TIZANIDINE HYDROCHLORIDE
Clinical safety rating: safe
Animal studies have demonstrated safety
Tizanidine is a centrally acting alpha2-adrenergic agonist that reduces spasticity by increasing presynaptic inhibition of motor neurons. It binds to alpha2-adrenergic receptors in the spinal cord and brain, inhibiting excitatory neurotransmitter release (e.g., glutamate, aspartate) and facilitating glycinergic inhibition.
| Metabolism | Primarily hepatic via CYP1A2 isoenzyme; forms inactive metabolites. Coadministration with CYP1A2 inhibitors or inducers alters tizanidine exposure significantly. |
| Excretion | Approximately 60% of the dose is excreted in urine (mainly as metabolites, <5% unchanged) and 20% in feces. Renal clearance accounts for the majority of elimination, with a renal clearance of about 2 L/h. |
| Half-life | Terminal elimination half-life is approximately 2.5 hours (range 2–4 hours). In patients with renal impairment (CrCl <25 mL/min), half-life may be prolonged up to 14 hours due to reduced clearance. |
| Protein binding | Approximately 30% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Volume of distribution is approximately 2.4 L/kg (range 2–3 L/kg), indicating extensive tissue distribution beyond plasma volume. |
| Bioavailability | Oral bioavailability is about 40% (range 30–50%) due to extensive first-pass metabolism. Bioavailability may be increased by up to 50% when taken with food. |
| Onset of Action | Oral: Onset of action occurs within 30–60 minutes; peak effect at 1–2 hours. Sublingual: Faster onset, within 15–30 minutes. |
| Duration of Action | Duration of action is approximately 4–8 hours following oral administration, corresponding to the half-life. Clinically, the antispastic effect may persist for 3–6 hours, requiring multiple daily doses. |
Initial: 2 mg orally every 6-8 hours as needed; may increase by 2-4 mg per dose up to a maximum of 36 mg/day. Usual maintenance: 2-4 mg three times daily.
| Dosage form | CAPSULE |
| Renal impairment | Creatinine clearance <25 mL/min: Start with 2 mg once daily; titrate slowly (maximum 12 mg/day). For CCr ≥25 mL/min: no adjustment needed. |
| Liver impairment | Child-Pugh Class A: no adjustment. Child-Pugh Class B: start at 2 mg once daily; titrate cautiously. Child-Pugh Class C: contraindicated. |
| Pediatric use | Not recommended for children <18 years due to lack of safety and efficacy data. |
| Geriatric use | Initiate at 2 mg once daily; titrate slowly due to increased risk of hypotension and sedation. Maximum 8 mg/day in elderly. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Strong CYP1A2 inhibitors (eg fluvoxamine) can significantly increase levels Can cause hypotension and sedation.
| Breastfeeding | No data on tizanidine excretion in human milk; M/P ratio unknown. Due to potential for hypotension and sedation in the infant, caution advised. Consider alternatives or discontinue breastfeeding. |
| Teratogenic Risk | No adequate and well-controlled studies in pregnant women. Animal studies (rats, rabbits) at doses up to 10 mg/kg showed increased fetal resorptions, reduced fetal weight, and skeletal variations. First trimester: insufficient data to quantify risk. Second/third trimester: potential for maternal hypotension, bradycardia, and resulting uteroplacental hypoperfusion. Use only if benefit outweighs risk. |
■ FDA Black Box Warning
None.
| Common Effects | Dryness in mouth Sleepiness Tiredness Dizziness |
| Serious Effects |
["Hypersensitivity to tizanidine or any component","Concomitant use with fluvoxamine or ciprofloxacin (potent CYP1A2 inhibitors) due to increased tizanidine levels and risk of hypotension/sedation","Severe hepatic impairment (Child-Pugh Class C)"]
| Precautions | ["Hypotension and bradycardia, especially with concurrent antihypertensives","Hepatotoxicity (monitor LFTs)","Sedation, dizziness; avoid driving or hazardous activities","Abrupt discontinuation may cause rebound hypertension and tachycardia","Risk of withdrawal reactions (hypertension, tachycardia, hypertonia)"] |
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| Fetal Monitoring | Monitor maternal blood pressure and heart rate during therapy, especially at initiation or dose titration. In late pregnancy, periodic fetal heart rate monitoring may be considered due to potential for maternal hypotension. |
| Fertility Effects | Animal studies: No clear evidence of impaired fertility at therapeutic doses. Human data insufficient to draw conclusions. |