Should Stivarga (Regorafenib) be taken with food or on an empty stomach?

Regorafenib (Stivarga) Should Be Taken With a Low-Fat Meal

Regorafenib should be taken with a low-fat meal that contains less than 30% fat to optimize absorption and efficacy. 1

Evidence-Based Rationale

The FDA label for Stivarga (regorafenib) provides clear guidance on administration with food:

• In the pivotal clinical trials (CORRECT and GRID) that led to FDA approval, regorafenib was administered with a low-fat breakfast 1
• Pharmacokinetic studies show that food significantly affects regorafenib absorption:
  • A low-fat meal (319 calories and 8.2g fat) increased the mean AUC of regorafenib by 36% 1
  • A low-fat meal also increased the bioavailability of active metabolites M-2 and M-5 by 40% and 23%, respectively, compared to fasting conditions 1

Administration Guidelines

Recommended Approach

• Take the standard dose of 160mg (four 40mg tablets) once daily with a low-fat breakfast
• Continue for the first 21 days of each 28-day cycle
• Maintain consistent timing of administration relative to meals

What Constitutes a Low-Fat Meal

A low-fat meal should contain:

• Approximately 300-320 calories
• Less than 30% of calories from fat (approximately 8-10g of fat)
• Examples: toast with jam, fruit, and skim milk; cereal with low-fat milk and fruit

Clinical Implications

Taking regorafenib with food has important implications for:

1. Efficacy: The clinical trials that demonstrated survival benefit used administration with a low-fat meal 1

2. Bioavailability: Food increases the absorption of both the parent drug and its active metabolites, which is essential for therapeutic effect 1

3. Consistency: Taking the medication consistently with similar meals helps maintain stable drug levels

Managing Side Effects

Regorafenib has significant side effects that require careful management:

• Common adverse events include hand-foot skin reaction, diarrhea, hypertension, and fatigue 2
• Taking with food may help mitigate some gastrointestinal side effects, though this must be balanced with the specific food requirements
• In clinical trials, dose interruptions and reductions were required in 58% and 50% of patients, respectively 2

Important Considerations

• Avoid high-fat meals: A high-fat meal (945 calories, 54.6g fat) alters the metabolite profile differently than a low-fat meal, decreasing some active metabolites 1
• Maintain consistency: Take at approximately the same time each day with similar food content
• Adherence is critical: The GEIS guidelines emphasize that checking adherence to treatment is the first recommended measure when evaluating treatment failure 2

Common Pitfalls to Avoid

1. Taking on an empty stomach, which reduces bioavailability
2. Taking with a high-fat meal, which alters the metabolite profile
3. Inconsistent timing or food content, which may lead to variable drug levels
4. Discontinuing due to side effects rather than discussing dose modifications with healthcare providers

Following these evidence-based recommendations for taking regorafenib with a low-fat meal will help optimize treatment outcomes while managing side effects appropriately.