MEMIN – G1/G2
Glimepiride and Metformin Hydrochloride Tablets
DESCRIPTION
Memin-G
is a fixed dose combination (FDC) of Glimepiride and Metformin Hydrochloride.
It contains
Glimepiride which is chemically 1-
[[p-[2-(3-Ethyl-4-methyl-2-oxo-3-pyrroline-1 carboxamido)
ethyl]phenyl]-sulphonyl]-3-(trans-4 methylcyclohexyl) urea and Metformin
Hydrochloride which is chemically 1, 1-dimethyl
biguanide hydrochloride. Memin-G is white to
off-white, round, flat, bevel edged, uncoated tablet scored on one side and
plain on the other.
COMPOSITION
Each uncoated tablet of
Memin-G1contains:
Glimepiride
................................ 1mg
Metformin Hydrochloride IP
..... 500mg
Each uncoated tablet of
Memin-G2 contains:
Glimepiride
................................ 2mg
Metformin Hydrochloride IP
..... 500mg
PHARMACOLOGY
Glimepiride
Glimepiride reduces blood
glucose levels by correcting both defective insulin secretion and
peripheral insulin resistance. It interacts with
specific receptors at the plasma membrane of the insulin releasing pancreatic beta- cells where it inhibits ATP-
sensitive K+ channels resulting in depolarization
of the cell membrane, opening of voltage sensitive Ca2+ channels, increase in
intracellular calcium levels and subsequent insulin
release1.
Metformin
Metformin
acts as an antihyperglycaemic agent by improving hepatic and peripheral tissue
sensitivity to insulin. It also appears to have
beneficial effect on serum lipid levels and so on fibrinolytic activity. Metformin therapy is not associated
with increase in body weight.2 Metformin decreases
glucose production, decreases intestinal absorption of glucose and improves
insulin sensitivity by increasing peripheral glucose uptake and utilization
RATIONALITY FOR COMBINATION
OF GLIMEPIRIDE AND METFORMIN
Sulfonylureas and biguanides
act complementary to each other. Both compounds have an
additive antihyperglycaemic effect without increasing
the adverse effects of either pharmacological
class.
Glimepiride acts via stimulating b cells
of pancreas to release insulin and also increases peripheral sensitivity of insulin. Metformin acts via
enhanced peripheral glucose uptake and utilization. It also reduces hepatic glucose production,
thereby metformin diminishes insulin resistance.
There are reports in which combination
treatment of sulfonylurea with metformin has been reported to achieve satisfactory glycaemic control for
several years. Such combination has been reported
to be quite useful studies where secondary sulfonylurea failure. The
combination may therefore provide additional
glycaemic control (blood glucose lowering effect by 20%).
Glimepiride has less propensity to cause
hypoglycaemia and increase in body weight as compared to other sulfonylurea.
Since metformin is reported to have
predominant peripheral
mechanism of action, therefore it lacks
the anabolic effects of sulfonylureas and does not cause
weight gain.
Metformin is associated with a decrease
in fasting and postprandial plasma insulin and triglyceride levels, increase in HDL-cholesterol, increase
of tissue plasminogen activator, decrease in
platelet aggregation.
Pharmacokinetically the two drugs appear
to be compatible, as metformin is not plasma protein
bound and does not get metabolized in liver. So
interaction with glimepiride (having 99% plasma protein
binding and metabolized via liver) does not appear to be possible. Hence the combination of
glimepiride and metformin would help in treatment of NIDDM.
PHARMACOKINETICS
Glimepiride:-
Glimepiride is rapidly and completely
absorbed after oral administration. The oral bioavailability is
approximately 100%. Following oral administration of
1 mg single dose to healthy volunteers,peak serum concentration ( (Cmax) of
103+ 34 ng/ml occurred within 2-3 hours. More than 99% of the drug is bound to plasma proteins. Glimepiride is
completely biotransformed by hepatic oxidative
metabolism into cyclohexylhydroxymethyl derivative( M1) which is further
metabolizedto form a carboxyl derivative ( M2) by cytosolic enzymes. After a
single dose, the elimination half life ( t1/2)
of glimepiride is 5 hours. The urinary excretion of metabolites accounts for
60% of dose, the remainder is found as
metabolites in faeces2.
Metformin:-
Metformin has absolute oral
bioavailability of 50-60%. GIT absorption is complete within 6 hrs of
ingestion within metformin is rapidly distributed in
body after absorption. The renal elimination of metformin
is biphasic. 95% of the absorbed metformin is eliminated during primary
elimination phase having half-life of 6 hours.
Rest of the 5% is eliminated during slow terminal elimination phase with mean half-life of 20 hours. Metformin is not
bound to plasma proteins, 40-60% of the dose
is recovered as unchanged drug in urine with a further 30% recovered as
unchanged drug
in faeces.3
INDICATIONS
Non insulin dependent diabetes mellitus
not sufficiently controlled by sulphonylurea therapy atmaximum tolerated dose
and in monotherapy treatment failure.
CONTRAINDICATIONS
Insulin-dependent diabetes mellitus,
renal or hepatic failure, alcoholism, NIDDM complicated by
severe ketosis and acidosis, diabetic precoma and
coma, patients undergoing surgery, after severe
trauma or during infections, chronic obstructive pulmonary disease, coronary
heart disease, cardiac failure, peripheral
vascular disease, pregnancy, known hypersensitivity to the drug.
WARNINGS
AND PRECAUTIONS
Hypoglycaemia may occur if the patient's
dietary intake is reduced or after accidental or deliberate overdose or after severe exercise, trauma and
stress. Hypoglycaemic symptoms can be reduced
by prescribing a diabetic meal plan. Immediate intervention should be done if
signs and symptoms of hypoglycaemia occur.
Adjust dose of drug according to blood and urinary
glucose levels during the first few months. However,
there have been few reports of lactic acidosis with Metformin in patients of
renal or liver disease.
Usage in pregnancy and
lactation
There are no well controlled studies of
use of glimepiride and metformin (as an individual therapy)
in pregnant women and lactating mothers. Therefore,
Memin-G2 should only be used if potential benefit
outweigh the risk involved.
Pediatric use
Safety and effectiveness of
the drug in children have not been established.
DRUG INTERACTIONS
Glimepiride:-
The hypoglycemic action of
sulfonylureas may be potentiated by certain drugs, including
nonsteroidal anti-inflammatory drugs and other drugs
that are highly protein bound, such as
salicylates, sulfonamides,
monoamine oxidase inhibitors, and beta adrenergic blocking agents.
Coadministration of aspirin
and Glimepiride led to a 34% decrease in the mean Glimepiride AUC
and, therefore, a 34% increase in the mean CL/f. The
mean Cmax had a decrease of 4%. Blood glucose
and serum C-peptide concentrations were unaffected and no hypoglycemic symptoms
were reported.
Coadministration of either
cimetidine (800 mg once daily) or ranitidine (150 mg bid) with a single
4-mg oral dose of Glimepiride did not significantly
alter the absorption and disposition of Glimepiride.
Concomitant administration
of propanolol (40 mg tid) and Glimepiride significantly increased
Cmax, AUC, and t1/2 of Glimepiride by 23%, 22% and
15% respectively, and it decreased CL/f by
18%.
Concomitant administration
of Glimepiride (4 mg once daily) did not alter the pharmacokinetic
characteristics of R- and S-warfarin enantiomers
following administrationofa single dose (25 of racemic warfarin
to healthy subjects. No changes were observed in warfarin plasma protein
binding.The responses of serum glucose, insulin,
C-peptide, and plasma glucagon to 2 mg Glimepiride were unaffected by coadministration of ramipril (an ACE
inhibitor) 5 mg once daily in normal subjects.
No hypoglycemic symptoms were reported.
Metformin:-
Drug interactions of
metformin is seen with phenprocoumon, hyperglycemic agent (e.g. -thiazides,
corticosteroids and others), alcohol, furosemide, nifedipine and cationic drugs
(amiloride, digoxin, morphine, procainamide,
quinidine, quinine, ranitidine, triamterene,trimethoprim and cimetidine,
vancomycin). The absorption of metformin may be
reduced by acarbose and guar gum.
ADVERSE REACTIONS
Vomiting, gastrointestinal
pain and diarrhoea have been reported, but the incidence in placebo-controlled
trials was less than 1%. Isolated transaminase elevations have been
reported.Cholestatic jaundice has been reported to occur rarely with
sulfonylureas. Allergic skin reactions,e.g., pruritus, erythema, urticaria, and
morbilliform or maculopapular eruptions, occur in less than
1% of treated patients. Cases of hyponatremia have been reported with Glimepiride
and all other sulfonylureas, most often in
patients who are on other medications or have medical conditions known to cause
hyponatremia or increase release of antidiuretic
hormone. Change in accommodation and / or
blurred vision may occur.
Nausea, diarrhoea, gastric
pain, constipation, vomiting, metallic taste in mouth.Rash, pruritus,
urticaria, erythema and flushing Headache and dizziness .Impaired
gastrointestinal absorption of vitamin B12 and folic acid has been associated
with long- term metformin therapy .Measurement of serum vitamin B12 level is advised on an
annual basis as metformin interfere with B12
absorption from intrinsic factor complex.
OVERDOSE AND TREATMENT
Hypoglycaemia may occur in
case of an overdosage. In the event of an overdosage, gastric
lavage should be performed and correction of
hypoglycaemia should be attempted by intravenous administration of hypertonic glucose (10 or 30%) with continued
monitoring of the patient's blood glucose
levels.
DOSAGE AND ADMINISTRATION
1-2 tablets once daily to a
maximum of 4 tablets/day
REFERENCES
1. Drugs 1998 Apr; 55(4) s:
563-584.
2. Am. J. Health - Syst.
Pharm 1997; 54(Apr. 15): 893 - 903
3. Drugs 1995; 49(5): 721 -
49
