Drug Interaction Report

GENERALLY AVOID: Coadministration of topical tacrolimus with other immunosuppressive agents may potentiate the immunosuppressive effects of topical tacrolimus. However, data concerning its safety and efficacy in combination with immunosuppressants are not available. According to the prescribing information, rare cases of skin malignancy and lymphoma have been reported in patients who have received treatment with topical calcineurin inhibitors, including topical tacrolimus. On the other hand, systemic exposure from topical tacrolimus is reported to be less than 1 ng/mL. In addition, the lowest tacrolimus blood concentration from topical application at which systemic effects can be observed is unknown.

MANAGEMENT: According to the manufacturer, use of topical tacrolimus in immunocompromised patients is not recommended. Therefore, until further information is available, it may be advisable to avoid its concomitant use with other immunosuppressants. Screening for the development of malignancy during and after treatment may also be considered.

GENERALLY AVOID: Grapefruit and grapefruit juice may significantly increase the plasma concentrations of lorlatinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruit. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients treated with lorlatinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. If coadministration is unavoidable, some authorities recommend reducing the initial dosage of lorlatinib from 100 mg orally once daily to 75 mg orally once daily. In patients who have had a dosage reduction to 75 mg orally once daily due to adverse reactions, the lorlatinib dosage should be further reduced to 50 mg orally once daily upon initiation of a potent CYP450 3A4 inhibitor. After 3 plasma half-lives following discontinuation of the potent CYP450 3A4 inhibitor, the lorlatinib dosage may be increased to that used prior to initiation of the inhibitor.