Diabetes mellitus, type 2, treatment:
Note: May be used as an adjunctive agent or alternative monotherapy for patients in whom initial therapy with lifestyle intervention and metformin failed or who cannot take metformin. Meglitinides are associated with a greater risk of hypoglycemia than other noninsulin antidiabetic agents (AACE/ACE [Garber 2020]; ADA 2021).
Initial:
HbA 1c <8%: Oral: 0.5 mg before each meal (up to 4 times/day).
HbA 1c ≥8%: Oral: 1 to 2 mg before each meal (up to 4 times/day).
Dosage adjustment: At intervals of ≥1 week, may double the dose with each meal until adequate glycemic control is achieved; usual maintenance dose: 0.5 to 1 mg before each meal (1.5 to 3 mg/day) (maximum: 4 mg/dose [16 mg/day]) (DeFronzo 1999; manufacturer’s labeling).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Note: Although <2% of repaglinide is eliminated unchanged in the urine, Cmax is doubled and AUCs are tripled in patients with severe kidney impairment compared to those with normal kidney function, potentially due to a decrease in hepatic metabolism and clearance (Marbury 2000).
Altered kidney function:
CrCl ≥40 mL/minute: Oral: No dosage adjustment necessary (Hasslacher 2003; Lalau 2015; MacCallum 2014; Schumacher 2001).
CrCl <40 mL/minute: Oral: Initial: 0.5 mg once daily with largest meal; gradually increase to 0.5 mg before each meal (up to 4 times/day) (Berns 2022; Hasslacher 2003; expert opinion). If response is inadequate, may further increase dose at intervals of ≥1 week by doubling the dose with each meal until adequate glycemic control is achieved, up to a maximum of 2 mg before each meal (up to 4 times/day) (expert opinion).
Hemodialysis, intermittent (thrice weekly): Not dialyzable (Marbury 2000):
Oral: Initial: 0.5 mg once daily with largest meal; gradually increase to 0.5 mg before each meal (up to 4 times/day) (Gianchandani 2017; expert opinion). If response is inadequate, may further increase dose at intervals of ≥1 week by doubling the dose with each meal until adequate glycemic control is achieved, up to a maximum of 2 mg before each meal (up to 4 times/day).
Peritoneal dialysis: Unlikely to be dialyzed (highly protein bound) (expert opinion):
Oral: Initial: 0.5 mg once daily with largest meal; gradually increase to 0.5 mg before each meal (up to 4 times/day) (Gianchandani 2017; expert opinion). If response is inadequate, may further increase dose at intervals of ≥1 week by doubling the dose with each meal until adequate glycemic control is achieved, up to a maximum of 2 mg before each meal (up to 4 times/day).
CRRT: Oral: Avoid use (expert opinion).
PIRRT (eg, sustained, low-efficiency diafiltration): Oral: Avoid use (expert opinion).
There are no dosage adjustments provided in the manufacturer's labeling. Use with caution; consider longer intervals between dosage adjustments.
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral:
Prandin: 1 mg [DSC], 2 mg [DSC] [contains corn starch]
Generic: 0.5 mg, 1 mg, 2 mg
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
GlucoNorm: 0.5 mg, 1 mg, 2 mg
Generic: 0.5 mg, 1 mg, 2 mg
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.
Diabetes mellitus, type 2, treatment: To improve glycemic control in adults with type 2 diabetes mellitus as an adjunct to diet and exercise.
Prandin may be confused with Avandia
Repaglinide may be confused with rasagiline
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>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%, postmarketing, and/or case reports: 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)
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)
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:
• Bariatric surgery:
– Altered absorption: Absorption may be altered given the anatomic and transit changes created by gastric bypass and sleeve gastrectomy surgery (Mingrone 2016; Mechanick 2020).
– Hypoglycemia: May increase the risk of hypoglycemia after gastric bypass, sleeve gastrectomy, and gastric band (Mechanick 2020). Insulin secretion and sensitivity may be partially or completely restored after these procedures (gastric bypass is most effective, followed by sleeve and, finally, band) (Korner 2009; Peterli 2012). First-phase insulin secretion and hepatic insulin sensitivity have been shown to be significantly improved in the immediate days after gastric bypass and sleeve gastrectomy. The restorative effects of these procedures on peripheral insulin sensitivity may occur later in the 3- to 12-month period after surgery. Where possible, the selection of antidiabetic agents without the potential for hypoglycemia is advised.
• 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.
Other warnings/precautions:
• Appropriate use: Not for use in patients with diabetic ketoacidosis or patients with type 1 diabetes mellitus.
• Hospitalized patients: Consider temporary discontinuation of noninsulin antidiabetic agents and initiation or continuation of insulin therapy during hospitalization (ADA 2021). In noncritically ill hospitalized patients, continued use of repaglinide may be considered if there are no contraindications, regular nutritional intake is expected, and blood glucose is well controlled; close monitoring and subsequent dosage adjustments are recommended (ADA/AACE [Moghissi 2009]; Bogun 2013; Inzucchi 2006).
Substrate of CYP2C8 (major), CYP3A4 (major), OATP1B1/1B3 (SLCO1B1/1B3); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Androgens: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: 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. Risk X: Avoid combination
Beta-Blockers (Beta1 Selective): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Beta-Blockers (Nonselective): May enhance the hypoglycemic effect of Antidiabetic Agents. Beta-Blockers (Nonselective) may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Bortezomib: May enhance the therapeutic effect of Antidiabetic Agents. Bortezomib may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: 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. Risk D: Consider therapy modification
CycloSPORINE (Systemic): May increase the serum concentration of Repaglinide. Management: Limit the daily repaglinide dose to a maximum of 6 mg with concurrent use of cyclosporine, and monitor closely for increased repaglinide effects. Risk D: Consider therapy modification
CYP2C8 Inhibitors (Moderate): May increase the serum concentration of Repaglinide. Risk C: Monitor therapy
CYP2C8 Inhibitors (Strong): May increase the serum concentration of Repaglinide. Risk X: Avoid combination
CYP2C8 Inhibitors (Weak): May increase the serum concentration of Repaglinide. Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Repaglinide. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Repaglinide. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Repaglinide. Risk C: Monitor therapy
Darolutamide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Eltrombopag: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Encorafenib: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Erythromycin (Systemic): May increase the serum concentration of Repaglinide. Risk C: Monitor therapy
Etilefrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Glucagon-Like Peptide-1 Agonists: May enhance the hypoglycemic effect of Meglitinides. Management: Consider meglitinide dose reductions when used in combination with glucagon-like peptide-1 agonists, particularly when also used with basal insulin. Risk D: Consider therapy modification
Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Herbal Products with Glucose Lowering Effects: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy
HMG-CoA Reductase Inhibitors (Statins): May increase the serum concentration of Repaglinide. Risk C: Monitor therapy
Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Risk C: Monitor therapy
Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy
Irbesartan: May increase the serum concentration of Repaglinide. Risk C: Monitor therapy
Lapatinib: May increase the serum concentration of CYP2C8 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Leflunomide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Letermovir: May increase the serum concentration of Repaglinide. Management: Monitor for increased repaglinide effects/toxicities (ie, hypoglycemia) if combined with letermovir. When letermovir is coadministered with cyclosporine, the use of repaglinide is not recommended. Risk C: Monitor therapy
Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2C8 Substrates (High Risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may increase the serum concentration of CYP2C8 Substrates (High Risk with Inhibitors or Inducers). Risk C: Monitor therapy
Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Quinolones: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Quinolones may diminish the therapeutic effect of Agents with Blood Glucose Lowering Effects. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Risk C: Monitor therapy
RifAMPin: May decrease the serum concentration of Repaglinide. Risk C: Monitor therapy
Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Salicylates: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Spironolactone: May increase the serum concentration of CYP2C8 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Taurursodiol: May increase the serum concentration of CYP2C8 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Teriflunomide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Tucatinib: May increase the serum concentration of Repaglinide. Risk C: Monitor therapy
Voclosporin: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
When given with food, the AUC of repaglinide is decreased. Taking medication without eating may cause hypoglycemia. Management: Administer within 30 minutes prior to a meal. If a meal is skipped, skip dose for that meal.
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.
Poorly controlled diabetes during pregnancy can be associated with an increased risk of adverse maternal and fetal outcomes, including diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, delivery complications, major malformations, stillbirth, and macrosomia. 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 (ADA 2021; Blumer 2013).
Agents other than repaglinide are currently recommended to treat diabetes mellitus in pregnancy (ADA 2021).
It is not known if repaglinide is present in breast milk.
Due to the potential for hypoglycemia in the breastfed infant, breastfeeding is not recommended by the manufacturer
Individualized medical nutrition therapy based on American Diabetes Association recommendations is an integral part of therapy.
Monitor fasting blood glucose (individualize frequency based on treatment regimen, hypoglycemia risk, and other patient-specific factors; some patients may be candidates for continuous glucose monitoring) (ADA 2021). During dose adjustment, fasting glucose can be used to determine response.
HbA1c: Monitor at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; monitor quarterly in patients in whom treatment goals have not been met, or with therapy change. Note: In patients prone to glycemic variability (eg, patients with insulin deficiency), or in patients whose HbA1c is discordant with serum glucose levels or symptoms, consider evaluating HbA1c in combination with blood glucose levels and/or a glucose management indicator (ADA 2021; KDIGO 2020).
Recommendations for glycemic control in patients with diabetes:
Nonpregnant adults with diabetes (ADA 2021):
HbA1c: <7% (a more aggressive [<6.5%] or less aggressive [<8%] HbA1c goal may be targeted based on patient-specific characteristics). Note: In patients using a continuous glucose monitoring system, a goal of time in range >70% with time below range <4% is recommended and is similar to a goal HbA1c <7%.
Preprandial capillary blood glucose: 80 to 130 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics).
Peak postprandial capillary blood glucose (~1 to 2 hours after a meal): <180 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics).
Older adults (≥65 years of age) (ADA 2021):
Note: Consider less strict targets in patients who are using insulin and/or insulin secretagogues (sulfonylureas, meglitinides) (ES [LeRoith 2019]).
HbA1c: <7% to 7.5% (healthy); <8% to 8.5% (complex/intermediate health). Note: Individualization may be appropriate based on patient and caregiver preferences and/or presence of cognitive impairment. In patients with very complex or poor health (ie, limited remaining life expectancy), consider making therapy decisions based on avoidance of hypoglycemia and symptomatic hyperglycemia rather than HbA1c level.
Preprandial capillary blood glucose: 80 to 130 mg/dL (healthy); 90 to 150 mg/dL (complex/intermediate health); 100 to 180 mg/dL (very complex/poor health).
Bedtime capillary blood glucose: 80 to 180 mg/dL (healthy); 100 to 180 mg/dL (complex/intermediate health); 110 to 200 mg/dL (very complex/poor health).
Classification of hypoglycemia (ADA 2021):
Level 1: 54 to 70 mg/dL; hypoglycemia alert value; initiate fast-acting carbohydrate (eg, glucose) treatment.
Level 2: <54 mg/dL; threshold for neuroglycopenic symptoms; requires immediate action.
Level 3: Hypoglycemia associated with a severe event characterized by altered mental and/or physical status requiring assistance.
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
Protein binding, plasma: >98% to albumin
Metabolism: Hepatic via CYP3A4 and CYP2C8 isoenzymes and glucuronidation to inactive metabolites
Bioavailability: 56% ± 9%
Half-life elimination: ~1 hour
Time to peak, plasma: 1 hour
Excretion: Feces (~90%, <2% as unchanged drug); Urine (~8%, 0.1% as unchanged drug)
Altered kidney function: AUC and Cmax are increased in severe renal impairment.
Hepatic function impairment: Higher and more prolonged serum concentrations have been observed in patients with moderate to severe hepatic impairment.
Tablets (Repaglinide Oral)
0.5 mg (per each): $0.24 - $3.66
1 mg (per each): $0.24 - $3.66
2 mg (per each): $0.24 - $3.66
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