PRANDIN Tablet Ref.[27459] Active ingredients: Repaglinide

5.1 Hypoglycemia

All glinides, including PRANDIN, can cause hypoglycemia [see Adverse Reactions (6.1)]. Severe hypoglycemia can cause seizures, may be life-threatening, or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery).

Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions (7)], or in patients who experience recurrent hypoglycemia.

Factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content), changes in level of physical activity, changes to co-administered medication [see Drug Interactions (7)], and concomitant use with other antidiabetic agents. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations (8.6, 8.7)].

Patients should administer PRANDIN before meals and be instructed to skip the dose of PRANDIN if a meal is skipped. In patients who experience hypoglycemia, the dose of PRANDIN should be reduced [see Dosage and Administration (2.1)]. Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.

5.2 Serious Cardiovascular Adverse Reactions with Concomitant Use with NPH-insulin

Across seven controlled trials, 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 Adverse Reactions (6.1)]. PRANDIN is not indicated for use in combination with NPH-insulin.

5.3 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with PRANDIN.

The following serious adverse reaction is also described elsewhere in the labeling:

Hypoglycemia [see Warnings and Precautions (5.1)]

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*:

^* 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 HbA_1c 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):

^*: 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.

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

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:

Risk Summary

Limited data with PRANDIN and repaglinide use in pregnant woman are insufficient to inform a drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].

Repaglidine was shown not to be teratogenic in animal studies (rats and rabbits). Embryotoxicity, abnormal limb development in rat fetusus was observed in female rats exposed to high doses in the last stage of pregnancy.

The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with a HbA_1c>7 and has been reported to be as high as 20% to 25% in women with a HbA_1c>10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

8.1.102 Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity.

Data

Human Data

There are no adequate data on the developmental risks associated with use of PRANDIN in pregnant women.

Animal Data

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.

Risk Summary

There is no information regarding the presence of PRANDIN in human milk, the effects on the breastfeeding infant, or the effects on milk production. Repaglinide was detected in rat milk, though due to species-specifics differences in lactation physiology, animal data may not reliably predict drug levels in human milk. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for PRANDIN and any potential adverse effects on the breastfed infant from PRANDIN or from underlying maternal conditions.

Clinical Considerations

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.

Data

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.

Safety and effectiveness have not been established in pediatric patients.

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.

Pharmacokinetic studies of repaglinide were conducted in patients with mild to moderate renal function impairment (CrCl = 40 to 80 mL/min), and severe renal function impairment (CrCl = 20 to 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.

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.