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Drug Interactions between Fortovase and Symdeko

This report displays the potential drug interactions for the following 2 drugs:

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Interactions between your drugs

Major

saquinavir ivacaftor

Applies to: Fortovase (saquinavir) and Symdeko (ivacaftor / tezacaftor)

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of ivacaftor, which is primarily metabolized by the isoenzyme. In study subjects, ivacaftor systemic exposure (AUC) increased by 8.5-fold when it was administered concomitantly with ketoconazole, a potent CYP450 3A4 inhibitor. When lumacaftor/ivacaftor was coadministered with itraconazole, another potent CYP450 3A4 inhibitor, lumacaftor pharmacokinetics were not affected, but ivacaftor peak plasma concentration (Cmax) and AUC increased by an average of 3.7- and 4.3-fold, respectively. Due to the induction effect of lumacaftor on CYP450 3A4, at steady state the net AUC of ivacaftor is not expected to exceed that when given in the absence of lumacaftor at a dosage of 150 mg every 12 hours (the approved dosage of ivacaftor monotherapy). For this reason, no dosage adjustment is recommended when CYP450 3A4 inhibitors are initiated in patients already receiving lumacaftor/ivacaftor, whereas a dosage reduction for lumacaftor/ivacaftor is recommended when initiating treatment in patients receiving potent CYP450 3A4 inhibitors. When tezacaftor/ivacaftor was coadministered with itraconazole, tezacaftor and ivacaftor AUC increased by 4-fold and 15.6-fold, respectively. Likewise, elexacaftor AUC has also been reported to increase 2.8-fold by itraconazole.

MANAGEMENT: Please consult manufacturer's product labeling for complete dosing information.
For ivacaftor - For patients aged 6 months and older the ivacaftor dose should be reduced from 1 tablet or 1 packet of oral granules twice a day to 1 tablet or 1 packet of oral granules twice a week (i.e., every 3 to 4 days) during coadministration with potent CYP450 3A4 inhibitors. For example, a patient taking ivacaftor 150 mg tablet twice a day should reduce their ivacaftor dose to a 150 mg tablet twice a week and a patient taking ivacaftor 50 mg oral granule packet twice a day should reduce their ivacaftor dose to 50 mg oral granule packet twice a week, etc. Use of ivacaftor with moderate or strong CYP450 3A4 inhibitors is not recommended in patients less than 6 months of age.
For lumacaftor/ivacaftor - No dosage adjustment is necessary when CYP450 3A4 inhibitors are initiated in patients who are already receiving lumacaftor /ivacaftor. However, the initial dose of lumacaftor/ivacaftor in patients who are currently receiving potent CYP450 3A4 inhibitors, should be reduced to 1 tablet once a day or 1 packet every other day for the first week of treatment, then increased to the recommended dose. If lumacaftor/ivacaftor is interrupted for more than one week and then re-initiated while receiving potent CYP450 3A4 inhibitors, the dosage should be similarly reduced to 1 tablet daily or 1 packet every other day for the first week of treatment re-initiation.
For tezacaftor/ivacaftor - The morning dose of tezacaftor/ivacaftor should be reduced to one tablet twice a week, approximately 3 to 4 days apart, and the evening ivacaftor dose should not be taken during treatment with potent CYP450 3A4 inhibitors.
For elexacaftor/tezacaftor/ivacaftor - The morning dose of 2 elexacaftor/tezacaftor/ivacaftor tablets once a day should be reduced to 2 tablets twice a week, approximately 3 to 4 days apart, and the evening ivacaftor dose should not be taken during treatment with potent CYP450 3A4 inhibitors.

References

  1. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  2. Cerner Multum, Inc. "Australian Product Information." O 0
  3. "Product Information. Kalydeco (ivacaftor)." Vertex Pharmaceuticals (2012):
  4. "Product Information. Orkambi (ivacaftor-lumacaftor)." Vertex Pharmaceuticals (2015):
  5. "Product Information. Symdeko (ivacaftor-tezacaftor)." Vertex Pharmaceuticals (2022):
  6. "Product Information. Trikafta (elexacaftor/ivacaftor/tezacaftor)." Vertex Pharmaceuticals (2019):
View all 6 references

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Drug and food interactions

Moderate

saquinavir food

Applies to: Fortovase (saquinavir)

ADJUST DOSING INTERVAL: Food significantly increases the absorption of saquinavir.

MONITOR: Coadministration with grapefruit juice may increase the plasma concentrations of saquinavir. The primary mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In eight healthy volunteers, ingestion of 400 mL of grapefruit juice prior to administration of a 600 mg dose of saquinavir mesylate increased the area under the plasma concentration-time curve and oral bioavailability of saquinavir by 50% and 100%, respectively, compared to water; however, the increase is not considered clinically relevant. A high degree of intersubject variability in the grapefruit juice effect was also observed. The extent to which this interaction may occur with the saquinavir free base soft gelatin capsule is unknown. However, the saquinavir soft gelatin capsule formulation is no longer commercially available.

MANAGEMENT: Saquinavir mesylate should be taken with meals or within 2 hours after eating to enhance bioavailability. Patients should be advised to avoid the consumption of large amounts of grapefruit and grapefruit juice during saquinavir therapy unless otherwise directed by their doctor, as the interaction is unreliable and subject to a high degree of interpatient variation.

References

  1. "Product Information. Invirase (saquinavir)." Roche Laboratories PROD (2001):
  2. Kupferschmidt HHT, Fattinger KE, Ha HR, Follath F, Krahenbuhl S "Grapefruit juice enhances the bioavailability of the HIV protease inhibitor saquinavir in man." Br J Clin Pharmacol 45 (1998): 355-9
  3. Bailey DG, Malcolm J, Arnold O, Spence JD "Grapefruit juice-drug interactions." Br J Clin Pharmacol 46 (1998): 101-10
  4. Eagling VA, Profit L, Back DJ "Inhibition of the CYP3A4-mediated metabolism and P-glycoprotein-mediated transport of the HIV-I protease inhibitor saquinavir by grapefruit juice components." Br J Clin Pharmacol 48 (1999): 543-52
  5. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  6. Cerner Multum, Inc. "Australian Product Information." O 0
View all 6 references

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Moderate

ivacaftor food

Applies to: Symdeko (ivacaftor / tezacaftor)

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of ivacaftor. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Elexacaftor and tezacaftor are also CYP450 3A4 substrates in vitro and may interact similarly with grapefruit juice, whereas lumacaftor is not expected to interact.

ADJUST DOSING INTERVAL: According to prescribing information, systemic exposure to ivacaftor increased approximately 2.5- to 4-fold, systemic exposure to elexacaftor increased approximately 1.9- to 2.5-fold, and systemic exposure to lumacaftor increased approximately 2-fold following administration with fat-containing foods relative to administration in a fasting state. Tezacaftor exposure is not significantly affected by administration of fat-containing foods.

MANAGEMENT: Patients treated with ivacaftor-containing medications should avoid consumption of grapefruit juice and any food that contains grapefruit or Seville oranges. All ivacaftor-containing medications should be administered with fat-containing foods such as eggs, avocados, nuts, meat, butter, peanut butter, cheese pizza, and whole-milk dairy products. A typical cystic fibrosis diet will satisfy this requirement.

References

  1. "Product Information. Kalydeco (ivacaftor)." Vertex Pharmaceuticals (2012):
  2. "Product Information. Orkambi (ivacaftor-lumacaftor)." Vertex Pharmaceuticals (2015):
  3. "Product Information. Symdeko (ivacaftor-tezacaftor)." Vertex Pharmaceuticals (2022):
  4. "Product Information. Trikafta (elexacaftor/ivacaftor/tezacaftor)." Vertex Pharmaceuticals (2019):
View all 4 references

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Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

See also

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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