CYP1A2 Inhibitors and Tizanidine: A Dangerous Interaction
CYP1A2 inhibitors are contraindicated with tizanidine because they dramatically increase tizanidine plasma concentrations, causing potentially life-threatening hypotension, bradycardia, and excessive sedation. 1
Mechanism of Interaction
Tizanidine is primarily metabolized by the cytochrome P450 1A2 (CYP1A2) enzyme system. When CYP1A2 inhibitors are co-administered:
- They block the metabolism of tizanidine, leading to significantly increased plasma concentrations
- Studies show up to 10-fold increases in tizanidine's area under the curve (AUC) 2
- Peak concentrations can increase by 7-fold (range 4-fold to 21-fold) 2
Clinical Consequences of the Interaction
Cardiovascular Effects
- Severe hypotension (up to 35 mmHg decrease in systolic blood pressure) 2
- Bradycardia
- Syncope
- Shock in severe cases
- Potential for cardiorespiratory arrest 3
Neurological Effects
- Excessive sedation and drowsiness
- Impaired psychomotor performance
- Dizziness
- Increased risk of falls and fractures 3
Evidence from Clinical Studies
Real-world data confirms the severity of this interaction:
A retrospective analysis of the WHO pharmacovigilance database found that despite the contraindication, co-administration of tizanidine and CYP1A2 inhibitors (particularly ciprofloxacin) occurs in clinical practice, resulting in severe adverse effects primarily affecting the central nervous and cardiovascular systems 4
A cohort study demonstrated that patients receiving tizanidine with ciprofloxacin had a 43% increased likelihood of hypotension compared to those not receiving ciprofloxacin (adjusted odds ratio: 1.43,95% CI: 1.25-1.63) 5
Disproportionality analysis of FDA Adverse Event Reporting System showed significantly increased reporting odds ratios for hypotension with tizanidine plus ciprofloxacin (ROR 28.1,95% CI 19.2-41.2) and tizanidine plus fluvoxamine (ROR 36.9,95% CI 13.1-103.4) 3
Specific CYP1A2 Inhibitors to Avoid with Tizanidine
The following medications are known CYP1A2 inhibitors and should not be co-administered with tizanidine:
- Fluoroquinolone antibiotics: especially ciprofloxacin 6
- Antidepressants: fluvoxamine 1
- Oral contraceptives 6
- Other known inhibitors: cimetidine, methoxsalen 6
Clinical Implications
The FDA drug label for fluvoxamine explicitly states: "Fluvoxamine is a potent inhibitor of CYP1A2 and tizanidine is a CYP1A2 substrate. The effect of fluvoxamine (100 mg daily for 4 days) on the pharmacokinetics and pharmacodynamics of a single 4 mg dose of tizanidine has been studied in 10 healthy subjects. Tizanidine Cmax was increased approximately 12-fold, elimination half-life was increased by almost 3-fold, and AUC increased 33-fold." 1
The combination can result in fatal outcomes, as reported in pharmacovigilance data 4
Alternative Approaches
For patients requiring muscle relaxation who are on CYP1A2 inhibitors:
- Consider gabapentin as an alternative, starting at 100-300 mg at bedtime and increasing to 300-600 mg/day in divided doses 7
- Other muscle relaxants that don't rely on CYP1A2 metabolism may be appropriate alternatives
Key Takeaways
The interaction between tizanidine and CYP1A2 inhibitors is not merely theoretical but has been documented to cause serious adverse events in clinical practice
Despite being contraindicated, this dangerous combination continues to be prescribed, highlighting the need for increased awareness
Always perform a thorough medication review before prescribing tizanidine to avoid this potentially life-threatening drug interaction