Drug Interaction Between Norethisterone 5mg and Itraconazole 200mg
Itraconazole significantly increases norethisterone levels through potent CYP3A4 inhibition, requiring close monitoring for progestin-related side effects and consideration of alternative contraception methods during concurrent therapy. 1
Mechanism of Interaction
Itraconazole is a potent inhibitor of the CYP3A4 enzyme system, which is the primary metabolic pathway for norethisterone, leading to reduced metabolism and elevated serum concentrations of the progestin. 1, 2
The interaction occurs through both hepatic CYP3A4 inhibition and effects on intestinal drug-metabolizing enzymes, resulting in substantially increased norethisterone bioavailability. 1
Among azole antifungals, itraconazole demonstrates particularly high inhibitory effects on CYP3A4 activity compared to fluconazole or echinocandins. 2
Clinical Consequences and Risks
Elevated norethisterone levels manifest as increased progestin-related adverse effects, including breakthrough bleeding, breast tenderness, mood changes, and headaches. 1
Potential thromboembolic risk may increase if norethisterone levels become excessively elevated, particularly in patients with additional risk factors such as smoking, obesity, or thrombophilia. 1
Paradoxically, unpredictable pharmacokinetics can potentially compromise contraceptive efficacy in some patients despite elevated norethisterone levels, though this is less common than side effect concerns. 1
The interaction is bidirectional in nature, where both drug levels can theoretically be affected, though the primary clinical concern is elevated norethisterone. 1
Monitoring Requirements
Assess for signs and symptoms of progestin excess when these medications are coadministered, specifically monitoring for breakthrough bleeding patterns, breast tenderness, mood disturbances, and headaches. 1
Consider therapeutic drug monitoring for itraconazole to avoid excessive serum concentrations that would amplify the interaction, with serum levels measured after at least 2 weeks of therapy to ensure adequate but not excessive drug exposure. 3, 1
Review all current medications for potentially deleterious drug interactions before initiating itraconazole therapy, as multiple CYP3A4 substrates can have cumulative effects. 1
Management Recommendations
Counsel patients about potential changes in bleeding patterns and increased progestin-related side effects before initiating concurrent therapy. 1
Consider alternative contraception methods during itraconazole therapy, such as barrier methods as backup, to ensure contraceptive reliability and avoid complications from elevated progestin levels. 1
The duration of interaction persists as long as both medications are coadministered and for several days after discontinuation due to itraconazole's long half-life (approximately 24 hours at steady state). 3, 1
If itraconazole therapy is essential and prolonged (as commonly required for fungal infections lasting 3-12 months), strongly consider switching to non-hormonal contraception for the duration of antifungal treatment. 3, 1
Special Populations
Patients with genetic polymorphisms affecting CYP3A4 enzymes may experience more pronounced interactions between itraconazole and norethisterone, though routine genetic testing is not currently recommended. 1
- CYP2C19 polymorphisms do not significantly contribute to itraconazole metabolism differences and are not relevant to this interaction. 1
Common Pitfalls to Avoid
Failing to recognize the bidirectional nature of hormonal and azole interactions where both drug levels can be affected, and inadequate patient counseling about potential breakthrough bleeding or contraceptive reliability concerns. 1
Not considering the cumulative effect when patients are on multiple CYP3A4 substrates simultaneously with itraconazole, which can lead to unexpected toxicity. 1
Overlooking that the interaction persists for several days after discontinuing itraconazole due to its long elimination half-life and tissue accumulation. 1, 4
Assuming that all azole antifungals have equivalent interaction potential—fluconazole has significantly less CYP3A4 inhibition than itraconazole and may be considered as an alternative when clinically appropriate for the fungal infection being treated. 2