What is the best approach to managing the interaction between pantoprazole (Protonix) and cabotegravir/rilpivirine (antiretroviral therapy)?

Managing Pantoprazole and Cabotegravir/Rilpivirine Interaction

Pantoprazole is contraindicated with rilpivirine-containing products, including cabotegravir/rilpivirine, and must be discontinued or switched to an alternative acid suppression strategy before initiating or continuing this antiretroviral regimen. 1

Understanding the Mechanism of Interaction

The interaction between pantoprazole (a proton pump inhibitor) and rilpivirine is pharmacologically significant:

• Rilpivirine requires gastric acidity for optimal absorption, and PPIs like pantoprazole reduce intragastric acidity, leading to decreased rilpivirine exposure 1
• Reduced rilpivirine concentrations can result in virologic failure and promote development of drug resistance, which is particularly concerning given the prolonged half-life of long-acting injectable rilpivirine (13-28 weeks) 2
• The FDA drug label explicitly states that concomitant use of pantoprazole with rilpivirine-containing products is contraindicated 1

Recommended Management Algorithm

Step 1: Discontinue Pantoprazole Immediately

• Stop pantoprazole before initiating or continuing cabotegravir/rilpivirine therapy 1
• The contraindication applies to both oral and long-acting injectable formulations of rilpivirine 1

Step 2: Switch to H2-Receptor Antagonist (Famotidine)

• Famotidine 40mg daily is the preferred alternative for acid suppression in patients requiring cabotegravir/rilpivirine 3
• Famotidine does not significantly reduce gastric acidity to the same extent as PPIs and maintains adequate rilpivirine absorption 3
• Continue famotidine throughout the entire duration of injectable therapy, including during the oral lead-in phase and maintenance injections 3

Step 3: Implement Oral Lead-In Phase with Monitoring

• Initiate a 4-5 week oral lead-in phase with oral cabotegravir and rilpivirine while on famotidine to assess tolerability and confirm adequate rilpivirine levels 3
• Monitor HIV RNA at 4-6 weeks after starting oral therapy to ensure the famotidine substitution maintains adequate rilpivirine levels and virologic suppression 3
• Assess GERD symptom control on famotidine during this period to ensure adequate acid suppression without compromising antiretroviral efficacy 3

Step 4: Transition to Long-Acting Injections

• Proceed to long-acting cabotegravir 400mg/rilpivirine 600mg intramuscular injections every 4-8 weeks only if the oral lead-in demonstrates successful virologic suppression and tolerability 3
• Continue famotidine 40mg daily throughout injectable therapy to maintain GERD control while preserving rilpivirine absorption 3

Step 5: Ongoing Monitoring

• Monitor HIV RNA every 3 months for the first year after switching to long-acting cabotegravir/rilpivirine 3
• Be aware that long-acting cabotegravir/rilpivirine carries a 1-2% risk of virologic failure with emergence of 2-class resistance even with adherence, a risk not observed with oral ART 3
• Risk factors for virologic failure include rilpivirine-associated resistance at baseline, viral subtype A6, and BMI >30 3

Critical Pitfalls to Avoid

Do Not Use Alternative PPIs

• All PPIs (omeprazole, esomeprazole, lansoprazole, rabeprazole, dexlansoprazole) share the same contraindication with rilpivirine due to their mechanism of profound acid suppression 1
• Switching from pantoprazole to another PPI does not resolve the interaction 1

Do Not Attempt Dose Separation

• Time separation between PPI and rilpivirine administration does not eliminate the interaction because PPIs cause prolonged suppression of gastric acid secretion lasting 24+ hours 1

Monitor for Inadequate GERD Control

• If famotidine provides insufficient GERD symptom control, consider switching to an alternative antiretroviral regimen that does not contain rilpivirine rather than resuming PPI therapy 3, 1
• Dolutegravir-based regimens or bictegravir-based regimens do not have clinically significant interactions with PPIs and may be appropriate alternatives if acid suppression with a PPI is medically necessary 4

Be Aware of Long Elimination Half-Life Implications

• Rilpivirine has an elimination half-life of 13-28 weeks with intramuscular administration, meaning subtherapeutic concentrations from drug interactions can persist for months and increase resistance risk 2
• Among patients with virologic failure on every 8-week dosing, 75% developed rilpivirine resistance and 60% developed integrase inhibitor resistance 3

Alternative Antiretroviral Regimens if PPI is Essential

If a patient has severe GERD requiring PPI therapy and cannot be adequately controlled with H2-receptor antagonists:

• Consider switching to dolutegravir-based or bictegravir-based regimens, which do not have contraindications with PPIs 4
• Dolutegravir/lamivudine or bictegravir/tenofovir alafenamide/emtricitabine are appropriate alternatives for virologically suppressed patients 4