(re PAG li nide)
Diabetes mellitus, type 2: Management of type 2 diabetes mellitus (noninsulin dependent, NIDDM) as an adjunct to diet and exercise; may be used in combination with metformin or thiazolidinediones (US labeling) or metformin or rosiglitazone (Canadian labeling)
Hypersensitivity to repaglinide or any component of the formulation; diabetic ketoacidosis, with or without coma; type 1 diabetes (insulin dependent, IDDM); concurrent gemfibrozil therapy
Canadian labeling: Additional contraindications (not in US labeling): Severe hepatic impairment; concurrent use with clopidogrel
Diabetes mellitus, type 2: Oral:
Patients not previously treated or whose HbA1c is <8%: Initial: 0.5 mg before each meal
Patients previously treated with blood glucose-lowering agents whose HbA1c is ≥8%: Initial: 1 or 2 mg before each meal.
Dose adjustment: Determine dosing adjustments by blood glucose response, usually fasting blood glucose. Double the preprandial dose up to 4 mg until satisfactory blood glucose response is achieved. At least 1 week should elapse to assess response after each dose adjustment.
Dose range: 0.5-4 mg taken with meals. Repaglinide may be dosed preprandially 2, 3, or 4 times/day in response to changes in the patients meal pattern. Maximum recommended daily dose: 16 mg.
Patients receiving other oral hypoglycemic agents: When repaglinide is used to replace therapy with other oral hypoglycemic agents, it may be started the day after the final dose is given. Observe patients carefully for hypoglycemia because of potential overlapping of drug effects. When transferred from longer half-life sulfonylureas (eg, chlorpropamide), close monitoring may be indicated for up to ≥1 week.
Combination therapy: If repaglinide monotherapy does not result in adequate glycemic control, metformin or a thiazolidinedione may be added. Or, if metformin or thiazolidinedione therapy does not provide adequate control, repaglinide may be added. The starting dose and dose adjustments for combination therapy are the same as repaglinide monotherapy. Carefully adjust the dose of each drug to determine the minimal dose required to achieve the desired pharmacologic effect. Failure to do so could result in an increase in the incidence of hypoglycemic episodes. Use appropriate monitoring of FPG and HbA1c measurements to ensure that the patient is not subjected to excessive drug exposure or increased probability of secondary drug failure. If glucose is not achieved after a suitable trial of combination therapy, consider discontinuing these drugs and using insulin.
Refer to adult dosing.
US labeling:
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).
Canadian labeling: Initial: No dosage adjustment necessary; titrate carefully.
There are no dosage adjustments provided in the manufacturer 's labeling. Use with caution; use conservative initial and maintenance doses and longer intervals between dosage adjustments. The Canadian labeling contraindicates use in severe impairment.
Oral: Administer 15 minutes before meals; however, time may vary from immediately preceding a meal to as long as 30 minutes before a meal. If the patient misses a meal or is unable to take anything by mouth, repaglinide should not be administered to avoid hypoglycemia. Patients consuming extra meals should be instructed to add a dose for the extra meal.
Take repaglinide 15-30 minutes before meals. Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy. May cause hypoglycemia. Must be able to recognize symptoms of hypoglycemia (palpitations, tachycardia, sweaty palms, diaphoresis, lightheadedness).
Do not store above 25 ‚ °C (77 ‚ °F). Protect from moisture.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Prandin: 0.5 mg, 1 mg, 2 mg
Generic: 0.5 mg, 1 mg, 2 mg
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: Consider a repaglinide dose adjustment and monitor for increased repaglinide effects (eg, hypoglycemia) if combined with clopidogrel. Canadian labeling states that this combination is contraindicated. 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
Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. 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
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
Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Pegvisomant: 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
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 Johns 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
Monitor fasting blood glucose (periodically) and glycosylated hemoglobin (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 2016a]) with a goal of decreasing these levels towards the normal range. During dose adjustment, fasting glucose can be used to determine response.
>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%)
Neuromuscular & skeletal: Back pain (5% to 6%), arthralgia (3% to 6%)
Respiratory: Sinusitis (3% to 6%), bronchitis (2% to 6%)
Miscellaneous: Allergy (1% to 2%)
<1% (Limited to important or life-threatening): Anaphylactoid reaction, arrhythmia, hemolytic anemia, hepatic dysfunction (severe), hepatitis, hypertension, leukopenia, MI, pancreatitis, Stevens-Johnson syndrome, thrombocytopenia, visual disturbances (transient)
AUC and Cmax are increased in severe renal function impairment.
Higher and more prolonged serum concentrations have been observed in patients with moderate to severe hepatic function impairment.
Concerns related to adverse effects:
- Hypoglycemia: May cause hypoglycemia; appropriate patient selection, dosage, and patient education are important to avoid hypoglycemic episodes. Ethanol may increase risk of hypoglycemia; instruct patients to avoid ethanol.
Disease-related concerns:
- Adrenal/pituitary impairment: Use with caution in patients with adrenal and/or pituitary impairment; may be more susceptible to glucose-lowering effects.
- Cardiovascular mortality: Some studies suggest that oral hypoglycemic drugs may be associated with increased cardiovascular mortality. Theoretically, repaglinide may also increase cardiovascular events, but there are no long-term studies assessing this concern.
- Hepatic impairment: Use with caution in patients with hepatic impairment; may be more susceptible to glucose-lowering effects. The Canadian labeling contraindicates use in severe hepatic impairment.
- Renal impairment: Use with caution in patients with severe renal impairment; may be more susceptible to glucose-lowering effects.
- Stress-related states: It may be necessary to discontinue repaglinide and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).
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.
- NPH insulin: Not indicated for use in combination with NPH insulin; 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.
Special populations:
- Debilitated patients: Use with caution in debilitated patients; may be more susceptible to glucose-lowering effects.
- Elderly: Use with caution in the elderly; may be more susceptible to glucose-lowering effects.
- Malnourished patients: Use with caution in malnourished patients; may be more susceptible to glucose-lowering effects.
C
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 2015; 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 2015; Blumer 2013; Kitzmiller 2008). Prior to pregnancy, effective contraception should be used until glycemic control is achieved (Kitzmiller 2008). Other agents are currently recommended to treat diabetes in pregnant women (ACOG 2013; Blumer 2013).
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.
Rapid and complete
Vd: 31 L
Hepatic via CYP3A4 and CYP2C8 isoenzymes and glucuronidation to inactive metabolites
Feces (~90%, <2% as unchanged drug); Urine (~8%, 0.1% as unchanged drug)
Single dose: Increased insulin levels: ~15-60 minutes
Plasma: ~1 hour
4-6 hours
~1 hour
Plasma: >98% to albumin
- 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.