Rofecoxib is no longer available on the market due to safety concerns, specifically an increased risk of cardiovascular events like heart attack and stroke. Therefore, the combination of rofecoxib and tizanidine is not used in clinical practice. This document will focus on tizanidine, addressing its usage, mechanism of action, dosage, side effects, contraindications, and other important information.
Usage
- Medical Conditions: Tizanidine is primarily prescribed for muscle spasticity associated with conditions like multiple sclerosis, spinal cord injuries, stroke, and cerebral palsy. It can also be used for muscle spasms related to musculoskeletal issues such as back pain.
- Pharmacological Classification: Tizanidine is a central alpha-2 adrenergic agonist and skeletal muscle relaxant.
- Mechanism of Action: Tizanidine acts on alpha-2 adrenergic receptors in the central nervous system (CNS), primarily in the spinal cord. This action reduces the release of excitatory neurotransmitters, leading to decreased muscle tone and spasticity.
Alternate Names
- International Nonproprietary Name (INN): Tizanidine
- Brand Names: Zanaflex, Sirdalud, others (vary by region)
How It Works
- Pharmacodynamics: Tizanidine’s primary effect is to reduce muscle tone and spasticity by decreasing excitatory neurotransmitter release in the CNS. It also has mild analgesic and sedative properties.
- Pharmacokinetics:
- Absorption: Tizanidine is well-absorbed orally.
- Metabolism: Primarily metabolized by the CYP1A2 enzyme in the liver. This is a crucial point for drug interactions.
- Elimination: Mainly excreted by the kidneys. Dose adjustment is necessary in patients with renal impairment.
- Mode of Action: Tizanidine binds to presynaptic alpha-2 adrenergic receptors in the spinal cord, inhibiting the release of excitatory amino acids, such as glutamate and aspartate. This leads to a reduction in neuronal excitability and a decrease in muscle tone.
- Receptor Binding/Enzyme Inhibition: Alpha-2 adrenergic agonist; significantly affected by CYP1A2 inhibitors.
- Elimination Pathways: Primarily renal excretion; hepatic metabolism by CYP1A2.
Dosage
Standard Dosage
Adults:
- Initial: 2 mg orally every 6 to 8 hours as needed.
- Titration: Increase dose by 2 to 4 mg at 1- to 4-day intervals, as tolerated, until the desired effect is achieved.
- Maximum: 36 mg per day, divided into 3 or 4 doses.
- Important Considerations:
- Consistency with meals: Take either consistently with food or on an empty stomach. Do not switch between these options during treatment.
- Formulation: Tablets and capsules have different absorption profiles, particularly with food. Once a formulation is chosen, it should not be changed.
Children:
The use of tizanidine in children is generally not recommended due to limited safety and efficacy data. If used off-label, dosing must be carefully individualized by a physician based on the child’s age, weight, and clinical condition.
Special Cases:
- Elderly Patients: Start with a lower dose and titrate cautiously due to increased sensitivity to side effects.
- Patients with Renal Impairment: Initiate therapy with 2 mg once daily and titrate slowly based on creatinine clearance and tolerability. Focus on increasing the individual dose rather than the dosing frequency.
- Patients with Hepatic Dysfunction: Use with caution; consider dose reduction and close monitoring. Severe hepatic impairment is a contraindication.
- Patients with Comorbid Conditions: Adjust dosage based on the specific comorbidity and the patient’s overall health status.
Clinical Use Cases
Tizanidine dosage recommendations are based on the spasticity level and patient response. Specific dosage guidelines for procedures like intubation, surgical procedures, mechanical ventilation, ICU use, and emergency situations are not universally established. Dosage must be determined by the attending physician based on the clinical context.
Dosage Adjustments
Dosage adjustments are crucial in specific populations (as detailed above) and for drug interactions (see Drug Interactions).
Side Effects
Common Side Effects
- Drowsiness, dizziness, dry mouth, fatigue, hypotension, weakness, asthenia, nausea, abdominal pain, constipation
Rare but Serious Side Effects
- Liver dysfunction (hepatotoxicity), hallucinations, severe hypotension, bradycardia, allergic reactions
Long-Term Effects
- Potential for liver damage with prolonged use. Regular liver function tests are essential.
- Dependence may develop with chronic use. Tapering is necessary upon discontinuation.
Adverse Drug Reactions (ADR)
- Hepatotoxicity, severe allergic reactions, profound hypotension, bradycardia requiring intervention
Contraindications
- Hypersensitivity to tizanidine
- Concurrent use of strong CYP1A2 inhibitors like fluvoxamine and ciprofloxacin
- Severe hepatic impairment
Drug Interactions
- CYP1A2 Inhibitors: Concomitant use with strong CYP1A2 inhibitors is contraindicated. Use with other CYP1A2 inhibitors (e.g., amiodarone, cimetidine, oral contraceptives) is not recommended or requires careful monitoring and dose adjustment.
- CNS Depressants (e.g., alcohol, sedatives): Additive sedative effects. Avoid concurrent use.
- Antihypertensives: May potentiate hypotension. Close blood pressure monitoring is essential.
- Other Medications: Consult a drug interaction database for a comprehensive list.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Formerly Category C, current FDA classification unavailable due to rofecoxib’s withdrawal. Use only if the potential benefit outweighs the risk to the fetus.
- Fetal Risks: Animal studies have shown increased gestation duration and prenatal/postnatal loss at high doses. Human data are limited.
- Breastfeeding: Tizanidine may be excreted in breast milk. Use with caution and monitor the infant for potential side effects.
Drug Profile Summary (Tizanidine only)
- Mechanism of Action: Central alpha-2 adrenergic agonist.
- Side Effects: Drowsiness, dizziness, dry mouth, fatigue, hypotension, hepatotoxicity (rare).
- Contraindications: Hypersensitivity, concurrent use of fluvoxamine or ciprofloxacin, severe hepatic impairment.
- Drug Interactions: CYP1A2 inhibitors, CNS depressants, antihypertensives.
- Pregnancy & Breastfeeding: Use with caution; potential risks.
- Dosage: Adults: Starting 2 mg every 6-8 hours, up to 36 mg/day, titrated as tolerated.
- Monitoring Parameters: Blood pressure, heart rate, liver function tests.
Popular Combinations
Tizanidine may be used in conjunction with physical therapy and other spasticity management strategies. Due to the withdrawal of rofecoxib, it is no longer combined with it. Other muscle relaxants like baclofen may be used in combination with tizanidine.
Precautions
- Monitor blood pressure, especially during dose titration.
- Assess liver function regularly, especially with prolonged use.
- Caution in elderly patients and those with renal or hepatic impairment.
- Avoid alcohol and other CNS depressants.
- Driving restrictions may be necessary due to sedation.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Tizanidine?
A: Adults: Initial dose is 2 mg every 6-8 hours, titrated as needed up to a maximum of 36 mg/day. Dosage adjustments are needed for renal/hepatic impairment and elderly patients.
Q2: What are the common side effects of Tizanidine?
A: Drowsiness, dizziness, dry mouth, fatigue, and hypotension.
Q3: Can Tizanidine be used during pregnancy?
A: Only if the potential benefit justifies the risk to the fetus. Consult with a specialist.
Q4: How should Tizanidine be administered?
A: Orally, consistently with or without food. Do not alter food intake once a pattern is established.
Q5: What are the contraindications for Tizanidine?
A: Hypersensitivity, concurrent use with fluvoxamine or ciprofloxacin, and severe hepatic impairment.
Q6: Does Tizanidine interact with other medications?
A: Yes, it interacts with CYP1A2 inhibitors, CNS depressants, and antihypertensives. Consult a drug interaction resource for details.
Q7: What monitoring parameters are important for patients taking Tizanidine?
A: Blood pressure, heart rate, and liver function tests.
Q8: What are the signs of Tizanidine overdose?
A: Severe hypotension, bradycardia, excessive drowsiness, and potentially hallucinations. Seek immediate medical attention.
Q9: Can Tizanidine be used in children?
A: Generally not recommended due to limited data. If used, dosing must be individualized under close medical supervision.
