What are the potential interactions between tizanidine (Zanaflex) and ciprofloxacin (Cipro)?

Tizanidine and Ciprofloxacin: Absolute Contraindication

The concurrent use of tizanidine and ciprofloxacin is absolutely contraindicated and must be avoided under all circumstances due to life-threatening hypotension, severe sedation, and documented fatal outcomes. 1

Mechanism of the Interaction

• Ciprofloxacin potently inhibits CYP1A2, the primary metabolic pathway for tizanidine, causing a dramatic 10-fold increase in tizanidine plasma concentrations (AUC) and a 7-fold increase in peak levels 2
• This interaction occurs through inhibition of presystemic (first-pass) metabolism rather than systemic clearance, explaining why tizanidine's elimination half-life increases only minimally (1.5 to 1.8 hours) despite massive concentration increases 2
• The FDA drug label explicitly states: "Concomitant administration of tizanidine and ciprofloxacin is contraindicated" due to potentiation of hypotensive and sedative effects 1

Clinical Consequences and Severity

Cardiovascular Effects

• Systolic blood pressure drops by an average of 35 mm Hg (compared to 15 mm Hg with tizanidine alone) 2
• Diastolic blood pressure decreases by 24 mm Hg (versus 11 mm Hg with tizanidine alone) 2
• Hypotension risk increases with an adjusted odds ratio of 1.43 in real-world hospital data 3
• The reporting odds ratio for hypotension when tizanidine is listed as suspect/interacting drug with ciprofloxacin is 28.1 (95% CI 19.2-41.2) 4

Central Nervous System Effects

• Severe sedation and drowsiness are significantly potentiated 2
• Cognitive impairment measured by Digit Symbol Substitution Test shows marked deterioration 2
• CNS depression can progress to cardiorespiratory arrest in severe cases 5

Documented Fatal Outcomes

• Two fatal cases have been reported in the WHO global pharmacovigilance database among 91 cases of concurrent tizanidine-ciprofloxacin use 5
• Most adverse events affected the nervous system and cardiac function, particularly when combined with other CNS or cardiovascular depressants 5

Real-World Prevalence of This Error

• Despite the formal contraindication, 3.6% of tizanidine encounters involved concurrent ciprofloxacin administration across 221 U.S. hospitals 3
• In Swiss claims data, 199 patients were exposed to this contraindicated combination in a 2-year period 6
• The combination resulted in increased outpatient physician visits at 14 days (OR 1.61) and 30 days (OR 1.59), with trends toward increased hospitalizations 6

Clinical Management Algorithm

If Patient is Currently Taking Tizanidine

1. Absolutely do not prescribe ciprofloxacin 1
2. Select an alternative antibiotic that does not inhibit CYP1A2:
   • Azithromycin (does not inhibit CYP1A2) 7
   • Beta-lactams (amoxicillin, cephalosporins)
   • Avoid other fluoroquinolones as they may have similar effects
3. If a fluoroquinolone is absolutely necessary for resistant infection, discontinue tizanidine and wait for adequate washout before starting the fluoroquinolone 5

If Patient is Currently Taking Ciprofloxacin

1. Do not initiate tizanidine during ciprofloxacin therapy 1
2. Wait at least 3-5 days after completing ciprofloxacin before starting tizanidine to allow for complete elimination of the CYP1A2 inhibitor
3. Consider alternative muscle relaxants that are not CYP1A2 substrates (e.g., baclofen, cyclobenzaprine)

If Inadvertent Co-Administration Has Occurred

1. Immediately discontinue both medications if clinically feasible 5
2. Monitor blood pressure continuously for at least 24 hours 2
3. Assess for severe sedation and respiratory depression 5
4. Provide supportive care with IV fluids for hypotension
5. Avoid abrupt tizanidine discontinuation in chronic users; taper if patient has been on long-term therapy 8

Other CYP1A2 Inhibitors to Avoid with Tizanidine

While ciprofloxacin is the most potent and well-documented interaction, fluvoxamine also shows dangerous interactions with tizanidine (ROR for hypotension 36.9,95% CI 13.1-103.4) 4. Other CYP1A2 inhibitors requiring caution include:

• Fluvoxamine (strongest inhibitor after ciprofloxacin) 4
• Other fluoroquinolones (though ciprofloxacin is most potent)
• Zafirlukast (ROR for falls 16.0) 4

High-Risk Patient Populations

• Older adults are at dramatically increased fall risk due to combined sedation and hypotension 7, 4
• Patients with hepatic or renal dysfunction have reduced clearance of both medications 8
• Patients on polypharmacy with other CNS depressants (opioids, benzodiazepines, gabapentinoids) face compounded risks 8
• Patients with baseline hypotension or cardiovascular disease are at highest risk for hemodynamic collapse 2

Key Pitfalls to Avoid

• Do not assume the interaction is dose-dependent and manageable with dose reduction—even standard doses cause dangerous elevations 2
• Do not rely on temporal separation (taking medications at different times of day)—ciprofloxacin's CYP1A2 inhibition persists throughout the dosing interval 2
• Do not overlook this interaction in emergency settings where both drugs are commonly prescribed for musculoskeletal complaints and infections 3
• Remember that the American Geriatrics Society specifically added this interaction to their 2019 Beers Criteria as a drug-drug interaction to avoid in older adults 7