Oral
DOSAGE AND ADMINISTRATION
For the treatment
of Type II (non-insulin dependent, NIDDM) Diabetes Mellitus uncontrolled
by diet alone:
For monotherapy:
Oral dosage – Adult: Initially, 500 mg once daily with the evening
meal. Increase in increments of 500 mg weekly, as needed, upto a maximum
of 2000 mg once daily with the evening meal. If glycaemic control is not
achieved with 2000 mg once daily, a trial of the extended – release
tablets as 1000 mg twice daily should be considered. If doses of >2000
mg/day are required, change to the appropriate dosage of immediate release
metformin tablets is divided doses.
Elderly or debilitated patients: Same as adult’s dosage. Avoid use if >= 80 years of age unless normal renal function is documented. In general, do not titrate to the maximum dose.
Adolescent & children: Safe and effective use has not been established.
Switching to metformin
from other antidiabetic therapy:
Adults and elderly: When transferring from
antidiabetic agents other than chlorpropamide, no transition period is required.
When transferring from chlorpropamide, use caution during the first 2 weeks;
there may be prolonged retention of chlorpropamide in the body, which may
increase the potential for hypoglycaemia.
Addition of a sulfonylurea
or an alpha-glucosidase inhibitor to metformin:
Adults and elderly: After 4 weeks of the
maximum dose of metformin as described in monotherapy without adequate response,
consider the gradual addition of an oral sulphonylurea, even if prior failure
to a sulphonylurea has occurred. If after 1-3 months of concomitant therapy
responses are unsatisfactory, consider insulin therapy and discontinuation
of oral agents.
Addition of metformin
in combination with insulin therapy:
Adults: The current
insulin dose should be continued; initiate metformin dose at 500 mg after
approximately 1 week and by 500 mg/day every week thereafter until adequate
glycaemic control is achieved. The dose should not exceed 2000 mg/day. The
insulin dose should usually be decreased by 10-25% when fasting plasma glucose
decrease to <120 mg/dl. Individualize dosage of antidiabetic drugs as
needed.
Elderly or debilitated patients: Avoid use if >= 80 years of age unless
normal renal function is documented. In general, do not titrate to the maximum
dose.
Adolescents and Children: Safe and effective use has not been established.
Patients
with hepatic Impairment:
Generally avid metformin use in hepatic impairment, hepatic disease increases
the risk of metformin-associated lactic acidosis.
Patients
with renal Impairment:
CrC1= 60 ml/min: No dosage adjustment required.
CrC1 = 60 ml/min: Metformin use is contraindicated.
2. THERAPEUTIC
/ DIAGNOSTIC CLAIMS
· Monotherapy for adults (above 17 yrs) with Type
II Diabetes
Mellitus as an adjunct to diet and exercise.
· Concomitant therapy with sulphonylurea or insulin.
3. DESCRIPTION
OF DOSAGE FORM
Metformin is an oral biguanide antidiabetic agent, which has a sustained
release tablet provides type II diabetic patients a convenient once daily
formulation that ensures better patient compliance.
WARNINGS
AND PRECAUTIONS:
DRUG INTERACTIONS:
Certain medications used concomitantly with metformin may increase the risk
of lactic acidosis. Cationic drugs that are eliminated by renal tubular
secretions (e.g: amiloride, cimetidine, digoxin, morphine, procainamide,
quinidine, ranitidine, or vancomycin may decrease metformin elimination
by competing form common renal tubular transport systems. Hence, careful
patient monitoring and dose adjustment of metformin and/or interfering cationic
drug is recommended.
Metformin may result in suboptimal oral vitamin B12 absorption by competitively blocking the calcium dependent binding of the intrinsic factor vitamin B12 complex to its receptor. The reaction very rarely results in pernicious anemia that is reversible with discontinuation of metformin or with cyanocobalamin, vitamin B12, supplementation.
Nifedipine enhances the absorption of metformin, (maximum by 20% and increase the amount of metformin excreted in the urine.)
Concomitant administration of catopril or enalpril increase sensitivity to insulin. Dosage of the oral antidiabetic agent may need to be reduced.
If salicylates are administered or discontinued in patients receiving oral antidiabetic agents, patients should be monitored for hypoglycemia or loss of blood glucose control.
Interactions between thiazide diuretics and oral antidiabetics agents decreases insulin sensitivity thereby leading to glucose intolerance and hyperglycaemia, thus leading to a loss of diabetic control. Hence diabetic patients should be monitored closely.
Patients receiving estrogens,
progestins or oral contraceptives, phenytoin, quinolones should be closely
monitered for loss of diabetic control when therapy is instituted or discontinued.
4. CONTRAINDICATIONS
Absolute contraindications:
Acidemia.
Acute myocardial infarction.
Breast-feeding.
Cardiogenic shock.
Diabetic ketoacidosis.
Hepatic disease.
Hypoxia.
Lactic acidosis/Metabolic acidosis.
Renal failure.
Sepsis.
Surgery.
Radiographic contrast administration.
-Do not use metformin in patients who have known metformin hypersensitivity.
-Use metformin with caution in the elderly. Metformin is substantially excreted by the kidney and the risk of adverse reactions is greater in patients with reduced renal function. Because aging is associated with dose selection and titrations.
-Metformin is classified
in FDA pregnancy risk category B, metformin is not recommended for use during
pregnancy.
6. SIDE EFFECTS
Gastrointestinal adverse effects are seen in patients taking metformin-anorexia,
nausea/vomiting, abdominal discomfort, dyspepsia, flatulence, diarrhea and
metallic taste in mouth. These side effects tend to decline with continued
use and can be minimized by initiating therapy with low dose.
Weight loss may occur during therapy with metformin, perhaps as a result
of its ability to cause anorexia.
Lactic acidosis is a rare, but serious, metabolic complication that can
occur if metformin accumulates during treatment.
7. TOXIC EFFECTS:
MUTAGENICITY
No evidence of mutagenicity or chromosomal damage was observed in vivo in a micronucleus test in mice or in in-vitro test systems, including microbial (Ames test) and mammalian (mouse lymphoma and human lymphocytes) assays.
CARCINOGENICITY
No evidence of carcinogenic potential was seen in a 104-week study in male and female rats receiving metformin hydrochloride dosages upto and including 00 mg/kg daily or in a 91-week study in male and female mice receiving metformin hydrochloride at dosages up to and including 1500 mg/kg daily: these dosages are about 3 times the maximum recommended human daily dosage based on body surface area. However, an increased incidence of benign stromal uterine polyps was observed in female rats treated with 900 mg/kg of metformin hydrochloride daily.
Not expected to produce cancer in humans under occupational exposure conditions. Metformin hydrochloride is not listed as carcinogen by IARC, NTP or US OSHA.
TERATOGENECITY
Reproduction studies in rats and rabbits given metformin hydrochloride dosages of 600 mg/kg daily (about twice the maximum recommended human daily dosage based on body surface area or about 2 and 6 times the maximum recommended human daily dosage of extended release tablets (2 g) based on body surface area comparisons with rats and rabbits, respectively) have not revealed evidence of harm to the fetus.
There are no adequate and controlled studies to date using metformin in pregnant women. Limited data from uncontrolled or retrospective studies are conflicting with regard to the effects of long-term maternal therapy with metformin hydrochloride (1.5-3 g daily) on neonatal morbidity (e.g. congenital malformations) and mortality. Metformin should be used during pregnancy only when clearly needed.