REPAGLINIDE Drug Interactions: What You Need to Know

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 tablets 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 tablets 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 are co-administered with cyclosporine. CYP2C8 and CYP3A4 Inhibitors Intervention: Repaglinide tablets 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 tablets 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 tablets 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 tablets 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 is co-administered with these drugs. Examples: beta-blockers, clonidine, guanethidine, and reserpine Clopidogrel : Avoid concomitant use; if used concomitantly initiate at 0.5 mg before each meal and limit total daily dose to 4 mg ( 7 ) Cyclosporine : Limit daily dose of repaglinide to 6 mg and increase frequency of glucose monitoring when co-administered ( 7 ) CYP2C8 and CYP3A4 Inhibitors and Drugs That May Increase the Risk of Hypoglycemia : Co-administration may require repaglinide tablets dose reductions and increased frequency of glucose monitoring ( 7 ) CYP2C8 and CYP3A4 Inducers and Drugs That May Decrease the Blood Glucose Lowering Effect of repaglinide tablets : Co-administration may require repaglinide tablets dose increases and increased frequency of glucose monitoring ( 7 )

Drugs That May Blunt

Signs and Symptoms of Hypoglycemia : Increased frequency of glucose monitoring may be required when co-administered ( 7 )

Repaglinide tablets are contraindicated in patients with:

• Concomitant use of gemfibrozil [see Drug Interactions ( 7.1 )]
• Known hypersensitivity to repaglinide or any inactive ingredients
• Concomitant use with gemfibrozil ( 4 )
• Known hypersensitivity to repaglinide or any inactive ingredients ( 4 )

AND PRECAUTIONS

• Hypoglycemia: repaglinide tablets may cause hypoglycemia. Skip the scheduled dose of repaglinide tablets if a meal is skipped to reduce the risk of hypoglycemia. Reduce the dose of repaglinide tablets if hypoglycemia occurs. ( 5.1 )
• Serious Cardiovascular Adverse Reactions with Concomitant NPH-insulin: repaglinide tablets are not indicated for use in combination with NPH-insulin. ( 5.2 )
• Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with repaglinide tablets. ( 5.3 )

5.1 Hypoglycemia All glinides, including repaglinide tablets, can cause hypoglycemia <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>. Severe hypoglycemia can cause seizures, may be life-threatening, or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery). Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) <span class="opacity-50 text-xs">[see Drug Interactions ( 7 )]</span>, or in patients who experience recurrent hypoglycemia. Factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content), changes in level of physical activity, changes to co-administered medication <span class="opacity-50 text-xs">[see Drug Interactions ( 7 )]</span>, and concomitant use with other antidiabetic agents. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 , 8.7 )]</span>. Patients should administer repaglinide tablets before meals and be instructed to skip the dose of repaglinide tablets if a meal is skipped. In patients who experience hypoglycemia, the dose of repaglinide tablets should be reduced <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 )]</span>. Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.

5.2 Serious Cardiovascular Adverse Reactions with Concomitant Use with NPH-insulin Across seven controlled trials, there were six serious adverse events of myocardial ischemia in patients treated with repaglinide tablets plus NPH-insulin from two studies, and one event in patients using insulin formulations alone from another study [See Adverse Reactions ( 6.1 )]. Repaglinide tablets are not indicated for use in combination with NPH-insulin.

5.3 Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with repaglinide tablets.