Drug Interactions between dexamethasone / ketorolac / moxifloxacin and lenacapavir

MONITOR CLOSELY: Concomitant administration of corticosteroids may potentiate the risk of tendinitis and tendon rupture associated with fluoroquinolone treatment. The mechanism is unknown. Tendinitis and tendon rupture have most frequently involved the Achilles tendon, although cases involving the rotator cuff (the shoulder), the hand, the biceps, and the thumb have also been reported. Some have required surgical repair or resulted in prolonged disability. Tendon rupture can occur during or up to several months after completion of fluoroquinolone therapy.

MANAGEMENT: Caution is recommended if fluoroquinolones are prescribed in combination with corticosteroids, particularly in patients with other concomitant risk factors (e.g., age over 60 years; recipient of kidney, heart, and/or lung transplant). Patients should be advised to stop taking the fluoroquinolone, avoid exercise and use of the affected area, and promptly contact their physician if they experience pain, swelling, or inflammation of a tendon. In general, fluoroquinolones should only be used to treat conditions that are proven or strongly suspected to be caused by bacteria and only if the benefits outweigh the risks.

GENERALLY AVOID: Coadministration with certain corticosteroids (e.g., dexamethasone (doses > 16 mg daily)), may reduce plasma concentrations and pharmacologic effects of lenacapavir. The proposed mechanism is dexamethasone dose-dependent induction of CYP450 3A4, the primary isoenzyme responsible for lenacapavir metabolism. According to lenacapavir product labeling, concomitant administration of systemic dexamethasone with lenacapavir may result in decreased lenacapavir plasma concentrations potentially leading to loss of lenacapavir virologic response, resistance development, and therefore coadministration is not recommended. Drug studies evaluating the potential interactions following coadministration of lenacapavir with systemic dexamethasone (doses > 16 mg daily) observed dose-dependent CYP450 3A4 induction. Additionally, some literature noted a potential for loss of lenacapavir efficacy following concomitant administration with systemic betamethasone. However, clinical data evaluating this interaction are limited. Coadministration of lenacapavir with another moderate CYP450 3A4 inducer, efavirenz (600 mg once daily), reduced the systemic exposure (AUC) and peak plasma concentration (Cmax) of lenacapavir by 56% and 36%, respectively.

MONITOR CLOSELY: Coadministration with lenacapavir, a moderate CYP450 3A4 inhibitor, may increase the plasma concentrations of dexamethasone and betamethasone, substrates of the CYP450 3A4 isoenzyme. Concomitant administration can increase systemic exposure (AUC) of the corticosteroid(s), increasing the risk for Cushing's syndrome and adrenal syndrome. In pharmacokinetic studies in fed subjects without HIV, coadministration of oral lenacapavir (600 mg twice daily for 2 days, then a single 600 mg dose) with the sensitive CYP450 3A4 substrate midazolam (single 2.5 mg dose orally at the same time as the single lenacapavir dose) led to an increase in midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) by 1.9-fold and 3.6-fold, respectively.

MANAGEMENT: Given its narrow therapeutic index and the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiviral drug levels, concomitant use of lenacapavir, with systemic dexamethasone (doses > 16 mg daily) or systemic betamethasone should generally be avoided. If coadministration is clinically necessary, considering alternative corticosteroids without CYP450 3A4 inducing properties and monitoring lenacapavir's virologic response may be advisable. When dexamethasone is used, some authorities recommend a 2-week washout period before initiating lenacapavir to account for dexamethasone's prolonged inducing effect. In addition, due to the moderate CYP450 3A4 inhibiting properties of lenacapavir, caution is advised if lenacapavir is coadministered with dexamethasone or betamethasone. Lenacapavir's manufacturer recommends initiating with the lowest dose of systemic corticosteroids with gradual titration, while monitoring for corticosteroid safety. Clinicians should be aware that due to lenacapavir's long half-life, the effect may persist for up to 9 months after the last subcutaneous dose, so caution and monitoring for adverse effects are also advised during this time.

MONITOR: The combined use of corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the potential for serious gastrointestinal (GI) toxicity, including inflammation, bleeding, ulceration, and perforation. In a large, case-control study of elderly patients, those who used corticosteroids and NSAIDs concurrently had an estimated relative risk (RR) for peptic ulcer disease and GI hemorrhage of 14.6 compared to those who used neither. Corticosteroid use was associated with a doubling of the risk (estimated RR = 2.0), but the risk was confined to those who also used NSAIDs. It is possible that both categories of agents are ulcerogenic and have additive effects on the GI mucosa during coadministration. Some investigators have also suggested that the primary effect of corticosteroids in this interaction is to delay healing of erosions caused by NSAIDs rather than cause de novo ulcerations.

MANAGEMENT: Caution is advised if corticosteroids and NSAIDs are used together, especially in patients with a prior history of peptic ulcer disease or GI bleeding and in elderly and debilitated patients. During concomitant therapy, patients should be advised to take the medications with food and to immediately report signs and symptoms of GI ulceration and bleeding such as severe abdominal pain, dizziness, lightheadedness, and the appearance of black, tarry stools. The selective use of prophylactic anti-ulcer therapy (e.g., antacids, H2-antagonists) may be considered.

MONITOR: Coadministration with nonsteroidal anti-inflammatory drugs (NSAIDs) may potentiate the risk of central nervous system toxicity sometimes associated with fluoroquinolone use. The interaction has been reported most often with enoxacin. It may occur with other fluoroquinolones as well, but is poorly documented. The exact mechanism of interaction is unknown. Some investigators suggest that the piperazine ring of fluoroquinolones may inhibit the binding of gamma-aminobutyric acid (GABA) to brain receptors and that NSAIDs may synergistically add to this effect. Patients with a history of seizures may be at greater risk.

MANAGEMENT: Clinical monitoring for signs of CNS stimulation such as tremors, involuntary muscle movements, hallucinations, or seizures is recommended if fluoroquinolone antibiotics are prescribed in combination with NSAIDs.