Gemfibrozil

Usage

• Gemfibrozil is prescribed to lower high levels of fats (triglycerides) and raise “good” cholesterol (HDL) in the blood. It can also moderately lower “bad” cholesterol (LDL). It’s primarily used to treat severe hypertriglyceridemia (high triglycerides), sometimes in combination with other lipid-lowering therapies. It may also be used for mixed hyperlipidemia (high cholesterol and triglycerides) when statins are contraindicated or not tolerated. In specific cases, it may be used for primary hypercholesterolemia (high cholesterol) if statins are not an option.
• Pharmacological Classification: Gemfibrozil is classified as a fibrate, a type of lipid-lowering agent.
• Mechanism of Action: Gemfibrozil activates peroxisome proliferator-activated receptor alpha (PPAR-α). This action leads to several changes in lipid metabolism, including increased lipoprotein lipase activity (which breaks down triglycerides), decreased hepatic triglyceride production, and increased HDL cholesterol levels. It also inhibits peripheral lipolysis and reduces hepatic removal of free fatty acids.

Alternate Names

• Gemfibrozil is the generic name.
• Brand Names: Lopid, Lopid OD®

How It Works

• Pharmacodynamics: Gemfibrozil primarily affects lipid metabolism by activating PPAR-α, leading to a reduction in triglycerides (30-60%) and an increase in HDL cholesterol. It also moderately lowers LDL cholesterol and apolipoprotein B.
• Pharmacokinetics: Gemfibrozil is administered orally and is well-absorbed. It reaches peak serum concentrations within 1-2 hours. It’s highly protein-bound (99%). Gemfibrozil is metabolized in the liver into inactive metabolites and excreted primarily in the urine (70%) and feces (6%). It has a short half-life of about 1.5 hours.
• Mode of Action: Gemfibrozil’s action is mediated through PPAR-α. This receptor, upon activation, regulates the transcription of genes involved in lipid metabolism.
• Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: The primary mechanism is PPAR-α activation. Gemfibrozil also inhibits CYP2C8, which can affect the metabolism of other drugs.
• Elimination Pathways: Primarily renal excretion (70%) with a smaller portion eliminated through feces (6%).

Dosage

Standard Dosage

Adults:

• The standard dosage range is 900-1200 mg daily.
• 900 mg can be taken as a single dose 30 minutes before the evening meal.
• 1200 mg is generally split into two doses of 600 mg, taken 30 minutes before breakfast and the evening meal. The maximum daily dose is 1500 mg.
• Dosages exceeding 1200 mg have not shown improved efficacy in lowering lipid levels.
• Lipid profiles should be monitored periodically and the therapy reevaluated if no improvement is observed after three months of continuous use.

Children: Gemfibrozil is generally not recommended for use in children due to the lack of safety and efficacy data.

Special Cases:

• Elderly Patients: Start with a lower dose and titrate cautiously, considering renal function.
• Patients with Renal Impairment: For mild to moderate renal impairment (GFR 30-80 mL/min), start with 900 mg daily and carefully monitor renal function before increasing the dose. Gemfibrozil is contraindicated in severe renal impairment.
• Patients with Hepatic Dysfunction: Gemfibrozil is contraindicated in patients with hepatic impairment, including primary biliary cirrhosis.
• Patients with Comorbid Conditions: Underlying conditions such as diabetes and hypothyroidism should be optimally managed before and during Gemfibrozil therapy. Caution is advised in patients with a history of gallstones or gallbladder disease.

Clinical Use Cases Gemfibrozil is not typically used in acute settings such as intubation, surgical procedures, mechanical ventilation, ICU care, or emergency situations like cardiac arrest. Its primary role is in the long-term management of chronic lipid disorders.

Side Effects

Common Side Effects:

• Indigestion, heartburn, abdominal pain
• Diarrhea, nausea, vomiting, constipation, flatulence
• Dizziness, headache
• Muscle or joint pain
• Decreased libido, impotence
• Numbness or tingling sensations
• Changes in taste perception
• Cold symptoms (stuffy nose, sneezing, sore throat)

Rare but Serious Side Effects:

• Gallstones (cholelithiasis), cholecystitis
• Myopathy, rhabdomyolysis, myositis (especially with statin use)
• Liver dysfunction (elevated liver enzymes)
• Severe abdominal pain, persistent nausea/vomiting, jaundice, dark urine
• Allergic reactions (rash, hives, difficulty breathing, swelling)
• Blood disorders (anemia, leukopenia, thrombocytopenia)
• Kidney problems (worsening renal function)

Long-Term Effects: Chronic complications associated with prolonged use include an increased risk of gallstones and potentially liver or kidney problems. Regular monitoring is recommended.

Contraindications

• Hypersensitivity to gemfibrozil
• Severe hepatic or renal impairment (including primary biliary cirrhosis)
• Pre-existing gallbladder disease (including gallstones)
• Concurrent use with simvastatin, repaglinide, dasabuvir, or selexipag

Drug Interactions

• Statins: Concomitant use with simvastatin or high-dose rosuvastatin (40mg) is contraindicated due to an increased risk of myopathy and rhabdomyolysis. Caution is advised with other statins.
• Bile Acid Sequestrants: Take at least 2 hours before or after gemfibrozil.
• Repaglinide: Avoid concurrent use due to increased repaglinide levels.
• Selexipag, Dasabuvir: Contraindicated due to increased risk of adverse events.
• Anticoagulants (e.g., warfarin): Monitor INR closely and adjust warfarin dose as needed.
• Other drugs metabolized by CYP2C8 (e.g., repaglinide, pioglitazone): Gemfibrozil inhibits CYP2C8 and may increase the levels of these drugs.
• OATP1B1 substrates (e.g., atorvastatin, rosuvastatin): Dose adjustments may be required due to OATP1B1 inhibition by Gemfibrozil.

Pregnancy and Breastfeeding

• Pregnancy: Gemfibrozil is a Pregnancy Category C drug. Animal studies have shown adverse effects, and there are no adequate studies in humans. Use only if the potential benefit outweighs the potential risk.
• Breastfeeding: Gemfibrozil is excreted in breast milk and may cause adverse effects in infants. Breastfeeding while taking gemfibrozil is not recommended.

Drug Profile Summary

• Mechanism of Action: PPAR-α agonist, leading to reduced triglyceride production and increased HDL.
• Side Effects: Common: GI issues, dizziness, headache, muscle/joint pain. Serious: Gallstones, myopathy, liver/kidney problems.
• Contraindications: Severe liver/kidney disease, gallbladder disease, concurrent use with certain drugs (simvastatin, repaglinide, dasabuvir, selexipag).
• Drug Interactions: Statins, anticoagulants, drugs metabolized by CYP2C8, OATP1B1 substrates.
• Pregnancy & Breastfeeding: Generally avoided.
• Dosage: 900-1200 mg daily in divided doses.
• Monitoring Parameters: Lipid profile, liver function tests, renal function, creatine kinase (if on statins).

Popular Combinations Although not recommended, gemfibrozil is sometimes combined with statins (other than simvastatin or high-dose rosuvastatin) in cases of severe mixed hyperlipidemia when the benefits are deemed to outweigh the risks. This requires close monitoring for myopathy and rhabdomyolysis.

Precautions

• General Precautions: Monitor lipid levels, liver function, and renal function regularly. Assess for gallbladder disease.
• Specific Populations: See Dosage - Special Cases.
• Lifestyle Considerations: Lifestyle modifications, including diet, exercise, and weight control, should be continued during Gemfibrozil therapy. Limit alcohol intake.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Gemfibrozil?

A: The recommended dosage for adults is 900-1200 mg daily, taken 30 minutes before meals. Lower doses may be considered for elderly patients or those with mild to moderate renal impairment.

Q2: What are the primary uses of Gemfibrozil?

A: Gemfibrozil is primarily used to lower triglycerides and increase HDL cholesterol in patients with severe hypertriglyceridemia.

Q3: Can Gemfibrozil be used during pregnancy?

A: Gemfibrozil is generally avoided during pregnancy due to potential risks to the fetus. Consult with a specialist to carefully weigh the benefits and risks.

Q4: What are the common side effects of Gemfibrozil?

A: Common side effects include gastrointestinal issues (indigestion, abdominal pain, diarrhea), dizziness, headache, and muscle or joint pain.

Q5: Are there any serious side effects I should be aware of?

A: Yes, rare but serious side effects include gallstones, myopathy (especially with statins), liver problems, and allergic reactions.

Q6: What drugs interact with Gemfibrozil?

A: Gemfibrozil interacts with several medications, including statins (especially simvastatin), repaglinide, anticoagulants, and some drugs metabolized by CYP2C8.

Q7: What precautions should be taken in patients with kidney problems?

A: In patients with mild to moderate renal impairment, the dose should be started at 900 mg daily and renal function should be carefully monitored. Gemfibrozil is contraindicated in severe renal impairment.

Q8: What should patients do if they miss a dose of Gemfibrozil?

A: If a dose is missed, take it as soon as possible. However, if it is almost time for the next dose, skip the missed dose and resume the regular dosing schedule. Do not double the dose.

Q9: How does Gemfibrozil work to lower triglycerides?

A: Gemfibrozil activates PPAR-α, leading to increased breakdown of triglycerides, decreased triglyceride production in the liver, and increased HDL cholesterol.

Q10: Can Gemfibrozil be used with other lipid-lowering medications?

A: It can be combined with other medications, but caution is needed, particularly with statins. Concurrent use with simvastatin or high-dose rosuvastatin is contraindicated. The potential benefits and risks must be evaluated carefully by a healthcare professional.