Trizoryl

Uses

This is used for an adjunct to diet and exercise as a once-daily combination therapy to improve glycemic control in patients with type 2 diabetes who are already treated with a combination of Pioglitazone and a sulfonylurea or whose diabetes is not adequately controlled with a sulfonylurea alone, or for those patients who have initially responded to Pioglitazone alone and require additional glycemic control.

Trizoryl is also used to associated treatment for these conditions: Type 2 Diabetes MellitusDiabetes, Diabetic Neuropathies, Type 2 Diabetes Mellitus

How Trizoryl 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.

Pioglitazone is a selective agonist at peroxisome proliferator-activated receptor-gamma (PPARγ) in target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ increases the transcription of insulin-responsive genes involved in the control of glucose and lipid production, transport, and utilization. Through this mechanism, pioglitazone both enhances tissue sensitivity to insulin and reduces the hepatic production of glucose (i.e. gluconeogenesis) - insulin resistance associated with type 2 diabetes mellitus is therefore improved without an increase in insulin secretion by pancreatic beta cells.

Dosage

Trizoryl dosage

Selecting the starting dose of Glimepiride & Pioglitazone should be based on the patient's current regimen of Pioglitazone and/or sulfonylurea. Those patients who may be more sensitive to antihyperglycemic drugs should be monitored carefully during dose adjustment. It is recommended that a single dose of Pioglitazone & Glimepiride be administered once daily with the first main meal.

Starting dose for patients currently on Glimepiride monotherapy: Based on the usual starting dose of Pioglitazone (15 mg or 30 mg daily), Pioglitazone & Glimepiride may be initiated at 30 mg/2 mg or 30 mg/4 mg tablet strengths oncedaily, and adjusted after assessingadequacy of therapeutic response.

Starting dose for patients currently on Pioglitazone monotherapy: Based on the usual starting doses of Glimepiride (1 mg or 2 mg once daily), and Pioglitazone 15 mg or 30 mg, Pioglitazone & Glimepiride may be initiated at 30 mg/2 mg once daily, and adjusted after assessing adequacy of therapeutic response.

Starting dose for patients switching from combination therapy of Pioglitazone plus Glimepiride as separate tablets: Pioglitazone & Glimepiride may be initiated with 30 mg/2 mg or 30 mg/4 mg tablet strengths based on the dose of Pioglitazone and Glimepiride already being taken. Patients who are not controlled with 15 mg of Pioglitazone in combination with Glimepiride should be carefully monitored when switched to Pioglitazone & Glimepiride.

Starting dose for patients currently on a different sulfonylurea monotherapy or switching from combination therapy of Pioglitazone plus a different sulfonylurea:No exact dosage relationship exists between Glimepiride and the other sulfonylurea agents. Therefore, based on the maximum starting dose of 2 mg Glimepiride, Pioglitazone & Glimepiride should be limited initially to a starting dose of 30 mg/2 mg once daily, and adjusted after assessing adequacy of therapeutic response.

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

Side Effects

Pioglitazone: The most common adverse experiences with Pioglitazone monotherapy (≥5%) were upper respiratory tract infection, injury, and headache. Overall, the types of adverse experiences reported when Pioglitazone was used in combination with a sulfonylurea were similar to those during monotherapy with Pioglitazone. Other adverse events reported in at least 5% of patients in controlled clinical studies between placebo and Pioglitazone monotherapy included myalgia (2.7% and 5.4%), tooth disorder (2.3% and 5.3%), diabetes mellitus aggravated (8.1% and 5.1%) and pharyngitis (0.8% and 5.1%), respectively. In monotherapy studies, edema was reported for 4.8% (with doses from 7.5 mg to 45 mg) of patients treated with Pioglitazone versus 1.2% of placebo treated patients.

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 (1.7%), asthenia (1.6%), headache (1.5%), and nausea (1.1%). 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.

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.

The oral TDLo observed in mice is 24 mg/kg for 4 days and for rats is 3 mg/kg for 6 days.

One instance of overdose was reported during clinical trials with pioglitazone in which a patient took an oral dose of 120mg daily for four days, followed by 180mg daily for seven days - this patient did not report any adverse clinical symptoms during this time. In the event of overdosage, employ symptomatic and supportive measures according to the patient's clinical status.

Precaution

General: Due to the mechanisms of action, Pioglitazone is active only in the presence of endogenous insulin. Therefore, combination of Pioglitazone and Glimepiride should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Hypoglycemia: All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Elderly patients are particularly susceptible to hypoglycemic action of glucose lowering drugs. 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. At such times, it may be necessary to withhold combination of Pioglitazone and Glimepiride and temporarily administer insulin. Combination of Pioglitazone and Glimepiride may be reinstituted after the acute episode is resolved.

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

Weight Gain: Dose-related weight gain was seen with Pioglitazone alone and in combination with other hypoglycemic agents. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.

Hepatic Effects: Liver enzymes should be checked prior to the initiation of therapy with combination of Pioglitazone and Glimepiride in all patients and periodically thereafter per the clinical judgment of the healthcare professional. Therapy with combination of Pioglitazone and Glimepiride should not be initiated in patients with increased baseline liver enzyme levels (ALT >2.5X upper limit of normal). If at any time ALT levels increase to >3X the upper limit of normal in patients on therapy with combination of Pioglitazone and Glimepiride, liver enzyme levels should be rechecked as soon as possible. If ALT levels remain >3X the upper limit of normal, therapy with combination of Pioglitazone and Glimepiride should be discontinued. If any patient develops symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, and anorexia, and/or dark urine, liver enzymes should be checked.

Interaction

Glimepiride: Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, and isoniazid. When these drugs are administered to a patient receiving Glimepiride, the patient should be closely observed for loss of control. When these drugs are withdrawn from a patient receiving Glimepiride, the patient should be observed closely for hypoglycemia. A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the IV, topical, or vaginal preparations of miconazole is not known. Potential interactions of Glimepiride with other drugs metabolized by cytochrome P450 2C9 also include phenytoin, diclofenac, ibuprofen, naproxen, and mefenamic acid.

Pioglitazone: Co-administration of Pioglitazone and an oral contraceptive resulted in decrease in ethinyl estradiol plasma concentrations. There were no significant changes in norethindrone AUC (0-24h) and Cmax. In other drug-drug interaction studies, Pioglitazone had no significant effect on the pharmacokinetics of fexofenadine, metformin, digoxin, warfarin, ranitidine, or theophylline.

Volume of Distribution

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

The average apparent volume of distribution of pioglitazone is 0.63 ± 0.41 L/kg.

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.

Following oral administration of pioglitazone, peak serum concentrations are observed within 2 hours (T_max) - food slightly delays the time to peak serum concentration, increasing T_max to approximately 3-4 hours, but does not alter the extent of absorption. Steady-state concentrations of both parent drug and its primary active metabolites are achieved after 7 days of once-daily administration of pioglitazone. C_max and AUC increase proportionately to administered doses.

Half Life

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

The mean serum half-life of pioglitazone and its metabolites (M-III and M-IV) range from 3-7 hours and 16-24 hours, respectively.

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.

The apparent clearance of orally administered pioglitazone is 5-7 L/h.

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.

Approximately 15-30% of orally administered pioglitazone is recovered in the urine. The bulk of its elimination, then, is presumed to be through the excretion of unchanged drug in the bile or as metabolites in the feces.

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 Pioglitazone and Glimepiride should not be used during pregnancy.

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

Contraindication

Combination of Pioglitazone and Glimepiride is contraindicated in patients with:

• Known hypersensitivity to Pioglitazone or Glimepiride or any of the components of combination of Pioglitazone or Glimepiride.
• Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.

Special Warning

Pediatric Uses: Safety and effectiveness of combination of Pioglitazone and Glimepiride in pediatric patients have not been established.Geriatric use:

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

Acute Overdose

Symptoms: Severe hypoglycaemia with coma, seizure, or neurological impairment.

Management: Admin glucagon or IV glucose. Additional carbohydrate intake may be necessary as hypoglycaemia may recur after apparent clinical recovery.

Storage Condition

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

Innovators Monograph

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