Drug Interactions: Integrase Inhibitors and Cations

Antacids, laxatives, mineral supplements, and other compounds that contain metal cations (eg, calcium, magnesium, aluminum, and iron) may decrease levels of integrase inhibitors if taken close in time to each other. Results of two studies help to assess the magnitude of this effect and assist in determining how to manage it.

A study in HIV-infected subjects on stable raltegravir (RAL)-containing ART examined the effects on RAL levels of 2 antacids, calcium carbonate antacid (Tums Ultra 1,000 mg, 3 tablets) and magnesium/aluminum hydroxide antacid (Mintox Maximum Strength, 20 mL).[1] Compared with administration of RAL alone:

  • Simultaneous administration of calcium carbonate antacid with RAL resulted in 32% reduction in C12hr and 55% reduction in AUC
  • Simultaneous administration of magnesium/aluminum with RAL resulted in 63% reduction in C12hr and 49% reduction in AUC
  • Administration of magnesium/aluminum either 2 hours before or 2 hours after RAL resulted in 57% reduction in C12hr and 51-30% reduction in AUC

A study in HIV-uninfected persons examined the effects of calcium (calcium carbonate 1,200 mg) and iron (ferrous fumarate 324 mg) supplements on dolutegravir (DTG) (50 mg once daily).[2] Compared with administration of DTG alone:

  • Administration of DTG and calcium together on an empty stomach resulted in approximately 40% decrease in DTG AUC and C24hr
  • Administration of DTG and iron together on an empty stomach resulted in approximately 55% decrease in DTG AUC and C24hr
  • Administration of DTG with either calcium or iron together with food, and administration of either calcium or iron 2 hours after DTG did not reduce DTG concentrations

Based on these and other data, the prescribing information for the integrase inhibitors includes dosing recommendations for their use with polyvalent cations:

  • RAL:
    • Do not administer RAL and magnesium/aluminum hydroxide antacids simultaneously or within 2 hours of each other.
    • No dosing separation is necessary when coadministering RAL and calcium carbonate antacids.
  • DTG:
    • DTG should be administered at least 2 hours before or at least 6 hours after medications containing polyvalent cations, but DTG can be taken together with supplements containing calcium or iron if they are also taken with food.[3]
  • Elvitegravir:
    • Separate elvitegravir/cobicistat/emtricitabine/tenofovir (Stribild) and antacid administration by at least 2 hours.


  1. Isentress prescribing information and info from manufacturer. Merck & Co. April 2014.
  2. Song I, Borland J, Arya N, et al. The effect of calcium and iron supplements on the pharmacokinetics of dolutegravir in healthy subjects. In: Program and abstracts of the 15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy; May 19-21, 2014; Washington, DC. Abstract P13.
  3. Tivicay Prescribing Information. ViiV Healthcare. May 2014.

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Topic(s): Drug Interactions