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U.S. Brand
Names |
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Actos™ |
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Pharmacological Index |
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Antidiabetic Agent (Thiazolidinedione) |
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Use |
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Type 2 diabetes, monotherapy: Adjunct to diet and exercise, to improve
glycemic control
Type 2 diabetes, combination therapy with sulfonylurea, metformin, or
insulin: When diet, exercise, and a single agent alone does not result in
adequate glycemic control |
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Pregnancy Risk
Factor |
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C |
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Pregnancy/Breast-Feeding
Implications |
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Treatment during mid-late gestation was associated with delayed parturition,
embryotoxicity and postnatal growth retardation in animal models. In animal
studies, pioglitazone has been found to be excreted in milk. It is not known
whether pioglitazone is excreted in human milk. Should not be administered to a
nursing woman. |
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Contraindications |
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Hypersensitivity to pioglitazone or any component of the formulation. Active
liver disease (transaminases >2.5 times the upper limit of normal at
baseline). Contraindicated in patients who have experienced jaundice during
troglitazone therapy. |
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Warnings/Precautions |
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Should not be used in diabetic ketoacidosis. Mechanism requires the presence
of insulin, therefore use in type 1 diabetes is not recommended. May potentiate
hypoglycemia when used in combination with sulfonylureas or insulin. Use with
caution in premenopausal, anovulatory women - may result in a resumption of
ovulation, increasing the risk of pregnancy. Use with caution in patients with
anemia (may reduce hemoglobin and hematocrit). Use with caution in patients with
heart failure or edema - may increase plasma volume and/or increase cardiac
hypertrophy. In general, use should be avoided in patients with NYHA class III
or IV heart failure. Use with caution in patients with elevated transaminases
(AST or ALT) - see Contraindications and Monitoring Parameters. Idiosyncratic
hepatotoxicity has been reported with another thiazolidinedione agent
(troglitazone) - monitoring should include periodic determinations of liver
function. |
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Adverse
Reactions |
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>10%:
Endocrine & metabolic: Decreased serum triglycerides, increased HDL
cholesterol
Gastrointestinal: Weight gain
Respiratory: Upper respiratory tract infection (13.2%)
1% to 10%:
Cardiovascular: Edema (4.8%)
Central nervous system: Headache (9.1%), fatigue (3.6%)
Endocrine & metabolic: Aggravation of diabetes mellitus (5.1%),
hypoglycemia (range 2% to 15% when used in combination with sulfonylureas or
insulin)
Hematologic; Anemia (1%)
Neuromuscular & skeletal: Myalgia (5.4%)
Respiratory: Sinusitis (6.3%), pharyngitis (5.1%)
<1%: Elevated transaminases, elevated CPK
In combination trials with sulfonylureas or insulin, the incidence of edema
was as high as 15%. |
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Overdosage/Toxicology |
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Experience in overdose is limited. Symptoms may include hypoglycemia.
Treatment is supportive. |
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Drug
Interactions |
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Substrate for cytochrome P-450 isoenzyme 2C8 (CYP2C8) and 3A4 (CYP3A4)
Increased effect/toxicity: Ketoconazole ( in vitro) inhibits
metabolism of pioglitazone. Other inhibitors of CYP3A4, including itraconazole,
are likely to decrease pioglitazone metabolism. Patients receiving inhibitors of
CYP3A4 should have their glycemic control evaluated more frequently.
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Mechanism of
Action |
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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. |
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Pharmacodynamics/Kinetics |
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Onset: Delayed, may require several weeks to maximal effect
Absorption: Time to peak: Within 2 hours
Distribution: Protein binding: 99.8% Vss (apparent): 0.63 L/kg
Metabolism: Hepatic (99%), including metabolism by cytochrome P-450 isoenzyme
2C8 (CYP2C8) and isoenzyme 3A4 (CYP3A4) to both active and inactive metabolites
Half-life: 3-7 hours (parent); 16-24 hours (total)
Elimination: As metabolites, in urine (15% to 30%) and feces
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Usual Dosage |
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Adults: Oral:
Combination therapy:
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 <100 mg/dL. Doses >30 mg/day have not been evaluated in combination
regimens.
A 1-week washout period is recommended in patients with normal liver enzymes
who are changed from troglitazone to pioglitazone therapy.
Dosage adjustment in renal impairment: No dosage adjustment is
required.
Dosage adjustment in hepatic impairment: Clearance is significantly
lower in hepatic impairment. Therapy should not be initiated if the patient
exhibits active liver disease or increased transaminases (>2.5 times the
upper limit of normal) at baseline.
Elderly patients: No dosage adjustment is recommended in elderly patients.
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Dietary
Considerations |
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Management of type 2 diabetes should include diet
control. |
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Administration |
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Oral: May be taken without regard to meals |
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Monitoring
Parameters |
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Hemoglobin A1c, liver enzymes (prior to initiation and every 2
months for the first year of treatment, then periodically). 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 rosiglitazone should
be discontinued. |
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Dental Health: Local
Anesthetic/Vasoconstrictor
Precautions |
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No information available to require special precautions |
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Dental Health:
Effects on Dental Treatment |
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Pioglitazone-dependent diabetics should be appointed for dental treatment in
morning in order to minimize chance of stress-induced
hypoglycemia |
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Patient
Information |
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Use exactly as directed (do not increase dose or frequency or discontinue
without consulting prescriber). May be taken without regard to meals; avoid
alcohol while taking this medication. If dose is missed, take as soon as
possible. If dose is missed completely one day, do not double dose the next day.
Follow dietary, exercise, and glucose monitoring instructions of prescriber
(more frequent monitoring may be advised in periods of stress, trauma, surgery,
increased exercise etc). Report respiratory infection, unusual weight gain,
aggravation of hyper- or hypoglycemic condition, unusual swelling of
extremities, fatigue, yellowing of skin or eyes, dark urine, pale stool,
nausea/vomiting, or muscle pain. Pregnancy/breast-feeding precautions:
Inform prescriber if you are or intend to be pregnant. Use alternate means of
contraception if using oral contraceptives. Breast-feeding is not
recommended. |
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Dosage Forms |
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Tablet: 15 mg, 30 mg, 45 mg |
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