No Clinically Significant Drug Interaction Between Plaquenil and Macrobid
There is no documented clinically significant drug interaction between hydroxychloroquine (Plaquenil) and nitrofurantoin (Macrobid), and these medications can be used together safely when clinically indicated.
Evidence Base
The available evidence does not identify any pharmacokinetic or pharmacodynamic interaction between these two agents:
Pharmacokinetic Considerations
Hydroxychloroquine is metabolized primarily through CYP3A4/5, CYP2C8, and CYP2D6 pathways, and acts as a weak inhibitor of CYP2D6 and P-glycoprotein 1, 2. Research specifically examining hydroxychloroquine's transporter interactions found it does not inhibit BCRP or OATP transporters, though it does inhibit P-gp at concentrations exceeding 10 µM 2.
Nitrofurantoin has minimal systemic absorption and does not undergo significant hepatic metabolism. The FDA label indicates that nitrofurantoin's primary drug interactions involve antacids containing magnesium trisilicate (which reduce absorption) and uricosuric drugs like probenecid (which increase serum levels) 3. Nitrofurantoin is not a substrate, inhibitor, or inducer of the cytochrome P450 enzymes that metabolize hydroxychloroquine.
Pharmacodynamic Considerations
While hydroxychloroquine carries risks of QT prolongation 1, 4, nitrofurantoin is not associated with cardiac conduction abnormalities or QT prolongation. The FDA label for Macrobid does not list cardiac effects among its adverse reactions 3.
Both drugs can cause peripheral neuropathy as rare adverse effects 5, 1, but this represents additive toxicity rather than a true drug-drug interaction. The risk remains low with standard dosing.
Clinical Implications
When Co-Administration is Appropriate
- Urinary tract infections in patients with autoimmune disease: This is the most common scenario where these drugs would be prescribed together
- Standard dosing applies: Hydroxychloroquine ≤5.0 mg/kg/day (typically 200-400 mg daily) 6, 7 and nitrofurantoin 100 mg twice daily with food 3
Monitoring Recommendations
No specific additional monitoring is required beyond standard care for each medication:
- For hydroxychloroquine: Baseline and periodic ophthalmologic screening (annually after 5 years of use), baseline ECG if cardiac risk factors present 5, 6, 7
- For nitrofurantoin: Monitor for pulmonary symptoms, hepatotoxicity, and peripheral neuropathy with prolonged use 3
Important Caveats
Avoid nitrofurantoin in patients with G6PD deficiency 8, though this is independent of hydroxychloroquine use. While nitrofurantoin appears less likely to cause hemolysis than primaquine in G6PD-deficient individuals, caution is warranted 8.
Pulmonary toxicity: Both drugs can rarely cause pulmonary complications. One case report documented severe pulmonary fibrosis with methotrexate and nitrofurantoin co-administration 9, highlighting that drug-induced pulmonary toxicity can be additive. While this involved methotrexate rather than hydroxychloroquine, clinicians should remain vigilant for respiratory symptoms when using multiple agents with pulmonary toxicity potential.
Comprehensive Drug Interaction Reviews
Multiple systematic reviews of hydroxychloroquine drug interactions, particularly in the COVID-19 context, identified numerous clinically significant interactions with other medications 10, 11, 12. Notably, nitrofurantoin does not appear in any of these comprehensive interaction analyses, further supporting the absence of a clinically meaningful interaction between these agents.