Pioglitazone (Actos) is a drug used to treat patients with Diabetes Mellitus Type 2 as monotherapy or with other diabetes medications. It is also available in combination with other medicines such as glimepiride and metformin. Rosiglitazone belongs to the same class of medicine, however, because of its association with heart failure, it is no more available in the markets. Pioglitazone also causes fluid retention, weight gain, and eye problems and is, therefore, less favored nowadays.

Indications of Pioglitazone:

• Type II Diabetes mellitus:

  • It is used to improve glycemic control in adults with type 2 diabetes mellitus in addition to diet and exercise.
• It is also used as off-lable medicine in the treatment of fatty liver diseases.

Pioglitazone (Actos) Dose in Adults

Pioglitazone (Actos) use in the Treatment of Type 2 Diabetes mellitus:

Pioglitazone (Actos) usual initial dose:

• 15 to 30 mg per oral once daily.

  • Dose in patients with asymptomatic NYHA class I or II heart failure:

    • Initiate cautiously with 15 mg per oral once daily.
    • Note: Not recommended in patients with symptomatic heart failure and contraindicated with stage III or IV heart failure.

  • Dosage titration:

    • Based on HbA1C, the dosage may be increased in 15 mg increments with careful monitoring of adverse effects (eg, weight gain, edema, signs/symptoms of heart failure) up to a maximum of 45 mg once daily;
    • Consider limiting dose to ≤30 mg/day in case of heart failure.

  • Dosage adjustment for hypoglycemia with combination therapy:

    • The dose should be decreased if using with sulphonylureas.
    • Dose reduction by 10% to 25% with insulin.

  • Dosage adjustment with strong CYP2C8 inhibitors (eg, gemfibrozil):

    • Maximum recommended dose: 15 mg once daily.

Use in Children with Diabetes:

The safety and efficacy of the drug in children has not been established.

Pregnancy Risk Category: C

• The information regarding pregnancy and pioglitazone is not available.
• For glucose control, you should also use other agents during pregnancy
• Thiazolidinediones may increase your risk of getting pregnant. It can induce ovulation in premenopausal women who are ovulatory.
• Thiazolidinediones should not be used in females under the age of 18.

Pioglitazone use during breastfeeding

• It is not known if the drug is secreted in breast milk.
• According to the manufacturer breastfeeding during therapy is a decision that should be made after considering the risks and benefits to the infant as well as the benefits to the mother.

Pioglitazone (Actos) Dose adjustment in renal disease:

No dosage adjustment is necessary.

Pioglitazone Dose adjustment in liver disease:

• Hepatic impairment before initiation

  • There is no dosage adjustment; be cautious if your baseline liver tests are abnormal.

• Treatment for hepatic impairment: If you suspect liver injury:

  • It is important to withhold treatment and have serum liver tests done. This will allow you to investigate possible causes.
  • Hold therapy if an alternative cause is not found and ALT >3x the upper normal limit
  • Therapy should only be used if an alternative etiology has been identified.

Common Side Effects of Pioglitazone (Actos):

• Cardiovascular:

  • Edema

• Endocrine and metabolic:

  • Hypoglycemia

• Respiratory:

  • Upper respiratory tract infection

Rare Side Effects of Pioglitazone:

• Cardiovascular:

  • Cardiac failure

• Central nervous system:

  • Headache

• Neuromuscular & skeletal:

  • Bone fracture
  • Myalgia

• Respiratory:

  • Sinusitis
  • Pharyngitis

Frequency of side effects Not Defined:

• Endocrine & Metabolic:

  • Decreased Serum Triglycerides
  • Increased HDL-Cholesterol
  • Weight Gain
  • Weight Loss

• Hematologic & Oncologic:

  • Decreased Hematocrit
  • Decreased Hemoglobin

Contraindications to Pioglitazone:

• Hypersensitivity to pioglitazone and any component of the formulation
• NYHA Class III/IV Heart Failure
• Pregnancy
• Any stage of heart disease (eg NYHA Class I II, III, IV).
• Liver impairment severe
• Hematuria macroscopica
• A history of bladder carcinoma or active bladder malignancy

Warnings and precautions

• Bladder cancer

  • Pioglitazone can increase the risk of bladder malignancy. Patients with active bladder cancer should avoid it.

• Edema

  • Pre-existing edema may be exacerbated or new onset.

• Fractures

  • Females who have been treated with pioglitazone, especially the lower limbs and distal uppers, are at greater risk of breaking bones.

• Heart Failure/cardiac Effects: [US Boxed Warn]

  • Pioglitazone and thiazolidinediones can cause or exacerbate heart disease. This may lead to rapid weight gain, dyspnea and edema.
  • It is necessary to reduce the dose and avoid its use in patients with symptomatic heart disease.

• Hematologic effects

  • Anemia can result from a decreased Hb/hematocrit, probably because of an increase in plasma volume.

• Hepatic effects

  • Severe hepatic dysfunction can be observed.
  • During therapy, it is important to monitor for any signs or symptoms of liver injury.

• Hypoglycemia

  • Pioglitazone should not be taken with insulin or any other diabetes medications. A dosage reduction is necessary to reduce the risk of hypoglycemia.

• Macular edema

  • Pioglitazone can cause macular edema, which is characterized by blurred vision and decreased visual acuity.Patients should undergo regular eye examinations while receiving therapy.

• Weight loss

  • Weight gain due to dose-related factors such as fluid retention and fat deposition can occur.

• Bariatric surgery

  • Absorption altered:
    • Absorption can be affected by changes during gastrectomy/sleeve operation.
  • Weight loss
    • Gastric bypass results in weight gain. Other agents should also be considered.

• Type 1 Diabetes

  • It is not recommended for type 1 diabetes and diabetic ketoacidosis patients. Insulin is required to activate the mechanism.

• Hepatic impairment

  • To rule out liver impairment, it is important to perform liver function tests before and after the treatment.
  • Therapy should be monitored for any signs or symptoms of liver injury (e.g., fatigue, anorexia and jaundice, dark urine or right upper abdominal discomfort).
  • If these symptoms occur, therapy should be stopped.
  • Therapy should be stopped if serum ALT exceeds 3x ULN with no known cause.
  • Patients with serum ALT 3x ULN or serum total bilirubin 2x ULN are at high risk of severe drug-induced liver injury.

Pioglitazone: Drug Interaction

Monitoring parameters:

• Blood glucose levels
• Hemoglobin A (at minimum twice per year)
• Before and after therapy, liver enzymes (ALT and AST, alkaline phosphatase and total bilirubin).
• Weight gain
• Ophthalmic examination
• Heart failure symptoms and signs
• Signs and symptoms of bladder cancer include dysuria (macroscopic hematuria), dysuria, and urinary urgency.

How to administer Pioglitazone (Actos)?

• It can be given orally without regard to food.

Mechanism of action of Pioglitazone (Actos):

• Pioglitazone, a thiazolidinedione anti-hyperglycemic agent, is also known as Pioglitazone. 
• It improves insulin response in target cells, which results in a decrease of blood glucose and an increase in pancreatic insulin secretion. 
• It needs insulin to work. Pioglitazone (PPARgamma) is a powerful and selective agonist of peroxisome proliferator activated receptor-gamma. 
• The activation of the PPARgamma-receptors can influence the production of many gene products that are involved in glucose or lipid metabolism.
• PPAR gamma can be found in greater amounts in cells of the renal collecting tubules.
•  Thiazolidinedione stimulation increases sodium reabsorption, which leads to fluid retention.

The beginning of action: Delayed Peak effectGlucose control can be done for several weeks. Protein bindingPioglitazone >99%, active metabolites>98%; primarily to Albumin Metabolism: Hepatic (99%), via CYP2C8 or 3A4 to active metabolites. M-III, MIV are the major circulating active metabolites Eliminating half-life Parent drug: 3-7 hours M-III and M–IV metabolites: 16-24 hours Time to reach peak: 2 hours; delayed when you eat Excretion: Found in urine (25-30%) and feces as metabolites

International Brands of Pioglitazone:

• Actos
• ACCEL Pioglitazone
• ACH-Pioglitazone
• ACT Pioglitazone
• Actos
• APO-Pioglitazone
• AuroPioglitazone
• DOM-Pioglitazone
• JAMP-Pioglitazone
• MINT-Pioglitazone
• MYLANPioglitazone
• PHL-Pioglitazone
• PMS-Pioglitazone
• PRO-Pioglitazone
• RANPioglitazone
• RATIO-Pioglitazone
• SANDOZ Pioglitazone
• TEVA-Pioglitazone
• VANPioglitazone
• Accotaz
• Acpio
• Acstin
• Actos
• Actozon
• Actozone
• Anxotos
• Apogar
• Cereluc
• Chronoreg
• Deculin
• Diabetin
• Diabetone
• Diaglit
• DMZone
• Gitazone
• Glacera
• Glezone
• Gliabetes
• Glidipion
• Gliozac
• Glita
• Glitaz
• Glitis
• Glito
• Glitter
• Glizone
• Glubosil
• Glucemin
• Gluconon
• Glustin
• Glutason
• Insulact
• Insulact Forte
• Kai Bao Wei Yuan
• Lispecip
• Newpio
• Nilgar
• Ogli
• Paglitaz
• Pidus
• Pio
• Pioglit
• Pioglite
• Piolidone
• Piomed
• Piomin
• Pionix
• Piosafe 15
• Piosugar
• Piota
• Piouno
• Piozer
• Piozon
• Piozone
• Pizaccord
• Politone
• Ppar
• Prabetic
• Prialta
• Protaz
• Relexil
• Senzulin
• Uniglit
• Utmos
• Vexazone
• Zactos
• Zacts
• Zolid

Pioglitazone Brands in Pakistan: