Actos (as pioglitazone hydrochloride) 15 MG Oral Tablet
DRUG INTERACTIONS
7 Strong CYP2C8 inhibitors (e.g., gemfibrozil) increase pioglitazone concentrations.
Limit ACTOS dose to 15 mg daily.
( 2.3 , 7.1 ) CYP2C8 inducers (e.g., rifampin) may decrease pioglitazone concentrations.
( 7.2 ) 7.1 Strong CYP2C8 Inhibitors An inhibitor of CYP2C8 (e.g., gemfibrozil) significantly increases the exposure (area under the serum concentration-time curve or AUC) and half-life of pioglitazone.
Therefore, the maximum recommended dose of ACTOS is 15 mg daily if used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ].
7.2 CYP2C8 Inducers An inducer of CYP2C8 (e.g., rifampin) may significantly decrease the exposure (AUC) of pioglitazone.
Therefore, if an inducer of CYP2C8 is started or stopped during treatment with ACTOS, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dose of 45 mg for ACTOS [see Clinical Pharmacology (12.3) ] .
OVERDOSAGE
10 During controlled clinical trials, one case of overdose with ACTOS was reported.
A male patient took 120 mg per day for four days, then 180 mg per day for seven days.
The patient denied any clinical symptoms during this period.
In the event of overdosage, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms.
DESCRIPTION
11 ACTOS (pioglitazone hydrochloride) is an oral antidiabetic medication.
Pioglitazone [(±)-5-[[4-[2-(5-ethyl-2-pyridinyl) ethoxy] phenyl] methyl]-2,4-] thiazolidinedione monohydrochloride contains one asymmetric carbon, and the compound is synthesized and used as the racemic mixture.
The two enantiomers of pioglitazone interconvert in vivo .
No differences were found in the pharmacologic activity between the two enantiomers.
The structural formula is as shown: Pioglitazone hydrochloride is an odorless white crystalline powder that has a molecular formula of C 19 H 20 N 2 O 3 S•HCl and a molecular weight of 392.90 daltons.
It is soluble in N,N -dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether.
ACTOS is available as a tablet for oral administration containing 15 mg, 30 mg, or 45 mg of pioglitazone (as the base) formulated with the following excipients: lactose monohydrate NF, hydroxypropylcellulose NF, carboxymethylcellulose calcium NF, and magnesium stearate NF.
Chemical Structure Figure 1
CLINICAL STUDIES
14 14.1 Monotherapy Three randomized, double-blind, placebo-controlled trials with durations from 16 to 26 weeks were conducted to evaluate the use of ACTOS as monotherapy in patients with type 2 diabetes.
These trials examined ACTOS at doses up to 45 mg or placebo once daily in a total of 865 patients.
In a 26-week dose-ranging monotherapy trial, 408 patients with type 2 diabetes were randomized to receive 7.5 mg, 15 mg, 30 mg, or 45 mg of ACTOS, or placebo once daily.
Therapy with any previous antidiabetic agent was discontinued 8 weeks prior to the double-blind period.
Treatment with 15 mg, 30 mg, and 45 mg of ACTOS produced statistically significant improvements in HbA1c and fasting plasma glucose (FPG) at endpoint compared to placebo (see Figure 1 , Table 17 ).
Figure 1 shows the time course for changes in HbA1c in this 26-week study.
Figure 1 Mean Change from Baseline for HbA1c in a 26-Week Placebo-Controlled Dose-Ranging Study (Observed Values) Table 17: Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Monotherapy Trial Placebo ACTOS 15 mg Once Daily ACTOS 30 mg Once Daily ACTOS 45 mg Once Daily Total Population HbA1c (%) N=79 N=79 N=85 N=76 Baseline (mean) 10.4 10.2 10.2 10.3 Change from baseline (adjusted mean Adjusted for baseline, pooled center, and pooled center by treatment interaction ) 0.7 -0.3 -0.3 -0.9 Difference from placebo (adjusted mean ) 95% Confidence Interval -1.0 p ≤ 0.05 vs.
placebo (-1.6, -0.4) -1.0 (-1.6, -0.4) -1.6 (-2.2, -1.0) Fasting Plasma Glucose (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 268 267 269 276 Change from baseline (adjusted mean ) 9 -30 -32 -56 Difference from placebo (adjusted mean ) 95% Confidence Interval -39 (-63, -16) -41 (-64, -18) -65 (-89, -42) In a 24-week placebo-controlled monotherapy trial, 260 patients with type 2 diabetes were randomized to one of two forced-titration ACTOS treatment groups or a mock-titration placebo group.
Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double-blind period.
In one ACTOS treatment group, patients received an initial dose of 7.5 mg once daily.
After four weeks, the dose was increased to 15 mg once daily and after another four weeks, the dose was increased to 30 mg once daily for the remainder of the trial (16 weeks).
In the second ACTOS treatment group, patients received an initial dose of 15 mg once daily and were titrated to 30 mg once daily and 45 mg once daily in a similar manner.
Treatment with ACTOS, as described, produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo (Table 18).
Table 18: Glycemic Parameters in a 24-Week Placebo-Controlled Forced-Titration Monotherapy Trial Placebo ACTOS 30 mg Final dose in forced titration Once Daily ACTOS 45 mg Once Daily Total Population HbA1c (%) N=83 N=85 N=85 Baseline (mean) 10.8 10.3 10.8 Change from baseline (adjusted mean Adjusted for baseline, pooled center, and pooled center by treatment interaction ) 0.9 -0.6 -0.6 Difference from placebo (adjusted mean ) 95% Confidence Interval -1.5 p ≤ 0.05 vs.
placebo (-2.0, -1.0) -1.5 (-2.0, -1.0) Fasting Plasma Glucose (mg/dL) N=78 N=82 N=85 Baseline (mean) 279 268 281 Change from baseline (adjusted mean ) 18 -44 -50 Difference from placebo (adjusted mean ) 95% Confidence Interval -62 (-82, -0.41) -68 (-88, -0.48) In a 16-week monotherapy trial, 197 patients with type 2 diabetes were randomized to treatment with 30 mg of ACTOS or placebo once daily.
Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double-blind period.
Treatment with 30 mg of ACTOS produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo (Table 19).
Table 19: Glycemic Parameters in a 16-Week Placebo-Controlled Monotherapy Trial Placebo ACTOS 30 mg Once Daily Total Population HbA1c (%) N=93 N=100 Baseline (mean) 10.3 10.5 Change from baseline (adjusted mean Adjusted for baseline, pooled center, and pooled center by treatment interaction ) 0.8 -0.6 Difference from placebo (adjusted mean ) 95% Confidence Interval -1.4 p ≤ 0.050 vs.
placebo (-1.8, -0.9) Fasting Plasma Glucose (mg/dL) N=91 N=99 Baseline (mean) 270 273 Change from baseline (adjusted mean ) 8 -50 Difference from placebo (adjusted mean ) 95% Confidence Interval -58 (-77, -38) 14.2 Combination Therapy Three 16-week, randomized, double-blind, placebo-controlled clinical trials were conducted to evaluate the effects of ACTOS (15 mg and/or 30 mg) on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA1c ≥ 8%) despite current therapy with a sulfonylurea, metformin, or insulin.
In addition, three 24-week randomized, double-blind clinical trials were conducted to evaluate the effects of ACTOS 30 mg vs.
ACTOS 45 mg on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA1c ≥ 8%) despite current therapy with a sulfonylurea, metformin, or insulin.
Previous diabetes treatment may have been monotherapy or combination therapy.
Add-on to Sulfonylurea Trials : Two clinical trials were conducted with ACTOS in combination with a sulfonylurea.
Both studies included patients with type 2 diabetes on any dose of a sulfonylurea, either alone or in combination with another antidiabetic agent.
All other antidiabetic agents were withdrawn at least 3 weeks prior to starting study treatment.
In the first study, 560 patients were randomized to receive 15 mg or 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their current sulfonylurea regimen.
Treatment with ACTOS as add-on to sulfonylurea produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo add-on to sulfonylurea (Table 20).
Table 20: Glycemic Parameters in a 16-Week Placebo-Controlled, Add-on to Sulfonylurea Trial Placebo + Sulfonylurea ACTOS 15 mg + Sulfonylurea ACTOS 30 mg + Sulfonylurea Total Population HbA1c (%) N=181 N=176 N=182 Baseline (mean) 9.9 10.0 9.9 Change from baseline (adjusted mean Adjusted for baseline, pooled center, and pooled center by treatment interaction ) 0.1 -0.8 -1.2 Difference from placebo + sulfonylurea (adjusted mean ) 95% Confidence Interval -0.9 p ≤ 0.05 vs.
placebo + sulfonylurea (-1.2, -0.6) -1.3 (-1.6, -1.0) Fasting Plasma Glucose (mg/dL) N=182 N=179 N=186 Baseline (mean) 236 247 239 Change from baseline (adjusted mean ) 6 -34 -52 Difference from placebo + sulfonylurea (adjusted mean ) 95% Confidence Interval -39 (-52, -27) -58 (-70, -46) In the second trial, 702 patients were randomized to receive 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current sulfonylurea regimen.
The mean reduction from baseline at Week 24 in HbA1c was 1.6% for the 30 mg dose and 1.7% for the 45 mg dose (see Table 21 ).
The mean reduction from baseline at Week 24 in FPG was 52 mg/dL for the 30 mg dose and 56 mg/dL for the 45 mg dose.
The therapeutic effect of ACTOS in combination with sulfonylurea was observed in patients regardless of the sulfonylurea dose.
Table 21: Glycemic Parameters in a 24-Week Add-on to Sulfonylurea Trial ACTOS 30 mg + Sulfonylurea ACTOS 45 mg + Sulfonylurea 95% CI = 95% confidence interval Total Population HbA1c (%) N=340 N=332 Baseline (mean) 9.8 9.9 Change from baseline (adjusted mean Adjusted for baseline, pooled center, and pooled center by treatment interaction ) -1.6 -1.7 Difference from 30 mg daily ACTOS + sulfonylurea (adjusted mean ) (95% CI) -0.1 (-0.4, 0.1) Fasting Plasma Glucose (mg/dL) N=338 N=329 Baseline (mean) 214 217 Change from baseline (adjusted mean ) -52 -56 Difference from 30 mg daily ACTOS + sulfonylurea (adjusted mean ) (95% CI) -5 (-12, 3) Add-on to Metformin Trials : Two clinical trials were conducted with ACTOS in combination with metformin.
Both trials included patients with type 2 diabetes on any dose of metformin, either alone or in combination with another antidiabetic agent.
All other antidiabetic agents were withdrawn at least 3 weeks prior to starting study treatment.
In the first trial, 328 patients were randomized to receive either 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their current metformin regimen.
Treatment with ACTOS as add-on to metformin produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo add-on to metformin (see Table 22 ).
Table 22: Glycemic Parameters in a 16-Week Placebo-Controlled, Add-on to Metformin Trial Placebo + Metformin ACTOS 30 mg + Metformin Total Population HbA1c (%) N=153 N=161 Baseline (mean) 9.8 9.9 Change from baseline (adjusted mean Adjusted for baseline, pooled center, and pooled center by treatment interaction ) 0.2 -0.6 Difference from placebo + metformin (adjusted mean ) 95% Confidence Interval -0.8 p ≤ 0.05 vs.
placebo + metformin (-1.2, -0.5) Fasting Plasma Glucose (mg/dL) N=157 N=165 Baseline (mean) 260 254 Change from baseline (adjusted mean ) -5 -43 Difference from placebo + metformin (adjusted mean ) 95% Confidence Interval -38 (-49, -26) In the second trial, 827 patients were randomized to receive either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current metformin regimen.
The mean reduction from baseline at Week 24 in HbA1c was 0.8% for the 30 mg dose and 1.0% for the 45 mg dose (see Table 23 ).
The mean reduction from baseline at Week 24 in FPG was 38 mg/dL for the 30 mg dose and 51 mg/dL for the 45 mg dose.
Table 23: Glycemic Parameters in a 24-Week Add-on to Metformin Study ACTOS 30 mg + Metformin ACTOS 45 mg + Metformin 95% CI = 95% confidence interval Total Population HbA1C (%) N=400 N=398 Baseline (mean) 9.9 9.8 Change from baseline (adjusted mean Adjusted for baseline, pooled center, and pooled center by treatment interaction ) -0.8 -1.0 Difference from 30 mg daily ACTOS + Metformin (adjusted mean ) (95% CI) -0.2 (-0.5, 0.1) Fasting Plasma Glucose (mg/dL) N=398 N=399 Baseline (mean) 233 232 Change from baseline (adjusted mean ) -38 -51 Difference from 30 mg daily ACTOS + Metformin (adjusted mean ) (95% CI) -12 p ≤ 0.05 vs.
30 mg daily ACTOS + metformin (-21, -4) The therapeutic effect of ACTOS in combination with metformin was observed in patients regardless of the metformin dose.
Add-on to Insulin Trials : Two clinical trials were conducted with ACTOS in combination with insulin.
Both trials included patients with type 2 diabetes on insulin, either alone or in combination with another antidiabetic agent.
All other antidiabetic agents were withdrawn prior to starting study treatment.
In the first trial, 566 patients were randomized to receive either 15 mg or 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their insulin regimen.
Treatment with ACTOS as add-on to insulin produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo add-on to insulin (see Table 24 ).
The mean daily insulin dose at baseline in each treatment group was approximately 70 units.
The majority of patients (75% overall, 86% treated with placebo, 77% treated with ACTOS 15 mg, and 61% treated with ACTOS 30 mg) had no change in their daily insulin dose from baseline to the final study visit.
The mean change from baseline in daily dose of insulin (including patients with no insulin dose modifications) was -3 units in the patients treated with ACTOS 15 mg, -8 units in the patients treated with ACTOS 30 mg, and -1 unit in patients treated with placebo.
Table 24: Glycemic Parameters in a 16-Week Placebo-Controlled, Add-on to Insulin Trial Placebo + Insulin ACTOS 15 mg + Insulin ACTOS 30 mg + Insulin Total Population HbA1C (%) N=177 N=177 N=185 Baseline (mean) 9.8 9.8 9.8 Change from baseline (adjusted mean Adjusted for baseline, pooled center, and pooled center by treatment interaction ) -0.3 -1.0 -1.3 Difference from placebo + Insulin (adjusted mean ) 95% Confidence Interval -0.7 p ≤ 0.05 vs.
placebo + insulin (-1.0, -0.5) -1.0 (-1.3, -0.7) Fasting Plasma Glucose (mg/dL) N=179 N=183 N=184 Baseline (mean) 221 222 229 Change from baseline (adjusted mean ) 1 -35 -48 Difference from placebo + Insulin (adjusted mean ) 95% Confidence Interval -35 (-51, -19) -49 (-65, -33) In the second trial, 690 patients receiving a median of 60 units per day of insulin were randomized to receive either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current insulin regimen.
The mean reduction from baseline at Week 24 in HbA1c was 1.2% for the 30 mg dose and 1.5% for the 45 mg dose.
The mean reduction from baseline at Week 24 in FPG was 32 mg/dL for the 30 mg dose and 46 mg/dL for the 45 mg dose (see Table 25 ).
The mean daily insulin dose at baseline in both treatment groups was approximately 70 units.
The majority of patients (55% overall, 58% treated with ACTOS 30 mg, and 52% treated with ACTOS 45 mg) had no change in their daily insulin dose from baseline to the final study visit.
The mean change from baseline in daily dose of insulin (including patients with no insulin dose modifications) was -5 units in the patients treated with ACTOS 30 mg and -8 units in the patients treated with ACTOS 45 mg.
The therapeutic effect of ACTOS in combination with insulin was observed in patients regardless of the insulin dose.
Table 25: Glycemic Parameters in a 24-Week Add-on to Insulin Trial ACTOS 30 mg + Insulin ACTOS 45 mg + Insulin 95% CI = 95% confidence interval Total Population HbA1c (%) N=328 N=328 Baseline (mean) 9.9 9.7 Change from baseline (adjusted mean Adjusted for baseline, pooled center, and pooled center by treatment interaction ) -1.2 -1.5 Difference from 30 mg daily ACTOS + Insulin (adjusted mean ) (95% CI) -0.3 p ≤ 0.05 vs.
30 mg daily ACTOS + insulin (-0.5, -0.1) Fasting Plasma Glucose (mg/dL) N=325 N=327 Baseline (mean) 202 199 Change from baseline (adjusted mean ) -32 -46 Difference from 30 mg daily ACTOS + Insulin (adjusted mean ) (95% CI) -14 (-25, -3)
HOW SUPPLIED
16 / STORAGE AND HANDLING ACTOS is available in 15 mg, 30 mg, and 45 mg tablets as follows: 15 mg tablet: White to off-white, round, convex, non-scored tablet with “ACTOS” on one side, and “15” on the other, available in: NDC 64764-151-04 Bottles of 30 NDC 64764-151-05 Bottles of 90 NDC 64764-151-06 Bottles of 500 30 mg tablet: White to off-white, round, flat, non-scored tablet with “ACTOS” on one side, and “30” on the other, available in: NDC 64764-301-14 Bottles of 30 NDC 64764-301-15 Bottles of 90 NDC 64764-301-16 Bottles of 500 45 mg tablet: White to off-white, round, flat, non-scored tablet with “ACTOS” on one side, and “45” on the other, available in: NDC 64764-451-24 Bottles of 30 NDC 64764-451-25 Bottles of 90 NDC 64764-451-26 Bottles of 500 Storage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
Keep container tightly closed, and protect from light, moisture and humidity.
RECENT MAJOR CHANGES
Indications and Usage Important Limitations of Use ( 1.2 ) 01/2011 Dosage and Administration Recommendations for All Patients ( 2.1 ) 01/2011 Coadministration with Strong CYP2C8 Inhibitors ( 2.3 ) 01/2011 Warnings and Precautions Hepatic Effects ( 5.3 ) 01/2011 Urinary Bladder Tumors ( 5.5 ) 07/2011
GERIATRIC USE
8.5 Geriatric Use A total of 92 patients (15.2%) treated with ACTOS in the three pooled 16 to 26-week double-blind, placebo-controlled, monotherapy, trials were ≥65 years old and 2 patients (0.3%) were ≥75 years old.
In the two pooled 16 to 24-week add-on to sulfonylurea trials, 201 patients (18.7 %) treated with ACTOS were ≥ 65 years old and 19 (1.8%) were ≥ 75 years old.
In the two pooled 16 to 24 week add-on to metformin trials, 155 patients (15.5%) treated with ACTOS were ≥65 years old and 19 (1.9%) were ≥75 years old.
In the two pooled 16 to 24 week add-on to insulin trials, 272 patients (25.4%) treated with ACTOS were ≥65 years old and 22 (2.1%) were ≥75 years old.
In PROactive, 1068 patients (41.0%) treated with ACTOS were ≥65 years old and 42 (1.6%) were ≥75 years old.
In pharmacokinetic studies with pioglitazone, no significant differences were observed in pharmacokinetic parameters between elderly and younger patients.
These clinical experiences have not identified differences in effectiveness and safety between the elderly (≥ 65 years) and younger patients although small sample sizes for patients ≥75 years old limit conclusions [see Clinical Pharmacology (12.3) ] .
DOSAGE FORMS AND STRENGTHS
3 Round tablet contains pioglitazone as follows: 15 mg: White to off-white, debossed with “ACTOS” on one side and “15” on the other 30 mg: White to off-white, debossed with “ACTOS” on one side and “30” on the other 45 mg: White to off-white, debossed with “ACTOS” on one side and “45” on the other Tablets: 15 mg, 30 mg, and 45 mg ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action ACTOS is a thiazolidinedione that depends on the presence of insulin for its mechanism of action.
ACTOS decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output.
Pioglitazone is not an insulin secretagogue.
Pioglitazone is an 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.
Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.
In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulinemia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes.
The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance.
Because pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.
INDICATIONS AND USAGE
1 ACTOS is a thiazolidinedione and an agonist for peroxisome proliferator-activated receptor (PPAR) gamma indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings.
( 1.1 , 14 ) Important Limitation of Use: Not for treatment of type 1 diabetes or diabetic ketoacidosis.
( 1.2 ) 1.1 Monotherapy and Combination Therapy ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings [see Clinical Studies (14) ] .
1.2 Important Limitation of Use ACTOS exerts its antihyperglycemic effect only in the presence of endogenous insulin.
ACTOS should not be used to treat type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings.
Use caution in patients with liver disease [see Warnings and Precautions (5.3) ] .
PEDIATRIC USE
8.4 Pediatric Use Safety and effectiveness of ACTOS in pediatric patients have not been established.
Use in pediatric patients is not recommended for the treatment of diabetes due to lack of long-term safety data.
Risks including fractures and other adverse effects associated with ACTOS have not been determined in this population [see Warnings and Precautions (5.4) ].
PREGNANCY
8.1 Pregnancy Pregnancy Category C.
There are no adequate and well-controlled studies of ACTOS in pregnant women.
Animal studies show increased rates of post-implantation loss, delayed development, reduced fetal weights, and delayed parturition at doses 10 to 40 times the maximum recommended human dose.
ACTOS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Clinical Considerations : Abnormal blood glucose concentrations during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality.
Most experts recommend the use of insulin during pregnancy to maintain blood glucose concentrations as close to normal as possible for patients with diabetes.
Animal Data : In animal reproductive studies, pregnant rats and rabbits received pioglitazone at doses up to approximately 17 (rat) and 40 (rabbit) times the maximum recommended human oral dose (MRHD) based on body surface area (mg/m 2 ); no teratogenicity was observed [see Nonclinical Toxicology (13.3) ] .
Increases in embryotoxicity (increased postimplantation losses, delayed development, reduced fetal weights, and delayed parturition) occurred in rats that received oral doses approximately 10 or more times the MRHD (mg/m 2 basis).
No functional or behavioral toxicity was observed in rat offspring.
When pregnant rats received pioglitazone during late gestation and lactation, delayed postnatal development, attributed to decreased body weight, occurred in rat offspring at oral maternal doses approximately 2 or more times the MRHD (mg/m 2 basis).
In rabbits, embryotoxicity occurred at oral doses approximately 40 times the MRHD (mg/m 2 basis).
NUSRING MOTHERS
8.3 Nursing Mothers It is not known whether ACTOS is secreted in human milk.
Pioglitazone is secreted in the milk of lactating rats.
Because many drugs are excreted in human milk, and because of the potential for ACTOS to cause serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or discontinue ACTOS, taking into account the importance of ACTOS to the mother.
BOXED WARNING
WARNING: CONGESTIVE HEART FAILURE Thiazolidinediones, including ACTOS, cause or exacerbate congestive heart failure in some patients [see Warnings and Precautions (5.1) ] .
After initiation of ACTOS, and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea, and/or edema).
If heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of ACTOS must be considered.
ACTOS is not recommended in patients with symptomatic heart failure.
Initiation of ACTOS in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated [see Contraindications (4) and Warnings and Precautions (5.1) ] .
WARNING: CONGESTIVE HEART FAILURE See full prescribing information for complete boxed warning.
Thiazolidinediones, including ACTOS, cause or exacerbate congestive heart failure in some patients.
( 5.1 ) After initiation of ACTOS, and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea, and/or edema).
If heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of ACTOS must be considered.
( 5.1 ) ACTOS is not recommended in patients with symptomatic heart failure.
Initiation of ACTOS in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated.
( 4 , 5.1 )
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Congestive heart failure: Fluid retention may occur and can exacerbate or lead to congestive heart failure.
Combination use with insulin and use in congestive heart failure NYHA Class I and II may increase risk.
Monitor patients for signs and symptoms.
( 5.1 ) Edema: Dose-related edema may occur.
( 5.2 ) Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal.
Causality cannot be excluded.
If liver injury is detected, promptly interrupt ACTOS and assess patient for probable cause, then treat cause if possible, to resolution or stabilization.
Do not restart ACTOS if liver injury is confirmed and no alternate etiology can be found.
( 5.3 ) Fractures: Increased incidence in female patients.
Apply current standards of care for assessing and maintaining bone health.
( 5.4 ) Bladder cancer: Preclinical and clinical trial data, and results from an observational study suggest an increased risk of bladder cancer in pioglitazone users.
The observational data further suggest that the risk increases with duration of use.
Do not use in patients with active bladder cancer.
Use caution when using in patients with a prior history of bladder cancer ( 5.5 ) Hypoglycemia: When used with insulin or an insulin secretagogue, a lower dose of the insulin or insulin secretagogue may be needed to reduce the risk of hypoglycemia.
( 5.6 ) Macular edema: Postmarketing reports.
Recommend regular eye exams in all patients with diabetes according to current standards of care with prompt evaluation for acute visual changes.
( 5.7 ) Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with ACTOS or any other anti-diabetic drug.
( 5.9 ) 5.1 Congestive Heart Failure ACTOS, like other thiazolidinediones, can cause dose-related fluid retention when used alone or in combination with other antidiabetic medications and is most common when ACTOS is used in combination with insulin.
Fluid retention may lead to or exacerbate congestive heart failure.
Patients should be observed for signs and symptoms of congestive heart failure.
If congestive heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of ACTOS must be considered [see Boxed Warning , Contraindications (4) , and Adverse Reactions (6.1) ] .
5.2 Edema In controlled clinical trials, edema was reported more frequently in patients treated with ACTOS than in placebo-treated patients and is dose-related [see Adverse Reactions (6.1) ] .
In postmarketing experience, reports of new onset or worsening edema have been received.
ACTOS should be used with caution in patients with edema.
Because thiazolidinediones, including ACTOS, can cause fluid retention, which can exacerbate or lead to congestive heart failure, ACTOS should be used with caution in patients at risk for congestive heart failure.
Patients treated with ACTOS should be monitored for signs and symptoms of congestive heart failure [see Boxed Warning , Warnings and Precautions (5.1) and Patient Counseling Information (17.1) ] .
5.3 Hepatic Effects There have been postmarketing reports of fatal and non-fatal hepatic failure in patients taking ACTOS, although the reports contain insufficient information necessary to establish the probable cause.
There has been no evidence of drug-induced hepatotoxicity in the ACTOS controlled clinical trial database to date [see Adverse Reactions (6.1) ] .
Patients with type 2 diabetes may have fatty liver disease or cardiac disease with episodic congestive heart failure, both of which may cause liver test abnormalities, and they may also have other forms of liver disease, many of which can be treated or managed.
Therefore, obtaining a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) and assessing the patient is recommended before initiating ACTOS therapy.
In patients with abnormal liver tests, ACTOS should be initiated with caution.
Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.
In this clinical context, if the patient is found to have abnormal liver tests (ALT greater than 3 times the upper limit of the reference range), ACTOS treatment should be interrupted and investigation done to establish the probable cause.
ACTOS should not be restarted in these patients without another explanation for the liver test abnormalities.
Patients who have serum ALT greater than three times the reference range with serum total bilirubin greater than two times the reference range without alternative etiologies are at risk for severe drug-induced liver injury, and should not be restarted on ACTOS.
For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with ACTOS can be used with caution.
5.4 Fractures In PROactive (the Prospective Pioglitazone Clinical Trial in Macrovascular Events), 5238 patients with type 2 diabetes and a history of macrovascular disease were randomized to ACTOS (N=2605), force-titrated up to 45 mg daily or placebo (N=2633) in addition to standard of care.
During a mean follow-up of 34.5 months, the incidence of bone fracture in females was 5.1% (44/870) for ACTOS versus 2.5% (23/905) for placebo.
This difference was noted after the first year of treatment and persisted during the course of the study.
The majority of fractures observed in female patients were nonvertebral fractures including lower limb and distal upper limb.
No increase in the incidence of fracture was observed in men treated with ACTOS (1.7%) versus placebo (2.1%).
The risk of fracture should be considered in the care of patients, especially female patients, treated with ACTOS and attention should be given to assessing and maintaining bone health according to current standards of care.
5.5 Urinary Bladder Tumors Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study [see Nonclinical Toxicology (13.1) ].
In two 3-year trials in which ACTOS was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking ACTOS compared to 5/3679 (0.14%) in patients not taking ACTOS.
After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on ACTOS and two (0.05%) cases on placebo.
A five-year interim report of an ongoing 10-year observational cohort study found a non-significant increase in the risk for bladder cancer in subjects ever exposed to ACTOS, compared to subjects never exposed to ACTOS (HR 1.2 [95% CI 0.9 – 1.5]).
Compared to never exposure, a duration of ACTOS therapy longer than 12 months was associated with an increase in risk (HR 1.4 [95% CI 0.9 – 2.1]), which reached statistical significance after more than 24 months of ACTOS use (HR 1.4 [95% CI 1.03 – 2.0]).
Interim results from this study suggested that taking ACTOS longer than 12 months increased the relative risk of developing bladder cancer in any given year by 40% which equates to an absolute increase of 3 cases in 10,000 (from approximately 7 in 10,000 [without ACTOS] to approximately 10 in 10,000 [with ACTOS]).
There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors.
Consequently, ACTOS should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with ACTOS should be considered in patients with a prior history of bladder cancer.
5.6 Hypoglycemia Patients receiving ACTOS in combination with insulin or other anti-diabetic medications (particularly insulin secretagogues such as sulfonylureas) may be at risk for hypoglycemia.
A reduction in the dose of the concomitant anti-diabetic medication may be necessary to reduce the risk of hypoglycemia [see Dosage and Administration (2.2) ].
5.7 Macular Edema Macular edema has been reported in postmarketing experience in diabetic patients who were taking ACTOS or another thiazolidinedione.
Some patients presented with blurred vision or decreased visual acuity, but others were diagnosed on routine ophthalmologic examination.
Most patients had peripheral edema at the time macular edema was diagnosed.
Some patients had improvement in their macular edema after discontinuation of the thiazolidinedione.
Patients with diabetes should have regular eye exams by an ophthalmologist according to current standards of care.
Patients with diabetes who report any visual symptoms should be promptly referred to an ophthalmologist, regardless of the patient’s underlying medications or other physical findings [see Adverse Reactions (6.1) ] .
5.8 Ovulation Therapy with ACTOS, 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 ACTOS [see Use in Specific Populations (8.1) ] .
This effect has not been investigated in clinical trials, so the frequency of this occurrence is not known.
Adequate contraception in all premenopausal women treated with ACTOS is recommended.
5.9 Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with ACTOS or any other anti-diabetic drug.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION See FDA-Approved Medication Guide (17.2) .
17.1 Instructions It is important to instruct patients to adhere to dietary instructions and to have blood glucose and glycosylated hemoglobin tested regularly.
During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly.
Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on ACTOS should immediately report these symptoms to a physician.
Tell patients to promptly stop taking ACTOS and seek immediate medical advice if there is unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine as these symptoms may be due to hepatotoxicity.
Tell patients to promptly report any sign of macroscopic hematuria or other symptoms such as dysuria or urinary urgency that develop or increase during treatment as these may be due to bladder cancer.
Tell patients to take ACTOS once daily.
ACTOS can be taken with or without meals.
If a dose is missed on one day, the dose should not be doubled the following day.
When using combination therapy with insulin or other antidiabetic medications, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members.
Therapy with ACTOS, 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 ACTOS.
Therefore, adequate contraception should be recommended for all pre-menopausal women who are prescribed ACTOS.
17.2 FDA-Approved Medication Guide See attached leaflet.
DOSAGE AND ADMINISTRATION
2 Initiate ACTOS at 15 mg or 30 mg once daily.
Limit initial dose to 15 mg once daily in patients with NYHA Class I or II heart failure.
( 2.1 ) If there is inadequate glycemic control, the dose can be increased in 15 mg increments up to a maximum of 45 mg once daily.
( 2.1 ) The maximum recommended dose of ACTOS is 15 mg once daily in patients taking strong CYP2C8 inhibitors (e.g., gemfibrozil).
( 2.3 , 7.1 ) Obtain liver tests before starting ACTOS.
If abnormal, use caution when treating with ACTOS, investigate the probable cause, treat (if possible) and follow appropriately.
Monitoring liver tests while on ACTOS is not recommended in patients without liver disease.
( 5.3 ) 2.1 Recommendations for all patients ACTOS should be taken once daily and can be taken without regard to meals.
The recommended starting dose for patients without congestive heart failure is 15 mg or 30 mg once daily.
The recommended starting dose for patients with congestive heart failure (NYHA Class I or II) is 15 mg once daily.
The dose can be titrated in increments of 15 mg up to a maximum of 45 mg once daily based on glycemic response as determined by HbA1c.
After initiation of ACTOS or with dose increase, monitor patients carefully for adverse reactions related to fluid retention such as weight gain, edema, and signs and symptoms of congestive heart failure [see Boxed Warning and Warnings and Precautions (5.2) ] .
Liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) should be obtained prior to initiating ACTOS.
Routine periodic monitoring of liver tests during treatment with ACTOS is not recommended in patients without liver disease.
Patients who have liver test abnormalities prior to initiation of ACTOS or who are found to have abnormal liver tests while taking ACTOS should be managed as described under Warnings and Precautions [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3) ] .
2.2 Concomitant use with an insulin secretagogue or insulin If hypoglycemia occurs in a patient co-administered ACTOS and an insulin secretagogue (e.g., sulfonylurea), the dose of the insulin secretagogue should be reduced.
If hypoglycemia occurs in a patient co-administered ACTOS and insulin, the dose of insulin should be decreased by 10% to 25%.
Further adjustments to the insulin dose should be individualized based on glycemic response.
2.3 Coadministration with strong CYP2C8 inhibitors Coadministration of ACTOS and gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone exposure approximately 3-fold.
Therefore, the maximum recommended dose of ACTOS is 15 mg daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ].