Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV

Tables

Table 4. Significant Pharmacokinetic Interactions between Drugs Used to Treat or Prevent Opportunistic Infections

This table lists the known, predicted, or suspected pharmacokinetic (PK) interactions between drugs used for the treatment or prevention of HIV-associated opportunistic infections (OIs). Many of the drugs listed in this table may also interact with antiretroviral (ARV) drugs. Clinicians should see the Drug–Drug Interactions tables in the most current Adult and Adolescent Antiretroviral Guidelines to assess interaction potentials between OI drugs and ARV drugs.

Throughout the table, three recommendations are commonly used when concomitant administration of two drugs may lead to untoward consequences. The rationales for these recommendations are summarized below:

Do not coadminister.

There is either strong evidence or strong likelihood that the PK interaction cannot be managed with a dose modification of one or both drugs and will or may result in either—

• Increase in concentrations of one or both drugs, which may lead to excessive risk of toxicity; or
• Decrease in concentrations of one or both drugs, which may render one or both drugs ineffective.

Coadministration should be avoided, if possible.

There is a potential for significant PK interactions. If other more favorable options exist, clinicians are advised to consider changing components of the regimen to accommodate a safer or more effective regimen. However, coadministration of the drugs may be necessary when there are no other acceptable therapeutic options that provide a more favorable benefit-to-risk ratio. Therapeutic drug monitoring, if available, may facilitate any necessary dose adjustments.

Use with caution.

Drug combinations are recommended to be used with caution when—

• PK studies have shown a moderate degree of interaction of unknown clinical significance; or
• Based on the known metabolic pathway of the two drugs, there is a potential for PK interaction of unknown clinical significance.

Rifamycin-Related Induction Interactions

Rifamycin antibiotics are potent inducers of Phase 1 and Phase 2 drug metabolizing reactions. They also affect various transporters. When a rifamycin antibiotic must be combined with an interacting drug, close monitoring for clinical efficacy of the coadministered agent is advised. Therapeutic drug monitoring, if available, may facilitate any necessary dose adjustments.

• Rifampin (also known as rifampicin): Interactions may not be apparent in the first several days of rifampin therapy. However, with daily doses of rifampin, enzyme induction increases over a week or more. Based on limited data, larger daily doses of rifampin (e.g., 1,200 mg or more) appear to produce the same maximum induction as lower doses, but the induction effect occurs more rapidly.
• Rifabutin: In general, rifabutin as a cytochrome P450 3A4 (CYP3A4) inducer is about 40% of the potency of rifampin, but this can vary by substrate and enzymatic reaction.
• Rifapentine: In general, daily rifapentine is at least as potent an inducer as rifampin. However, the potential for drug interactions with once-weekly rifapentine is not well studied. Reduced exposure of concurrent drugs that are CYP3A4 substrates is likely to occur with once-weekly rifapentine, with the extent varying by drug.

Pharmacodynamic Interactions

Pharmacodynamic interactions are not addressed in this table. For example, many of the drug classes listed below independently possess a risk for QTc prolongation, including azoles, macrolides, and certain anti-tuberculosis and antimalarial medications. Coadministration of drugs in these classes may require monitoring for QTc prolongation, particularly in patients with predisposing risk factors.

Therapeutic Drug Monitoring

Drug interactions can alter oral absorption or systemic clearance of drugs. More than one interaction can occur at the same time, with potentially opposing effects. Therapeutic drug monitoring (TDM), if available, may facilitate any necessary dose adjustments in these complicated patients. TDM allows the clinician to make informed, individualized decisions about dose adjustments that are more precise than standardized dose adjustments based upon anticipated, average effects. Drug names below marked with asterisk (*) are known to have assays available in the United States and, typically, in Europe as well.

Note: To avoid redundancy, drug–drug interactions are listed only once by primary drug (listed alphabetically). Subsequently, when an interacting agent becomes the primary drug, guideline users are referred to the entry for the initial primary drug. See the Clarithromycin row for the first example of this format.