Pioglitazone

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Authored by: Rlweber 08:48, 4 April 2007 (PDT)

Pioglitazone Quick Reference

IUPAC Name
(±)-5-4-2-(5-ethyl-2-pyridinyl)ethoxy-phenylmethyl-2-4
Chemical Information
Empirical Formula	C19H20N2O3S
Molecular Weight	356.44
General Drug Information
Classification	Thiazolidinedione; Antihyperglycemic Agents
Schedule	Legend
How Supplied	Oral Tablets: 15, 30, 45 mg
Trade Names	Actos
Pregnancy Category	C
Breast Feeding	Pioglitazone should not be used in breast-feeding females. Although it is unknown if pioglitazone is excreted into human breast milk, studies indicate that it is excreted into animal breast-milk.
Generic Availability	Generic currently not available
Patent Expiration Date	January 17, 2011, June 19, 2016, August 9, 2016
Administration Information
Route(s)	Oral
Method(s)	Oral: Take without regards to food
Pharmacokinetic Information
Absorption	F = unknown
	Cmax = unknown
	tmax = Within 2 hours
Distribution	Vd = 0.63 ± 0.41 L/kg
	Protein binding = >99%
Metabolism	extensively metabolized by oxidation and hydroxylation. Pioglitazone metabolites partly convert to sulfate or glucuronide conjugates.
Excretion	t1/2 = Pioglitazone: 3-7 hours; Pioglitazone Metabolites: 16-24 hours
	Negligible renal excretion; Piogitazone is mainly excreted as metabolites and conjugates in the feces, or excreted unchanged into the bile.

Contents 1 Brand/Trade Names of Drug 2 Generic Name of Drug 3 Description 4 Mechanism of action 5 Time Required for Therapeutic Response 6 Pharmacokinetics 6.1 Absorption 6.2 Distribution 6.3 Metabolism 6.4 Excretion 7 Special Population Pharmacokinetics 8 Indications 8.1 FDA Approved Indications 9 Dosage 10 Administration 11 Monitoring Parameters 12 Contraindications/Precautions 12.1 Contraindications/Warnings 12.2 Pregnancy indications 12.3 Breast-feeding indications 13 Drug-Drug Interactions 14 Drug-Food-Herb Interactions 15 Adverse Reactions/Side Effects 16 Overdosage Measures 17 Product Information and Distribution 18 Pharmacogenomic information 19 Patient Information 20 References 20.1 Efficacy Trial Articles 20.2 Therapeutic Class Comparison Trial Articles 20.3 Pharmacokinetics Articles 20.4 Drug Interaction Articles 21 Images 22 External Links

Brand/Trade Names of Drug

Actos®

Generic Name of Drug

Pioglitazone (pye oh GLI ta zone)

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Description

Pioglitazone is an oral antihyperglycemic agent agent used in the treatment of type II diabetes mellitus.^[1] It received final FDA-approval on July 16, 1999.^[2] It is used as monotherapy, or in conjunction with sulfonylureas, metformin, or insulin.^[1] Aside from its efficacy in hyperglycemia, pioglitazone also has a favorable effect on triglycerides, low-density lipoproteins and high-density lipoproteins.^[1] It it also more effective in lowering triglycerides when compared to rosiglitazone.^[2] The average reduction in hemoglobin A1C is 1%-2%.^[1] Although pioglitazone is more effective in reducing the blood glucose and plasma A1C when used in combination with insulin, the risk of edema, weight gain, and heart failure are increased as well.^[3]

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Mechanism of action

Pioglitazone is a member of the thiazolidinedione drug family. Thiazolidinediones work by decreasing peripheral insulin resistance and decreasing hepatic gluconeogenesis.^[1] The end result is decreased hepatic glucose output and an increased insulin-dependent glucose disposal.^[1] Pioglitazone is a highly selective and potent agonist for the peroxisome proliferator activated receptor (PPARγ).^[1] Activation of these receptors modulates the transcription of insulin responsive genes involved in lipid metabolism and glucose control. PPAR receptors are found in the liver, adipose tissue, and skeletal muscle.^[1] Insulin must also be present for these actions to take place.^[1]

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Time Required for Therapeutic Response

• Initial: Within several weeks.^[4]
• Maximum: Within 3-4 months.^[4]

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Pharmacokinetics

Absorption

The presence of pioglitazone in the serum is measurable 30 minutes after oral ingestion in the fasting state.^[5] The Cmax occurs within 2 hours of an oral dose in the fasting state.^[5]. Although food delays the time to peak concentrations by 1 to 2 hours, it does not affect the extent of absorption.^[5].

Distribution

Pioglitazone is extensively protein bound (>99%).^[5]. The main serum protein it binds to is serum albumin, although it does bind to other serum proteins.^[5].

Metabolism

In vitro studies have shown multiple CYP isoenzymes to be involved in the metabolism of pioglitazone.^[5]. The main isoenzyme includes CYP2C8, with activity seen with CYP3A4 and CYP1A1 to a lesser extent.^[5]. Pioglitazone is mainly metabolized by oxidation and hydroxylation.^[5]. Its metabolites are also converted to sulfate and glucuronide conjugates.^[5]. Its active metabolites include M-II, M-III and M-IV.^[5].

Excretion

Pioglitazone is mainly excreted as metabolites and conjugates.^[5]. An oral dose is eliminated as metabolites in the feces, or excreted unchanged into the bile.^[5]. The clearance of pioglitazone is 5-7 L/hour, with a half-life of 3-7 hours (pioglitazone) and 16-24 hours (metabolites).^[5]. Approximately 15-30% of pioglitazone is recovered in the urine following an oral dose.^[5].

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Special Population Pharmacokinetics

• Renal insufficiency: No dose adjustments are required for patients with renal dysfunction.

• Hepatic insufficiency: Although patients with not experience a change in the mean AUC concentration, they will experience a 45% reduction in mean peak concentrations.

• Hemodialysis: Due to its high protein binding, pioglitazone is not expected to be removed by hemodialysis.

• Geriatric: The elderly population will experience higher AUC and longer terminal half-lives when compared to normal healthy younger patients. These changes were not considered to be statistically significant.

• Pediatric No pharmacokinetic data is available for the pediatric population.

• Gender: Females experience a higher AUC and Cmax when compared to males (60% and 20%, respectively). The reduction in hemoglobin A1C was slightly greater for females, with an average mean difference of 0.5%. The manufacturer recommends no dose adjustment based on gender.

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Indications

FDA Approved Indications

• Diabetes Mellitus Type II

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Dosage

• Diabetes Mellitus
  • Starting Dose: 15 or 30 mg by mouth once daily
  • Titration Schedule: Can increase dose by 15 mg
  • Maintenance Dose: Maintenance dose is based on patient response. Dose can be titrated up to 45 mg by mouth once daily.

• Maximum Dosage Limits
  • Adults: 45 mg orally/daily
  • Elderly: 45 mg orally/daily
  • Adolescents and children >=10 years: Safety and efficacy has not been established in this population.
  • Children < 10 years: Safety and efficacy has not been established in this population.

• Dosage Adjustment
  • Renal insufficiency: No dose adjustments are needed in patients with renal impairment when pioglitazone is used as monotherapy. .
  • Hepatic insufficiency: Pioglitazone should not be used in patients with ALT levels 2.5 times the upper normal limit, or in those with active liver disease.
  • Hemodialysis: No supplemental doses are needed. Pioglitazone is not removed by hemodialysis.
  • Geriatric: No dose adjustments are needed in this population.
  • Pediatric: Safety and efficacy has not been established in this population.
  • Gender: No dose adjustments are needed in this population

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Administration

• Route: Oral
• Method: Take dose with a full glass of water with meals at the same time each day.
• Special considerations: Although recommended, pioglitazone does not need to be taken with food.

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Monitoring Parameters

• Blood Glucose
• Hemoglobin A1C
• LFTs

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Contraindications/Precautions

Contraindications/Warnings

• Known hypersensitivity to pioglitazone or any of its components.^[5]
• Cardiac Failure^[5]
• Hypoglycemia^[5]
• Edema^[5]
• Weight gain^[5]
• Hepatic Disease^[5]

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Pregnancy indications

• Pregnancy category: C

• Teratogenicity: Pioglitazone was not teratogenic in rats at doses 17-40 times the maximum recommended dose.^[5] Delayed parturition and embryotoxicity occurred in rats at doses 10 times the recommended human oral doses.^[5] Embryotoxicity occurred in rabbits at 40 times the recommended human oral dose. Delayed postnatal development occurred in rats at doses 2 times the maximum recommended human oral dose.^[5] No well-controlled studies have been performed in human pregnant females, and pioglitazone is not recommended for use during pregnancy.^[5] Pioglitazone should only be used during pregnancy if the benefits outweigh the risk of therapy.^[5]

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Breast-feeding indications

• Secretion into breast milk: Pioglitazone is excreted into rat breast milk. Pioglitazone should not be used in breast-feeding women since it is not known if it is excreted into human milk.

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Drug-Drug Interactions

Pioglitazone Drug/Drug Interaction Chart

Severity Level	Increased Effect/Toxicity	Decreased Effect
4	None Known	None Known
3	Insulin[6]	Oral Contraceptives[5] Progestins[7]
2	Androgens[8] Ketoconazole[5] ACE Inhibitors[8] Antidiabetic Medications[5] Beta-blockers/Clonidine[8] Disopyramide[9] Bexarotene[10] Fibric Acid Derivatives[11] Fluoxetine[11] Protease Inhibitors[5] Trimethoprim[12] Mecasermin recombinant/Mecasermin rinfabate[13] MAOIs[14] Dexfenfluramine/Fenfluramine[2]	Atypical Antipsychotics[15] Beta-blockers/Clonidine[8] Corticosteroids[6] Estrogens[16]. .
1	None Known	Carbamazepine[4] Phenytoin[17] Rifampin[5] Phenobarbital[18]

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Drug-Food-Herb Interactions

Pioglitazone Drug/Food/Herb Interaction Chart

Severity Level	Increased Effect/Toxicity	Decreased Effect
4	None Known	None Known
3	None Known	None Known
2	Garlic[19] Green Tea[20] Horse Chestnut[21] Chromium[5] Aloe[4] Ginger[4] Ginseng[4] Bilberry[4]	None
1	None Known	None Known

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Adverse Reactions/Side Effects

Pioglitazone is generally well-tolerated in patients, with a similar adverse event profile when compared to placebo.^[22] Common adverse events included upper respiratory tract infections and headache. The incidence of these adverse events was not statistically different between treatment and placebo group.^[22]

Pioglitazone Adverse Reactions Chart^[4].

Incidence	Body System	Adverse Reactions
> 10 %	Endocrine and Metabolism	Decreased serum triglycerides, increased HDL-cholesterol
> 10 %	Gastrointestinal	Weight Gain
> 10 %	Respiratory	Upper Respiratory Tract Infection (13%)
1-10%	Cardiovascular	Edema (5%) (higher incidence~ 15% when pioglitazone is combined with insulin and/or sulfonylureas)
	CNS	Headache (9%), Fatigue (4%)
	Endocrine and Metabolism	Aggravation of diabetes mellitus (5%), Hypoglycemia (2%-15% when combined with insulin and/or sulfonylurea)
	Hematologic	Anemia (1%)
	Neuromuscular and Skeletal	Myalgia (5%)
	Respiratory	Sinusitis (6%), Pharyngitis (5%)
<1%	All	Congestive Heart Failure, elevated CPK, elevated transaminases, hepatitis, hepatic failure (very rare)

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Overdosage Measures

In the one overdose case that occurred during clinical trials, no symptoms were reported. The patient took 120 mg orally daily of pioglitazone for four days, followed by 180 mg orally daily for seven days.^[5]. The manufacturer recommends appropriate supportive care for an overdose and close monitoring of clinical signs and symptoms.^[5].

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Product Information and Distribution

Actos Product Availability Information- Oral Tablets

Name	Manufacturer	Dosage Form	Strength	Quantity	NDC	Storage
Actos[2]	Takeda Pharmaceuticals North America Inc	Oral Tablets	15 mg	30	64764-0151-04	15-30°C (59-86°F)
				90	64764-0151-05
				500	64764-0151-06

Actos Product Availability Information- Oral Tablets

Name	Manufacturer	Dosage Form	Strength	Quantity	NDC	Storage
Actos[2]	Takeda Pharmaceuticals North America Inc	Oral Tablets	30 mg	30	64764-0301-14	15-30°C (59-86°F)
				90	64764-0301-15
				500	64764-0301-16

Actos Product Availability Information- Oral Tablets

Name	Manufacturer	Dosage Form	Strength	Quantity	NDC	Storage
Actos[2]	Takeda Pharmaceuticals North America Inc	Oral Tablets	45 mg	30	64764-0451-24	15-30°C (59-86°F)
				90	64764-0451-25
				500	64764-0451-26

• Manufacturers/Distributors

Takeda Pharmaceuticals North America Inc

• Inactive ingredients

carboxymethylcellulose, hydroxypropyl cellulose, lactose,magnesium stearate

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Pharmacogenomic information

Pioglitazone Pharmacogenomic Information

Novel insulin sensitizers: pharmacogenomic aspects

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Patient Information

• Although recommended to be taken with food, pioglitazone can be taken with or without food.
• Take dose with full glass (8 oz) of water.
• Take dose at the same time each day.
• Avoid alcohol.
• Monitor blood sugar on a regular basis.
• Follow a diabetic-diet
• Discuss with physician is you are pregnant, plan to become pregnant or are breast-feeding.
• Discuss with physician if you are diagnosed with heart problems.
• Diet and exercise are non-pharmacological ways to control blood sugar.
• Low blood sugar, weight gain and swelling of hands/leg/feet is more likely to occur when taking pioglitazone with other Antihyperglycemic Agents and/or insulin. Monitor for swelling and weight gain on a continuous basis.

• Common Side Effects: headache, weight gain (Report to your physician if these side effects are bothersome)

• Rare Side Effects: swelling of hands/legs/feet, blurred vision, difficulty breathing, vomiting, diarrhea, skin rash and muscle pain (Report these side effects to your physician right away)

• Ask your prescriber or pharmacist before you start any new prescription, herbal or over-the counter medication, or before you take any medications for cough, cold or allergies.

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References

1. ↑ ^{1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8} Wells, Dipiro, Schwinghammer, et al. Pharmacotherapy Handbook Fifth Edition. Pages 170-183.
2. ↑ ^{2.0 2.1 2.2 2.3 2.4 2.5} Pioglitazone(Actos®)Monograph.Clinical Pharmacology (database on the internet) Available at www.clinicalpharmacolgy.com.
3. ↑ Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione use, fluid retention, and congestive heart failure. A consensus statement from the American Heart Association (AHA) and the American Diabetes Association( ADA). Circulation 2003;108:2941—8.
4. ↑ ^{4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7} Lexi-Comp (2003). Drug Information Handbook. 11th Edition., APhA.
5. ↑ ^{5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 5.12 5.13 5.14 5.15 5.16 5.17 5.18 5.19 5.20 5.21 5.22 5.23 5.24 5.25 5.26 5.27 5.28 5.29 5.30 5.31 5.32} Actos® (pioglitazone) package insert. Takeda Chemical Industries, Ltd.: Osaka, Japan: 2006 Oct.
6. ↑ ^6.0 6.1 NovoLog® (Insulin aspart) package insert. Princeton, NJ: Novo Nordisk Pharmaceuticals, Inc.; 2007 Jan.
7. ↑ Prometrium® (progesterone) package insert. Marietta, GA: Solvay Pharmaceuticals Inc.; 1998 Dec.
8. ↑ ^{8.0 8.1 8.2 8.3} Gilbert RE, Cooper ME, Krum H. Drug Administration in Patients with Diabetes Mellitus, Safety Considerations. Drug Safety 1998;18:441—55.
9. ↑ Norpace® (disopyramide) package insert. Chicago, IL: GD Searle LLC; 2001 Sept.
10. ↑ Targretin® (bexarotene capsules) package insert. San Diego CA: Ligand Pharmaceuticals Inc.; 2003 April.
11. ↑ ^11.0 11.1 Pandit MK, Burke J, Gustafson AB, et al. Drug-induced disorders of glucose tolerance. Ann Intern Med 1993;118:529—39.
12. ↑ Jaakkola T, Laitila J, Neuvonen PJ, et al. Pioglitazone is metabolised by CYP2C8 and CYP3A4 in vitro: potential for interactions with CYP2C8 inhibitors. Basic Clin Pharmacol Toxicol 2006;99:44—51.
13. ↑ IPLEX™ (mecasermin rinfabate) package insert. Glen Allen, VA: Insmed Incorporated; 2005 Dec.
14. ↑ Gilbert RE, Cooper ME, Krum H. Drug Administration in Patients with Diabetes Mellitus, Safety Considerations. Drug Safety 1998;18:441—55.
15. ↑ Luna B, Feinglos MN. Drug-induced hyperglycemia. JAMA 2001;286:1945—8.
16. ↑ Premarin® (conjugated estrogens, equine) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2003 Jul
17. ↑ Carter BL, Small RE, Mandel MD et al. Phenytoin-induced hyperglycemia. Am J Hosp Pharm 1981;38:1508—12.
18. ↑ Totah RA, Retti AE. Cytochrome P450 2C8: substrates, inhibitors, pharmacogenetics, and clinical relevance. Clin Pharmacol Ther 2005;77:341—52.
19. ↑ Sheela CG, Kumud K, Augusti KT. Anti-diabetic effects of onion and garlic sulfoxide amino acids in rats. Planta Med 1995;61:356—7.
20. ↑ Shimizu M, Kobayashi Y, Suzuki M, et al. Regulation of intestinal glucose transport by tea catechins. Biofactors 2000;13:61—5.
21. ↑ Yoshikawa M, Murakami T, Matsuda H, et al. Bioactive saponins and glycosides. III. Horse chestnut. (1): The structures, inhibitory effects on ethanol absorption, and hypoglycemic activity of escins Ia, Ib, IIa, IIb, and IIIa from the seeds of Aesculus hippocastanum L. Chem Pharm Bull (Tokyo) 1996;44:1454—64.
22. ↑ ^22.0 22.1 S Aronoff, S Rosenblatt, S Braithwaite, et al. (2000). "Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose-response study. The Pioglitazone 001 Study Group." Diabetes Care 23 (11):1605-1611.

Efficacy Trial Articles

1. Bakker-Arkema, Hanefeld M. (2001). "Pharmacokinetics and clinical efficacy of pioglitazone." Int J Clin Pract Suppl. 121: 19-25
2. Rosenstock, Einhord, Hershon, et al. (2002). "Efficacy and safety of pioglitazone in type 2 diabetes: A randomised, placebo-controlled study in patients receiving stable insulin therapy." International journal of clinical practice. 56 (4): 251-257
3. Kemnitz JW, Elson DF, Roecker EB, et al. (1994). "Pioglitazone increases insulin sensitivity, reduces blood glucose, insulin, and lipid levels, and lowers blood pressure, in obese, insulin-resistant rhesus monkeys." Diabetes 43 (2): 204-211.
4. S Aronoff, S Rosenblatt, S Braithwaite, et al. (2000). "Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose-response study. The Pioglitazone 001 Study Group." Diabetes Care 23 (11):1605-1611. Full Text Here
5. [The PROactive Study: Prospective Pioglitazone Clinical Trial In macrovascualr Events]

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Therapeutic Class Comparison Trial Articles

1. Boyle PJ, King AB, Olansky L, et al. (2002). "Effects of pioglitazone and rosiglitazone on blood lipid levels and glycemic control in patients with type 2 diabetes mellitus: a retrospective review of randomly selected medical records." Clin Ther 24 (3):378-96.
2. Olansky L, Marchetti A, Lau H. (2003). "Multicenter retrospective assessment of thiazolidinedione monotherapy and combination therapy in patients with type 2 diabetes: comparative subgroup analyses of glycemic control and blood lipid levels." Clin Ther. 25 Suppl B:B64-80.

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Pharmacokinetics Articles

1. Bakker-Arkema, Hanefeld M. (2001). "Pharmacokinetics and clinical efficacy of pioglitazone." Int J Clin Pract Suppl. 121: 19-25
2. Klemens, Hans-Hellmut, Lutz, et al. (2003). "The pharmacokinetics of pioglitazone in patients with impaired renal function." British Journal of Clinical Pharmacology. 55(4): 368-374.
3. Christensen, Meibohm, Capparelli, et al. (2005). "Single- and Multiple-Dose Pharmacokinetics of Pioglitazone in Adolescents With Type 2 Diabetes." Journal of Clinical Pharmacology. 45:1137-1144. Full Text Here

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Drug Interaction Articles

1. Jaakkola T, Laitila J, Neuvonen PJ, et al. (2006). "Pioglitazone is metabolised by CYP2C8 and CYP3A4 in vitro: potential for interactions with CYP2C8 inhibitors." 99(1): 44-51.
2. Ryan EA, Pick ME, Marceau C. (2001) "Use of alternative medicines in diabetes mellitus." Diabet Med. 18 (3)242-245.
3. Yoshikawa M, Murakami T, Matsuda H, et al. (1996). "Bioactive saponins and glycosides. III. Horse chestnut. (1): The structures, inhibitory effects on ethanol absorption, and hypoglycemic activity of escins Ia, Ib, IIa, IIb, and IIIa from the seeds of Aesculus hippocastanum L." Chem Pharm Bull (Tokyo). 44(8):1454-64.
4. Anderson RA, Cheng N, Bryden NA, et al. (1997) "Elevated intakes of supplemental chromium improve glucose and insulin variables in individuals with type 2 diabetes." Diabetes 46(11):1786-91.
5. Shimizu M, Kobayashi Y, Suzuki M, et al. (2000). "Regulation of intestinal glucose transport by tea catechins." Biofactors 13(1-4):61-65.
6. Sabu MC, Smitha K, Kuttan R. (2002). "Anti-diabetic activity of green tea polyphenols and their role in reducing oxidative stress in experimental diabetes." J Ethnopharmacol. 83(1-2):109-16.

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Images

Pioglitazone 15 mg, 30 mg, 45 mg

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External Links

• Manufacturers/Distributors

Takeda Pharmaceuticals North America Inc

• Clinical Treatment Guidelines

1. Diabetes Mellitus: Institute for Clinical Systems Improvement (ICSI)Guidelines.

• Diabetic Associations

1. American Diabetes Association.
2. American Dietetic Association.
3. National Diabetes Education Program.

• Patient Information Pages

1. Managing your Diabetes;
2. Accu-chek Glucose Meter;
3. BD Diabetes Glucose Record Sheets
4. Glucose Control-Diabetic Diet
5. Actos Homepage
6. Actos Coupon

• Healthcare Professional Information Pages

1. Actos Health Professional Page;
2. Pioglitazone Package Insert

• Other Resources

1. American Heart Association
2. National Cholesterol Education Program.

• Pill Identifier

Pill Identifier.

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