Pioglitazone Hydrochloride Tablets
1. NAME OF THE MEDICINAL PRODUCT
ACTOVISTA 30 mg uncoated tablets.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each uncoated tablet contains:
equivalentto Pioglitazone: 30mg
3. PHARMACEUTICAL FORM
For oral administration.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
ACTOVISTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings.
4.2 Posology and method of administration
Pioglitazone may be initiated at 15 mg or 30 mg once daily. The dose may be increased in increments up to 45 mg once daily.
In combination with insulin, the current insulin dose can be continued upon initiation of Pioglitazone therapy. If patients report hypoglycaemia, the dose of insulin should be decreased.
Pioglitazone is contraindicated in patients with:
– hypersensitivity to the active substance or to any of the excipients
– cardiac failure or history of cardiac failure (NYHA stages I to IV)
– hepatic impairment
– diabetic ketoacidosis.
4.4 Special warnings and precautions for use
CONGESTIVE HEART FAILURE
Thiazolidinediones, including ACTOVISTA, cause or exacerbate congestive heart failure in some patients. After initiation of ACTOVISTA, 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 ACTOISTA must be considered. ACTOVISTA is not recommended in patients with symptomatic heart failure.
Initiation of ACTOVISTA in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated.
4.5 Interaction with other medicinal products and other forms of Interaction
Interaction studies have shown that Pioglitazone has no relevant effect on either the pharmacokinetics or pharmacodynamics of digoxin, warfarin, phenprocoumon and metformin. Co-administration of Pioglitazone with sulphonylureas does not appear to affect the pharmacokinetics of the sulphonylurea. Studies in man suggest no induction of the main inducible cytochrome P450, 1A, 2C8/9 and 3A4. In vitro studies have shown no inhibition of any subtype of cytochrome P450. Interactions with substances metabolised by these enzymes, e.g. oral contraceptives, cyclosporin, calcium channel blockers, and HMGCoA reductase inhibitors are not to be expected.
Co-administration of Pioglitazone with gemfibrozil (an inhibitor of cytochrome P450 2C8) is reported to result in a 3-fold increase in AUC of Pioglitazone. Since there is a potential for an increase in dose-related adverse events, a decrease in the dose of Pioglitazone may be needed when gemfibrozil is concomitantly administered. Close monitoring of glycaemic control should be considered. Co-administration of Pioglitazone with rifampicin (an inducer of cytochrome P450 2C8) is reported to result in a 54% decrease in AUC of Pioglitazone. The Pioglitazone dose may need to be increased when rifampicin is concomitantly administered. Close monitoring of glycaemic control should be considered.
4.6 Pregnancy and lactation
There are no adequate human data to determine the safety of Pioglitazone during pregnancy. Foetal growth restriction was apparent in animal studies with Pioglitazone. This was attributable to the action of Pioglitazone in diminishing the maternal hyperinsulinaemia and increased insulin resistance that occurs during pregnancy thereby reducing the availability of metabolic substrates for foetal growth. The relevance of such a mechanism in humans is unclear and Pioglitazone should not be used in pregnancy.
Pioglitazone has been shown to be present in the milk of lactating rats. It is not known whether Pioglitazone is secreted in human milk. Therefore, Pioglitazone should not be administered to breast-feeding women.
4.7 Undesirable effects
Infections and Infestations: Upper respiratory tract infection, bronchitis, sinusitis
Blood and lymphatic system disorders: Anaemia
Metabolism and nutrition disorders: Hypo-glycaemia, appetite increased
Nervous system disorders: Hypo-aesthesia, headache, dizziness, insomnia
Eye disorders: Visual disturbance, maccular oedema
Ear and labyrinth disorders: Vertigo
Cardiac disorder: Heart failure.
In clinical studies, patients have taken Pioglitazone at higher than the recommended highest dose of 45 mg daily.
The maximum reported dose of 120 mg/day for four days, then 180 mg/day for seven days was not associated with any symptoms.
Hypoglycaemia may occur in combination with sulphonylureas or insulin. Symptomatic and general supportive measures should be taken in case of overdose.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pioglitazone effects may be mediated by a reduction of insulin resistance. Pioglitazone appears to act via activation of specific nuclear receptors (peroxisome proliferator activated receptor gamma) leading to increased insulin sensitivity of liver, fat and skeletal muscle cells in animals. Treatment with Pioglitazone has been shown to reduce hepatic glucose output and to increase peripheral glucose disposal in the case of insulin resistance.
5.2 Pharmacokinetic properties
Following oral administration, Pioglitazone is rapidly absorbed, and peak plasma concentrations of unchanged Pioglitazone are usually achieved 2 hours after administration. Absorption is not influenced by food intake. Absolute bioavailability is greater than 80%.
The estimated volume of distribution in humans is 0.251/kg.
Pioglitazone and all active metabolites are extensively bound to plasma protein (>99%).
Pioglitazone undergoes extensive hepatic metabolism by hydroxylation of aliphatic methylene groups. This is predominantly via cytochrome P450 2C8 although other isoforms may be involved to a lesser degree. Three of the six identified metabolites are active (M-II, M-III, and M-IV). When activity, concentrations and protein binding are taken into account, Pioglitazone and metabolite M-III contribute equally to efficacy.
Following oral administration of radio labelled Pioglitazone to man, recovered label was mainly in faeces (55%) and a lesser amount in urine (45%). The mean plasma elimination half life of unchanged Pioglitazone in man is 5 to 6 hours and for its total active metabolites 16 to 23 hours.
6. PRARMACEUTICAL PARTICULARS
6.1 Shelf life
6.2 Special precaution for storage
Store at 15°C to 30°C. Keep in the original container and protect from light.
KEEP OUT OF REACH OF CHILDREN
7. MARKETING AUTHORISATION HOLDER
Manufactured in India by
8. MARKETING AUTHORISATION NUMBER(S)
Sole Distributor in Nigeria
…One Goal, Total Wellness.
60, Ogunlana Drive, Surulere, Lagos-Nigeria.