Repaglinide

Mechanism of Action

Increases insulin secretion by blocking ATP potassium channels on beta islet cells, which facilitates calcium entry through calcium channels; increased intracellular calcium stimulates insulin release from pancreatic beta cells

Absorption

Bioavailability: 56%

Onset: 15-60 min (increased insulin levels)

Duration: 4-6 hr

Peak plasma time: 1 hr

Distribution

Protein bound: >98%

Vd: 31 L

Metabolism

Metabolized extensively in liver, by CYP3A4 and CYP2C8

Metabolites: Oxidized dicarboxylic acid, aromatic amine, acyl glucuronide (inactive)

Elimination

Half-life: 1 hr

Total body clearance: 38 L/hr

Excretion: Feces (90%); urine (8%)

Tell your doctor about all prescription, non-prescription, illegal, recreational, herbal, nutritional, or dietary drugs you're taking, especially those listed in the Warning section or any of the following:

• Acetophenazine (Tindal)
• Arthritis drugs
• Aspirin
• Blood-pressure medicines
• Carbamazepine (Tegretol)
• Chloramphenicol (Chloromycetin)
• Chlorpromazine (Thorazine)
• Contraceptives (such as birth-control pills)
• Corticosteroids
• Erythromycin
• Estrogens
• Fluphenazine (Prolixin)
• Isoniazid (Nydrazid, Rifamate)
• Ketoconazole (Nizoral)
• Mesoridazine (Serentil)
• Perphenazine (Trilafon)
• Phenelzine (Nardil)
• Phenobarbital (Luminal)
• Phenytoin (Dilantin)
• Probenecid (Benemid)
• Prochlorperazine (Compazine)
• Promazine (Sparine)
• Promethazine (Phenergan)
• Rifampin (Rifadin, Rimactane, Rifamate)
• Thioridazine (Mellaril)
• Tranylcypromine (Parnate)
• Trifluoperazine (Stelazine)
• Triflupromazine (Vesprin)
• Trimeprazine (Temaril)
• Troglitazone (Rezulin)
• Warfarin (Coumadin)
• Water pills (diuretics)
• Vitamins

Repaglinide and Alcohol

Alcohol can cause a decrease in blood sugar.

Ask your doctor about consuming alcoholic beverages while you are taking repaglinide.

Repaglinide and Other Interactions

You may experience dizziness while taking this medicine.

Don't drive or operate machinery until you know you can do so safely.

If you take too much repaglinide, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

Repaglinide is an oral diabetes medicine that helps control blood sugar levels by causing the pancreas to produce insulin.

Repaglinide is used together with diet and exercise to improve blood sugar control in adults with type 2 diabetes mellitus. This medicine is not for treating type 1 diabetes.

Repaglinide may also be used for purposes not listed in this medication guide.

Contraindications

• Sole therapy in patients with type 1 (insulin-dependent) diabetes mellitus or in patients with diabetes complicated by acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma.1 5 61 71

• Known hypersensitivity to repaglinide or any ingredient in the formulation.1 61

Warnings/Precautions

General Precautions

Potential for hypoglycemia.1 5 14 80 81 99 100 101 102 104 105 Debilitated, malnourished, or geriatric patients and those with hepatic or severe renal impairment or adrenal or pituitary insufficiency may be particularly susceptible.1 5 61 Strenuous exercise, alcohol ingestion, insufficient caloric intake, or use in combination with other antidiabetic agents may increase risk.1 5 61 71

Hypoglycemia may be difficult to recognize in geriatric patients or in those receiving β-adrenergic blocking agents.1 5 Increased risk of serious hypoglycemia in patients with hepatic failure, who may have reduced clearance of repaglinide and diminished gluconeogenic capacity.1 5 61 64

Appropriate patient selection, patient education, and careful attention to dosage are important to avoid hypoglycemic episodes.1

Possible loss of glycemic control during periods of stress (e.g., fever, trauma, infection, surgery).1 31 61 71 Temporary discontinuance of repaglinide and administration of insulin may be required.1 31 61 71 May reinstitute after the acute episode is resolved based on clinician judgment.40 71

Specific Populations

Category C.1 Abnormal maternal blood glucose concentrations during pregnancy may be associated with a higher incidence of congenital abnormalities.1 31 48 71

Most experts recommend use of insulin during pregnancy.1 14 56 64 71 109

Distributed into milk in rats; not known whether distributed into human milk.1

Discontinue nursing or the drug.1 14 71

Safety and efficacy of repaglinide in children <18 years of age not established.40 71 However, the American Diabetes Association (ADA) states that most pediatric diabetologists use oral antidiabetic agents in children with type 2 diabetes mellitus because of greater patient compliance and convenience for the patient’s family.109

Safety and efficacy appear to be similar in geriatric and younger patients except for the expected age-related increase in cardiovascular morbidity observed with repaglinide and other comparative oral antidiabetic agents.1 5 14 1 5 14 101 (See Absorption: Special Populations under Pharmacokinetics.) No increase in frequency and severity of hypoglycemia in geriatric versus younger patients receiving repaglinide.1 14 101

Individualize antidiabetic therapy when implementing strict glycemic control considering advanced age, comorbid conditions, preexisting clinically relevant microvascular and macrovascular complications or other vascular risk factors, degree of hyperglycemia, and life expectancy.31 58

Use with caution.1 5 59 71

Use with caution.1 5 61

Common Adverse Effects

Hypoglycemia,1 5 14 80 81 99 100 101 102 104 105 upper respiratory tract infection,1 headache,1 64 71 80 81 arthralgia,1 sinusitis,1 nausea,1 diarrhea,1 back pain.1

Your doctor will want to check your progress at regular visits, especially during the first few weeks you take repaglinide. Blood and urine tests may be needed to check for unwanted effects.

Do not take gemfibrozil (Lopid®) while you are taking repaglinide. Using these medicines together may cause unwanted effects.

It is very important to follow carefully any instructions from your health care team about:

• Alcohol—Drinking alcohol may cause severe low blood sugar. Discuss this with your health care team.
• Other medicines—Do not take other medicines during the time you are taking repaglinide unless they have been discussed with your doctor. This especially includes nonprescription medicines such as aspirin, and medicines for appetite control, asthma, colds, cough, hay fever, or sinus problems.
• Counseling—Other family members need to learn how to prevent side effects or help with side effects if they occur. Also, patients with diabetes may need special counseling about diabetes medicine dosing changes that might occur because of lifestyle changes, such as changes in exercise and diet. Furthermore, counseling on contraception and pregnancy may be needed because of the problems that can occur in patients with diabetes during pregnancy.
• Travel—Keep a recent prescription and your medical history with you. Be prepared for an emergency as you would normally. Make allowances for changing time zones and keep your meal times as close as possible to your usual meal times.

In case of emergency—There may be a time when you need emergency help for a problem caused by your diabetes. You need to be prepared for these emergencies. It is a good idea to wear a medical identification (ID) bracelet or neck chain at all times. Also, carry an ID card in your wallet or purse that says that you have diabetes and a list of all of your medicines.

repaglinide may cause hypoglycemia (low blood sugar). This is more common when repaglinide is taken together with certain medicines. Low blood sugar must be treated before it causes you to pass out (unconsciousness). People feel different symptoms of low blood sugar. It is important that you learn which symptoms you usually have so you can treat it quickly. Talk to your doctor about the best way to treat low blood sugar.

Hyperglycemia (high blood sugar) may occur if you do not take enough or skip a dose of your medicine, overeat or do not follow your meal plan, have a fever or infection, or do not exercise as much as usual. High blood sugar can be very serious and must be treated right away. It is important that you learn which symptoms you have in order to treat it quickly. Talk to your doctor about the best way to treat high blood sugar.

repaglinide may make you dizzy or drowsy. Avoid driving, using machines, or doing anything else that could be dangerous until you know how repaglinide affects you.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Higher and more prolonged serum concentrations have been observed in patients with moderate to severe hepatic impairment.

CrCl ≥40 mL/minute: No dosage adjustment necessary.

CrCl 20 to 40 mL/minute: Initial: 0.5 mg with meals; titrate carefully.

CrCl <20 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Hemodialysis: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Abiraterone Acetate: May increase the serum concentration of CYP2C8 Substrates. Monitor therapy

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Atazanavir: May increase the serum concentration of Repaglinide. Management: Use of repaglinide or other narrow therapeutic index CYP2C8 substrates with atazanavir without concurrent ritonavir is not recommended. If repaglinide is used with ritonavir-boosted atazanavir, no significant interaction is expected. Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Clopidogrel: May increase the serum concentration of Repaglinide. Management: Avoid use of clopidogrel and repaglinide if possible; if the combination must be used, limit total repaglinide daily dose to no more than 4 mg. This is contraindicated in some non-US labeling. Consider therapy modification

CycloSPORINE (Systemic): May increase the serum concentration of Repaglinide. Monitor therapy

CYP2C8 Inducers (Strong): May increase the metabolism of CYP2C8 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C8 Inhibitors (Moderate): May decrease the metabolism of CYP2C8 Substrates. Monitor therapy

CYP2C8 Inhibitors (Strong): May decrease the metabolism of CYP2C8 Substrates. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Repaglinide. Management: The addition of a CYP2C8 inhibitor to this drug combination may substantially increase the magnitude of increase in repaglinide exposure. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP2C8 Substrates. Management: Seek alternatives to the CYP2C8 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May increase the serum concentration of Repaglinide. Monitor therapy

Eltrombopag: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Gemfibrozil: May increase the serum concentration of Repaglinide. The addition of itraconazole may augment the effect of gemfibrozil on repaglinide. Avoid combination

Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

HMG-CoA Reductase Inhibitors: May increase the serum concentration of Repaglinide. Monitor therapy

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Leflunomide: May increase the serum concentration of Repaglinide. Specifically, the active metabolite of leflunomide may increase repaglinide concentrations. Monitor therapy

Macrolide Antibiotics: May increase the serum concentration of Repaglinide. Exceptions: Azithromycin (Systemic); Fidaxomicin; Roxithromycin; Spiramycin. Monitor therapy

MAO Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP2C8 Substrates. Management: Use CYP2C8 substrates at the lowest recommended dose, and monitor closely for adverse effects (including myopathy), during and in the 2 weeks following mifepristone treatment. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Prothionamide: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

RifAMPin: May decrease the serum concentration of Repaglinide. Management: Consider alternatives to this combination. Dose timing may substantially affect this interaction; in clinical studies, the lowest magnitude of interaction was seen when repaglinide was given 1 h after rifampin (compared to 0, 12, or 24 h). Consider therapy modification

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Telaprevir: May increase the serum concentration of Repaglinide. Monitor therapy

Teriflunomide: May increase the serum concentration of Repaglinide. Monitor therapy

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Trimethoprim: May decrease the metabolism of Repaglinide. Monitor therapy

Commonly reported side effects of repaglinide include: hypoglycemia. See below for a comprehensive list of adverse effects.

Individualize therapy:
Dose preprandially 2, 3, or 4 times a day
-For patients not previously treated with antidiabetic agents or whose glycosylated hemoglobin (HbA1c) is less than 8%:
Initial dose: 0.5 mg orally with each meal
-For patients previously treated with antidiabetic agents or whose HbA1c is 8% or higher:
Initial dose: 1 or 2 mg orally with each meal

Dose Adjustments: Based upon blood glucose response, double the preprandial dose up to a maximum meal time dose of 4 mg until satisfactory glycemic response is achieved; allow at least 1 week to assess response after each dose adjustment.
Recommended Dose Range: 0.5 to 4 mg orally with each meal
Maximum Daily Dose: 16 mg per day

Comments:
-Fasting blood glucose concentrations are generally used to adjust doses, however, postprandial glucose levels may be used in patients whose pre-meal blood glucose levels are satisfactory but whose overall glycemic control (HbA1c) is inadequate.
-When hypoglycemia occurs in patients taking this drug in combination with a thiazolidinedione or metformin, the dose of this drug should be reduced.

Use: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Use with caution; allow longer intervals between dose adjustments to fully assess response.