Gemfibrozil with Pioglitazone Interaction Details

Brand Names Associated with Gemfibrozil

Brand Names Associated with Pioglitazone

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Dec 02, 2023

Interaction Effect

Increased pioglitazone exposure

Interaction Summary

Coadministration of pioglitazone and a strong CYP2C8 inhibitor, such as gemfibrozil, significantly increases the exposure and half-life of pioglitazone. Additionally, concomitant use of a thiazolidinedione (such as pioglitazone) and a fibrate (such as gemfibrozil) may increase the risk of severe hypoglycemia, which may occur immediately or with a delayed-onset (after the first month of therapy) . When concomitant use is required, the maximum dose of pioglitazone should be 15 mg/day .

Severity

Major

Onset

Unspecified

Evidence

Established

How To Manage Interaction

Coadministration of pioglitazone and a strong CYP2C8 inhibitor, such as gemfibrozil, significantly increases the exposure and half-life of pioglitazone. Additionally, concomitant use of a thiazolidinedione (such as pioglitazone) and a fibrate (such as gemfibrozil) may increase the risk of severe hypoglycemia, which may occur immediately or with a delayed-onset (after the first month of therapy) . When concomitant use is required, the maximum dose of pioglitazone should be 15 mg/day .

Mechanism Of Interaction

Inhibition of CYP2C8-mediated metabolism of pioglitazone

Literature Reports

A) Concomitant use of pioglitazone and gemfibrozil did not result in an increased risk of severe hypoglycemia resulting in emergency department treatment or hospitalization during the first 30 days compared with pioglitazone and pravastatin, though the risk was significantly increased during the first 180 days (adjusted HR, 1.6; 95% CI, 1.32 to 1.93) in a propensity-score adjusted analysis (n=11,531). The risk of severe hypoglycemia increased monotonically with time during later months of concomitant use, with the highest risk of 2.6-fold noted during days 120 to 180. The mechanism for this interaction may be more complex than CYP2C8 inhibition by fibrates and may include a pharmacodynamic interaction involving the impact of fibrates on glucose. Patients received a thiazolidinedione (rosiglitazone or pioglitazone) and an antihyperlipidemic (atorvastatin, fenofibrate, fluvastatin, gemfibrozil, lovastatin, pravastatin, rosuvastatin, or simvastatin) during the study. Pravastatin served as the reference exposure as it is a negligible inhibitor of CYP450 isoenzymes and would not be expected to interact .

B) The pioglitazone AUC increased 3.2-fold and the t(1/2) increased 2.7 fold when coadministered with gemfibrozil in a randomized, placebo-controlled, 4-phase crossover study. Healthy, male volunteers (N=12) were randomized to placebo or gemfibrozil 600 mg twice daily orally for 4 days. On day 3, a single dose of pioglitazone 15 mg orally was administered. After a 4-week washout, volunteers received the alternate of placebo or gemfibrozil. The mean AUC (0 to infinity) of pioglitazone was 5.25 mg x hours (hr)/L (+/- 2.33 mg x hr/L) for the placebo phase and 16.91 mg x hr/L (+/- 5.47 mg x hr/L) for the gemfibrozil phase. The mean t(1/2) of pioglitazone was 8.3 hours (+/- 2.2 hours) for the placebo phase and 22.7 hours (+/- 7.6 hours) for the gemfibrozil phase. The AUCs (0 to 48 hr) of the pioglitazone metabolites (M-III and M-IV) were significantly decreased during the gemfibrozil phase compared with the placebo phase .

C) The AUC of pioglitazone increased 3.4-fold, and the t(1/2) of pioglitazone and its metabolites approximately doubled when coadministered with gemfibrozil in a randomized, 2-phase, crossover study. Healthy, male volunteers (N=10) were randomized to placebo or gemfibrozil 600 mg twice daily orally for a week. On day 4, a single dose of pioglitazone 30 mg orally was administered. After a 2-week washout, volunteers received the alternate of placebo or gemfibrozil. The mean AUC (0 to infinity) of pioglitazone was 11.1 mcg x hours (hr)/mL (range, 8.3 to 13.8 mcg x hr/mL) for the placebo phase and 37.5 mcg x hr/mL (range, 30.5 to 44.5 mcg x hr/mL) for the gemfibrozil phase. The mean t(1/2) of pioglitazone was 6.5 hours (range, 5.1 to 7.6 hours) for the placebo phase and 15.1 hours (range, 13.4 to 17.1 hours) for the gemfibrozil phase. The AUCs of the pioglitazone metabolites (M-III and M-IV) were not significantly different between the placebo and gemfibrozil phase. The half-lives for M-III and M-IV increased from 25.6 hours and 24.6 hours, respectively, for the placebo phase to 50 hours and 44 hours, respectively, for the gemfibrozil phase .

Gemfibrozil Overview

• Gemfibrozil is used with diet changes (restriction of cholesterol and fat intake) to reduce the amount of cholesterol and triglycerides (other fatty substances) in the blood in certain people with very high triglycerides who are at risk of pancreatic disease (conditions affecting the pancreas, a gland that produces fluid to break down food and hormones to control blood sugar). Gemfibrozil is also used in people with a combination of low high-density lipoprotein (HDL; 'good cholesterol') levels and high low-density lipoprotein (LDL; 'bad cholesterol') and triglyceride levels to reduce the risk of heart disease. Gemfibrozil is in a class of lipid-regulating medications called fibrates. It works by reducing the production of triglycerides in the liver.

Pioglitazone Overview

• Pioglitazone is used with a diet and exercise program and sometimes with other medications, to treat type 2 diabetes (condition in which the body does not use insulin normally and therefore cannot control the amount of sugar in the blood). Pioglitazone is in a class of medications called thiazolidinediones. It works by increasing the body's sensitivity to insulin, a natural substance that helps control blood sugar levels. Pioglitazone is not used to treat type 1 diabetes (condition in which the body does not produce insulin and, therefore, cannot control the amount of sugar in the blood) or diabetic ketoacidosis (a serious condition that may develop if high blood sugar is not treated).

• Over time, people who have diabetes and high blood sugar can develop serious or life-threatening complications, including heart disease, stroke, kidney problems, nerve damage, and eye problems.Taking medication(s), making lifestyle changes (e.g., diet, exercise, quitting smoking), and regularly checking your blood sugar may help to manage your diabetes and improve your health. This therapy may also decrease your chances of having a heart attack, stroke, or other diabetes-related complications such as kidney failure, nerve damage (numb, cold legs or feet; decreased sexual ability in men and women), eye problems, including changes or loss of vision, or gum disease. Your doctor and other healthcare providers will talk to you about the best way to manage your diabetes.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.