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Product Name
:
PLIZONE
Chemical Name
:
Pioglitazone (HCl)
Therapeutic Category
:
Anti-diabetic drugs
Pharmacologic Category
:
Antidiabetic Agent, Thiazolidinedione
Pharmaceutical Form
:
Tablets
Composition
:
Pioglitazone (HCl) 15mg / 30mg
Dosing
 
Dosing: Adult
Type 2 diabetes: Oral:
Monotherapy: Initial: 15-30 mg once daily; if response is inadequate, the dosage may be increased in increments up to 45 mg once daily; maximum recommended dose: 45 mg once daily
Combination therapy:
Note: Maximum recommended dose: 45 mg/day
With sulfonylureas: Initial: 15-30 mg once daily; dose of sulfonylurea should be reduced if the patient reports hypoglycemia
With metformin: Initial: 15-30 mg once daily; it is unlikely that the dose of metformin will need to be reduced due to hypoglycemia
With insulin: Initial: 15-30 mg once daily; dose of insulin should be reduced by 10% to 25% if the patient reports hypoglycemia or if the plasma glucose falls to below 100 mg/dL.
Dosage adjustment in patients with CHF (NYHA Class II) in mono- or combination therapy: Oral: Initial: 15 mg once daily; may be increased after several months of treatment, with close attention to heart failure symptoms

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No adjustment is necessary.

Dosing: Hepatic Impairment

Clearance is significantly lower in hepatic impairment (Child-Pugh Grade B/C). Therapy should not be initiated if the patient exhibits active liver disease or increased transaminases (>2.5 times ULN) at baseline. During treatment if ALT levels elevate >3 times ULN, the test should be repeated as soon as possible. If ALT levels remain >3 times ULN or if the patient is jaundiced, therapy should be discontinued.
Use
 
Type 2 diabetes mellitus (noninsulin dependent, NIDDM), monotherapy: Adjunct to diet and exercise, to improve glycemic control
Type 2 diabetes mellitus (noninsulin dependent, NIDDM), combination therapy with sulfonylurea, metformin, or insulin: When diet, exercise, and a single agent alone does not result in adequate glycemic control
Adverse Reactions
 
>10%:
Cardiovascular: Edema (5%; in combination trials with sulfonlyureas or insulin, the incidence of edema was as high as 15%)
Respiratory: Upper respiratory tract infection (13%)
1% to 10%:
Cardiovascular: Heart failure (requiring hospitalization; up to 6% in patients with prior macrovascular disease)
Central nervous system: Headache (9%), fatigue (4%)
Hematologic: Anemia (≤2%)
Neuromuscular & skeletal: Myalgia (5%)
Respiratory: Sinusitis (6%), pharyngitis (5%)
<1% (Limited to important or life-threatening): Bladder cancer, blurred vision, CPK increased, dyspnea (associated with weight gain and/or edema), fractures (females; usually in distal upper limbs or distal lower limbs), hepatic failure (very rare), hepatitis, macular edema (new onset or worsening), transaminases increased, pulmonary edema, rhabdomyolysis, visual acuity decreased
Frequency not defined: HDL-cholesterol increased, hematocrit/hemoglobin decreased, hypoglycemia (in combination trials with sulfonylureas or insulin), serum triglycerides decreased, weight gain/loss
Contraindications
 
Hypersensitivity to pioglitazone or any component of the formulation; NYHA Class III/IV heart failure (initiation of therapy)
Canadian labeling: Additional Contraindications (not is U.S. labeling): Any stage of heart failure (eg, NYHA Class I, II, III, IV); serious hepatic impairment; pregnancy
Warnings / Precautions Drug
 
Boxed warnings:
• Heart failure/cardiac effects: See “Concerns related to adverse effects” below.
Concerns related to adverse effects:
• Fractures: Increased incidence of bone fractures in females treated with pioglitazone; majority of fractures occurred in the lower limb and distal upper limb. Consider risk of fracture prior to initiation and during use.
• Heart failure/cardiac effects: [U.S. Boxed Warning]: Thiazolidinediones, including pioglitazone, may cause or exacerbate heart failure; closely monitor for signs and symptoms of heart failure (eg, rapid weight gain, dyspnea, edema), particularly after initiation or dose increases. Not recommended for use in any patient with symptomatic heart failure. In the U.S., initiation of therapy is contraindicated in patients with NYHA class III or IV heart failure; if used in patients with NYHA class II (systolic) heart failure, initiate at lowest dosage and monitor closely. In Canada, use is contraindicated in patients with any stage of heart failure (NYHA I, II, III, IV). Use with caution in patients with edema; may increase plasma volume and/or cause fluid retention. Dose reduction or discontinuation is recommended if heart failure suspected.
• Hematologic effects: May decrease hemoglobin/hematocrit; effects may be related to increased plasma volume. Use with caution in patients with anemia.
• Weight gain: Dose-related weight gain observed with use; mechanism unknown but likely associated with fluid retention and fat accumulation.
Disease-related concerns:
• Diabetes, type 1: Mechanism requires the presence of insulin; therefore, use in type 1 diabetes (insulin dependent, IDDM) or diabetic ketoacidosis is not recommended.
• Hepatic impairment: Use with caution in patients with elevated transaminases (AST or ALT); do not initiate in patients with active liver disease of ALT >2.5 times the upper limit of normal at baseline. During therapy, if ALT >3 times the upper limit of normal, reevaluate levels promptly and discontinue if elevation persists or if jaundice occurs at any time during use. Idiosyncratic hepatotoxicity has been reported with another thiazolidinedione agent (troglitazone); avoid use in patients who previously experienced jaundice during troglitazone therapy.
• Macular edema/diabetic retinopathy: Use with caution in patients with pre-existing macular edema or diabetic retinopathy; postmarketing events of new-onset or worsening diabetic macular edema with decreased visual acuity have been reported.
Concurrent drug therapy issues:
• Insulin (Canadian labeling; not in U.S. labeling): Concomitant use with insulin is not indicated.
• Metformin/sulfonylureas (Canadian labeling; not in U.S. labeling): Pioglitazone may be added to metformin or a sulfonylurea (if metformin is contraindicated or not tolerated) if glycemic control is inadequate. The use of triple therapy (pioglitazone in combination with metformin and a sulfonylurea) is not indicated due to increased risks of congestive heart failure and fluid retention.
Special populations:
• Pediatrics: Safety and efficacy have not been established in children.
• Premenopausal/anovulatory females: Use with caution in premenopausal, anovulatory women; may result in a resumption of ovulation, increasing the risk of pregnancy.
Metabolism/Transport Effects
Substrate of CYP2C8 (major), 3A4 (minor); Inhibits CYP2C8 (moderate), 2C9 (weak), 2C19 (weak) Induces CYP3A4 (weak)
Interactions
 
Bile Acid Sequestrants: May decrease the absorption of Antidiabetic Agents (Thiazolidinedione). Risk D: Consider therapy modification
Conivaptan: May increase the serum concentration of CYP3A4 Substrates (Low risk). Risk C: Monitor therapy
Corticosteroids (Orally Inhaled): May diminish the hypoglycemic effect of Antidiabetic Agents. In some instances, corticosteroid-mediated HPA axis suppression has led to episodes of acute adrenal crisis, which may manifest as enhanced hypoglycemia, particularly in the setting of insulin or other antidiabetic agent use. Risk C: Monitor therapy
Corticosteroids (Systemic): May diminish the hypoglycemic effect of Antidiabetic Agents. In some instances, corticosteroid-mediated HPA axis suppression has led to episodes of acute adrenal crisis, which may manifest as enhanced hypoglycemia, particularly in the setting of insulin or other antidiabetic agent use. Risk C: Monitor therapy
CYP2C8 Inducers (Highly Effective): May increase the metabolism of CYP2C8 Substrates (High risk). Risk C: Monitor therapy
CYP2C8 Inhibitors (Moderate): May decrease the metabolism of CYP2C8 Substrates (High risk). Risk C: Monitor therapy
CYP2C8 Inhibitors (Strong): May decrease the metabolism of CYP2C8 Substrates (High risk). Risk D: Consider therapy modification
CYP2C8 Substrates (High risk): CYP2C8 Inhibitors (Moderate) may decrease the metabolism of CYP2C8 Substrates (High risk). Risk C: Monitor therapy
Deferasirox: May increase the serum concentration of CYP2C8 Substrates (High risk). Risk C: Monitor therapy
Gemfibrozil: May decrease the metabolism of Antidiabetic Agents (Thiazolidinedione). Risk C: Monitor therapy
Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemic Agents. Risk C: Monitor therapy
Hypoglycemic Agents: May enhance the adverse/toxic effect of other Hypoglycemic Agents. Risk C: Monitor therapy
Insulin: May enhance the fluid-retaining effect of Antidiabetic Agents (Thiazolidinedione). Risk C: Monitor therapy
Luteinizing Hormone-Releasing Hormone Analogs: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Pegvisomant: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Pregabalin: May enhance the fluid-retaining effect of Antidiabetic Agents (Thiazolidinedione). Risk C: Monitor therapy
Rifampin: May increase the metabolism of Antidiabetic Agents (Thiazolidinedione). Risk C: Monitor therapy
Saxagliptin: CYP3A4 Inducers may decrease the serum concentration of Saxagliptin. Risk C: Monitor therapy
Somatropin: May diminish the hypoglycemic effect of Antidiabetic Agents. Risk D: Consider therapy modification
Thiazide Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Trimethoprim: May decrease the metabolism of Antidiabetic Agents (Thiazolidinedione). Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Caution with ethanol (may cause hypoglycemia).
Food: Peak concentrations are delayed when administered with food, but the extent of absorption is not affected. Pioglitazone may be taken without regard to meals.
Herb/Nutraceutical: Caution with alfalfa, aloe, bilberry, bitter melon, burdock, celery, damiana, fenugreek, garcinia, garlic, ginger, ginseng (American), gymnema, marshmallow, and stinging nettle (may cause hypoglycemia).
Pregnancy
 
C
Pregnancy Implications
Pioglitazone is classified as pregnancy category C due to adverse effects observed in animal studies. The use of pioglitazone in pregnant women is limited to very few case reports where pregnancy occurred during treatment for polycystic ovarian syndrome (PCOS); details concerning fetal outcomes are limited. Thiazolidinediones may cause ovulation in anovulatory premenopausal women, increasing the risk of pregnancy; adequate contraception in premenopausal women is recommended. Maternal hyperglycemia can be associated with adverse effects in the fetus, including macrosomia, neonatal hyperglycemia, and hyperbilirubinemia; the risk of congenital malformations is increased when the Hb A1c is above the normal range. Diabetes can also be associated with adverse effects in the mother. Poorly-treated diabetes may cause end-organ damage that may in turn negatively affect obstetric outcomes. Physiologic glucose levels should be maintained prior to and during pregnancy to decrease the risk of adverse events in the mother and the fetus. Until additional safety and efficacy data are obtained, the use of oral agents is generally not recommended as routine management of GDM or type 2 diabetes mellitus during pregnancy. Insulin is the drug of choice for the control of diabetes mellitus during pregnancy.
Lactation
 
Excretion in breast milk unknown/not recommended
Monitoring Parameters
 
Hemoglobin A1c, serum glucose; signs and symptoms of heart failure; liver enzymes prior to initiation and periodically during treatment (per clinician judgment). If the ALT is increased to >2.5 times the upper limit of normal, liver function testing should be performed more frequently until the levels return to normal or pretreatment values. Patients with an elevation in ALT >3 times the upper limit of normal should be rechecked as soon as possible. If the ALT levels remain >3 times the upper limit of normal, therapy with pioglitazone should be discontinued. Routine ophthalmic exams are recommended; patients reporting visual deterioration should have a prompt referral to an ophthalmologist and consideration should be given to discontinuing pioglitazone.
Reference Range
Recommendations for glycemic control in adults with diabetes:
Hb A1c: <7%
Preprandial capillary plasma glucose: 70-130 mg/dL
Peak postprandial capillary blood glucose: <180 mg/dL
Mechanism of Action
 
Thiazolidinedione antidiabetic agent that lowers blood glucose by improving target cell response to insulin, without increasing pancreatic insulin secretion. It has a Mechanism of Action that is dependent on the presence of insulin for activity. Pioglitazone is a potent and selective agonist for peroxisome proliferator-activated receptor-gamma (PPARgamma). Activation of nuclear PPARgamma receptors influences the production of a number of gene products involved in glucose and lipid metabolism. PPARgamma is abundant in the cells within the renal collecting tubules; fluid retention results from stimulation by thiazolidinediones which increases sodium reabsorption.
Pharmacodynamics / Kinetics
 
Onset of action: Delayed
Peak effect: Glucose control: Several weeks
Distribution: Vss (apparent): 0.63 L/kg
Protein binding: Pioglitazone >99% and active metabolites >98%; primarily to albumin
Metabolism: Hepatic (99%) via CYP2C8 and 3A4 to both active and inactive metabolites
Half-life elimination: Parent drug: 3-7 hours; Total: 16-24 hours
Time to peak: ~2 hours; delayed with food
Excretion: Urine (15% to 30%) and feces as metabolites
 
   
 
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