Side Effects of Prandin (repaglinide)

Prandin (repaglinide) is a meglitinide used to lower blood sugar (glucose) in patients with type 2 diabetes.

Glucose intolerance that causes diabetes type 2 is caused by reduced insulin secretion from the pancreas after meals and resistance of the body's cells to insulin's effect which is to stimulate the cells to remove glucose from the blood. This leads to high levels of glucose in the blood.

Like sulfonylureas, Prandin stimulates cells in the pancreas to produce insulin. Prandin may be more potent in persons with more moderate abnormalities of blood glucose levels.

Prandin is different because it has a rapid onset of action and a short duration of action. When taken just prior to meals, it promotes the release of insulin that normally occurs with meals and is responsible for preventing blood glucose levels from becoming high. It has been shown to lower hemoglobin A1c (HbA1c) levels by 1.6% to 1.9%.  

Common side effects of Prandin include

• low blood glucose (hypoglycemia) (symptoms include hunger, nausea, tiredness, perspiration, headache, heart palpitations, numbness around the mouth, tingling in the fingers, tremors, muscle weakness, blurred vision, cold temperature, excessive yawning, irritability, confusion, and loss of consciousness),
• headache,
• nausea,
• vomiting,
• diarrhea,
• constipation,
• stomach pain,
• back pain,
• upper respiratory infections,
• chest pain, and
• hair loss.

Serious side effects of Prandin include

• pancreatitis,
• liver failure,
• severe skin reactions, and
• anemia.

Drug interactions of Prandin include ketoconazole, itraconazole, fluconazole, erythromycin, and clarithromycin, which may prevent the metabolism of Prandin, causing blood levels of Prandin to rise, resulting in an increased glucose-lowering effect and dangerous hypoglycemic reactions.

Elimination of Prandin may be increased with barbiturates, carbamazepine, and rifampin and can result in lower blood levels of Prandin and hyperglycemia.

Some drugs increase blood sugar and reverse the effects of Prandin, such as diuretics, amphetamines, glucocorticoids, estrogens, isoniazid, phenothiazines, phenytoin, somatropin, decongestants, and thyroid drugs.

Anabolic steroids or androgens can increase the risk of developing hypoglycemia.

Monoamine oxidase inhibitors (MAOIs), salicylates, and selective serotonin reuptake inhibitors (SSRIs) also can increase the effects of Prandin and worsen the chance of developing hypoglycemia.

Beta-blockers can cause hypoglycemia or hyperglycemia, and can also blunt some of the body's responses to hypoglycemia such as rapid heart rate, making it difficult for patients to recognize and treat hypoglycemic reactions.

Gemfibrozil should not be combined with Prandin because gemfibrozil may increase blood levels of Prandin and lead to hypoglycemia.

Atazanavir and trimethoprim can increase blood levels of Prandin, leading to increased risks of hypoglycemia. No adequate human studies on the effects of Prandin on the fetus have been done.

Physicians must weigh the potential benefits and risks of Prandin when considering its use in pregnant women. It is unknown if Prandin accumulates in breast milk. Because of the possibility of hypoglycemia in nursing infants, it is recommended Prandin is not recommended for use while breastfeeding.

Hypoglycemia (low blood glucose) is the most frequent side effect and it occurs somewhat less frequently with repaglinide than with sulfonylureas such as glyburide and glipizide. Some symptoms of hypoglycemia include:

• hunger,
• nausea,
• tiredness,
• perspiration,
• headache,
• heart palpitations,
• numbness around the mouth,
• tingling in the fingers,
• tremors,
• muscle weakness,
• blurred vision,
• cold temperature,
• excessive yawning,
• irritability,
• confusion, or
• loss of consciousness.

Other common side effects include:

• headache,
• nausea,
• vomiting,
• diarrhea,
• constipation,
• stomach pain,
• back pain,
• upper respiratory infections, and
• chest pain.

Side effects that have been reported post-marketing inlcude:

• hair loss,
• pancreatitis,
• liver failure,
• severe skin reactions, and
• anemia.

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

• Hypoglycemia

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*

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.
• Hypoglycemia was reported in 16% of 1228 Prandin patients, 20% of 417 glyburide patients, and 19% of 81 glipizide patients in 1year 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 naive 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)

• 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.

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.

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-JohnsonSyndrome
• 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