Zolid/ZolidPlus

Zolid/ZolidPlus

pioglitazone

pioglitazone + metformin

Manufacturer:

Getz Pharma

Distributor:

Getz Bros
Full Prescribing Info
Contents
Zolid: Pioglitazone HCl. ZolidPlus: Metformin HCl, pioglitazone HCl.
Description
Pioglitazone is [(±)-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl)-2-4-] thiazolidinedione monohydrochloride and has a molecular formula of C19H20N2O3S-HCl.
ZolidPlus: Each film-coated tablet contains metformin HCl 500 mg and pioglitazone HCl 15 mg.
Pioglitazone and metformin HCl is an advanced diabetes treatment that combines 2 important diabetes medications. Pioglitazone is an effective drug for reducing blood glucose if there is inadequate control on the conventional agents alone and metformin HCl which lowers the amount of sugar produced by the liver.
Metformin HCl is N,N-dimethylimidodicarbonimidic diamide hydrochloride and it is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. It has a molecular formula of C4H11N5·HCl.
Action
Zolid: Pioglitazone is an oral antidiabetic agent used in the management of type 2 diabetes mellitus [also known as non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes] that acts primarily by decreasing insulin resistance. Pioglitazone belongs to a different chemical class and has a different pharmacological action than the sulfonylureas, metformin or the α-glucosidase inhibitors.
Pharmacology: Mechanism of Action: Pioglitazone decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPARγ), PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle and liver.
Zolid: Pioglitazone is a thiazolidinedione antidiabetic agent that depends on the presence of insulin for its mechanism of action. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.
ZolidPlus: Insulin resistance is known to play a major role in the pathogenesis of type 2 diabetes.
Metformin HCl is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycemia.
Metformin HCl may act via 3 mechanisms: By reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis; in muscle, by modestly increasing insulin sensitivity, improving peripheral glucose uptake and utilization; and by delaying intestinal glucose absorption.
Pharmacokinetics: Absorption: Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 min, with peak concentrations observed within 2 hrs. Food slightly delays the time to peak serum concentration for 3-4 hrs, but does not alter the extent of absorption.
ZolidPlus: Metformin HCl is slowly and incompletely absorbed from the gastrointestinal tract. The absolute bioavailability of a single 500 mg dose is reported to be about 50-60% given under fasting conditions. Food decreases the extent and slightly delays the absorption of metformin.
Distribution: Pioglitazone is extensively protein bound (>99%) in human serum, principally to serum albumin. Pioglitazone also binds to other serum proteins, but with lower affinity. Metabolites M-III and M-IV also are extensively bound (>98%) to serum albumin.
Zolid: The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose administration is 0.63±0.41 (mean±SD) L/kg of body weight.
ZolidPlus: Metformin HCl is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. The blood peak is lower than the plasma peak and appears at approximately the same time.
Metabolism: Pioglitazone undergoes extensive hepatic metabolism by hydroxylation of aliphatic, methylene groups (in Zolid); extensively metabolized by hydroxylation and oxidation; the metabolites also partly converted to glucuronide or sulfate conjugates (in ZolidPlus). This is predominantly via cytochrome P-450 2CB and 3A4. Three of the 6 metabolites formed are active. The major circulating metabolite is M-IV (1-hydroxyethyl pioglitazone), which accounts for most of the drug-related material in human plasma and probably accounts for much of the therapeutic efficacy.
ZolidPlus: Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination: Following oral administration, approximately 15-30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces.
The mean serum t½ of pioglitazone and total pioglitazone ranges from 3-7 hrs and 16-24 hrs, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5-7 L/hr.
ZolidPlus: Metformin HCl: Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hrs.
Special Populations: Renal Insufficiency: In patients with renal impairment, plasma concentrations of pioglitazone and its metabolites are lower than those seen in subjects with normal renal function, but with similar oral clearance of parent medicine. Thus free (unbound) pioglitazone concentration remains unchanged. Dose adjustment in patients with renal dysfunction is not recommended.
ZolidPlus: Metformin HCl: In subjects with decreased renal function, the plasma and blood t½ of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance.
Hepatic Insufficiency: Patients with impaired hepatic function (Child-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone mean peak concentrations but no change in the mean AUC values.
ZolidPlus: Metformin HCl: No pharmacokinetics studies of metformin have been conducted in subjects with hepatic insufficiency.
Elderly: Zolid: No clinically significant differences between elderly and young subjects were observed.
Children: Zolid: Pharmacokinetic data in the pediatric population are not available.
Gender: Zolid: The mean Cmax and AUC values were increased 20-60% in females. Since the therapy should be individualized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone.
Indications/Uses
Zolid: Zolid is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (NIDDM). It can also be taken alone as monotherapy, or it can be used in combination with sulfonylurea, metformin or insulin when diet and exercise plus the single agent does not result in adequate glycemic control.
ZolidPlus: For patients with type 2 diabetes mellitus when single agent therapy is inadequate or for patients requiring combined or more intensive therapy.
Dosage/Direction for Use
Zolid: Zolid tablets are taken once daily with or without meals and should be taken about the same time everyday. However, skipping meals while taking this medicine is not advised. Zolid can cause hypoglycemia.
Adults: Monotherapy: Initial Dose: 15 or 30 mg once daily, increasing after 4 weeks to 45 mg once daily if greater therapeutic effect is needed.
Combination Therapy: Zolid in Combination with Sulfonylureas, Insulin or Metformin: Initial dose: 15 or 30 mg once daily. It may be possible to achieve metabolic control at a reduced dose of sulfonylurea, insulin or metformin. If there is a particular risk of hypoglycemia, pioglitazone can be introduced at a dose of 15 mg. For patients already on insulin, pioglitazone should be introduced at a dose of 15 mg once daily.
Maximum Recommended Dose: 45 mg once daily since doses >45 mg once daily have not been studied.
Hepatic Impaired Patients: The intrinsic clearance of pioglitazone may be reduced in patients with hepatic disease. Dosage should start at 15 mg and be increased cautiously.
ZolidPlus: The use of antihyperglycemic therapy in the management of type 2 diabetes should be individualized on the basis of effectiveness and tolerability while not exceeding the maximum recommended daily dose of pioglitazone 45 mg and metformin 2550 mg. Selecting the starting dose of ZolidPlus should be based on the patient's current regimen of pioglitazone and/or metformin.
Starting Dose for Patients Inadequately Controlled on Metformin Monotherapy: Based on the usual starting dose of pioglitazone 15-30 mg daily, ZolidPlus may be initiated at 15 mg/500 mg tablet once or twice daily and gradually titrated after assessing adequacy of therapeutic response.
Starting Dose for Patients Who Initially Responded to Pioglitazone Monotherapy and Require Additional Glycemic Control: Based on the usual starting doses of metformin 500 mg twice daily or 850 mg daily, ZolidPlus may be initiated at 15 mg/500 mg twice daily and gradually titrated after assessing adequacy of therapeutic response.
Starting Dose for Patients Switching from Combination Therapy of Pioglitazone + Metformin as Separate Tablets: ZolidPlus may be initiated with 15 mg/500 mg tablet based on the dose of pioglitazone and metformin already being taken.
Administration: ZolidPlus should be given in daily divided doses with meals to reduce the gastrointestinal side effects associated with metformin.
Contraindications
Zolid: Patients with known hypersensitivity to thiazolidinediones or any components of Zolid.
ZolidPlus: Hypersensitivity to pioglitazone, metformin HCl or any component of ZolidPlus.
Cardiac failure or history of cardiac failure (NYHA class III or IV); hepatic impairment or evidence of active liver disease; acute or chronic disease which may cause tissue hypoxia eg, cardiac or respiratory failure, recent myocardial infarction, shock; acute alcohol intoxication, alcoholism; renal failure or dysfunction (creatinine clearance <60 mL/min), which may also result from conditions eg, cardiovascular collapse (shock), acute myocardial infarction and septicemia.
Warnings
Zolid: Cardiac Failure and Other Cardiac Effects: Pioglitazone, like other thiazolidinediones, can cause fluid retention when used alone or in combination with other antidiabetic agents including insulin. Patients should be observed for signs and symptoms of heart failure. Fluid retention may lead to or exacerbate heart failure. Pioglitazone should be discontinued if any deterioration in cardiac status occurs.
ZolidPlus: Pioglitazone: Congestive Heart Failure: Thiazolidinediones cause or exacerbate congestive heart failure in some patients. After initiation of pioglitazone and after dose increases, the patient should be observed carefully for sign and symptoms of heart failure including excessive, rapid weight gain, dyspnea and/or edema. If these signs and symptoms develop, the heart failure should be managed according to the current standard of care. Furthermore, discontinuation or dose reduction of drug must be considered.
Pioglitazone is not recommended in patients with symptomatic heart failure. Initiation of ZolidPlus in patients with essential NYHA class III or IV heart failure is contraindicated.
Metformin HCl: Lactic acidosis is rare, but serious metabolic complication that can occur due to metformin accumulation during treatment. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore be significantly decreased by regular monitoring of renal function in patients taking metformin and by use of the minimum effective dose of metformin. The onset of lactic acidosis often is accompanied only by nonspecific symptoms eg, malaise, myalgias, respiratory distress, increasing somnolence and nonspecific abdominal distress. There may be associated hypothermia, hypotension and resistant bradyarrhythmias with more marked acidosis.
Special Precautions
General: Pioglitazone exerts its antihyperglycemic effect only in the presence of insulin. Therefore, pioglitazone should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
ZolidPlus: Inadequate response to a combination of metformin and a sulfonylurea may indicate falling insulin release; the introduction of pioglitazone has a limited role in these circumstances and insulin treatment should not be delayed.
Hypoglycemia: Patients receiving pioglitazone in combination with insulin or oral hypoglycemic agents may be at risk for hypoglycemia, and a reduction in the dose of the concomitant agent may be necessary.
Edema: Zolid: Pioglitazone should be used with caution in patients with edema.
Hematologic: Pioglitazone may cause decreases in hemoglobin and hematocrit causing anemia. Hemoglobin monitoring is recommended if patients exhibit any signs or symptoms of anemia.
Ovulation: Therapy with pioglitazone, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking pioglitazone. Thus, adequate contraception in premenopausal women should be recommended.
Hepatic Effects: Therapy with pioglitazone 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.
Zolid: Liver enzyme monitoring is recommended in all patients prior to initiation of therapy with pioglitazone and periodically thereafter.
ZolidPlus: Patients with mildly elevated liver enzymes (ALT levels at 1-2.5 times the upper limit of normal) at baseline or any time during therapy with ZolidPlus should be evaluated to determine the cause of the liver enzyme elevation. Initiation or continuation of therapy with pioglitazone + metformin HCl in patients with mildly elevated liver enzymes should proceed with caution and include appropriate clinical follow-up which may include more frequent liver enzyme monitoring
ZolidPlus: Cardiac Failure and Other Cardiac Effects: Pioglitazone, like other thiazolidinediones, can cause fluid retention when used alone or in combination with other antidiabetic agents including insulin. Fluid retention may lead to or exacerbate heart failure. If these signs and symptoms develop, the heart failure should be managed according to current standards of care.
Metformin HCl: Lactic acidosis is a very rare, but serious, metabolic complication that can occur due to metformin accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by assessing also other associated risk factors eg, poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition associated with hypoxia. Lactic acidosis is characterized by acidotic dyspnea, abdominal pain, and hypothermia followed by coma. If metabolic acidosis is suspected, treatment with ZolidPlus should be discontinued and the patient hospitalized immediately.
Intravascular administration of iodinated contrast agents in radiological studies can lead to renal failure. Therefore, due to the metformin active substance, ZolidPlus should be discontinued prior to or at the time of the test and not reinstituted until 48 hrs afterwards, and only after renal function has been re-evaluated and found to be normal.
ZolidPlus should be promptly discontinued when cardiovascular collapse (shock), acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia occur in patients.
Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving ZolidPlus. Since impaired hepatic function has been associated with some cases of lactic acidosis, ZolidPlus should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with hypoglycemic agents (eg, sulfonylureas or insulin) or ethanol. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking β-adrenergic blocking drugs.
Use in Pregnancy: Zolid: Pioglitazone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Use in Lactation: Zolid: It is not known whether pioglitazone is secreted in human milk. Because many drugs are excreted in human milk, pioglitazone should not be administered to a breastfeeding woman.
Use in Children: Zolid: Since data is unavailable for pediatric patients, use of pioglitazone is not recommended.
Use In Pregnancy & Lactation
Use in Pregnancy: Zolid: Pioglitazone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Use in Lactation: Zolid: It is not known whether pioglitazone is secreted in human milk. Because many drugs are excreted in human milk, pioglitazone should not be administered to a breastfeeding woman.
Adverse Reactions
Zolid: The adverse effects reported include: Upper respiratory tract infections, headache, sinusitis, myalgia, tooth disorder, aggravated diabetes mellitus and pharyngitis.
There was also a tendency to modest weight gain. Some people may also experience anemia and fluid retention. These side effects do not happen in all people.
There was an increase in occurrence of edema in the patients treated with pioglitazone and insulin compared to insulin alone.
Pioglitazone plus insulin developed dyspnea at some point during therapy.
ZolidPlus: In general treatment with ZolidPlus was well tolerated. The possible side effects include: Combination Therapy: Common: Anemia, visual disturbance, increased weight, arthralgia, headache, hematuria, erectile dysfunction. Uncommon: Flatulence.
Individual Active Substances of the Fixed-Dose Combination: Pioglitazone: Common: Upper respiratory tract infection and hypoesthesia. Uncommon: Sinusitis and insomnia.
Metformin HCl: Most Common: Taste disturbance, nausea, vomiting, diarrhea, abdominal pain, loss of appetite. Uncommon: Decrease in vitamin B12 absorption and serum levels, lactic acidosis.
Drug Interactions
Oral Contraceptives: Administration of another thiazolidinedione with an oral contraceptive containing ethinyl estradiol and norethindrone reduced the plasma concentrations of both hormones by approximately 30%, which could result in loss of contraception. Therefore, additional caution regarding contraception should be exercised in patients receiving pioglitazone and an oral contraceptive.
Zolid: Ketoconazole: Ketoconazole inhibited up to 85% of hepatic pioglitazone metabolism in vitro at a concentration equal molar to pioglitazone. Pending the availability of additional data. Patients receiving ketoconazole concomitantly with pioglitazone should be evaluated more frequently with respect to glycemic control.
Drug-Drug Relationships: Glipizide: Co-administration of pioglitazone and 5 mg glipizide administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of glipizide.
Metformin: Co-administration of a single dose of metformin (1000 mg) and pioglitazone after 7 days of pioglitazone did not alter the pharmacokinetics of the single dose of metformin.
Midazolam: Administration of pioglitazone for 15 days followed by a single 7.5-mg dose of midazolam syrup resulted in a 26% reduction in midazolam Cmax and AUC.
Nifedipine ER: In view of the high variability of nifedipine pharmacokinetics, the clinical significance of this finding is unknown.
ZolidPlus: Pioglitazone: An enzyme inhibitor of CYP2C8 (eg, gemfibrozil) may significantly increase the AUC of pioglitazone and an enzyme inducer of CYP2C8 (eg, rifampin) may significantly decrease the AUC of pioglitazone. Therefore, if an inhibitor or inducer of CYP2C8 is started or stopped during treatment with pioglitazone, changes in diabetes treatment may be needed based on clinical response.
Metformin HCl: Cationic Drugs: Cationic drugs (eg, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim and vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of ZolidPlus and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.
Furosemide: Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance.
Co-administration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively and increased the amount excreted in the urine. Tmax and t½ were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.
Others: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs and isoniazid. When such drugs are administered to a patient receiving ZolidPlus, the patient should be closely observed to maintain adequate glycemic control.
Storage
Store at temperatures not exceeding 30°C. Protect from heat, sunlight and moisture.
Shelf-Life: Zolid: 36 months.
MIMS Class
Antidiabetic Agents
ATC Classification
A10BG03 - pioglitazone ; Belongs to the class of thiazolidinediones. Used in the treatment of diabetes.
A10BD05 - metformin and pioglitazone ; Belongs to the class of combinations of oral blood glucose lowering drugs. Used in the treatment of diabetes.
Presentation/Packing
Zolid: Tab 15 mg x 14's, 30 mg x 14's. ZolidPlus: FC tab 28's.
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