Metformin HCL XR 500mg
1. ROUTE OF ADMINISTRATION
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 debilited
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 avoid metformin use in hepatic impairment,
hepatic disease increase 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 bformulation
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 monitered 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.
5.
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.
6. 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.
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