What Is Amaryl Used For

What is Amaryl and how is it used?

Amaryl is a prescription medicine used to treat the symptoms of Type 2 Diabetes Mellitus. Amaryl may exist used solitary or with other medications.

Amaryl belongs to a class of drugs called Antidiabetics, Sulfonylureas.

It is not known if Amaryl is safe and effective in children.

What are the possible side furnishings of Amaryl?

Amaryl may cause serious side effects including:

pale or yellowed skin,
nighttime colored urine,
confusion,
weakness, and
fever

Get medical help correct away, if you lot have any of the symptoms listed above.

The well-nigh mutual side effects of Amaryl include:

headache,
dizziness,
weakness,
nausea, and
depression blood sugar

Tell the dr. if yous have any side effect that bothers y'all or that does not go away.

These are not all the possible side effects of Amaryl. For more than information, ask your dr. or pharmacist.

Call your doc for medical advice about side effects. You may written report side furnishings to FDA at 1-800-FDA-1088.

Clarification

AMARYL is an oral sulfonylurea that contains the active ingredient glimepiride. Chemically, glimepiride is identified as i-[[p-[two-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) ethyl]phenyl]sulfonyl]-3-(trans-four-methylcyclohexyl)urea (C₂₄H₃₄N_ivO_vS) with a molecular weight of 490.62. Glimepiride is a white to yellow-white, crystalline, odorless to practically odorless pulverization and is practically insoluble in h2o. The structural formula is:

AMARYL (glimepiride) Structural Formula Illustration

AMARYL tablets contain the agile ingredient glimepiride and the following inactive ingredients: lactose (hydrous), sodium starch glycolate, povidone, microcrystalline cellulose, and magnesium stearate. In improver, AMARYL 1 mg tablets contain Ferric Oxide Red, AMARYL 2 mg tablets contain Ferric Oxide Yellowish and FD&C Blue #2 Aluminum Lake, and AMARYL 4 mg tablets contain FD&C Blue #2 Aluminum Lake.

3 pharmacies near 95032 accept coupons for Amaryl (Brand Names:Amaryl Tablets for 1MG)

INDICATIONS

AMARYL is indicated every bit an adjunct to diet and do to better glycemic control in adults with blazon 2 diabetes mellitus [see Clinical Studies].

Important Limitations Of Use

AMARYL should not be used for the treatment of type one diabetes mellitus or diabetic ketoacidosis, as it would not be effective in these settings.

DOSAGE AND Assistants

Recommended Dosing

AMARYL should be administered with breakfast or the first principal meal of the 24-hour interval.

The recommended starting dose of AMARYL is ane mg or 2 mg once daily. Patients at increased risk for hypoglycemia (eastward.grand., the elderly or patients with renal impairment) should be started on 1 mg one time daily [see WARNINGS AND PRECAUTIONS and Use in Specific Populations].

Afterwards reaching a daily dose of 2 mg, further dose increases can be made in increments of 1 mg or 2 mg based upon the patient'southward glycemic response. Uptitration should not occur more frequently than every i-ii weeks. A bourgeois titration scheme is recommended for patients at increased adventure for hypoglycemia [see WARNINGS AND PRECAUTIONS and Employ in Specific Populations].

The maximum recommended dose is 8 mg once daily.

Patients beingness transferred to AMARYL from longer half-life sulfonylureas (e.g., chlorpropamide) may have overlapping drug outcome for 1-2 weeks and should be accordingly monitored for hypoglycemia.

When colesevelam is coadministered with glimepiride, maximum plasma concentration and total exposure to glimepiride is reduced. Therefore, AMARYL should be administered at to the lowest degree 4 hours prior to colesevelam.

HOW SUPPLIED

Dosage Forms And Strengths

AMARYL is formulated as tablets of:

ane mg (pink, flat-faced, ellipsoidal with notched sides at double bisect, imprinted with "AMA RYL" on one side)
ii mg (green, flat-faced, oblong with notched sides at double bisect, imprinted with "AMA RYL" on one side)
four mg (blue, flat-faced, oblong with notched sides at double bisect, imprinted with "AMA RYL" on i side)

Storage And Treatment

AMARYL tablets are available in the post-obit strengths and package sizes:

1 mg (pinkish, apartment-faced, ellipsoidal with notched sides at double bifurcate, imprinted with "AMA RYL" on one side) in bottles of 100 (NDC 0039-0221-x)

two mg (green, apartment-faced, ellipsoidal with notched sides at double bisect, imprinted with "AMA RYL" on ane side) in bottles of 100 (NDC 0039-0222-x)

iv mg (blue, flat-faced, oblong with notched sides at double bisect, imprinted with "AMA RYL" on one side) in bottles of 100 (NDC 0039-0223-10)

Store at 25°C (77°F); excursions permitted to 20 - 25°C (68 - 77°F) (see USP Controlled Room Temperature).

Dispense in well-closed containers with condom closures.

sanofi-aventis U.Due south. LLC, Bridgewater, NJ 08807, A SANOFI COMPANY. Revised Dec 2016

SLIDESHOW

Type 2 Diabetes: Signs, Symptoms, Treatments Come across Slideshow

SIDE Furnishings

The following serious agin reactions are discussed in more detail below and elsewhere in the labeling:

Hypoglycemia [encounter WARNINGS AND PRECAUTIONS]
Hemolytic anemia [see WARNINGS AND PRECAUTIONS]

In clinical trials, the most common adverse reactions with AMARYL were hypoglycemia, dizziness, asthenia, headache, and nausea.

Clinical Trials Experience

Considering clinical trials are conducted nether widely varying weather, adverse reaction rates observed in the clinical trials of a drug cannot be straight compared to rates in the clinical trials of some other drug and may not reflect the rates observed in practice.

Approximately two,800 patients with type two diabetes have been treated with AMARYL in the controlled clinical trials. In these trials, approximately 1,700 patients were treated with AMARYL for at least 1 yr.

Tabular array 1 summarizes adverse events, other than hypoglycemia, that were reported in eleven pooled placebocontrolled trials, whether or not considered to exist possibly or probably related to report medication. Handling elapsing ranged from xiii weeks to 12 months. Terms that are reported correspond those that occurred at an incidence of ≥ 5% amidst AMARYL-treated patients and more commonly than in patients who received placebo.

Table 1: Eleven Pooled Placebo-Controlled Trials ranging from xiii weeks to 12 months : Adverse Events (Excluding Hypoglycemia) Occurring in ≥ 5% of AMARYL-treated Patients and at a Greater Incidence than with Placebo*

	AMARYL N=745 %	Placebo N=294 %
Headache	eight.2	7.8
Adventitious Injury†	5.8	3.4
Flu Syndrome	5.iv	iv.4
Nausea	5.0	3.4
Dizziness	5.0	two.iv
*AMARYL doses ranged from 1-16 mg administered daily †Insufficient information to determine whether whatever of the accidental injury events were associated with hypoglycemia

Hypoglycemia

In a randomized, double-blind, placebo-controlled monotherapy trial of 14 weeks elapsing, patients already on sulfonylurea therapy underwent a 3-calendar week washout flow so were randomized to AMARYL 1 mg, 4 mg, 8 mg or placebo. Patients randomized to AMARYL 4 mg or viii mg underwent forced-titration from an initial dose of i mg to these last doses, equally tolerated [encounter Clinical Studies]. The overall incidence of possible hypoglycemia (defined by the presence of at to the lowest degree ane symptom that the investigator believed might be related to hypoglycemia; a concurrent glucose measurement was not required) was 4% for AMARYL 1 mg, 17% for AMARYL 4 mg, 16% for AMARYL 8 mg and 0% for placebo. All of these events were cocky-treated.

In a randomized, double-blind, placebo-controlled monotherapy trial of 22 weeks duration, patients received a starting dose of either 1 mg AMARYL or placebo daily. The dose of AMARYL was titrated to a target fasting plasma glucose of 90-150 mg/dL. Final daily doses of AMARYL were 1, 2, 3, 4, 6 or viii mg [meet Clinical Studies]. The overall incidence of possible hypoglycemia (as divers above for the 14-week trial) for AMARYL vs. placebo was xix.7% vs. 3.2%. All of these events were selftreated.

Weight proceeds: AMARYL, like all sulfonylureas, can crusade weight gain [see Clinical Studies].

Allergic Reactions: In clinical trials, allergic reactions, such equally pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occurred in less than ane% of AMARYL-treated patients. These may resolve despite connected treatment with AMARYL. There are postmarketing reports of more serious allergic reactions (e.g., dyspnea, hypotension, shock) [see WARNINGS AND PRECAUTIONS].

Laboratory Tests

Elevated Serum Alanine Aminotransferase (ALT): In 11 pooled placebo-controlled trials of AMARYL, 1.nine% of AMARYL-treated patients and 0.8% of placebo-treated patients developed serum ALT greater than 2 times the upper limit of the reference range.

Postmarketing Experience

The following adverse reactions have been identified during post-blessing utilise of AMARYL. Because these reactions are reported voluntarily from a population of uncertain size, information technology is not ever possible to reliably guess their frequency or found a causal relationship to drug exposure.

Serious hypersensitivity reactions, including anaphylaxis, angioedema, and Stevens-Johnson Syndrome [come across WARNINGS AND PRECAUTIONS]
Hemolytic anemia in patients with and without G6PD deficiency [encounter WARNINGS AND PRECAUTIONS]
Harm of liver function (e.one thousand. with cholestasis and jaundice), as well as hepatitis, which may progress to liver failure.
Porphyria cutanea tarda, photosensitivity reactions and allergic vasculitis
Leukopenia, agranulocytosis, aplastic anemia, and pancytopenia
Thrombocytopenia (including severe cases with platelet count less than 10,000/μL) and thrombocytopenic purpura
Hepatic porphyria reactions and disulfiram-similar reactions
Hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH), most often in patients who are on other medications or who accept medical weather condition known to crusade hyponatremia or increment release of antidiuretic hormone
Dysgeusia
Alopecia

DRUG INTERACTIONS

Drugs Affecting Glucose Metabolism

A number of medications affect glucose metabolism and may require AMARYL dose adjustment and particularly close monitoring for hypoglycemia or worsening glycemic control.

The following are examples of medications that may increase the glucose-lowering effect of sulfonylureas including AMARYL, increasing the susceptibility to and/or intensity of hypoglycemia: oral anti-diabetic medications, pramlintide acetate, insulin, angiotensin converting enzyme (ACE) inhibitors, H2 receptor antagonists, fibrates, propoxyphene, pentoxifylline, somatostatin analogs, anabolic steroids and androgens, cyclophosphamide, phenyramidol, guanethidine, fluconazole, sulfinpyrazone, tetracyclines, clarithromycin, disopyramide, quinolones, and those drugs that are highly protein-bound, such as fluoxetine, nonsteroidal anti-inflammatory drugs, salicylates, sulfonamides, chloramphenicol, coumarins, probenecid and monoamine oxidase inhibitors. When these medications are administered to a patient receiving AMARYL, monitor the patient closely for hypoglycemia. When these medications are withdrawn from a patient receiving AMARYL, monitor the patient closely for worsening glycemic command.

The post-obit are examples of medications that may reduce the glucose-lowering consequence of sulfonylureas including AMARYL, leading to worsening glycemic control: danazol, glucagon, somatropin, protease inhibitors, atypical antipsychotic medications (east.thousand., olanzapine and clozapine), barbiturates, diazoxide, laxatives, rifampin, thiazides and other diuretics, corticosteroids, phenothiazines, thyroid hormones, estrogens, oral contraceptives, phenytoin, nicotinic acrid, sympathomimetics (e.g., epinephrine, albuterol, terbutaline), and isoniazid. When these medications are administered to a patient receiving AMARYL, monitor the patient closely for worsening glycemic control. When these medications are withdrawn from a patient receiving AMARYL, monitor the patient closely for hypoglycemia.

Beta-blockers, clonidine, and reserpine may atomic number 82 to either potentiation or weakening of AMARYL's glucose-lowering effect.

Both astute and chronic alcohol intake may potentiate or weaken the glucose-lowering action of AMARYL in an unpredictable fashion.

The signs of hypoglycemia may exist reduced or absent in patients taking sympatholytic drugs such as beta-blockers, clonidine, guanethidine, and reserpine.

Miconazole

A potential interaction between oral miconazole and sulfonylureas leading to severe hypoglycemia has been reported. Whether this interaction also occurs with other dosage forms of miconazole is not known.

Cytochrome P450 2C9 Interactions

In that location may be an interaction between glimepiride and inhibitors (e.one thousand., fluconazole) and inducers (e.1000., rifampin) of cytochrome P450 2C9. Fluconazole may inhibit the metabolism of glimepiride, causing increased plasma concentrations of glimepiride which may atomic number 82 to hypoglycemia. Rifampin may induce the metabolism of glimepiride, causing decreased plasma concentrations of glimepiride which may pb to worsening glycemic control.

Concomitant Administration Of Colesevelam

Colesevelam can reduce the maximum plasma concentration and total exposure of glimepiride when the two are coadministered. All the same, absorption is not reduced when glimepiride is administered four hours prior to colesevelam. Therefore, AMARYL should be administered at least 4 hours prior to colesevelam.

WARNINGS

Included equally part of the PRECAUTIONS department.

PRECAUTIONS

Hypoglycemia

All sulfonylureas, including AMARYL, can crusade severe hypoglycemia [run across ADVERSE REACTIONS]. The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. These impairments may present a risk in situations where these abilities are particularly important, such equally driving or operating other machinery. Severe hypoglycemia tin lead to unconsciousness or convulsions and may effect in temporary or permanent impairment of encephalon function or expiry.

Patients must be educated to recognize and manage hypoglycemia. Use caution when initiating and increasing AMARYL doses in patients who may be predisposed to hypoglycemia (e.yard., the elderly, patients with renal impairment, patients on other anti-diabetic medications). Debilitated or malnourished patients, and those with adrenal, pituitary, or hepatic harm are specially susceptible to the hypoglycemic activeness of glucose-lowering medications. Hypoglycemia is also more likely to occur when caloric intake is scarce, after severe or prolonged exercise, or when alcohol is ingested.

Early alarm symptoms of hypoglycemia may exist unlike or less pronounced in patients with autonomic neuropathy, the elderly, and in patients who are taking beta-adrenergic blocking medications or other sympatholytic agents. These situations may result in astringent hypoglycemia before the patient is enlightened of the hypoglycemia.

Hypersensitivity Reactions

There have been postmarketing reports of hypersensitivity reactions in patients treated with AMARYL, including serious reactions such as anaphylaxis, angioedema, and Stevens-Johnson Syndrome. If a hypersensitivity reaction is suspected, promptly discontinue AMARYL, assess for other potential causes for the reaction, and institute alternative treatment for diabetes.

Hemolytic Anemia

Sulfonylureas can cause hemolytic anemia in patients with glucose half-dozen-phosphate dehydrogenase (G6PD) deficiency. Considering AMARYL is a sulfonylurea, utilise caution in patients with G6PD deficiency and consider the use of a non-sulfonylurea alternative. In that location are besides postmarketing reports of hemolytic anemia in patients receiving AMARYL who did non have known G6PD deficiency [see ADVERSE REACTIONS].

Increased Chance Of Cardiovascular Bloodshed With Sulfonylureas

The assistants of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular bloodshed as compared to handling with diet lonely or diet plus insulin. This warning is based on the written report conducted by the University Group Diabetes Programme (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 not-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups UGDP reported that patients treated for 5 to 8 years with diet plus a stock-still dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular bloodshed approximately two-½ times that of patients treated with diet lone. A significant increment in total bloodshed was non observed, but the apply 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 report provide an acceptable basis for this warning. The patient should exist informed of the potential risks and advantages of AMARYL 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 use to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of activity and chemical structure.

Macrovascular Outcomes

In that location have been no clinical studies establishing conclusive testify of macrovascular hazard reduction with AMARYL or whatsoever other anti-diabetic drug.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, And Damage Of Fertility

Studies in rats at doses of upwards to 5000 parts per million (ppm) in complete feed (approximately 340 times the maximum recommended human dose, based on expanse) for xxx months showed no evidence of carcinogenesis. In mice, administration of glimepiride for 24 months resulted in an increment in benign pancreatic adenoma formation that was dose-related and was thought to be the issue of chronic pancreatic stimulation. No adenoma germination in mice was observed at a dose of 320 ppm in consummate feed, or 46-54 mg/kg torso weight/day. This is near 35 times the maximum man recommended dose of 8 mg once daily based on surface surface area.

Glimepiride was non-mutagenic in a bombardment of in vitro and in vivo mutagenicity studies (Ames test, somatic cell mutation, chromosomal abnormality, unscheduled Dna synthesis, and mouse micronucleus examination).

There was no upshot of glimepiride on male mouse fertility in animals exposed upward to 2500 mg/kg body weight ( > i,700 times the maximum recommended human dose based on surface area). Glimepiride had no effect on the fertility of male person and female person rats administered upwards to 4000 mg/kg trunk weight (approximately 4,000 times the maximum recommended man dose based on surface area).

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no acceptable and well-controlled studies of AMARYL in meaning women. In brute studies there was no increase in built anomalies, just an increase in fetal deaths occurred in rats and rabbits at glimepiride doses 50 times (rats) and 0.i times (rabbits) the maximum recommended homo dose (based on body surface area). This fetotoxicity, observed only at doses inducing maternal hypoglycemia, is believed to be directly related to the pharmacologic (hypoglycemic) action of glimepiride and has been similarly noted with other sulfonylureas. AMARYL should exist used during pregnancy only if the potential benefit justifies the potential run a risk to the fetus. Because data suggest that abnormal blood glucose during pregnancy is associated with a higher incidence of built abnormalities, diabetes treatment during pregnancy should maintain blood glucose as close to normal as possible.

Nonteratogenic Effects

Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers receiving a sulfonylurea at the time of commitment.

Nursing Mothers

It is not known whether AMARYL is excreted in human being milk. During pre- and postal service-natal studies in rats, significant concentrations of glimepiride were present in breast milk and the serum of the pups. Offspring of rats exposed to loftier levels of glimepiride during pregnancy and lactation developed skeletal deformities consisting of shortening, thickening, and bending of the humerus during the postnatal period. These skeletal deformations were determined to be the event of nursing from mothers exposed to glimepiride. Based on these animal data and the potential for hypoglycemia in a nursing infant, a decision should be fabricated whether to discontinue nursing or discontinue AMARYL, taking into account the importance of AMARYL to the mother.

Pediatric Use

The pharmacokinetics, efficacy and safety of AMARYL have been evaluated in pediatric patients with blazon 2 diabetes every bit described below. AMARYL is not recommended in pediatric patients because of its adverse effects on body weight and hypoglycemia.

The pharmacokinetics of a one mg single dose of AMARYL was evaluated in xxx patients with type 2 diabetes (male = vii; female = 23) between ages x and 17 years. The mean (± SD) AUC (339±203 ngÂ·hour/mL), Cmax (102±48 ng/mL) and t½ (3.1±one.7 hours) for glimepiride were comparable to historical data from adults (AUC(0-terminal) 315±96 ngÂ·hour/mL, Cmax 103±34 ng/mL and t½ 5.3±iv.ane hours).

The condom and efficacy of AMARYL in pediatric patients was evaluated in a single-blind, 24-calendar week trial that randomized 272 patients (8-17 years of historic period) with blazon 2 diabetes to AMARYL (n=135) or metformin (n=137). Both handling-naive patients (those treated with merely nutrition and practice for at least 2 weeks prior to randomization) and previously treated patients (those previously treated or currently treated with other oral antidiabetic medications for at to the lowest degree 3 months) were eligible to participate. Patients who were receiving oral antidiabetic agents at the time of study entry discontinued these medications before randomization without a washout period. AMARYL was initiated at 1 mg, and and then titrated upward to 2, 4 or viii mg (mean last dose 4 mg) through Calendar week 12, targeting a cocky-monitored fasting fingerstick blood glucose < 126 mg/dL. Metformin was initiated at 500 mg twice daily and titrated at Calendar week 12 upwards to 1000 mg twice daily (mean terminal dose 1365 mg).

Afterwards 24 weeks, the overall mean treatment difference in HbA1c between AMARYL and metformin was 0.ii%, favoring metformin (95% confidence interval -0.3% to +0.half-dozen%). Based on these results, the trial did not meet its primary objective of showing a similar reduction in HbA1c with AMARYL compared to metformin.

Table two: Change from Baseline in HbA and Body Weight in Pediatric Patients Taking Amaryl or Metformin

	Metformin	AMARYL
Treatment-Naive Patients*	North=69	Northward=72
HbA1C (%)
Baseline (mean)	8.2	8.3
Alter from baseline (adapted LS mean)†	-1.two	-1.0
Adjusted Handling Deviation‡(95%CI)	0.ii (-0.3; 0.6)
Previously Treated Patients*	Northward=57	N=55
HbA1C (%)
Baseline (hateful)	9.0	8.seven
Change from baseline (adjusted LS mean)†	-0.2	0.two
Adjusted Treatment Difference‡ (95%CI)	0.four (-0.4; ane.two)
Trunk Weight (kg)*	Northward=126	Northward=129
Baseline (mean)	67.3	66.5
Change from baseline (adjusted LS hateful)†	0.7	2.0
Adjusted Treatment Departure‡ (95% CI)	1.three (0.three; 2.3)
*Intent-to-treat population using final-ascertainment-carried-forward for missing information (AMARYL, n=127; metformin, n=126) †adapted for baseline HbA 1c and Tanner Stage ‡Difference is AMARYL - metformin with positive differences favoring metformin

The profile of adverse reactions in pediatric patients treated with AMARYL was like to that observed in adults [see ADVERSE REACTIONS].

Hypoglycemic events documented past claret glucose values < 36 mg/dL were observed in 4% of pediatric patients treated with AMARYL and in 1% of pediatric patients treated with metformin. One patient in each treatment group experienced a severe hypoglycemic episode (severity was determined by the investigator based on observed signs and symptoms).

Geriatric Use

In clinical trials of AMARYL, 1053 of 3491 patients (thirty%) were > 65 years of age. No overall differences in prophylactic or effectiveness were observed between these patients and younger patients, simply greater sensitivity of some older individuals cannot be ruled out.

There were no pregnant differences in glimepiride pharmacokinetics between patients with type 2 diabetes ≤ 65 years (n=49) and those > 65 years (due north=42) [see CLINICAL PHARMACOLOGY].

Glimepiride is substantially excreted past the kidney. Elderly patients are more likely to take renal damage. In addition, hypoglycemia may be hard to recognize in the elderly [run into DOSAGE AND Administration and WARNINGS AND PRECAUTIONS]. Utilise caution when initiating AMARYL and increasing the dose of AMARYL in this patient population.

Renal Damage

To minimize the risk of hypoglycemia, the recommended starting dose of AMARYL is ane mg daily for all patients with type 2 diabetes and renal impairment [see DOSAGE AND Administration and WARNINGS AND PRECAUTIONS].

A multiple-dose titration study was conducted in 16 patients with type 2 diabetes and renal harm using doses ranging from 1 mg to 8 mg daily for 3 months. Baseline creatinine clearance ranged from 10-60 mL/min. The pharmacokinetics of AMARYL were evaluated in the multiple-dose titration study and the results were consistent with those observed in patients enrolled in a single-dose study. In both studies, the relative total clearance of AMARYL increased when kidney role was impaired. Both studies too demonstrated that the elimination of the two major metabolites was reduced in patients with renal impairment [run into CLINICAL PHARMACOLOGY].

OVERDOSE

An overdosage of AMARYL, as with other sulfonylureas, tin produce severe hypoglycemia. Balmy episodes of hypoglycemia tin can exist treated with oral glucose. Severe hypoglycemic reactions constitute medical emergencies requiring firsthand handling. Severe hypoglycemia with blackout, seizure, or neurological harm can be treated with glucagon or intravenous glucose. Continued observation and boosted carbohydrate intake may be necessary considering hypoglycemia may recur after apparent clinical recovery [encounter WARNINGS AND PRECAUTIONS].

CONTRAINDICATIONS

AMARYL is contraindicated in patients with a history of a hypersensitivity reaction to:

Glimepiride or any of the product's ingredients [see WARNINGS AND PRECAUTIONS].

Sulfonamide derivatives: Patients who have adult an allergic reaction to sulfonamide derivatives may develop an allergic reaction to AMARYL. Do not use AMARYL in patients who accept a history of an allergic reaction to sulfonamide derivatives.

Reported hypersensitivity reactions include cutaneous eruptions with or without pruritus as well as more serious reactions (e.g. anaphylaxis, angioedema, Stevens-Johnson Syndrome, dyspnea) [run into WARNINGS AND PRECAUTIONS and Adverse REACTIONS].

CLINICAL PHARMACOLOGY

Mechanism Of Action

Glimepiride primarily lowers claret glucose past stimulating the release of insulin from pancreatic beta cells. Sulfonylureas bind to the sulfonylurea receptor in the pancreatic beta-cell plasma membrane, leading to closure of the ATP-sensitive potassium channel, thereby stimulating the release of insulin.

Pharmacodynamics

In healthy subjects, the time to reach maximal outcome (minimum blood glucose concentrations) was approximately two-iii hours afterwards unmarried oral doses of AMARYL. The effects of AMARYL on HbA1c, fasting plasma glucose, and postal service-prandial glucose have been assessed in clinical trials [see Clinical Studies].

Pharmacokinetics

Assimilation

Studies with unmarried oral doses of glimepiride in healthy subjects and with multiple oral doses in patients with type 2 diabetes showed peak drug concentrations (Cmax) 2 to 3 hours mail-dose. When glimepiride was given with meals, the hateful Cmax and AUC (expanse under the bend) were decreased past viii% and 9%, respectively.

Glimepiride does non accumulate in serum post-obit multiple dosing. The pharmacokinetics of glimepiride does not differ betwixt healthy subjects and patients with blazon ii diabetes. Clearance of glimepiride after oral administration does not change over the 1 mg to 8 mg dose range, indicating linear pharmacokinetics.

In good for you subjects, the intra- and inter-individual variabilities of glimepiride pharmacokinetic parameters were 15-23% and 24-29%, respectively.

Distribution

Later intravenous dosing in good for you subjects, the volume of distribution (Vd) was 8.8 L (113 mL/kg), and the full torso clearance (CL) was 47.viii mL/min. Protein binding was greater than 99.5%.

Metabolism

Glimepiride is completely metabolized by oxidative biotransformation afterwards either an intravenous or oral dose. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl derivative (M2). Cytochrome P450 2C9 is involved in the biotransformation of glimepiride to M1. M1 is further metabolized to M2 by one or several cytosolic enzymes. M2 is inactive. In animals, M1 possesses almost i-3rd of the pharmacological activity of glimepiride, but information technology is unclear whether M1 results in clinically meaningful effects on blood glucose in humans.

Excretion

When ¹⁴C-glimepiride was given orally to 3 healthy male person subjects, approximately 60% of the total radioactivity was recovered in the urine in 7 days. M1 and M2 accounted for eighty-90% of the radioactive decay recovered in the urine. The ratio of M1 to M2 in the urine was approximately iii:ii in two subjects and iv:1 in i subject. Approximately 40% of the total radioactivity was recovered in feces. M1 and M2 deemed for virtually lxx% (ratio of M1 to M2 was ane:3) of the radioactive decay recovered in feces. No parent drug was recovered from urine or feces. After intravenous dosing in patients, no significant biliary excretion of glimepiride or its M1 metabolite was observed.

Geriatric Patients

A comparing of glimepiride pharmacokinetics in patients with type 2 diabetes ≤ 65 years and those > 65 years was evaluated in a multiple-dose report using AMARYL 6 mg daily. There were no significant differences in glimepiride pharmacokinetics between the ii historic period groups. The mean AUC at steady state for the older patients was approximately thirteen% lower than that for the younger patients; the hateful weight-adjusted clearance for the older patients was approximately eleven% higher than that for the younger patients.

Gender

There were no differences between males and females in the pharmacokinetics of glimepiride when adjustment was made for differences in body weight.

Race

No studies take been conducted to assess the furnishings of race on glimepiride pharmacokinetics just in placebo-controlled trials of AMARYL in patients with type 2 diabetes, the reduction in HbA was comparable in Caucasians (n = 536), blacks (n = 63), and Hispanics (n = 63).

Renal Impairment

A single-dose, open-characterization study AMARYL 3 mg was administered to patients with mild, moderate and astringent renal impairment equally estimated by creatinine clearance (CLcr): Group I consisted of v patients with mild renal impairment (CLcr > 50 mL/min), Group Ii consisted of three patients with moderate renal impairment (CLcr = 20-50 mL/min) and Group III consisted of 7 patients with astringent renal damage (CLcr < 20 mL/min). Although, glimepiride serum concentrations decreased with decreasing renal function, Group Three had a 2.3-fold higher hateful AUC for M1 and an 8.vi-fold higher hateful AUC for M2 compared to corresponding hateful AUCs in Group I. The apparent terminal half-life (T½) for glimepiride did not alter, while the half-lives for M1 and M2 increased every bit renal part decreased. Mean urinary excretion of M1 plus M2 as a pct of dose decreased from 44.4% for Grouping I to 21.nine% for Group II and 9.3% for Group Three.

Hepatic Impairment

It is unknown whether in that location is an result of hepatic impairment on AMARYL pharmacokinetics considering the pharmacokinetics of AMARYL has not been adequately evaluated in patients with hepatic impairment.

Obese Patients

The pharmacokinetics of glimepiride and its metabolites were measured in a singledose report involving 28 patients with blazon 2 diabetes who either had normal body weight or were morbidly obese. While the tmax, clearance, and volume of distribution of glimepiride in the morbidly obese patients were similar to those in the normal weight group, the morbidly obese had lower Cmax and AUC than those of normal trunk weight. The hateful Cmax, AUC0-24, AUC0-∞ values of glimepiride in normal vs. morbidly obese patients were 547 ± 218 ng/mL vs. 410 ± 124 ng/mL, 3210 ± 1030 hours·ng/mL vs. 2820 ± 1110 hours·ng/mL and 4000 ± 1320 hours·ng/mL vs. 3280 ± 1360 hours·ng/mL, respectively.

Drug Interactions

Aspirin: In a randomized, double-bullheaded, 2-period, crossover study, healthy subjects were given either placebo or aspirin 1 gram three times daily for a total treatment period of 5 days. On Day four of each report period, a single 1 mg dose of AMARYL was administered. The AMARYL doses were separated past a fourteen-day washout period. Co-administration of aspirin and AMARYL resulted in a 34% decrease in the mean glimepiride AUC and a four% subtract in the mean glimepiride Cmax.

Colesevelam: Concomitant administration of colesevelam and glimepiride resulted in reductions in glimepiride AUC0-∞ and Cmax of 18% and 8%, respectively. When glimepiride was administered 4 hours prior to colesevelam, there was no pregnant change in glimepiride AUC0-∞ and Cmax, -6% and three%, respectively [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].

Cimetidine and Ranitidine: In a randomized, open-characterization, 3-way crossover study, good for you subjects received either a unmarried 4 mg dose of AMARYL alone, AMARYL with ranitidine (150 mg twice daily for 4 days; AMARYL was administered on Day 3), or AMARYL with cimetidine (800 mg daily for iv days; AMARYL was administered on 24-hour interval 3). Co-assistants of cimetidine or ranitidine with a single 4 mg oral dose of AMARYL did not significantly alter the absorption and disposition of glimepiride.

Propranolol: In a randomized, double-bullheaded, two-period, crossover study, healthy subjects were given either placebo or propranolol 40 mg three times daily for a total handling menstruum of 5 days. On Twenty-four hours 4 or each study period, a single 2 mg dose of AMARYL was administered. The AMARYL doses were separated by a 14-day washout menses. Concomitant administration of propranolol and AMARYL significantly increased glimepiride Cmax, AUC, and T½ by 23%, 22%, and 15%, respectively, and decreased glimepiride CL/f by 18%. The recovery of M1 and M2 from urine was not changed.

Warfarin: In an open-label, two-manner, crossover study, good for you subjects received iv mg of AMARYL daily for 10 days. Single 25 mg doses of warfarin were administered six days before starting AMARYL and on Day 4 of AMARYL assistants. The concomitant administration of AMARYL did not alter the pharmacokinetics of R- and Southward-warfarin enantiomers. No changes were observed in warfarin plasma protein bounden. AMARYL resulted in a statistically pregnant decrease in the pharmacodynamic response to warfarin. The reductions in mean surface area nether the prothrombin time (PT) curve and maximum PT values during AMARYL treatment were 3.3% and 9.ix%, respectively, and are unlikely to be clinically relevant.

Clinical Studies

Monotherapy

A total of 304 patients with type two diabetes already treated with sulfonylurea therapy participated in a 14-week, multicenter, randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of AMARYL monotherapy. Patients discontinued their sulfonylurea therapy and then entered a 3- week placebo washout period followed past randomization into 1 of 4 treatment groups: placebo (due north=74), AMARYL 1 mg (north=78), AMARYL 4 mg (n=76) and AMARYL eight mg (n=76). All patients randomized to AMARYL started 1 mg daily. Patients randomized to AMARYL four mg or eight mg had blinded, forced titration of the AMARYL dose at weekly intervals, start to 4 mg and then to 8 mg, as long equally the dose was tolerated, until the randomized dose was reached. Patients randomized to the 4 mg dose reached the assigned dose at Week two. Patients randomized to the eight mg dose reached the assigned dose at Week iii. One time the randomized dose level was reached, patients were to be maintained at that dose until Week 14. Approximately 66% of the placebo-treated patients completed the trial compared to 81% of patients treated with glimepiride one mg and 92% of patients treated with glimepiride four mg or 8 mg. Compared to placebo, treatment with AMARYL 1 mg, 4 mg and 8 mg daily provided statistically significant improvements in HbA1c compared to placebo (Table 3).

Table 3: 14-week Monotherapy Trial Comparing AMARYL to Placebo in Patients Previously Treated With Sulfonylurea Therapy*

	Placebo (Due north=74)	AMARYL
	Placebo (Due north=74)	1 mg (N=78)	4 mg (N=76)	viii mg (Due north=76)
HbA1C (%)
	n=59	n=65	north=65	n=68
Baseline (mean)	8.0	7.nine	7.9	8.0
Modify from Baseline (adjusted mean†)	1.five	0.3	-0.iii	-0.4
Difference from Placebo (adapted mean†) 95% confidence interval		-1.2* (-1.5, -0.viii)	-ane.eight* (-2.ane, -1.4)	-i.8* (-2.2, -ane.five)
Mean Baseline Weight (kg)
	n=67	north=76	northward=75	due north=73
Baseline (mean)	85.vii	84.3	86.1	85.5
Change from Baseline (adjusted hateful†)	-2.3	-0.2	0.v	1.0
Difference from Placebo (adjusted mean†) 95% confidence interval		2.0‡ (i.4, 2.7)	ii.8‡ (2.1, 3.v)	3.2‡ (2.5, 4.0)
*Intent-to-care for population using terminal observation on study †Least squares mean adapted for baseline value ‡p ≤ 0.001

A full of 249 patients who were treatment-naive or who had received express handling with antidiabetic therapy in the by were randomized to receive 22 weeks of treatment with either AMARYL (n=123) or placebo (n=126) in a multicenter, randomized, double-blind, placebo-controlled, dose-titration trial. The starting dose of AMARYL was i mg daily and was titrated upward or downwardly at 2-week intervals to a goal FPG of ninety-150 mg/dL. Blood glucose levels for both FPG and PPG were analyzed in the laboratory. Following 10 weeks of dose aligning, patients were maintained at their optimal dose (1, two, three, 4, 6 or 8 mg) for the remaining 12 weeks of the trial. Treatment with AMARYL provided statistically significant improvements in HbA1c and FPG compared to placebo (Table 4).

Table 4: 22-Week Monotherapy Trial Comparison AMARYL to Placebo in Patients Who Were Handling-Naïve or Who Had No Recent Handling with Antidiabetic Therapy*

	Placebo (N=126)	AMARYL (N=123)
HbA1C (%)	n=97	n=106
Baseline (mean)	9.1	9.three
Modify from Baseline (adapted meant)	-1.ane*	-ii.2*
Difference from Placebo (adapted meant)	-one.1*
95% confidence interval	(-1.5,-0.8)
Trunk Weight (kg)	n=122	n=119
Baseline (mean)	86.5	87.1
Modify from Baseline (adjusted meant)	-0.ix	1.viii
Difference from Placebo (adjusted meant)	2.7
95% confidence interval	(i.9, 3.half-dozen)
* Intent to care for population using final ascertainment on report † Least squares mean adapted for baseline value ‡ p ≤ 0.0001

PATIENT Information

Inform patients about the importance of adherence to dietary instructions, of a regular do program, and of regular testing of blood glucose.

Inform patients about the potential side furnishings of AMARYL including hypoglycemia and weight proceeds.

Explicate the symptoms and treatment of hypoglycemia too every bit conditions that predispose to hypoglycemia. Patients should be informed that the power to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially of import, such equally driving or operating other mechanism.

Patients with diabetes should exist brash to inform their healthcare provider if they are pregnant, contemplating pregnancy, breastfeeding, or contemplating breastfeeding.

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