 4 mg of Glimepiride and 8 mg of Rosiglitazone.

Sufficient time should be given to assess adequacy of therapeutic response. Fasting glucose should be used to determine the therapeutic response to Glimepiride plus Rosiglitazone.

For patients previously treated with sulfonylurea monotherapy switched to Glimepiride plus Rosiglitazone, 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 8 mg. As with other sulfonylurea-containing antidiabetic agents, no transition period is necessary when transferring patients to Glimepiride plus Rosiglitazone. Patients should be observed carefully (1 to 2 weeks) for hypoglycemia when being transferred from longer half life sulfonylureas (e.g., chlorpropamide) to Glimepiride plus Rosiglitazone due to potential overlapping of drug effect.

For patients previously treated with thiazolidinedione monotherapy switched to Glimepiride plus Rosiglitazone 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 Glimepiride plus Rosiglitazone 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 Glimepiride/8 mg Rosiglitazone.

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

Diaryl tablet must be swallowed without chewing and with sufficient amount of liquid (approximately ½ glass).

Side Effects

Glimepiride:

• Hypoglycemia: The incidence of hypoglycemia with Glimepiride is documented. In patients treated with Glimepiride, adverse events, other than hypoglycemia, considered to be possibly or probably related to study drug that occurred in more than 1% of patients included dizziness, asthenia, headache, and nausea.
• Dermatologic Reactions: 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.

Rosiglitazone: The most common adverse experiences with Rosiglitazone monotherapy were upper respiratory tract infection, injury, and headache. Overall, the types of adverse experiences reported when Rosiglitazone was used in combination with a sulfonylurea were similar to those during monotherapy with Rosiglitazone. Events of anemia and edema tended to be reported more frequently at higher doses, and were generally mild to moderate in severity and usually did not require discontinuation of treatment with Rosiglitazone. Angioedema and urticaria have been reported rarely with Rosiglitazone treatment.

Toxicity

The oral LD50 value in rats is > 10000 mg/kg. The intraperitoneal LD50 value in rats is reported to be 3950 mg/kg . Although glimepiride is reported to have fewer risks of hypoglycemia compared to other sulfonylureas such as glyburide, overdosage of glimepiride may result in severe hypoglycemia with coma, seizure, or other neurological impairment may occur. This can be treated with glucagon or intravenous glucose. Continued observation and additional carbohydrate intake may be necessary since hypoglycemia may recur after apparent clinical recovery.

In a study of rats given doses of up to 5000 parts per million (ppm) in complete feed for 30 months, there were no signs of carcinogenesis. Meanwhile, the administration of glimepiride at a dose much higher than the maximum human recommended dose for 24 months in mice resulted in an increase in benign pancreatic adenoma formation in a dose-related manner, which was thought to be the result of chronic pancreatic stimulation. Glimepiride was non-mutagenic in in vitro and in vivo mutagenicity studies. In male and female rat studies, glimepiride was shown to have no effects on fertility.

Side effects include fluid retention, congestive heart failure (CHF), liver disease

Precaution

Hypoglycemia: All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Debilitated or malnourished patients and those with adrenal, pituitary, renal, or hepatic insufficiency are particularly susceptible to the hypoglycemic action of glucose lowering drugs.

Loss of Control of Blood Glucose: 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.

Edema: Combination of Glimepiride and Rosiglitazone should be used with caution in patients with edema.

Since thiazolidinediones, including Rosiglitazone can cause fluid retention, which can exacerbate or lead to congestive heart failure, Combination of Glimepiride and Rosiglitazone should be used with caution in patients at risk for heart failure.

Weight Gain: Dose-related weight gain was seen with Rosiglitazone alone and in combination with other hypoglycemic agents.

Hepatic Effects: Liver enzymes should be checked prior to the initiation of therapy with combination of Glimepiride and Rosiglitazone in all patients and periodically thereafter per the clinical

Interaction

Glimepiride: Salicylates, sulfonamides, chloramphenicol, clarithromycin, coumarin anticoagulants, probenecid, CYP2C9 inhibitors, fibric acid derivatives, disopyramide, fluoxetine, quinolones, ACE inhibitors, MAOIs may potentiate the hypoglycaemic action of glimepiride. Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, oestrogens, phenytoin, nicotinic acid, sympathomimetics and CYP2C9 inducers may reduce hypoglycaemic effect of glimepiride. Reduced plasma concentration with colesevelam.

Rosiglitazone: Increased plasma cone with gemfibrozil. Decreased plasma cone with rifampicin.

Volume of Distribution

Following intravenous dosing in healthy subjects, the volume of distribution was 8.8 L (113 mL/kg).

• 17.6 L [oral volume of distribution Vss/F]
• 13.5 L [population mean, pediatric patients]
  

Elimination Route

Glimepiride is completely absorbed after oral administration within 1 hour of administration with a linear pharmacokinetics profile. Following administration of a single oral dose of glimepiride in healthy subjects and with multiple oral doses with type 2 diabetes, the peak plasma concentrations (Cmax) were reached after 2 to 3 hours post-dose. Accumulation does not occur after multiple doses. When glimepiride was given with meals, the time to reach Cmax was increased by 12% while the mean and AUC (area under the curve) were decreased by 8 to 9%, respectively. In a pharmacokinetic study of Japanese patients with T2DM, Cmax value in once-daily dose was higher than those in twice-daily doses. The absolute bioavailability of glimepiride is reported to be complete following oral administration.

The absolute bioavailability of rosiglitazone is 99%. Peak plasma concentrations are observed about 1 hour after dosing. Administration of rosiglitazone with food resulted in no change in overall exposure (AUC), but there was an approximately 28% decrease in C_max and a delay in T_max (1.75 hours). These changes are not likely to be clinically significant; therefore, rosiglitazone may be administered with or without food. Maximum plasma concentration (Cmax) and the area under the curve (AUC) of rosiglitazone increase in a dose-proportional manner over the therapeutic dose range.

Half Life

The elimination half-life of glimepiride is approximately 5 to 8 hours, which can increase up to 9 hours following multiple doses.

3-4 hours (single oral dose, independent of dose)

Clearance

A single-dose, crossover, dose-proportionality (1, 2, 4, and 8 mg) study in normal subjects and from a single- and multiple-dose, parallel, dose proportionality (4 and 8 mg) study in patients with type 2 diabetes (T2D) were performed. In these studies, the total body clearance was 52.1 +/- 16.0 mL/min, 48.5 +/- 29.3 mL/min in patients with T2D given a single oral dose, and 52.7 +/- 40.3 mL/min in patients with T2D given multiple oral doses. Following intravenous dosing in healthy subjects, the total body clearance was 47.8 mL/min.

• Oral clearance (CL) = 3.03 ± 0.87 L/hr [1 mg Fasting]
• Oral CL = 2.89 ± 0.71 L/hr [2 mg Fasting]
• Oral CL = 2.85 ± 0.69 L/hr [8 mg Fasting]
• Oral CL = 2.97 ± 0.81 L/hr [8 mg Fed]
• 3.15 L/hr [Population mean, Pediatric patients]

Elimination Route

Following oral administration of glimepiride in healthy male subjects, approximately 60% of the total radioactivity was recovered in the urine in 7 days, with M1 and M2 accounting for 80-90% of the total radioactivity recovered in the urine. The ratio of M1 to M2 was approximately 3:2 in two subjects and 4:1 in one subject. Approximately 40% of the total radioactivity was recovered in feces where M1 and M2 accounted for about 70% of the radioactivity and a ratio of M1 to M2 being 1:3. No parent drug was recovered from urine or feces.

Following oral or intravenous administration of [14C]rosiglitazone maleate, approximately 64% and 23% of the dose was eliminated in the urine and in the feces, respectively.

Pregnancy & Breastfeeding use

Pregnancy Category C. 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 monotherapy be used during pregnancy to maintain blood glucose levels as close to normal as possible. Combination of Glimepiride or Rosiglitazone should not be used during pregnancy.

Nursing mothers: No studies have been conducted with combination of Glimepiride or Rosiglitazone. It is not known whether Glimepiride and/or Rosiglitazone is excreted in human milk. Because many drugs are excreted in human milk, combination of Glimepiride or Rosiglitazone should not be administered to a nursing woman

Contraindication

Combination of Glimepiride and Rosiglitazone is contraindicated in patients with known hypersensitivity to Glimepiride or Rosiglitazone or any of the components of combination of Glimepiride or Rosiglitazone. Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.

Special Warning

Use in Pediatric patients: Safety and effectiveness of combination of Glimepiride or Rosiglitazone in pediatric patients have not been established.

Use in Geriatric patients:

• Glimepiride: The drug 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.
• Rosiglitazone: Results of the population pharmacokinetic analysis showed that age does not significantly affect the pharmacokinetics of Rosiglitazone. Therefore, no dosage adjustments are required for the elderly.

Acute Overdose

Accidental or intentional overdose may cause severe and prolonged hypoglycemia which may be life-threatening. In case of overdosage with Glimepiride, a doctor must be notified immediately. At the first signs of hypoglycemia, the patient must immediately take sugar, preferably glucose, unless a doctor has already started care.

Storage Condition

Store in a cool and dry place. Protect from light and moisture. Keep out the reach of the children.

Innovators Monograph

You find simplified version here Rosiglitazone and glimepiride