Download ACTOS (Pioglitazone Hydrochloride) Tablets: Efficacy, Side Effects, and Interactions and more Study notes Clinical Medicine in PDF only on Docsity!
ACTOS™
(Pioglitazone Hydrochloride) Tablets
DESCRIPTION ACTOS (pioglitazone hydrochloride) is an oral antidiabetic agent that acts primarily by decreasing insulin resistance. ACTOS is used in the management of type 2 diabetes mellitus (also known as non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes). Pharmacological studies indicate that ACTOS improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. ACTOS improves glycemic control while reducing circulating insulin levels.
Pioglitazone [(+)-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-] thiazolidinedione monohydrochloride belongs to a different chemical class and has a different pharmacological action than the sulfonylureas, metformin, or the α-glucosidase inhibitors. The molecule contains one asymmetric carbon, and the compound is synthesized and used as the racemic mixture. The two enantiomers of pioglitazone inter- convert 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.
CLINICAL PHARMACOLOGY
Mechanism of Action ACTOS is a thiazolidinedione antidiabetic agent 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. 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. 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.
Since pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.
Pharmacokinetics and Drug Metabolism Serum concentrations of total pioglitazone (pioglitazone plus active metabolites) remain elevated 24 hours after once daily dosing. Steady-state serum concentrations of both pioglitazone and total pioglitazone are achieved within 7 days. At steady state, two of the pharmacologically active metabolites of pioglitazone, Metabolites III (M-III) and IV (M-IV), reach serum concentrations equal to or greater than pioglitazone. In both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the peak total pioglitazone serum concentrations and 20% to 25% of the total area under the serum concentration-time curve (AUC).
Maximum serum concentration (Cmax), AUC, and trough serum concentrations (Cmin) for both pioglitazone and total pioglitazone increase proportionally at doses of 15 mg and
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 half-life of pioglitazone and total pioglitazone ranges from 3 to 7 hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to 7 L/hr.
Special Populations Renal Insufficiency : The serum elimination half-life of pioglitazone, M-III, and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 60 mL/min) to severe (creatinine clearance < 30 mL/min) renal impairment when compared to normal subjects. No dose adjustment in patients with renal dysfunction is recommended (see DOSAGE AND ADMINISTRATION).
Hepatic Insufficiency: Compared with normal controls, subjects 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.
ACTOS therapy should not be initiated if the patient exhibits clinical evidence of active liver disease or serum transaminase levels (ALT) exceed 2.5 times the upper limit of normal (see PRECAUTIONS, Hepatic Effects).
Elderly : In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are slightly higher and the terminal half-life values slightly longer than for younger subjects. These changes were not of a magnitude that would be considered clinically relevant.
Pediatrics : Pharmacokinetic data in the pediatric population are not available.
Gender : The mean Cmax and AUC values were increased 20% to 60% in females. As monotherapy and in combination with sulfonylurea, metformin, or insulin, ACTOS improved glycemic control in both males and females. In controlled clinical trials,
hemoglobin A1C (HbA1c) decreases from baseline were generally greater for females than for males (average mean difference in HbA1c 0.5%). Since therapy should be individualized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone.
Ethnicity : Pharmacokinetic data among various ethnic groups are not available.
Pharmacodynamics and Clinical Effects Clinical studies demonstrate that ACTOS improves insulin sensitivity in insulin-resistant patients. ACTOS enhances cellular responsiveness to insulin, increases insulin- dependent glucose disposal, improves hepatic sensitivity to insulin, and improves dysfunctional glucose homeostasis. In patients with type 2 diabetes, the decreased insulin resistance produced by ACTOS results in lower blood glucose concentrations, lower plasma insulin levels, and lower HbA1c values. Based on results from an open- label extension study, the glucose lowering effects of ACTOS appear to persist for at least one year. In controlled clinical trials, ACTOS in combination with sulfonylurea, metformin, or insulin had an additive effect on glycemic control.
Patients with lipid abnormalities were included in clinical trials with ACTOS. Overall, patients treated with ACTOS had mean decreases in triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol.
In a 26-week, placebo-controlled, dose-ranging study, mean triglyceride levels decreased in the 15 mg, 30 mg, and 45 mg ACTOS dose groups compared to a mean increase in the placebo group. Mean HDL levels increased to a greater extent in the ACTOS-treated patients than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in ACTOS-treated patients compared to placebo (Table 1).
in average weight was 2.3 kg and 3.7 kg for 15 mg and 30 mg of ACTOS, respectively, and 0 kg for placebo. In combination with metformin, the change in average weight was 1.0 kg for 30 mg of ACTOS and –1.4 kg for placebo.
Clinical Studies Monotherapy In the U.S., 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 studies examined ACTOS at doses up to 45 mg or placebo once daily in 865 patients.
In a 26-week dose-ranging study, 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 blood glucose (FBG) at endpoint compared to placebo (see Figure 1, Table 2).
Figure 1 shows the time course for changes in FBG and HbA1c for the entire study population in this 26-week study. Figure 1 Mean Change from Baseline for FBG and HbA1c in a 26-Week Placebo-Controlled Dose-Ranging Study
-80-
-60-
-40-
-20-
(^100) 20
0 2 4 6 8 10 12 14 16 18 20 22 24 26 Weeks Placebo 15 mg 30 mg 45 mg
-0.8 - -0.6-0.
-0.2^0
0.20.
0.60.
1
0 2 4 6 8 10 12 14 16 18 20 22 24 26 Weeks Placebo 15 mg 30 mg 45 mg
Mean Change From Baseline
HbA
1c^ (%)
Mean Change From Baseline
FBG (mg/dL)
FBG HbA1c
Table 2 shows HbA1c and FBG values for the entire study population.
Table 2 Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study
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= Baseline (mean) 10.4 10.2 10.2 10. Change from baseline (adjusted mean+) 0.7 -0.3 -0.3 -0. Difference from placebo (adjusted mean+) -1.0* -1.0* -1.6*
FBG (mg/dL) N=79 N=79 N=84 N= Baseline (mean) 268 267 269 276 Change from baseline (adjusted mean+) 9 -30 -32 - Difference from placebo (adjusted mean+) -39* -41* -65*
- (^) Adjusted for baseline, pooled center, and pooled center by treatment interaction
The study population included patients not previously treated with antidiabetic medication (naïve; 31%) and patients who were receiving antidiabetic medication at the time of study enrollment (previously treated; 69%). The data for the naïve and previously treated patient subsets are shown in Table 3. All patients entered an 8 week washout/run-in period prior to double-blind treatment. This run-in period was associated with little change in HbA1c and FBG values from screening to baseline for the naïve patients; however, for the previously-treated group, washout from previous anti-diabetic medication resulted in deterioration of glycemic control and increases in HbA1c and FBG. Although most patients in the previously-treated group had a decrease from baseline in HbA1c and FBG with ACTOS, in many cases the values did not return to screening levels by the end of the study. The study design did not permit the evaluation of patients who switched directly to ACTOS from another antidiabetic agent.
manner. Treatment with ACTOS, as described, produced statistically significant improvements in HbA1c and FBG at endpoint compared to placebo (see Table 4).
Table 4 Glycemic Parameters in a 24-Week Placebo-Controlled Forced-Titration Study
Placebo
ACTOS 30 mg+ Once Daily
ACTOS 45 mg+ Once Daily Total Population HbA1c (%) N=83 N=85 N= Baseline (mean) 10.8 10.3 10. Change from baseline (adjusted mean++) 0.9 -0.6 -0. Difference from placebo (adjusted mean++) -1.5* -1.5*
FBG (mg/dL) N=78 N=82 N= Baseline (mean) 279 268 281 Change from baseline (adjusted mean++) 18 -44 - Difference from placebo (adjusted mean++) -62* -68*
- (^) Final dose in forced titration ++ (^) Adjusted for baseline, pooled center, and pooled center by treatment interaction
For patients who had not been previously treated with antidiabetic medication (24%), mean values at screening were 10.1% for HbA1c and 238 mg/dL for FBG. At baseline, mean HbA1c was 10.2% and mean FBG was 243 mg/dL. Compared with placebo, treatment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbA1c of 2.3% and 2.6% and mean FBG of 63 mg/dL and 95 mg/dL, respectively. For patients who had been previously treated with antidiabetic medication (76%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbA1c and 216 mg/dL for FBG. At baseline, mean HbA1c was 10.7% and mean FBG was 290 mg/dL. Compared with placebo, treatment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbA1c of 1.3% and 1.4% and mean FBG of 55 mg/dL and 60 mg/dL, respectively. For many previously-treated patients, HbA1c and FBG had not returned to screening levels by the end of the study.
In a 16-week study, 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 FBG at endpoint compared to placebo (see Table 5).
Table 5 Glycemic Parameters in a 16-Week Placebo-Controlled Study
Placebo ACTOS 30 mgOnce Daily
Total Population HbA1c (%) N=93 N= Baseline (mean) 10.3 10. Change from baseline (adjusted mean+) 0.8 -0. Difference from placebo (adjusted mean+) -1.4*
FBG (mg/dL) N=91 N= Baseline (mean) 270 273 Change from baseline (adjusted mean+) 8 - Difference from placebo (adjusted mean+) -58*
- (^) Adjusted for baseline, pooled center, and pooled center by treatment interaction
For patients who had not been previously treated with antidiabetic medication (40%), mean values at screening were 10.3% for HbA1c and 240 mg/dL for FBG. At baseline, mean HbA1c was 10.4% and mean FBG was 254 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1c of 1.0% and mean FBG of 62 mg/dL. For patients who had been previously treated with antidiabetic medication (60%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbA1c and 216 mg/dL for FBG. At baseline, mean HbA1c was 10.6% and mean FBG was 287 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1c of 1.3% and mean FBG of 46 mg/dL. For many previously-treated patients, HbA1c and FBG had not returned to screening levels by the end of the study.
Combination Therapy Three 16-week, randomized, double-blind, placebo-controlled clinical studies were conducted to evaluate the effects of ACTOS on glycemic control in patients with type 2 diabetes who were inadaquately controlled (HbA1c ≥ 8%) despite current therapy with a
INDICATIONS AND USAGE
ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (non-insulin dependent diabetes mellitus, NIDDM). ACTOS is indicated for monotherapy. ACTOS is also indicated for use in combination with a sulfonylurea, metformin, or insulin when diet and exercise plus the single agent does not result in adequate glycemic control.
Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise. These efforts are important not only in the primary treatment of type 2 diabetes, but also to maintain the efficacy of drug therapy.
CONTRAINDICATIONS ACTOS is contraindicated in patients with known hypersensitivity to this product or any of its components.
PRECAUTIONS General ACTOS exerts its antihyperglycemic effect only in the presence of insulin. Therefore, ACTOS should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Hypoglycemia: Patients receiving ACTOS 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.
Ovulation: In premenopausal anovulatory patients with insulin resistance, treatment with thiazolidinediones, including ACTOS, may result in resumption of ovulation. As a consequence of their improved insulin sensitivity, these patients may be at risk for pregnancy if adequate contraception is not used.
Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in ACTOS-treated patients. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased
plasma volume and have not been associated with any significant hematologic clinical effects (see ADVERSE REACTIONS, Laboratory Abnormalities).
Edema: ACTOS should be used with caution in patients with edema. In double-blind clinical trials of patients with type 2 diabetes, mild to moderate edema was reported in patients treated with ACTOS (see ADVERSE REACTIONS).
Cardiac: In preclinical studies, thiazolidinediones, including pioglitazone, cause plasma volume expansion and pre-load-induced cardiac hypertrophy (see PRECAUTIONS, Animal Toxicology). In a six-month placebo-controlled study of 334 patients with type 2 diabetes and a long-term (one year or more) open-label study of more than 350 patients with type 2 diabetes, echocardiographic evaluation revealed no significant increase in mean left ventricular mass index or significant decrease in mean cardiac index in patients treated with ACTOS.
In clinical trials that excluded patients with New York Heart Association (NYHA) Class III and IV cardiac status, no increased incidence of serious cardiac adverse events potentially related to volume expansion (e.g., congestive heart failure) was observed. Patients with NYHA Class III and IV cardiac status were not studied in ACTOS clinical trials. ACTOS is not indicated in patients with NYHA Class III or IV cardiac status.
Hepatic Effects: Another drug of the thiazolidinedione class, troglitazone, has been associated with idiosyncratic hepatotoxicity, and very rare cases of liver failure, liver transplants, and death have been reported during postmarketing clinical use. In pre- approval controlled clinical trials in patients with type 2 diabetes, troglitazone was more frequently associated with clinically significant elevations of hepatic enzymes (ALT > 3 times the upper limit of normal) compared to placebo, and very rare cases of reversible jaundice were reported.
In clinical studies worldwide, over 4500 subjects have been treated with ACTOS. In U.S. clinical studies, over 2500 patients with type 2 diabetes received ACTOS. There was no evidence of drug-induced hepatotoxicity or elevation of ALT levels.
There are no data available to evaluate the safety of ACTOS in patients who experienced liver abnormalities, hepatic dysfunction, or jaundice while on troglitazone. ACTOS should not be used in patients who experienced jaundice while taking troglitazone. For patients with normal hepatic enzymes who are switched from troglitazone to ACTOS, a one-week washout is recommended before starting therapy with ACTOS.
Laboratory Tests FBG and HbA1c measurements should be performed periodically to monitor glycemic control and the therapeutic response to ACTOS.
Liver enzyme monitoring is recommended prior to initiation of therapy with ACTOS in all patients and periodically therafter (see PRECAUTIONS, General, Hepatic Effects and ADVERSE REACTIONS, Serum Transaminase Levels).
Information for Patients 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 should be told that blood tests for liver function will be performed prior to the start of therapy, every two months for the first year, and periodically thereafter. Patients should be told to seek immediate medical advice for unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine.
Patients should be told 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 oral hypoglycemic agents, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members.
In anovulatory, premenopausal women with insulin resistance, therapy with ACTOS may cause resumption of ovulation and contraceptive measures may need to be considered.
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. The pharmacokinetics of coadministration of ACTOS and oral contraceptives have not been evaluated in patients receiving ACTOS and an oral contraceptive. Therefore, additional caution regarding contraception should be exercised in patients receiving ACTOS and an oral contraceptive.
Glipizide: In healthy volunteers, coadministration of ACTOS (45 mg once daily) and glipizide (5.0 mg once daily) for seven days did not alter the steady-state pharmacokinetics of glipizide.
Digoxin: In healthy volunteers, coadministration of ACTOS (45 mg once daily) with digoxin (0.25 mg once daily) for seven days did not alter the steady-state pharmacokinetics of digoxin.
Warfarin: In healthy volunteers, coadministration of ACTOS (45 mg once daily) for seven days with warfarin did not alter the steady-state pharmacokinetics of warfarin. In addition, ACTOS has no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin therapy.
Metformin: In healthy volunteers, coadministration of metformin (1000 mg) and ACTOS (45 mg) after seven days of ACTOS (45 mg once daily) did not alter the pharmacokinetics of the single dose of metformin.
The cytochrome P450 isoform CYP3A4 is partially responsible for the metabolism of pioglitazone. Specific formal pharmacokinetic interaction studies have not been conducted with ACTOS and other drugs metabolized by this enzyme such as: erythromycin, astemizole, calcium channel blockers, cisapride, corticosteroids, cyclosporine, HMG-CoA reductase inhibitors, tacrolimus, trizolam, and trimetrexate, as
Animal Toxicology Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone HCl (approximately 11, 1, and 2 times the maximum recommended human oral dose for mice, rat, and dogs, respectively, based on mg/m^2 ). In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately 35 times the maximum recommended human oral dose based on mg/m^2 ). Heart enlargement was seen in a 13-week study in monkeys at oral doses of 8.9 mg/kg and above (approximately 4 times the maximum recommended human oral dose based on mg/m^2 ), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m^2 ).
Pregnancy Pregnancy Category C. Pioglitazone was not teratogenic in rats at oral doses up to 80 mg/kg or in rabbits given up to 160 mg/kg during organogenesis (approximately 17 and 40 times the maximum recommended human oral dose based on mg/m^2 , respectively). Delayed parturition and embryotoxicity (as evidenced by inceased postimplantation losses, delayed development and reduced fetal weights) were observed in rats at oral doses of 40 mg/kg/day and above (approximately 10 times the maximum recommended human oral dose based on mg/m^2 ). No functional or behavioral toxicity was observed in offspring of rats. In rabbits, embryotoxicity was observed at an oral dose of 160 mg/kg (approximately 40 times the maximum recommended human oral dose based on mg/m^2 ). Delayed postnatal development, attributed to decreased body weight, was observed in offspring of rats at oral doses of 10 mg/kg and above during late gestation and lactation periods (approximately 2 times the maximum recommended human oral dose based on mg/m^2 ).
There are no adequate and well-controlled studies in pregnant women. ACTOS should be used during pregnancy only if the potential benefits justifies the potential risk to the fetus.
Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality, most experts recommend that insulin
be used during pregnancy to maintain blood glucose levels as close to normal as possible.
Nursing Mothers Pioglitazone is secreted in the milk of lactating rats. It is not known whether ACTOS is secreted in human milk. Because many drugs are excreted in human milk, ACTOS should not be administered to a breast-feeding woman.
Pediatric Use Safety and effectiveness of ACTOS in pediatric patients have not been established.
Elderly Use Approximately 500 patients in placebo-controlled clinical trials of ACTOS were 65 and over. No significant differences in effectiveness and safety were observed between these patients and younger patients.
ADVERSE REACTIONS In worldwide clinical trials, over 3700 patients with type 2 diabetes have been treated with ACTOS. In U.S. clinical trials, over 2500 patients have received ACTOS, over 1100 patients have been treated for 6 months or longer, and over 450 patients for one year or longer.
The overall incidence and types of adverse events reported in placebo-controlled clinical trials of ACTOS monotherapy at doses of 7.5 mg, 15 mg, 30 mg, or 45 mg once daily are shown in Table 6.
