Prandin (Repaglinide)

HOW DOES PRANDIN WORK?

Prandin belongs to the class of drugs called meglitinides. It decreases blood glucose levels by causing insulin release from the pancreas. This mechanism requires functioning beta cells in the pancreatic islets. The amount of insulin produced is dependent on glucose, and therefore there is less insulin release with low glucose levels. Prandin works by closing ATP-dependent potassium channels located within the membranes of beta cells. This causes a potassium channel blockade, which depolarizes beta cells. Consequently, calcium channels open leading to an influx of calcium. This initiates the release of insulin. This phenomenon is highly selective for certain tissues with a low affinity for heart and skeletal tissues.

SIDE EFFECTS

Common side effects of Prandin may include:

• Diarrhea
• Nausea
• Weight gain
• Joint and back pain
• Headache
• Stuffy or runny nose
• Sneezing
• Cough
• Flu or cold symptoms
• Blurred vision
• Dizziness
• Hair loss

WARNINGS AND PRECAUTIONS

Hypoglycemia

All drugs belonging to the glinide class can cause hypoglycemia. Serious hypoglycemia can lead to life-threatening seizures and possibly death. Low glucose levels can hinder concentration and reaction time, making certain situations, like driving, dangerous during a hypoglycemic episode. Hypoglycemia can have a rapid onset and symptoms are variable. For example, diet, activity levels, and concomitant medications can affect hypoglycemia risk and presentation. Patients who have had diabetes long-term, experience diabetic nerve disease, experience recurrent hypoglycemia, or use beta-blockers may not be as sensitive to signs and symptoms of hypoglycemia. Those with renal or hepatic impairment may be more likely to experience hypoglycemia.

Individuals should take Prandin before meals and should not take Prandin if they skip a meal. If a patient experiences hypoglycemia, providers should decrease their dose to avoid future episodes. Patients and their caregivers should understand the signs and symptoms of hypoglycemia as well as how to manage it. Patients should actively monitor their blood glucose levels to prevent and manage low blood glucose levels. If individuals are at a high risk for developing hypoglycemia, it is important that they more frequently monitor their glucose levels.

Severe Cardiovascular Events with Simultaneous NPH Insulin Use

Seven well-controlled trials evaluated Prandin. Within these trials there were six reports of myocardial ischemia associated with concomitant use of Prandin and NPH insulin and one report with insulin alone. Therefore, simultaneous use of Prandin and NPH is not recommended.

Macrovascular Effects

There are no studies that have evaluated the macrovascular risk with Prandin use.

DRUG INTERACTIONS

Gemfibrozil

Gemfibrozil can increase Prandin concentrations to levels ten times higher than normal. Therefore, concomitant use of gemfibrozil and Prandin is not recommended.

Clopidogrel

Clopidogrel can significantly increase Prandin concentrations up to 5-fold. Therefore, use of Prandin and clopidogrel together should be avoided. If they must be administered together, Prandin should be started at a dose of 0.5 mg prior to each meal. Additionally, the total daily dose of Prandin should not be higher than 4 mg. If used together, patients should more frequently monitor their glucose levels.

Cyclosporine

Cyclosporine has been shown to elevate glucose levels 2.5-fold. If taken together, the total daily dose of Prandin should not exceed 6 mg daily. If used together, patients should more frequently monitor their glucose levels.

CYP2C8 and CYP3A4 Inhibitors

When administered with CYP2C8 or CYP3A4 inhibitors, Prandin doses may need to be decreased. If used together, patients should also more frequently monitor their glucose levels. Drugs that block CYP3A4 include antibacterial agents (e.g., clarithromycin and erythromycin) and antifungal agents (e.g., ketoconazole and itraconazole). Drugs that block CYP2C8 include gemfibrozil, trimethoprim, montelukast, clopidogrel, and deferasirox.

CYP2C8 and CYP3A4 Inducers

When administered with CYP2C8 or CYP3A4 inhibitors, Prandin doses may need to be increased. If used together, patients should also more frequently monitor their glucose levels. Drugs that induce CYP2C8 or CYP3A4 include carbamazepine, barbiturates, and rifampin.

Use With Other Drugs That May Cause Hypoglycemia

There is a higher risk of developing hypoglycemia when Prandin is used simultaneously with certain agents. When administered with these drugs, Prandin doses may need to be decreased. If used together, patients should also more frequently monitor their glucose levels. These drugs include:

• Atypical antipsychotics (e.g., olanzapine and clozapine)
• Calcium channel antagonists
• Corticosteroids
• Danazol
• Diuretics
• Estrogens and progestogens
• Glucagon
• Isoniazid
• Niacin
• Oral contraceptives
• Phenothiazines,
• Protease inhibitors
• Somatropin
• Sympathomimetic drugs (e.g., albuterol, epinephrine, terbutaline)
• Thyroid hormones

Use With Drugs That Mask Hypoglycemia Symptoms

If Prandin is used with medications that mask symptoms of hypoglycemia, patients should more frequently monitor their glucose levels. These agents include beta blockers, clonidine, reserpine, and guanethidine.

SPECIAL POPULATIONS

Pregnancy

There is limited evidence available on the use of Prandin in pregnant women. Therefore, no clear conclusions can be drawn around the risk of birth defects or miscarriages when using Prandin. However, no adverse effects occurred in pregnancy in the limited case reports available. The risk-benefit profile should be considered by the provider, as poorly controlled diabetes during pregnancy can lead to birth defects, stillbirth, or complications.

Lactation

No data exists on Prandin’s effect on human milk, a breastfed infant, or milk production. Prandin is present in animal milk and therefore is likely to be present in human milk. It is not recommended that lactating patients take Prandin as this may increase the infants risk of developing hypoglycemia.

Pediatrics

Prandin has not been studied in patients under the age of 18, and therefore safety and efficacy in pediatrics cannot be confirmed.

Geriatrics

In clinical trials, there was no difference in safety or effectiveness between younger patients and patients older than 65 years of age. There was no difference in the severity or frequency of hypoglycemia episodes. However, increased sensitivity in geriatric patients cannot be discounted. Older patients and providers should proceed with caution when using Prandin.

Renal Impairment

Prandin has been evaluated in pharmacokinetic studies in patients with renal impairment. Those with mild to moderate renal dysfunction do not require initial dose adjustments. Those with severe renal dysfunction should start Prandin at a dose of 0.5 mg and be titrated with caution. No studies evaluated Prandin in patients with creatinine clearances lower than 20 mL/min or renal failure patients needing hemodialysis.

Hepatic Impairment

One study evaluated 12 patients with chronic liver disease receiving Prandin. Those with moderate to severe liver dysfunction demonstrated increased and prolonged concentrations of Prandin in the blood. Prandin should be used with caution in those who have decreased liver function. In these patients, providers should utilize prolonged intervals between dose adjustments to aid in response assessment.