Adult Dosing

Type II diabetes mellitus

Immediate release tablet (Actoplus met)

• 15 mg/500 mg - 15 mg/850 mg PO qd-bid
• Titer the dose gradually as per therapeutic response
• Max: 45 mg/ 2550 mg (pioglitazone/metformin)

Extended release tablet (Actoplus met XR)

• 15 mg/1000 mg - 30 mg/1000 mg PO qpm
• Titer the dose gradually as per therapeutic response
• Max: 45 mg/ 2000 mg (pioglitazone/metformin)

• Administer the tablet with meals
• Do not cut, crush, chew the extended release tablet
• Response to therapy should be evaluated using HbA1c values after the drug therapy has been initiated for some period of time

Pediatric Dosing

• Safety and effectiveness in pediatric patients have not been established

[Outline]

• Adult Dosing
• Pediatric Dosing

• Type II diabetes mellitus; already treated with pioglitazone and metformin or have inadequate glycemic control on pioglitazone alone or metformin alone

• Hypersensitivity to any of the ingredients of the product
• New York Heart Association (NYHA) Class III or IV heart failure
• Symptomatic heart failure
• Renal disease or renal dysfunction
• Acute or chronic metabolic acidosis
• Diabetic ketoacidosis
• Type I diabetes
• Lactic acidosis
• Active liver diseases or ALT >2.5 x UNL
• Surgery
• Hypoxemia
• Sepsis
• Dehydration
• X-ray procedures with injectable contrast agents

• Thiazolidinediones causes or exacerbate congestive heart failure. Monitor the patients carefully for the signs and symptoms of heart failure like rapid weight gain, dyspnea, and/or edema. Discontinue the therapy if signs and symptoms of heart failure develops and manage it according to the current standards of care
• Pioglitazone/metformin therapy is not recommended in symptomatic heart failure and contraindicated in established NYHA Class III or IV heart failure
• Lactic acidosis, a metabolic complication rare but fatal occurs with metformin accumulation during pioglitazone/metformin therapy. The risk of lactic acidosis increases with sepsis, dehydration, excess alcohol intake, hepatic insufficiency, renal impairment, and acute congestive heart failure
• The onset of lactic acidosis often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress, low pH, increased anion gap and elevated blood lactate. Discontinue the therapy if acidosis suspected and immediately hospitalize the patient

Renal Dose Adjustment

• Renal impairment: Contraindicated

Hepatic Dose Adjustment

• Active liver disease or serum ALT >2.5 x UL of normal: Contraindicated
• Serum ALT<2.5x UL of normal: Caution advised; dose adjustments not defined

See Supplemental Patient Information

• Lactic acidosis, a rare metabolic complication but fatal occurs with metformin accumulation during pioglitazone/metformin therapy [US Black Box Warning]
• Thiazolidinediones causes or exacerbate congestive heart failure due to fluid retension [US Black Box Warning]
• Use lowest approved dose of pioglitazone in patients with type 2 diabetes and systolic heart failure (NYHA Class II). If dose acceleration is necessary, increase it gradually after several months of treatment and with careful monitoring for the signs and symptoms of CHF exacerbation
• Pioglitazone/metformin therapy does not reduce macrovascular risk
• Do not use pioglitazone/metformin in type I diabetes or diabetic ketoacidosis as pioglitazone exerts its antihyperglycemic effect only in the presence of insulin
• Pioglitazone in combination with insulin or oral hypoglycemic agents increases the risk of hypoglycemia, reduce the dose of concomitant hypoglycemic agent
• Pioglitazone alone or in combination with other hypoglycemic agents cause weight gain probably due to fluid retention and fat accumulation
• Thiazolidinediones causes ovulation in some premenopausal anovulatory women. Advice patient to use adequate contraception
• Decline in mean hemoglobin values by 2% to 4% occurs with pioglitazone. Patients taking pioglitazone/ metformin will have low Hb and hematocrit and have rarely been associated with any significant hematologic clinical effects
• Pioglitazone causes hepatitis and elevates liver enzyme levels. Evaluate serum ALT levels before starting pioglitazone/ metformin therapy and periodically during the treatment, any sign of hepatic dysfunction discontinue the therapy
• Consider risk of fracture in patients treated with pioglitazone especially females, provide attention to assess and maintain bone health according to current standards of care
• Impairment of renal function increases the risk of metformin accumulation and lactic acidosis. Monitor renal function prior to initiation of therapy and periodically thereafter, carefully titrated to establish the minimum dose for adequate glycemic effect. Discontinue the therapy on the evidence of renal dysfunction
• Be cautious while concomitant administration of drug that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin such as cationic drugs
• Temporarily discontinue the therapy in patients undergoing intravascular contrast studies with iodinated materials as it is associated with increased risk of renal dysfunction and lactic acidosis and also in patients undergoing major surgical procedure, associated with restricted intake of food and fluids
• Immediately discontinue the therapy in case of cardiovascular collapse, acute CHF, acute MI and other conditions of hypoxemia associated with lactic acidosis and prerenal azotemia
• Evaluate serum electrolytes and ketones, blood glucose, pyruvate and metformin levels in type 2 diabetic patient, previously well controlled on metformin who develops laboratory abnormalities or clinical illness, if acidosis, stop therapy and start alternative treatment
• Metformin therapy can cause a decrease to subnormal levels of previously normal serum vitamin B12 levels; measure hematologic parameters annually

Cautions: Use cautiously in

• Cardiac disease
• Risk of CHF
• NYHA Class I-II heart failure
• Elderly or debilitated patients
• Risk of hypoglycemia
• Female patients
• Premenopausal anovulatory women
• Edema
• Alcohol abuse

Supplemental Patient Information

• Patients should be instructed to avoid excessive use of alcohol while receiving treatment

Pregnancy Category:C

Breastfeeding: No studies available on the use of pioglitazone during breastfeeding, use alternate drug especially while nursing a newborn or preterm infant. Monitor breastfed infant's blood glucose during maternal therapy with hypoglycemic agents. This information is based upon LactMed database (available at http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT last accessed 21 December 2010).Well-conducted studies indicates very low level of metformin in milk and less than 0.5% of their mother's dosage received, in infants. Metformin levels in milk are relatively constant during maternal use, so breastfeeding timing with respect to the administration times is of little benefit. No adverse effects were found in breastfed infants in one prospective study. Use cautiously while nursing newborn and premature infants and those with renal impairment. This information is based upon LactMed database (available at http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT last accessed 21 December 2010). As per manufacturer data, no studies available with pioglitazone/metformin combination, however individual component metformin and pioglitazone are secreted in rat milk, manufacturer advises not to administer pioglitazone/metformin during breastfeeding. Consider insulin therapy if diet alone is inadequate for controlling blood glucose.

• CV: CHF, edema
• GI: Diarrhea, hepatotoxicity, nausea
• CNS: Headache, dizziness
• RESP: URTI
• METABOLIC: Lactic acidosis
• EENT: Sinusitis, pharyngitis, diabetic macular edema
• HEMA: Megaloblastic anemia
• ENDO: Hypoglycemia
• GU: Urinary Tract Infection, bladder cancer
• MISC: Weight gain
• MUSC: Fractures, myalgia
• LABTEST: Low hemoglobin and hematocrit, increase ALT, increase CPK

Pioglitazone

• Thiazolidinediones; Insulin-sensitizer, increases insulin-dependent glucose disposal and decreases hepatic glucose output by decreasing insulin resistance in the periphery and in the liver
• Extensively metabolized by liver to M-II and M-IV (hydroxy derivatives of pioglitazone) and M-III (keto derivative of pioglitazone)metabolite. CYP450: 2C8, 3A4 isoforms, extrahepatic CYP1A1
• Excretion in urine (15% to 30%), bile, feces
• Half life: 3-7 hrs pioglitazone; 16-24 hrs active metabolite

Metformin

• Hypoglycemic Agent; decreases hepatic glucose production and intestinal absorption of glucose. It increases peripheral glucose uptake and utilization by improving insulin sensitivity
• Not metabolized
• Renally excreted 90%
• Half life: 6.2 hrs (plasma); 17.6hrs (blood)

US Trade Name(s)

• Actoplus met
• Actoplus met XR

US Availability

pioglitazone/metformin (generic)

• TABS
• 15 mg/500 mg
• 15 mg/850 mg

Actoplus met (pioglitazone/metformin)

• TABS
• 15 mg/500 mg
• 15 mg/850 mg

Actoplus met XR (pioglitazone/metformin)

• ETABS
• 15 mg/1000 mg
• 30 mg/1000 mg

Canadian Trade Name(s)

• N/A

Canadian Availability

• N/A

UK Trade Name(s)

• Competact

UK Availability

Competact (pioglitazone/metformin)

• TABS
• 15 mg/850 mg

Australian Trade Name(s)

• N/A

Australian Availability

• N/A

[Outline]

Endocrine/Metabolic

Diabetic Medications

Antidiabetic Combinations

Pricing data from www.DrugStore.com in U.S.A.

• Actoplus Met 15-850 MG TABS [Bottle] (TAKEDA PHARMACEUTICALS)
  30 mg = $142.99
  90 mg = $409.99
• Actoplus Met 15-500 MG TABS [Bottle] (TAKEDA PHARMACEUTICALS)
  30 mg = $142.99
  90 mg = $405.97
• Actoplus met XR 30-1000 MG TB24 [Bottle] (TAKEDA PHARMACEUTICALS)
  30 mg = $309.99
  90 mg = $906.96
• Actoplus met XR 15-1000 MG TB24 [Bottle] (TAKEDA PHARMACEUTICALS)
  30 mg = $158.99
  90 mg = $456.96

Warning: This pricing information is subject to change at the sole discretion of DS Pharmacy. For the most current and up-to-date pricing information, please visit drugstore.com.

• Actoplus Met 15/500 MG Oral Tablet (Takeda Pharmaceuticals America, Inc.)
• Actoplus Met 15/850 MG Oral Tablet (Takeda Pharmaceuticals America, Inc.)
• Actoplus Met XR 15/1000 24 HR Extended Release Tablet (Takeda Pharmaceuticals America, Inc.)
• Actoplus Met XR 30/1000 24 HR Extended Release Tablet (Takeda Pharmaceuticals America, Inc.)