Data from FDA - Curated by EPG Health - Last updated 15 May 2018

Indication(s)

1 INDICATIONS AND USAGE PRANDIN is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitation of Use: PRANDIN should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. PRANDIN is a glinide indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (1) Limitation of Use: Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis (1)

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Advisory information

contraindications
4 CONTRAINDICATIONS PRANDIN is contraindicated in patients with: •Concomitant use of gemfibrozil [see Drug Interactions (7)] •Known hypersensitivity to repaglinide or any inactive ingredients •Concomitant use with gemfibrozil (4) •Known hypersensitivity to repaglinide or any inactive ingredients (4)
Adverse reactions
6 ADVERSE REACTIONS The following serious adverse reaction is also described elsewhere in the labeling: Hypoglycemia [see Warnings and Precautions (5.1)] The most common adverse reactions (5% or greater incidence) among patients treated with PRANDIN were: hypoglycemia, upper respiratory infection, headache, sinusitis, arthralgia, nausea, diarrhea, and back pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk at 1-800-727-6500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice. PRANDIN has been administered to 2931 individuals during clinical trials. Approximately 1500 of these individuals with type 2 diabetes have been treated for at least 3 months, 1000 for at least 6 months, and 800 for at least 1 year. The majority of these individuals (1228) received PRANDIN in one of five 1-year, active-controlled trials. Over one year, 13% of PRANDIN patients were discontinued due to adverse reactions. The most common adverse reactions leading to withdrawal were hyperglycemia, hypoglycemia, and related symptoms. Table 1 lists the common adverse reactions for PRANDIN patients compared to placebo in trials 12 to 24 weeks duration. Table 1: Adverse Reactions (%) occurring ≥ 2% in PRANDIN Treated Patients from Pool of 12 to 24 Week Placebo Controlled Trials* PRANDIN N=352 Placebo N=108 Upper Respiratory Infection 16 8 Headache 11 10 Sinusitis 6 2 Arthralgia 6 3 Nausea 5 5 Diarrhea 5 2 Back Pain 5 4 Rhinitis 3 3 Constipation 3 2 Vomiting 3 3 Paresthesia 3 3 Chest pain 3 1 Bronchitis 2 1 Dyspepsia 2 2 Urinary tract infection 2 1 Tooth disorder 2 0 Allergy 2 0 *See trial descriptions in Clinical Trials (14) Hypoglycemia In clinical trials with PRANDIN, hypoglycemia is the most commonly observed adverse reaction. Mild or moderate hypoglycemia occurred in 31% of PRANDIN treated patients and 7% of placebo treated patients [see Warnings and Precautions (5.1]). Hypoglycemia was reported in 16% of 1228 PRANDIN patients, 20% of 417 glyburide patients, and 19% of 81 glipizide patients in 1-year controlled trials. Of PRANDIN-treated patients with symptomatic hypoglycemia, none developed coma or required hospitalization. In a 24-week placebo controlled trial, patients who were naïve to oral hypoglycemic agent therapy and patients with a HbA1c below 8% at baseline had a higher frequency of hypoglycemia. Weight Gain There was no average gain in body weight when patients previously treated with oral hypoglycemic agents were switched to PRANDIN. The average weight gain in patients treated with PRANDIN and not previously treated with sulfonylurea drugs was 3.3%. Cardiovascular Events The incidence of total serious cardiovascular adverse events, including ischemia, was higher for PRANDIN (51/1228 or 4%) than for sulfonylurea drugs (13/498 or 3%) in controlled comparator clinical trials. Table 2: Summary of Serious Cardiovascular Events in Trials Comparing PRANDIN to Sulfonylureas (% of total patients with events) PRANDIN SU* Total Exposed 1228 498 Serious CV Events 4% 3% Cardiac Ischemic Events 2% 2% Deaths due to CV Events 0.5% 0.4% *: glyburide and glipizide Seven controlled clinical trials included PRANDIN combination therapy with NPH-insulin (n=431), insulin formulations alone (n=388) or other combinations (sulfonylurea plus NPH-insulin or PRANDIN plus metformin) (n=120). There were six serious adverse events of myocardial ischemia in patients treated with PRANDIN plus NPH-insulin from two studies, and one event in patients using insulin formulations alone from another study [see Warnings and Precautions (5.3)]. Combination Therapy with Thiazolidinediones Hypoglycemia During 24-week treatment clinical trials of PRANDIN-rosiglitazone or PRANDIN-pioglitazone combination therapy (a total of 250 patients in combination therapy), hypoglycemia (blood glucose < 50 mg/dL) occurred in 7% of patients in combination therapy compared to 7% for PRANDIN monotherapy, and 2% for thiazolidinedione monotherapy. Peripheral Edema and Heart Failure Peripheral edema was reported in 12 out of 250 (4.8%) PRANDIN-thiazolidinedione combination therapy patients and 3 out of 124 (2.4%) thiazolidinedione monotherapy patients, with no cases reported in these trials for PRANDIN monotherapy. There were reports in 2 of 250 patients (0.8%) treated with PRANDIN-thiazolidinedione therapy of episodes of edema with congestive heart failure. Both patients had a prior history of coronary artery disease and recovered after treatment with diuretic agents. No comparable cases in the monotherapy treatment groups were reported. Weight Gain Mean weight increases associated with combination, PRANDIN and pioglitazone therapy were 5.5 kg, 0.3 kg, and 2.0 kg respectively. Mean weight increases associated with combination, PRANDIN and rosiglitazone therapy were 4.5 kg, 1.3 kg, and 3.3 kg respectively. Infrequent Adverse Events (<1% of Patients) Less common adverse clinical or laboratory events observed in clinical trials included elevated liver enzymes, thrombocytopenia, leukopenia, and anaphylactoid reactions. 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post approval use of PRANDIN. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or a causal relationship to drug exposure. •Alopecia •Hemolytic anemia •Pancreatitis •Stevens-Johnson Syndrome •Severe hepatic dysfunction including jaundice and hepatitis

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION •The recommended starting dose is 0.5 mg orally before each meal if HbA1c is less than 8%; and 1 or 2 mg orally before each meal if HbA1c is 8% or greater. (2.1) •The recommended dose range is 0.5 mg to 4 mg before meals, with a maximum daily dose of 16 mg. (2.1) •The patient’s dose should be doubled up to 4 mg with each meal until satisfactory glycemic control is achieved. At least one week should elapse to assess response after each dose adjustment. (2.1) •Instruct patients to skip the dose of PRANDIN if a meal is skipped. In patients who experience hypoglycemia, the dose of PRANDIN should be reduced. (2.1; 5.1) •Instruct patients to take PRANDIN within 30 minutes before meals. (2.1) •In patients with severe renal impairment (CrCl = 20 – 40 mL/min), recommended starting dose is 0.5 mg orally before each meal. (2.2) •Dose modifications are required when used concominantly with some medications. (2.3,7 ) 2.1 Recommended Dosage and Administration The recommended starting dose for patients whose HbA1c is less than 8% is 0.5 mg orally before each meal. For patients whose HbA1c is 8% or greater the starting dose is 1 or 2 mg orally before each meal. The recommended dose range is 0.5 mg to 4 mg before meals, with a maximum daily dose of 16 mg. The patient’s dose should be doubled up to 4 mg with each meal until satisfactory glycemic control is achieved. At least one week should elapse to assess response after each dose adjustment. Instruct patients to take PRANDIN within 30 minutes before meals. PRANDIN may be dosed 2, 3, or 4 times a day in response to changes in the patient’s meal pattern. In patients who skip meals, instruct patients to skip the scheduled dose of PRANDIN to reduce the risk of hypoglycemia. In patients who experience hypoglycemia, the dose of PRANDIN should be reduced [see Warnings and Precautions (5.1)]. 2.2 Patients with Severe Renal Impairment In patients with severe renal impairment (CrCl = 20 – 40 mL/min) initiate PRANDIN 0.5 mg orally before each meal. Gradually titrate the dose, if needed to achieve glycemic control. 2.3 Dose Modifications for Drug Interactions Dosage adjustments are recommended in patients taking concomitant strong CYP3A4 or CYP2C8 inhibitors or strong CYP3A4 or CYP2C8 inducers [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Concomitant use with gemfibrozil is contraindicated [see Contraindications (4)]. Avoid concomitant use of PRANDIN with clopidogrel. If concomitant use can not be avoided, initiate PRANDIN at 0.5 mg before each meal and do not exceed a total daily dose of 4 mg [see Drug Interactions ( 7 ), Clinical Pharmacology ( 12.3 )] . Do not exceed a total daily dose of 6 mg of PRANDIN in patients receiving cyclosporine [see Drug Interactions (7), Clinical Pharmacology (12.3)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS •Nursing mothers: Discontinue PRANDIN or nursing (8.3) 8.1 Pregnancy Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. It is unknown whether PRANDIN can cause fetal harm when administered to a pregnant woman. PRANDIN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Repaglinide was not teratogenic in rats or rabbits at doses 40 times (rats) and approximately 0.8 times (rabbit) clinical exposure (on a mg/m2 basis) throughout pregnancy. Offspring of rat dams exposed to repaglinide at 15 times clinical exposure on a mg/m2 basis during days 17 to 22 of gestation and during lactation developed nonteratogenic skeletal deformities consisting of shortening, thickening, and bending of the humerus during the postnatal period. This effect was not seen at doses up to 2.5 times clinical exposure (on a mg/m2 basis) on days 1 to 22 of pregnancy or at higher doses given during days 1 to 16 of pregnancy. Relevant human exposure has not occurred to date and therefore the safety of PRANDIN administration throughout pregnancy or lactation cannot be established. 8.3 Nursing Mothers Although it is not known whether repaglinide is excreted in human milk some oral agents are known to be excreted by this route. Because the potential for hypoglycemia in nursing infants may exist, and because of the effects on nursing animals, a decision should be made as to whether PRANDIN should be discontinued in nursing mothers, or if mothers should discontinue nursing. If PRANDIN is discontinued and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered. In rat reproduction studies, measurable levels of repaglinide were detected in the breast milk of the dams and lowered blood glucose levels were observed in the pups. Cross fostering studies indicated that skeletal changes [see Use in Specific Populations (8.1)] could be induced in control pups nursed by treated dams, although this occurred to a lesser degree than those pups treated in utero. 8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients. 8.5 Geriatric Use In clinical studies of 24 weeks or greater duration, 415 patients were over 65 years of age and no patients were greater than 75 years of age. In one-year, active-controlled trials, no differences were seen in effectiveness or adverse events between these subjects and those less than 65. There was no increase in frequency or severity of hypoglycemia in older subjects, but greater sensitivity of some older individuals to PRANDIN therapy cannot be ruled out. 8.6 Renal Impairment Pharmacokinetic studies of repaglinide were conducted in patients with mild to moderate renal function impairment (CrCl = 40 – 80 mL/min), and severe renal function impairment (CrCl = 20 – 40 mL/min). Initial dose adjustment is not required in patients with mild to moderate renal dysfunction. However, patients with severe renal function impairment should initiate PRANDIN therapy with the 0.5 mg dose and be carefully titrated [see Dosage and Administration (2.2)]. Studies were not conducted in patients with creatinine clearances below 20 mL/min or patients with renal failure requiring hemodialysis. 8.7 Hepatic Impairment A single-dose study was conducted 12 patients with chronic liver disease. Patients with moderate to severe impairment of liver function had higher and more prolonged serum concentrations. Therefore, PRANDIN should be used cautiously in patients with impaired liver function. Longer intervals between dose adjustments may be needed to allow full assessment of response.
Pregnancy and lactation
8.3 Nursing Mothers Although it is not known whether repaglinide is excreted in human milk some oral agents are known to be excreted by this route. Because the potential for hypoglycemia in nursing infants may exist, and because of the effects on nursing animals, a decision should be made as to whether PRANDIN should be discontinued in nursing mothers, or if mothers should discontinue nursing. If PRANDIN is discontinued and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered. In rat reproduction studies, measurable levels of repaglinide were detected in the breast milk of the dams and lowered blood glucose levels were observed in the pups. Cross fostering studies indicated that skeletal changes [see Use in Specific Populations (8.1)] could be induced in control pups nursed by treated dams, although this occurred to a lesser degree than those pups treated in utero.

Interactions

7 DRUG INTERACTIONS • 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 PRANDIN 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 PRANDIN dose reductions and increased frequency of glucose monitoring (7) • CYP2C8 and CYP3A4 Inducers and Drugs That May Decrease the Blood Glucose Lowering Effect of PRANDIN: Co-administration may require PRANDIN 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) Clinically Important Drug Interactions with PRANDIN Table 3 includes a list of drugs with clinically important drug interactions when administered concomitantly with PRANDIN and instructions for preventing or managing them. Table 3: Clinically Important Drug Interactions with PRANDIN Gemfibrozil Clinical Impact: Gemfibrozil significantly increased repaglinide exposures by 8.1 fold [see Clinical Pharmacology (12.3)] Intervention: Do not administer PRANDIN to patients receiving gemfibrozil [see Contraindications (4)]. Clopidogrel Clinical Impact: Clopidogrel increased repaglinide exposures by 3.9-5.1 fold [see Clinical Pharmacology (12.3)] Intervention: Avoid concomitant use of PRANDIN with clopidogrel. If concomitant use can not be avoided, initiate PRANDIN 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 PRANDIN dose should be limited to 6 mg, and increased frequency of glucose monitoring may be required when PRANDIN is co-administered with cyclosporine. CYP2C8 and CYP3A4 Inhibitors Intervention: PRANDIN 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: PRANDIN 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: PRANDIN 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 PRANDIN Intervention: PRANDIN 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 PRANDIN is co-administered with these drugs. Examples: beta-blockers, clonidine, guanethidine, and reserpine

More information

Category Value
Authorisation number NDA020741
Agency product number 668Z8C33LU
Orphan designation No
Product NDC 68151-3565
Date Last Revised 28-12-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 200257
Marketing authorisation holder Carilion Materials Management