Tolazamide
A white or almost white crystalline powder, odourless or with
a slight odour. Very slightly soluble in water; slightly soluble
in alcohol; soluble in acetone: freely soluble in chloroform.
Adverse Effects, Treatment, Precautions and interactions as for sulphonylureas in general, like glimepiride.
GLIMEPIRIDE
------------
DRUG INTERACTIONS. 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,
chloramphenicol, coumarins, probenecid, monoamine oxidase inhibitors, and beta
adrenergic blocking agents. When these drugs are administered to a patient
receiving AMARYL(R), the patient should be observed closely for hypoglycemia.
When these drugs are withdrawn from a patient receiving AMARYL(R), the patient
should be observed closely for loss of glycemic control.
Certain drugs tend to produce hyperglycemia and may lead to loss of control.
These drugs include the thiazides and other diuretics, corticosteroids,
phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin,
nicotinic acid, sympathomimetics, and isoniazid. When these drugs are
administered to a patient receiving AMARYL(R), the patient should be closely
observed for loss of control. When these drugs are withdrawn from a patient
receiving AMARYL(R), the patient should be observed closely for hypoglycemia.
Coadministration of aspirin (1 g tid) and AMARYL(R) 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. Pooled data from clinical
trials showed no evidence of clinically significant adverse interactions with
uncontrolled concurrent administration of aspirin and other salicylates.
Coadministration of either cimetidine (800 mg once daily) or ranitidine (150 mg
bid) with a single 4-mg oral dose of AMARYL(R) did not significantly alter the
absorption and disposition of glimepiride, and no differences were seen in
hypoglycemic symptomatology. Pooled data from clinical trials showed no evidence
of clinically significant adverse interactions with uncontrolled concurrent
administration of H2-receptor antagonists.
Concomitant administration of propranolol (40 mg tid) and AMARYL(R)
significantly increased Cmax, AUC, and T1/2 of glimepiride by 23%, 22%, and 15%,
respectively, and it decreased CL/f by 18%. The recovery of M1 and M2 from
urine, however, did not change. The pharmacodynamic responses to glimepiride
were nearly identical in normal subjects receiving propranolol and placebo.
Pooled data from clinical trials in patients with NIDDM showed no evidence of
clinically significant adverse interactions with uncontrolled concurrent
administration of beta- blockers. However, if beta-blockers are used, caution
should be exercised and patients should be warned about the potential for
hypoglycemia.
Concomitant administration of AMARYL(R) (4 mg once daily) did not alter the
pharmacokinetic characteristics of R- and S-warfarin enantiomers following
administration of a single dose (25 mg) of racemic warfarin to healthy subjects.
No changes were observed in warfarin plasma protein binding. AMARYL(R) treatment
did result in a slight, but statistically significant, decrease in the
pharmacodynamic response to warfarin. The reductions in mean area under the
prothrombin time (PT) curve and maximum PT values during AMARYL(R) treatment
were very small (3.3% and 9.9%, respectively) and are unlikely to be clinically
important.
The responses of serum glucose, insulin, C- peptide, and plasma glucagon to 2 mg
AMARYL(R) were unaffected by coadministration of ramipril (an ACE inhibitor) 5
mg once daily in normal subjects. No hypoglycemic symptoms were reported. Pooled
data from clinical trials in patients with NIDDM showed no evidence of
clinically significant adverse interactions with uncontrolled concurrent
administration of ACE inhibitors.
A potential interaction between oral miconazole and oral hypoglycemic agents
leading to severe hypoglycemia has been reported. Whether this interaction also
occurs with the intravenous, topical, or vaginal preparations of miconazole is
not known. Potential interactions of glimepiride with other drugs metabolized by
cytochrome P450 II C9 also include phenytoin, diclofenac, ibuprofen, naproxen,
and mefenamic acid.
Although no specific interaction studies were performed, pooled data from
clinical trials showed no evidence of clinically significant adverse
interactions with uncontrolled concurrent administration of calcium-channel
blockers, estrogens, fibrates, NSAIDS, HMG CoA reductase inhibitors,
sulfonamides, or thyroid hormone.
CONTRAINDICATIONS:
AMARYL(R) is contraindicated in patients with
1. Known hypersensitivity to the drug.
2. Diabetic ketoacidosis, with or without coma. This condition should be
treated with insulin.
WARNINGS:
SPECIAL WARNING ON INCREASED RISK OF
CARDIOVASCULAR MORTALITY
THE ADMINISTRATION OF ORAL HYPOGLYCEMIC DRUGS HAS BEEN REPORTED TO BE ASSOCIATED
WITH INCREASED CARDIOVASCULAR MORTALITY AS COMPARED TO TREATMENT WITH DIET ALONE
OR DIET PLUS INSULIN. THIS WARNING IS BASED ON THE STUDY CONDUCTED BY THE
UNIVERSITY GROUP DIABETES PROGRAM (UGDP), A LONG- TERM, PROSPECTIVE CLINICAL
TRIAL DESIGNED TO EVALUATE THE EFFECTIVENESS OF GLUCOSE-LOWERING DRUGS IN
PREVENTING OR DELAYING VASCULAR COMPLICATIONS IN PATIENTS WITH NON-INSULIN-
DEPENDENT DIABETES. THE STUDY INVOLVED 823 PATIENTS WHO WERE RANDOMLY ASSIGNED
TO ONE OF FOUR TREATMENT GROUPS (DIABETES, 19 SUPP. 2: 747-830, 1970).
UGDP REPORTED THAT PATIENTS TREATED FOR 5 TO 8 YEARS WITH DIET PLUS A FIXED DOSE
OF TOLBUTAMIDE (1.5 GRAMS PER DAY) HAD A RATE OF CARDIOVASCULAR MORTALITY
APPROXIMATELY 2 1/2 TIMES THAT OF PATIENTS TREATED WITH DIET ALONE. A
SIGNIFICANT INCREASE IN TOTAL MORTALITY WAS NOT OBSERVED, BUT THE USE OF
TOLBUTAMIDE WAS DISCONTINUED BASED ON THE INCREASE IN CARDIOVASCULAR MORTALITY,
THUS LIMITING THE OPPORTUNITY FOR THE STUDY TO SHOW AN INCREASE IN OVERALL
MORTALITY. DESPITE CONTROVERSY REGARDING THE INTERPRETATION OF THESE RESULTS,
THE FINDINGS OF THE UGDP STUDY PROVIDE AN ADEQUATE BASIS FOR THIS WARNING. THE
PATIENT SHOULD BE INFORMED OF THE POTENTIAL RISKS AND ADVANTAGES OF AMARYL(R)
(GLIMEPIRIDE TABLETS) AND OF ALTERNATIVE MODES OF THERAPY.
ALTHOUGH ONLY ONE DRUG IN THE SULFONYLUREA CLASS (TOLBUTAMIDE) WAS INCLUDED IN
THIS STUDY, IT IS PRUDENT FROM A SAFETY STANDPOINT TO CONSIDER THAT THIS WARNING
MAY ALSO APPLY TO OTHER ORAL HYPOGLYCEMIC DRUGS IN THIS CLASS, IN VIEW OF THEIR
CLOSE SIMILARITIES IN MODE OF ACTION AND CHEMICAL STRUCTURE.
PRECAUTIONS:
GENERAL
Hypoglycemia: All sulfonylurea drugs are capable of producing severe
hypoglycemia. Proper patient selection, dosage, and instructions are important
to avoid hypoglycemic episodes. Patients with impaired renal function may be
more sensitive to the glucose-lowering effect of AMARYL(R). A starting dose of 1
mg once daily followed by appropriate dose titration is recommended in those
patients. Debilitated or malnourished patients, and those with adrenal,
pituitary, or hepatic insufficiency are particularly susceptible to the
hypoglycemic action of glucose-lowering drugs. Hypoglycemia may be difficult to
recognize in the elderly and in people who are taking beta-adrenergic blocking
drugs or other sympatholytic agents. Hypoglycemia is more likely to occur when
caloric intake is deficient, after severe or prolonged exercise, when alcohol is
ingested, or when more than one glucose-lowering drug is used.
Loss of control of blood glucose: When a patient stabilized on any diabetic
regimen is exposed to stress such as fever, trauma, infection, or surgery, a
loss of control may occur. At such times, it may be necessary to add insulin in
combination with AMARYL(R) or even use insulin monotherapy. The effectiveness of
any oral hypoglycemic drug, including AMARYL(R), in lowering blood glucose to a
desired level decreases in many patients over a period of time, which may be due
to progression of the severity of the diabetes or to diminished responsiveness
to the drug. This phenomenon is known as secondary failure, to distinguish it
from primary failure in which the drug is ineffective in an individual patient
when first given. Should secondary failure occur with AMARYL(R) monotherapy,
AMARYL(R)-insulin combination therapy may be instituted. Combined use of
glimepiride and insulin may increase the potential for hypoglycemia.
INFORMATION FOR PATIENTS
Patients should be informed of the potential risks and advantages of AMARYL(R)
and of alternative modes of therapy. They should also be informed about the
importance of adherence to dietary instructions, of a regular exercise program,
and of regular testing of blood glucose.
The risks of hypoglycemia, its symptoms and treatment, and conditions that
predispose to its development should be explained to patients and responsible
family members. The potential for primary and secondary failure should also be
explained.
LABORATORY TESTS
Fasting blood glucose should be monitored periodically to determine therapeutic
response. Glycosylated hemoglobin should also be monitored, usually every 3 to 6
months, to more precisely assess long-term glycemic control.
DRUG INTERACTIONS
(See ACTIONS/CLINICAL PHARMACOLOGY, DRUG INTERACTIONS.)
CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY
Studies in rats at doses of up to 5000 ppm in complete feed (approximately 340
times the maximum recommended human dose, based on surface area) for 30 months
showed no evidence of carcinogenesis. In mice, administration of glimepiride for
24 months resulted in an increase in benign pancreatic adenoma formation which
was dose related and is thought to be the result of chronic pancreatic
stimulation. The no-effect dose for adenoma formation in mice in this study was
320 ppm in complete feed, or 46-54 mg/kg body weight/day. This is about 35 times
the maximum human recommended dose of 8 mg once daily based on surface area.
Glimepiride was non-mutagenic in a battery of In Vitro and In Vivo mutagenicity
studies (Ames test, somatic cell mutation, chromosomal aberration, unscheduled
DNA synthesis, mouse micronucleus test).
There was no effect of glimepiride on male mouse fertility in animals exposed up
to 2500 mg/kg body weight (>1,700 times the maximum recommended human dose based
on surface area). Glimepiride had no effect on the fertility of male and female
rats administered up to 4000 mg/kg body weight (approximately 4,000 times the
maximum recommended human dose based on surface area).
PREGNANCY
TERATOGENIC EFFECTS. Pregnancy Category C. Glimepiride did not produce
teratogenic effects in rats exposed orally up to 4000 mg/kg body weight
(approximately 4,000 times the maximum recommended human dose based on surface
area) or in rabbits exposed up to 32 mg/kg body weight (approximately 60 times
the maximum recommended human dose based on surface area). Glimepiride has been
shown to be associated with intrauterine fetal death in rats when given in doses
as low as 50 times the human dose based on surface area and in rabbits when
given in doses as low as 0.1 times the human dose based on surface area. This
fetotoxicity, observed only at doses inducing maternal hypoglycemia, has been
similarly noted with other sulfonylureas, and is believed to be directly related
to the pharmacologic (hypoglycemic) action of glimepiride.
There are no adequate and well-controlled studies in pregnant women. On the
basis of results from animal studies, AMARYL(R) should not be used during
pregnancy. Because recent information suggests that abnormal blood glucose
levels during pregnancy are associated with a higher incidence of congenital
abnormalities, many experts recommend that insulin be used during pregnancy to
maintain glucose levels as close to normal as possible.
NONTERATOGENIC EFFECTS. In some studies in rats, offspring of dams exposed to
high levels of glimepiride during pregnancy and lactation developed skeletal
deformities consisting of shortening, thickening, and bending of the humerus
during the postnatal period. Significant concentrations of glimepiride were
observed in the serum and breast milk of the dams as well as in the serum of the
pups. These skeletal deformations were determined to be the result of nursing
from mothers exposed to glimepiride.
Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born
to mothers who were receiving a sulfonylurea drug at the time of delivery. This
has been reported more frequently with the use of agents with prolonged half-
lives. Patients who are planning a pregnancy should consult their physician, and
it is recommended that they change over to insulin for the entire course of
pregnancy and lactation.
NURSING MOTHERS
In rat reproduction studies, significant concentrations of glimepiride were
observed in the serum and breast milk of the dams, as well as in the serum of
the pups. Although it is not known whether AMARYL(R) is excreted in human milk,
other sulfonylureas are excreted in human milk. Because the potential for
hypoglycemia in nursing infants may exist, and because of the effects on nursing
animals, AMARYL(R) should be discontinued in nursing mothers. If AMARYL(R) is
discontinued, and if diet and exercise alone are inadequate for controlling
blood glucose, insulin therapy should be considered. (See above PREGNANCY,
NONTERATOGENIC EFFECTS.)
PEDIATRIC USE
Safety and effectiveness in pediatric patients have not been established.
DRUG INTERACTIONS:
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, chloramphenicol, coumarins,
probenecid, monoamine oxidase inhibitors, and beta adrenergic blocking agents.
When these drugs are administered to a patient receiving AMARYL(R), the patient
should be observed closely for hypoglycemia. When these drugs are withdrawn from
a patient receiving AMARYL(R), the patient should be observed closely for loss
of glycemic control.
Certain drugs tend to produce hyperglycemia and may lead to loss of control.
These drugs include the thiazides and other diuretics, corticosteroids,
phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin,
nicotinic acid, sympathomimetics, and isoniazid. When these drugs are
administered to a patient receiving AMARYL(R), the patient should be closely
observed for loss of control. When these drugs are withdrawn from a patient
receiving AMARYL(R), the patient should be observed closely for hypoglycemia.
Coadministration of aspirin (1 g tid) and AMARYL(R) 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. Pooled data from clinical
trials showed no evidence of clinically significant adverse interactions with
uncontrolled concurrent administration of aspirin and other salicylates.
Coadministration of either cimetidine (800 mg once daily) or ranitidine (150 mg
bid) with a single 4-mg oral dose of AMARYL(R) did not significantly alter the
absorption and disposition of glimepiride, and no differences were seen in
hypoglycemic symptomatology. Pooled data from clinical trials showed no evidence
of clinically significant adverse interactions with uncontrolled concurrent
administration of H2-receptor antagonists.
Concomitant administration of propranolol (40 mg tid) and AMARYL(R)
significantly increased Cmax, AUC, and T1/2 of glimepiride by 23%, 22%, and 15%,
respectively, and it decreased CL/f by 18%. The recovery of M1 and M2 from
urine, however, did not change. The pharmacodynamic responses to glimepiride
were nearly identical in normal subjects receiving propranolol and placebo.
Pooled data from clinical trials in patients with NIDDM showed no evidence of
clinically significant adverse interactions with uncontrolled concurrent
administration of beta- blockers. However, if beta-blockers are used, caution
should be exercised and patients should be warned about the potential for
hypoglycemia.
Concomitant administration of AMARYL(R) (4 mg once daily) did not alter the
pharmacokinetic characteristics of R- and S-warfarin enantiomers following
administration of a single dose (25 mg) of racemic warfarin to healthy subjects.
No changes were observed in warfarin plasma protein binding. AMARYL(R) treatment
did result in a slight, but statistically significant, decrease in the
pharmacodynamic response to warfarin. The reductions in mean area under the
prothrombin time (PT) curve and maximum PT values during AMARYL(R) treatment
were very small (3.3% and 9.9%, respectively) and are unlikely to be clinically
important.
The responses of serum glucose, insulin, C- peptide, and plasma glucagon to 2 mg
AMARYL(R) were unaffected by coadministration of ramipril (an ACE inhibitor) 5
mg once daily in normal subjects. No hypoglycemic symptoms were reported. Pooled
data from clinical trials in patients with NIDDM showed no evidence of
clinically significant adverse interactions with uncontrolled concurrent
administration of ACE inhibitors.
A potential interaction between oral miconazole and oral hypoglycemic agents
leading to severe hypoglycemia has been reported. Whether this interaction also
occurs with the intravenous, topical, or vaginal preparations of miconazole is
not known. Potential interactions of glimepiride with other drugs metabolized by
cytochrome P450 II C9 also include phenytoin, diclofenac, ibuprofen, naproxen,
and mefenamic acid.
Although no specific interaction studies were performed, pooled data from
clinical trials showed no evidence of clinically significant adverse
interactions with uncontrolled concurrent administration of calcium-channel
blockers, estrogens, fibrates, NSAIDS, HMG CoA reductase inhibitors,
sulfonamides, or thyroid hormone.
(See Also ACTIONS/CLINICAL PHARMACOLOGY, DRUG INTERACTIONS.)
ADVERSE REACTIONS:
The incidence of hypoglycemia with AMARYL(R), as documented by blood glucose
values <60 mg/dL, ranged from 0.9-1.7% in two large, well- controlled, 1-year
studies. (See WARNINGS and PRECAUTIONS.)
AMARYL(R) has been evaluated for safety in 2,013 patients in US controlled
trials, and in 1,551 patients in foreign controlled trials. More than 1,650 of
these patients were treated for at least 1 year.
Adverse events, other than hypoglycemia, considered to be possibly or probably
related to study drug that occurred in US placebo-controlled trials in more than
1% of patients treated with AMARYL(R) are shown below.
Adverse Events Occurring in >/=1%
AMARYL(R) Patients
AMARYL(R) PLACEBO
NO. % NO. %
Total Treated 746 100 294 100
Dizziness 13 1.7 1 0.3
Asthenia 12 1.6 3 1.0
Headache 11 1.5 4 1.4
Nausea 8 1.1 0 0.0
GASTROINTESTINAL REACTIONS
Vomiting, gastrointestinal pain, and diarrhea 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.
DERMATOLOGIC REACTIONS
Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform
or maculopapular eruptions, occur in less than 1% of treated patients. These may
be transient and may disappear despite continued use of AMARYL(R); if skin
reactions persist, the drug should be discontinued. Porphyria cutanea tarda and
photosensitivity reactions have been reported with sulfonylureas.
HEMATOLOGIC REACTIONS
Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic
anemia, and pancytopenia have been reported with sulfonylureas.
METABOLIC REACTIONS
Hepatic porphyria reactions and disulfiram-like reactions have been reported
with sulfonylureas; however, no cases have yet been reported with AMARYL(R).
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. The syndrome of inappropriate antidiuretic hormone (SIADH)
secretion has been reported with certain other sulfonylureas, and it has been
suggested that these sulfonylureas may augment the peripheral (antidiuretic)
action of ADH and/or increase release of ADH.
OTHER REACTIONS
Changes in accommodation and/or blurred vision may occur with the use of
AMARYL(R). This is thought to be due to changes in blood glucose, and may be
more pronounced when treatment is initiated. This condition is also seen in
untreated diabetic patients, and may actually be reduced by treatment. In
placebo-controlled trials of AMARYL(R), the incidence of blurred vision was
placebo, 0.7%, and AMARYL(R), 0.4%.
Pharmacokinetics of tolazamide :
Tolazamide is slowly absorbed from the gastro-in-
testinal tract, peak plasma concentrations occurring
4 to 8 hours after a dose by mouth, and is extensively
bound to plasma proteins. It has a half-life of about
7 hours. It is metabolised in the liver to metabolites
with some hypoglycaemic activity. About 85% of an
oral dose is excreted in the urine, chiefly as metabo-
lites.
Uses and Administration
Tolazamide is a sulphonylurea hypoglycaemic. It is given by mouth
in the treatment of type
2 diabetes mellitus and has a duration of ac-
tion of at least 10 hours and sometimes up to 20
hours. The usual initial dose in type 2 diabetes mel-
litus is 100 to 250 mg daily by mouth given as a sin-
gle dose with breakfast and increased if necessary at
weekly intervals by 100 to 250 mg usually to a max-
imum of I g daily: no further benefit is likely to be
gained with higher doses. Doses of 500 mg or more
daily may be given in divided doses.