What are the drug interaction risks and monitoring recommendations when ribociclib is co‑administered with the anti‑tuberculosis agents isoniazid, rifampicin, pyrazinamide, and ethambutol?

Ribociclib and Anti-Tuberculosis Drug Interactions

Critical Drug Interaction: Avoid Rifampicin with Ribociclib

Rifampicin is a potent CYP3A4 inducer and will significantly reduce ribociclib plasma concentrations, potentially leading to treatment failure of the cancer therapy—co-administration should be avoided. If tuberculosis treatment is absolutely necessary in a patient on ribociclib, alternative strategies must be employed.

Interaction Profile by Individual TB Drug

Rifampicin (Contraindicated)

• Rifampicin induces CYP3A4 and other drug-metabolizing enzymes, which will dramatically lower ribociclib levels 1
• This enzyme induction effect also impacts other medications metabolized via these pathways, making rifampicin the most problematic agent in this combination 1
• The induction effect persists throughout rifampicin therapy and requires dose adjustments of many co-administered drugs 1

Isoniazid (Caution Required)

• Isoniazid itself does not have significant CYP3A4 interactions, but hepatotoxicity monitoring becomes critical when combined with ribociclib 2, 3, 4
• Both ribociclib and isoniazid can cause hepatotoxicity; baseline and frequent liver function monitoring (weekly for first 2 weeks, then every 2 weeks for 2 months) is mandatory 1, 2, 3
• Rifampicin enhances isoniazid hepatotoxicity through enzyme induction, but this is less relevant if rifampicin is avoided 2, 4

Pyrazinamide (Caution Required)

• Pyrazinamide is hepatotoxic and requires the same intensive liver monitoring as isoniazid 1, 2, 5
• Late-onset hepatotoxicity (>1 month) is often pyrazinamide-related and carries a poorer prognosis than early isoniazid toxicity 2, 4
• If liver enzymes rise to ≥5 times normal or bilirubin increases, immediately discontinue rifampicin, isoniazid, and pyrazinamide 2, 3, 5

Ethambutol (Safest Option)

• Ethambutol is not hepatotoxic and has no significant drug-metabolizing enzyme interactions 1, 4
• Ethambutol is the safest TB drug to combine with ribociclib from a drug interaction perspective 1, 4
• Primary concern is ocular toxicity requiring baseline and periodic visual acuity monitoring 3

Recommended Management Algorithm

Step 1: Assess Treatment Priority

• Determine whether cancer treatment or TB treatment takes priority based on disease severity and life expectancy
• If ribociclib must be continued, rifampicin-free TB regimens are mandatory 1

Step 2: Alternative TB Regimen Without Rifampicin

• Use isoniazid and ethambutol for 12 months, supplemented with pyrazinamide for the initial 2 months 2, 3
• This extends treatment duration from 6 to 12 months but avoids the critical rifampicin interaction 2, 3
• For isoniazid-resistant TB, consider rifabutin as a potential rifampicin substitute, though CYP3A4 interaction data with ribociclib would need verification 1

Step 3: Intensive Hepatotoxicity Monitoring

• Obtain baseline AST, ALT, and bilirubin before starting TB therapy 2, 3
• Monitor liver function weekly for the first 2 weeks, then every 2 weeks for the first 2 months, then monthly 1, 2, 3
• Hold hepatotoxic TB drugs if AST/ALT rises to ≥5 times normal or any bilirubin elevation occurs 2, 3, 5

Step 4: Sequential Drug Reintroduction if Hepatotoxicity Occurs

• Stop all hepatotoxic drugs (isoniazid, pyrazinamide) and continue ethambutol until liver function normalizes 2, 3, 5
• Reintroduce isoniazid first at 50 mg/day, increasing to 300 mg/day over 2-3 days 2, 3
• Add pyrazinamide at 250 mg/day after 2-3 days without reaction, increasing to full dose 2, 3, 5
• Do not reintroduce pyrazinamide if it was the identified offending agent due to poor prognosis of recurrent pyrazinamide hepatitis 2, 4

Critical Pitfalls to Avoid

• Never use rifampicin with ribociclib—the enzyme induction will cause cancer treatment failure 1
• Do not discontinue pyrazinamide for asymptomatic hyperuricemia alone, as this is expected and clinically insignificant 5
• Avoid combined fixed-dose TB preparations during drug reintroduction, as individual agents must be identified 2, 5
• Do not delay stopping hepatotoxic drugs when transaminases reach 5 times normal—early intervention prevents fulminant hepatic failure 2, 3, 4

Multidrug-Resistant TB Considerations

• For MDR-TB (resistant to isoniazid and rifampicin), use pyrazinamide plus ethambutol or pyrazinamide plus a fluoroquinolone for 6-12 months 1
• Immunocompromised patients require 12 months of treatment; immunocompetent patients may be treated for 6 months 1
• Expert consultation is mandatory for MDR-TB management in patients on ribociclib 1, 2