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Repaglinide

Pronunciation

(re PAG li nide)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral:

Prandin: 0.5 mg [DSC], 1 mg, 2 mg [contains corn starch]

Generic: 0.5 mg, 1 mg, 2 mg

Brand Names: U.S.

  • Prandin

Pharmacologic Category

  • Antidiabetic Agent, Meglitinide Analog

Pharmacology

Nonsulfonylurea hypoglycemic agent which blocks ATP-dependent potassium channels, depolarizing the membrane and facilitating calcium entry through calcium channels. Increased intracellular calcium stimulates insulin release from the pancreatic beta cells. Repaglinide-induced insulin release is glucose-dependent.

Absorption

Complete

Distribution

Vd: 31 L

Metabolism

Hepatic via CYP3A4 and CYP2C8 isoenzymes and glucuronidation to inactive metabolites

Excretion

Feces (~90%, <2% as unchanged drug); Urine (~8%, 0.1% as unchanged drug)

Time to Peak

Plasma: 1 hour

Half-Life Elimination

~1 hour

Protein Binding

Plasma: >98% to albumin

Special Populations: Renal Function Impairment

AUC and Cmax are increased in severe renal impairment.

Special Populations: Hepatic Function Impairment

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

Use: Labeled Indications

Diabetes mellitus, type 2: To improve glycemic control in adults with type 2 diabetes mellitus (noninsulin dependent) as an adjunct to diet and exercise

Guideline recommendations: Meglitinides (eg, repaglinide) are generally not used in patients with type 2 diabetes except in specific situations, such as patients with irregular meal schedules, those who develop late postprandial hypoglycemia when taking a sulfonylurea, or instead of a sulfonylurea in patients with sulfa allergies (ADA 2017a).

Contraindications

Hypersensitivity to repaglinide or any component of the formulation; concurrent gemfibrozil therapy

Canadian labeling: Additional contraindications (not in US labeling): Severe hepatic impairment; concurrent use with clopidogrel; diabetic ketoacidosis, with or without coma; type 1 diabetes (insulin dependent)

Dosing: Adult

Diabetes mellitus, type 2: Oral:

Patients whose HbA1c is <8%: Initial: 0.5 mg before each meal (2, 3, or 4 times/day depending on number of meals); may double the dose with each meal at intervals of ≥1 week until adequate glycemic control is achieved; maximum: 4 mg/dose or 16 mg/day.

Patients whose HbA1c is ≥8%: Initial: 1 or 2 mg before each meal (2, 3, or 4 times/day depending on number of meals); may double the dose with each meal at intervals of ≥1 week until adequate glycemic control is achieved; maximum: 4 mg/dose or 16 mg/day.

Dosage adjustment for concomitant therapy:

Clopidogrel: Avoid concomitant use; if concomitant use is necessary, initiate repaglinide at 0.5 mg before each meal; maximum: 4 mg/day.

Cyclosporine: Maximum: 6 mg/day of repaglinide.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal 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).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling. Use with caution; consider longer intervals between dosage adjustments.

Administration

Oral: Administer within 30 minutes before meals; may be administered preprandially 2, 3, or 4 times/day in response to changes in meal pattern. If a meal is missed, do not administer next scheduled dose; if hypoglycemia occurs, reduce dose.

Dietary Considerations

Administer 30 minutes before meals. Individualized medical nutrition therapy based on ADA recommendations is an integral part of therapy.

Storage

Store at 20°C to 25°C (68°F to 77°F). Protect from moisture.

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2C8 Substrates (High risk with Inhibitors). 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 (High risk with Inducers). 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 (High risk with Inducers). 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 (High risk with Inhibitors). Monitor therapy

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

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

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). 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 (High risk with Inducers). 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 (High risk with Inducers). 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 (High risk with Inducers). 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 (Statins): 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

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

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

MiFEPRIStone: May increase the serum concentration of CYP2C8 Substrates (High risk with Inhibitors). 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 (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

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

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

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification

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

Quinolones: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolones 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 (High risk with Inducers). 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 (High risk with Inducers). Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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 (High risk with Inducers). Monitor therapy

Trimethoprim: May decrease the metabolism of Repaglinide. Monitor therapy

Adverse Reactions

>10%:

Central nervous system: Headache (9% to 11%)

Endocrine & metabolic: Hypoglycemia (16% to 31%)

Respiratory: Upper respiratory tract infection (10% to 16%)

1% to 10%:

Cardiovascular: Ischemia (4%), chest pain (2% to 3%)

Gastrointestinal: Diarrhea (4% to 5%), constipation (2% to 3%)

Genitourinary: Urinary tract infection (2% to 3%)

Hypersensitivity: Hypersensitivity reaction (1% to 2%)

Neuromuscular & skeletal: Back pain (5% to 6%), arthralgia (3% to 6%)

Respiratory: Sinusitis (3% to 6%), bronchitis (2% to 6%)

<1% (Limited to important or life-threatening): Alopecia, anaphylactoid reaction, blurred vision (transient), cardiac arrhythmia, ECG abnormality, hemolytic anemia, hepatic insufficiency (severe), hepatitis, hypertension, increased liver enzymes, jaundice, leukopenia, myocardial infarction, palpitations, pancreatitis, Stevens-Johnson syndrome, thrombocytopenia, visual disturbance (transient)

Warnings/Precautions

Concerns related to adverse effects:

• Hypoglycemia: Severe hypoglycemia may occur; risk may be increased by changes in meal patterns, changes in physical activity levels, changes to coadministered medications, and concomitant use with other antidiabetic agents.

Disease-related concerns:

• Cardiovascular effects: Some studies suggest oral hypoglycemic drugs may be associated with increased cardiovascular events. Theoretically, repaglinide may also increase cardiovascular events, but there are no long-term studies assessing this concern. Use in combination with NPH insulin is not indicated; in two studies, reports of myocardial ischemia (6 events) in patients using repaglinide plus insulin have caused concern. Further evaluation is required to assess the safety of this combination.

• Hepatic impairment: Use with caution in patients with hepatic impairment; may be more susceptible to glucose-lowering effects.

• Renal impairment: Use with caution in patients with severe renal impairment; may be more susceptible to glucose-lowering effects.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant drug-drug interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: Not for use in patients with diabetic ketoacidosis or patients with type 1 diabetes mellitus (insulin-dependent).

Monitoring Parameters

Monitor fasting blood glucose (periodically) and glycosylated HbA1c levels (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change [ADA 2017a]). During dose adjustment, fasting glucose can be used to determine response.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies. Repaglinide was shown to have a low potential to cross the placenta using an ex vivo perfusion model (Tertti 2011). Information describing the effects of repaglinide on pregnancy outcomes is limited.

In women with diabetes, maternal hyperglycemia can be associated with congenital malformations as well as adverse effects in the fetus, neonate, and the mother (ACOG 2005; ADA 2017c; Kitzmiller 2008; Metzger 2007). To prevent adverse outcomes, prior to conception and throughout pregnancy maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ACOG 2013; ADA 2017c; Blumer 2013; Kitzmiller 2008). Agents other than repaglinide are currently recommended to treat diabetes in pregnant women (ADA 2017c).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, rhinorrhea, rhinitis, diarrhea, or joint pain. Have patient report immediately to prescriber bruising, bleeding, angina, chills, pharyngitis, or signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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