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Pioglitazone Hydrochloride

Pronouncation: (PYE-oh-GLI-ta-zone HYE-droe-KLOR-ide)
Class: Thiazolidinedione

Trade Names:
Actos
- Tablet 15 mg
- Tablet 30 mg
- Tablet 45ߙmg

Pharmacology

Feedback for Pioglitazone Hydrochloride

As a treatment for...	Avg User Ratings [?]
Diabetes, Type 2	5 comments Rate it!	6.2

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Increases insulin sensitivity in muscle and adipose tissue, and inhibits hepatic gluconeogenesis.

Pharmacokinetics

Absorption

Rapid. T _max is 2 h (3 to 4 h if taken with food). Food slightly delays time to peak serum concentrations 3 to 4 h. Steady state is 7 days.

Distribution

Vd is 0.63 L/kg (single dose). Protein binding is extensive (more than 99%), mainly to albumin.

Metabolism

Extensively metabolized in the liver by hydroxylation and oxidation. The metabolites M-II (hydroxy derivative), M-IV (hydroxy derivative), and M-III (keto derivative) are active. The major isoforms involved include the CYP2C8, CYP3A4, and CYP1A1.

Elimination

15% to 30% excreted primarily as metabolites in urine. Excreted into bile (unchanged as metabolites) and then eliminated in the feces. Serum t _½ is 3 to 7 h (pioglitazone); 16 to 24 h (pioglitazone and active metabolites). Apparent Cl is 5 to 7 L/h.

Special Populations

Renal Function Impairment

No dosage adjustment in renal function impairment is recommended.

Hepatic Function Impairment

There is a 45% reduction in mean C _max but no change in AUC values. Do not initiate therapy in patients with active liver disease or increased ALT greater than 2.5 times ULN.

Elderly

AUC value is slightly higher; terminal t _½ is slightly longer.

Gender

The mean C _max is increased 20% and AUC increased 60% in women.

Ethnicity

Data are not available.

Children

Data are not available.

Indications and Usage

Type 2 diabetes, as monotherapy or as an adjunct to diet and exercise; also may be used in conjunction with a sulfonylurea, metformin, or insulin when diet, exercise, and a single agent alone does not result in adequate glycemic control in patients with type 2 diabetes mellitus.

Contraindications

Established New York Heart Association class III or IV heart failure; hypersensitivity to any component of the product.

Dosage and Administration

Monotherapy

PO Initially, 15 or 30 mg/day, up to 45ߙmg/day. If monotherapy is inadequate, consider combinations using same starting dose and adjust accordingly. May be given without regard to meals.

Pioglitazone dosage should not exceed 45 mg once daily in monotherapy or in combination therapy.

Sulfonylureas
Combination Therapy Adults

PO In combination with sulfonylureas, the recommended dosage of pioglitazone is 15 or 30 mg every day. If patient reports hypoglycemia, decrease the sulfonylurea dose.

Metformin
Combination Therapy Adults

PO In combination with metformin, pioglitazone may be initiated at 15 or 30 mg every day.

Insulin
Combination Therapy Adults

PO In combination with insulin, the recommended dosage of pioglitazone is 15 or 30 mg every day. If the patient reports hypoglycemia or if plasma glucose concentrations decrease to less than 100 mg/dL, it is recommended that the insulin dose be decreased 10% to 25%. Individualize further adjustment based on glucose-lowering response.

Hepatic Function Impairment Adults

PO Treatment should not be initiated in patients exhibiting evidence of active liver disease or increased serum transaminase levels (ALT greater than 2.5 × ULN at the start of therapy).

Storage/Stability

Store at controlled room temperature (59° to 86°F). Protect from moisture and humidity.

Drug Interactions

Contraceptives, oral

Oral contraceptives may decrease both hormone components about 30%, potentially reducing contraceptive effectiveness.

CYP2C8 enzyme inhibitors (eg, azole antifungal agents [eg, ketoconazole], fluvoxamine, gemfibrozil, trimethoprim)

Pioglitazone plasma levels may be elevated, increasing the pharmacologic effects and adverse reactions.

CYP2C8 inducers (eg, rifampin)

Pioglitazone plasma concentrations may be reduced, decreasing the efficacy.

Midazolam

Plasma concentrations may be reduced by pioglitazone, decreasing the efficacy.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

CHF.

CNS

Headache (9%).

EENT

Pharyngitis (5%); macular edema (postmarketing).

GI

Tooth disorders (5%).

Hepatic

Elevated ALT.

Hematologic

Anemia (less than 2%); decrease in hemoglobin and hematocrit.

Lab Tests

Decreased hemoglobin and hematocrit levels, elevated ALT, elevated CPK levels.

Metabolic-Nutritional

Hypoglycemia.

Musculoskeletal

Bone fractures, myalgia (5%).

Respiratory

Upper respiratory tract infection (13%); sinusitis (6%).

Miscellaneous

Edema (5%).

Precautions

Warnings

Pioglitazone can cause or exacerbate CHF in some patients. Consider discontinuing or reducing the dose if symptoms of heart failure occur. Treatment of patients with symptomatic heart failure is not recommended.

Monitor

After starting treatment or increasing the dose, carefully observe patients for signs and symptoms of heart failure (including excessive, rapid weight gain; dyspnea; and/or edema). Monitor liver enzymes prior to the start of therapy and periodically thereafter.

Fasting blood glucose and hemoglobin A _1c (HbA _1c ) measurements should be performed periodically to monitor glycemic control and therapeutic response.

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Hepatic Function

Use with caution. Do not initiate therapy in patients with clinical evidence of active liver disease or baseline ALT more than 2.5 × ULN. Discontinue therapy if ALT increases to more than 3 × ULN and persists. Related drugs have reported rare hepatotoxicity.

Bone Fractures

Increased incidence of bone fractures noted in women but not men.

Diabetic Ketoacidosis

Not recommended.

Edema

Use caution; can cause fluid retention.

Hematologic

Decreases in Hgb and Hct (2% to 4%) have been reported and may be related to increases in plasma volume associated with pioglitazone therapy.

Hyperglycemia

May increase the risk of hypoglycemia when used in combination with other hypoglycemic agents; may need dose reduction of concomitant agents.

Ovulation

May result in ovulation in premenopausal anovulatory women; recommend contraception.

Type 1 diabetes

Not recommended.

Weight gain

Dose-related weight gain has been seen alone and in combination with other hypoglycemic agents.

Overdosage

Symptoms

No symptoms were reported after ingestion of 120 to 180 mg daily for 11 days.

Patient Information

Advise patient to take every day without regard to meals.
Educate patient, family, or caregiver regarding type 2 diabetes and its management.
Instruct patient that this drug is not a substitute for diet and exercise and to follow prescribed regimens.
Advise the patient that if a dose is missed on 1 day, the dose should not be doubled the next day.
Emphasize the importance of regular daily blood glucose monitoring and periodic HbA _1c tests.
Advise diabetic patient to carry medical identification (eg, card, bracelet).
Advise patient to report any of the following to health care provider immediately: abdominal pain, anorexia, dark urine, edema, fatigue, increase in weight, nausea, shortness of breath, vomiting, yellowing of skin or eyes, other symptoms of CHF.
Review symptoms of hypoglycemia and hyperglycemia and action plans to undertake in the event either occurs. Instruct patient to report hypoglycemic or hyperglycemic episodes to health care provider.
Advise patient that blood will be drawn to check liver function prior to starting therapy and about every 2ߙmo for 1 yr and periodically thereafter. Remind patient to keep appointments.
Caution women that drug can cause resumption of ovulation in premenopausal anovulatory women with insulin resistance. Address adequate contraceptive measures for these women.