Tizalud

Approved Indications:

• Spasticity Management:
• Adults with multiple sclerosis, spinal cord injury, or other neurological conditions: Tizanidine is indicated as a short-acting muscle relaxant for the management of increased muscle tone (spasticity). It provides symptomatic relief and improves muscle tone regulation.

Clinically Accepted Off-Label Uses:

• Chronic Myofascial Pain Syndrome: Used in combination with physical therapy and analgesics to reduce muscular tightness.
• Tension-Type Headaches and Migraine Prevention: May reduce frequency/intensity via muscle relaxation.
• Trigeminal Neuralgia: Occasionally used as adjunctive therapy.
• Fibromyalgia: May reduce muscle spasm and improve sleep.
• Temporomandibular Joint (TMJ) Dysfunction: Used for managing masticatory muscle hyperactivity.

General Adult Dosage for Spasticity:

• Initial dose: 2 mg orally every 6 to 8 hours as needed.
• Titration: Increase by 2 to 4 mg per dose every 1 to 4 days, based on clinical response and tolerability.
• Maximum dose: 36 mg per day, divided into 3–4 doses.
• Note: Tizanidine has a short duration of action; individual doses should be spaced at least 6 hours apart.

Special Populations:

• Elderly: Start at lower end of dosage range due to increased risk of hypotension and sedation.
• Renal Impairment (CrCl <25 mL/min): Start at 2 mg once daily and titrate slowly. Avoid high doses.
• Hepatic Impairment: Use with extreme caution. Tizanidine is extensively metabolized by the liver; avoid use in severe hepatic dysfunction.

Route of Administration:

• Oral (tablet or capsule). Capsules can be opened and sprinkled on food, but altering administration (with/without food) affects absorption.

Administration Notes:

• Be consistent with food intake status (always with or always without food).
• Abrupt discontinuation after high doses or long-term use should be avoided; taper slowly to reduce withdrawal symptoms such as rebound hypertension, tachycardia, and hypertonia.

Tizanidine is a centrally acting alpha-2 adrenergic receptor agonist. It primarily acts on the spinal cord by inhibiting presynaptic motor neuron excitatory signals. Tizanidine binds to alpha-2 receptors and decreases the release of excitatory neurotransmitters such as glutamate and aspartate, thereby reducing polysynaptic reflex activity. This suppression leads to decreased muscle spasticity without significantly affecting skeletal muscle strength, distinguishing it from direct-acting muscle relaxants. Its action is reversible and short-acting, allowing for flexible symptomatic control.

• Absorption: Rapid and complete oral absorption. Bioavailability varies:
• Tablets (fasted): Peak plasma concentration in ~1 hour.
• Capsules (fasted): Lower Cmax and AUC; food increases absorption significantly.
• Distribution: Widely distributed; 30% plasma protein bound.
• Metabolism: Extensively metabolized in the liver via CYP1A2.
• Metabolites: Multiple inactive metabolites.
• Elimination Half-Life: ~2.5 hours for the parent compound.
• Excretion: Primarily renal (60–70%) as metabolites; ~2–3% unchanged drug.
• Food Effect: Co-administration with food increases AUC by ~30% (capsule), ~10% (tablet); clinical implications vary by formulation.

• Pregnancy:
• FDA Category C (old classification): Animal studies have shown adverse fetal effects (e.g., developmental delays, embryo lethality), but there are no well-controlled studies in pregnant women. Use only if potential benefits justify the risks.
• Lactation:
• Unknown if tizanidine is excreted in human milk. Due to the potential for adverse effects in nursing infants (e.g., sedation, hypotonia), caution is advised. Consider discontinuing breastfeeding or the drug depending on necessity.
• Recommendation: Avoid during pregnancy unless essential. Use with caution during lactation.

• Primary Class: Centrally Acting Muscle Relaxant
• Subclass: Alpha-2 Adrenergic Agonist
• Generation: Non-benzodiazepine spasmolytic agent

• Hypersensitivity to tizanidine or any of its components
• Concomitant use with potent CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin)
• Severe hepatic impairment
• Known history of hypersensitive or idiosyncratic reactions to alpha-2 agonists

• Hepatotoxicity: Elevated liver enzymes and rare liver failure have been reported. Monitor liver function regularly.
• Hypotension: Risk of profound hypotension, especially when combined with antihypertensives. Monitor blood pressure.
• Sedation & CNS Depression: May impair alertness; caution with driving or operating machinery.
• Withdrawal/Rebound Hypertension: Taper slowly after long-term use to avoid rebound hypertension and tachycardia.
• Renal Impairment: Reduced clearance and increased plasma concentrations in renal dysfunction.
• Elderly: Increased sensitivity to side effects such as sedation and orthostatic hypotension.

Common Adverse Effects:

• Central Nervous System: Drowsiness, dizziness, fatigue, asthenia
• Gastrointestinal: Dry mouth, constipation, nausea
• Cardiovascular: Hypotension, bradycardia
• Musculoskeletal: Muscle weakness

Less Common but Serious Effects:

• Hepatotoxicity (elevated transaminases, rare hepatic failure)
• Hallucinations or psychotic-like symptoms
• Rebound hypertension on abrupt discontinuation
• QT prolongation (rare, potential with overdose)

Rare Effects:

• Urinary tract infections
• Visual disturbances
• Skin rash

Onset: Effects generally begin within 1–2 hours of dosing; side effects often dose-related and resolve with dose reduction.

Major Drug-Drug Interactions:

• CYP1A2 inhibitors (e.g., ciprofloxacin, fluvoxamine): Drastically increase tizanidine plasma levels → risk of hypotension, bradycardia, and CNS depression.
• Antihypertensives or diuretics: Enhanced risk of hypotension.
• Oral contraceptives (estrogens): May increase tizanidine levels.
• Other CNS depressants (e.g., benzodiazepines, opioids, alcohol): Additive sedation and respiratory depression risk.

Enzyme System:

• CYP1A2 substrate. Potent inhibitors significantly raise exposure; avoid or monitor carefully.

Drug-Food Interaction:

• Food affects bioavailability. Maintain consistent intake pattern regarding meals.

Drug-Alcohol Interaction:

• Increased CNS depression, hypotension risk. Alcohol should be avoided.

• FDA Label Update (Past 3 Years): Reiterated the absolute contraindication with fluvoxamine and ciprofloxacin due to fatal hypotensive events.
• Clinical Guidelines (Spasticity Management): Tizanidine remains a second-line option after baclofen in various guidelines (e.g., NICE, MS Society).
• Emphasis on Liver Monitoring: Regulatory authorities recommend baseline and periodic liver function testing during long-term use.

• Temperature: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C–30°C (59°F–86°F).
• Humidity & Light: Protect from excessive moisture and direct light.
• Handling Precautions: Store in original container; keep tightly closed.
• No reconstitution or refrigeration required.