What is the recommended dosing for Xanaflex (tizanidine) in a patient with muscle spasms due to a neurological condition or spinal injury, considering factors such as age, weight, and impaired renal function?

Tizanidine (Zanaflex) Dosing Guidelines

Standard Dosing Regimen

Start tizanidine at 2-4 mg as a single dose, then titrate gradually by 2-4 mg increments every 3-7 days to an effective dose, with a typical maintenance range of 8-24 mg/day divided into 2-3 doses (maximum 36 mg/day). 1, 2, 3

Initial Titration Protocol

• Begin with 2-4 mg at bedtime or as a single daytime dose to assess tolerability, as peak plasma concentrations occur 1 hour after dosing with a half-life of approximately 2 hours 1
• Increase by 2-4 mg every 3-7 days based on response and tolerability, as optimal dosage must be titrated over 2-4 weeks due to wide interpatient variability in effective plasma concentrations 2, 3
• Target maintenance dose of 8-24 mg/day in divided doses (typically 8 mg three times daily), with clinical trials using dosages ranging from 2-36 mg/day 2
• Maximum effects occur within 2 hours of administration, with duration of action lasting 4-6 hours, necessitating multiple daily doses for sustained effect 1

Dosing Frequency Considerations

• Administer in 2-3 divided doses per day rather than once daily, as the short half-life of approximately 2 hours requires frequent dosing to maintain therapeutic effect 1
• Space doses no more than 6-8 hours apart to avoid gaps in spasticity control, given the 4-6 hour duration of action 1

Special Population Adjustments

Elderly Patients

Reduce initial dose and titrate more slowly in elderly patients, as they clear tizanidine four times slower than younger subjects, leading to prolonged clinical effects and increased risk of hypotension. 1

• Start with 2 mg once daily at bedtime in elderly patients to minimize adverse effects 1
• Increase by 2 mg increments every 5-7 days (slower than standard titration) to allow adequate assessment of tolerability 3
• Monitor blood pressure closely, as elderly patients are more susceptible to orthostatic hypotension and sedation 1

Renal Impairment

In patients with creatinine clearance <25 mL/min, reduce individual doses rather than dosing frequency, as tizanidine clearance is reduced by more than 50%, leading to longer duration of clinical effect. 1

• Start with 2 mg once daily in patients with severe renal impairment (CrCl <25 mL/min) 1
• If higher doses are required, increase individual doses rather than dosing frequency to avoid excessive accumulation 1
• Monitor closely for dry mouth, somnolence, asthenia, and dizziness as indicators of potential overdose in renally impaired patients 1

Hepatic Impairment

Avoid tizanidine in patients with hepatic impairment, as pharmacokinetic differences have not been adequately studied and dose-related retinal degeneration and corneal opacities have been observed in animal studies. 1

Women Taking Oral Contraceptives

Reduce individual doses by approximately 50% in women taking oral contraceptives, as clearance of tizanidine is reduced by approximately 50% in this population. 1

• Start with 2 mg once daily and titrate more slowly than standard protocol 1
• Increase individual doses rather than dosing frequency during titration to minimize adverse effects 1

Food Effects on Absorption

Counsel patients that taking tizanidine with food increases peak plasma concentration by approximately 30% and delays time to peak by 25 minutes, potentially altering both efficacy and adverse effect profiles. 1

• Maintain consistent administration (either always with food or always without food) to ensure predictable therapeutic response 1
• If switching from fasted to fed administration, monitor for increased adverse effects due to higher peak concentrations 1

Critical Safety Considerations

Cardiovascular Monitoring

• Monitor blood pressure and heart rate regularly, as tizanidine can cause clinically significant orthostatic hypotension and bradycardia 1
• Warn patients about performing activities requiring alertness (driving, operating machinery) due to risk of sedation 1
• Avoid abrupt discontinuation, especially in patients on high doses for prolonged periods, to minimize risk of rebound hypertension, tachycardia, and hypertonia 1

Drug Interactions

• Avoid concurrent use with alcohol, as it increases tizanidine AUC by approximately 20% and Cmax by 15%, with additive CNS depressant effects 1
• Exercise extreme caution with CNS depressants (baclofen, benzodiazepines), as sedation is additive 1
• Avoid concurrent use with rofecoxib, as it may potentiate adverse effects including hallucinations, psychosis, somnolence, hypotonia, hypotension, tachycardia, and bradycardia 1

Discontinuation Protocol

Taper tizanidine gradually over at least 1 week when discontinuing therapy, decreasing the dose slowly to minimize risk of withdrawal and rebound hypertension, tachycardia, and hypertonia. 1

Expected Efficacy and Tolerability

• Reduction in mean muscle tone scores of 21-37% compared to 4-9% with placebo in controlled trials 2
• Improvement in muscle tone occurs in 60-82% of patients receiving tizanidine, comparable to baclofen (60-65%) and diazepam (60-83%) 2
• Most common adverse effects are dry mouth and somnolence/drowsiness, but subjective muscle weakness is reported less often than with baclofen or diazepam 2
• Global tolerability assessed as good to excellent in 44-100% of patients, compared to 38-90% with baclofen and 20-54% with diazepam 2

Critical Pitfalls to Avoid

• Never start at high doses without gradual titration, as this dramatically increases risk of hypotension and sedation 1, 3
• Never use standard doses in renal impairment or in women taking oral contraceptives without dose reduction 1
• Never discontinue abruptly, especially after prolonged use at high doses, due to risk of rebound hypertension and tachycardia 1
• Never assume normal renal function in elderly patients without calculating creatinine clearance, as age-related decline may be masked by normal serum creatinine 1