Repaglinide (Page 2 of 6)

6.2 Postmarketing Experience

The following additional adverse reactions have been identified during post approval use of repaglinide tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or a causal relationship to drug exposure.

Alopecia
Hemolytic anemia
Pancreatitis
Stevens-Johnson Syndrome
Severe hepatic dysfunction including jaundice and hepatitis

7 DRUG INTERACTIONS

Clinically Important Drug Interactions with Repaglinide Tablets

Table 3 includes a list of drugs with clinically important drug interactions when administered concomitantly with repaglinide tablets and instructions for preventing or managing them.

Table 3: Clinically Important Drug Interactions with Repaglinide Tablets

Gemfibrozil

Clinical Impact:

Gemfibrozil significantly increased repaglinide exposures by 8.1 fold [see Clinical Pharmacology (12.3)]

Intervention:

Do not administer repaglinide tablets to patients receiving gemfibrozil [see Contraindications (4)].

Clopidogrel

Clinical Impact:

Clopidogrel increased repaglinide exposures by 3.9-5.1 fold [see Clinical Pharmacology (12.3)]

Intervention:

Avoid concomitant use of repaglinide tablets with clopidogrel. If concomitant use cannot be avoided, initiate repaglinide tablets at 0.5 mg before each meal and do not exceed a total daily dose of 4 mg [see DOSAGE AND ADMINISTRATION (2.3)]. Increased frequency of glucose monitoring may be required during concomitant use.

Cyclosporine

Clinical Impact:

Cyclosporine increased low dose repaglinide exposures by 2.5 fold [see Clinical Pharmacology (12.3)]

Intervention:

Daily maximum repaglinide tablets dose should be limited to 6 mg, and increased frequency of glucose monitoring may be required when repaglinide tablets is co-administered with cyclosporine.

CYP2C8 and CYP3A4 Inhibitors

Intervention:

Repaglinide tablet dose reductions and increased frequency of glucose monitoring may be required when co-administered.

Examples:

Drugs that are known to inhibit CYP3A4 include antifungal agents (ketoconazole, itraconazole) and antibacterial agents (clarithromycin, erythromycin). Drugs that are known to inhibit CYP2C8 include trimethoprim, gemfibrozil, montelukast, deferasirox, and clopidiogrel.

CYP2C8 and CYP3A4 Inducers

Intervention:

Repaglinide tablet dose increases and increased frequency of glucose monitoring may be required when co-administered

Examples:

Drugs that induce the CYP3A4 and/or 2C8 enzyme systems include rifampin, barbiturates, and carbamezapine

Drugs That May Increase the Risk of Hypoglycemia

Intervention:

Repaglinide tablet dose reductions and increased frequency of glucose monitoring may be required when co-administered.

Examples:

Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, nonsteroidal anti-inflammatory agents (NSAIDs), pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics

Drugs That May Decrease the Blood Glucose Lowering Effect of Repaglinide Tablets

Intervention:

Repaglinide tablet dose increases and increased frequency of glucose monitoring may be required when co-administered.

Examples:

Atypical antipsychotics (e.g., olanzapine and clozapine), calcium channel antagonists, corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones.

Drugs That May Blunt Signs and Symptoms of Hypoglycemia

Intervention:

Increased frequency of glucose monitoring may be required when repaglinide tablets are co-administered with these drugs.

Examples:

beta-blockers, clonidine, guanethidine, and reserpine

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Limited available data from case reports and case series with repaglinide tablets use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). Teratogenicity was not observed in rats and rabbits administered repaglinide during organogenesis at approximately 60 and 1 times the maximum daily clinical dose, based on body surface area. No adverse developmental effects were observed in offspring of rats administered repaglinide during late gestation and lactation at approximately 4 times the maximum daily clinical dose (see Data).

The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20-25% in women with a HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth and macrosomia related morbidity.

Data

Animal Data

Repaglinide was not teratogenic in rats or rabbits at doses 60 times (rats) and approximately 1 times (rabbit) clinical exposure (on a mg/m2 basis) when administered during the period of organogenesis. Offspring of rat dams exposed to repaglinide at ≥22 times clinical exposure on a mg/m2 basis during days 17 to 22 of gestation and during lactation were less viable and developed skeletal deformations consisting of shortening, thickening, and bending of the humerus during the postnatal period. This effect was not seen at doses up to 4 times clinical exposure (on a mg/ m2 basis).

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