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Product Name
:
DE-PAIN
Chemical Name
:
Tizanidine (HCl)
Therapeutic Category
:
Neuromuscular drugs
Pharmacologic Category
:
Alpha2-Adrenergic Agonist
Pharmaceutical Form
:
Tablets
Composition
:
Tizanidine (HCl) 2mg / 4mg
Monitoring Parameters
Dosing
 
Dosing: Adult
Spasticity: Usual initial dose: 4 mg, may increase by 2-4 mg as needed for satisfactory reduction of muscle tone every 6-8 hours to a maximum of 3 doses in any 24 hour period
Range: 2-4 mg 3 times/day
Maximum: 36 mg/day

Dosing: Geriatric

No specific dosing guidelines exist; clearance is decreased; dose cautiously.

Dosing: Renal Impairment

Clcr <25 mL/minute: Use with caution; clearance reduced >50%. During initial dose titration, use reduced doses. If higher doses necessary, increase dose instead of increasing dosing frequency.

Dosing: Hepatic Impairment

Avoid use in hepatic impairment; if used, lowest possible dose should be used initially with close monitoring for adverse effects (eg, hypotension).
Use
 
Skeletal muscle relaxant used for treatment of muscle spasticity
Use - Unlabeled/Investigational
Tension headaches, low back pain, and trigeminal neuralgia
Adverse Reactions
 
Frequency percentages below reported during multiple-dose studies, unless specified otherwise.
>10%:
Cardiovascular: Hypotension (single-dose study with doses ≥8 mg: 16% to 33%)
Central nervous system: Somnolence (48%), dizziness (16%)
Gastrointestinal: Xerostomia (49%)
Neuromuscular & skeletal: Weakness (41%)
1% to 10%:
Cardiovascular: Bradycardia (single-dose study with doses ≥8 mg: 2% to 10%)
Central nervous system: Nervousness (3%), speech disorder (3%), visual hallucinations/delusions (3%; generally occurring in first 6 weeks of therapy), anxiety (1%), depression (1%), fever (1%)
Dermatologic: Rash (1%), skin ulcer (1%)
Gastrointestinal: Constipation (4%), vomiting (3%), abdominal pain (1%), diarrhea (1%), dyspepsia (1%)
Genitourinary: UTI (10%), urinary frequency (3%)
Hepatic: Liver enzymes increased (3% to 5%)
Neuromuscular & skeletal: Dyskinesia (3%), back pain (1%), myasthenia (1%), paresthesia (1%)
Ocular: Blurred vision (3%)
Respiratory: Pharyngitis (3%), rhinitis (3%)
Miscellaneous: Infection (6%), flu-like syndrome (3%), diaphoresis (1%)
<1%, frequency not defined, and postmarketing experience (limited to important or life-threatening): Adrenal insufficiency, allergic reaction, anemia, angina, arrhythmia, carcinoma, cholelithiasis, deafness, dementia, dyslipidemia, gastrointestinal hemorrhage, glaucoma, heart failure, hepatomegaly, hemiplegia, hepatic failure, hepatitis, hepatoma, hyperglycemia, hypokalemia, hyponatremia, hypoproteinemia, hypothyroidism, intestinal obstruction, jaundice, leukopenia, leukocytosis, MI, migraine, neuralgia, optic neuritis, palpitation, paralysis, postural hypotension, psychotic-like symptoms, pulmonary embolus, purpura, respiratory acidosis, retinal hemorrhage, seizure, sepsis, suicide attempt, syncope, thrombocythemia, thrombocytopenia, ventricular extrasystoles, ventricular tachycardia, vertigo
Contraindications
 
Hypersensitivity to tizanidine or any component of the formulation; concomitant therapy with ciprofloxacin or fluvoxamine (potent CYP1A2 inhibitors)
Warnings / Precautions Drug
 
Concerns related to adverse effects:
• Hepatic effects: Potential for hepatotoxicity; AST/ALT elevations (≥2 times baseline) and rarely hepatic failure have occurred; monitor aminotransferases prior to and during use.
• Hypotension: Dose-related significant hypotension (possibly with bradycardia or orthostatic hypotension) may occur; use with caution in patients with cardiac disease or those at risk for severe hypotensive effects.
• Sedation: Dose-related sedation common with use; significant and severe sedation may also occur; use with caution in patients at risk for sedative effects.
• Visual hallucinations: Use has been associated with visual hallucinations or delusions, generally in first 6 weeks of therapy; use caution in patients with psychiatric disorders.
Disease-related concerns:
• Hepatic impairment: Avoid or use extreme caution in patients with hepatic impairment; potential for effects likely due to extensive hepatic metabolism of tizanidine.
• Renal impairment: Use with caution in patients with renal impairment; clearance decreased significantly in severe impairment (Clcr <25 mL/minute) and dose reductions recommended.
Concurrent drug therapy issues:
• Antihypertensives: Hypotensive effects may be potentiated when used with antihypertensives. Should not be used with other alpha2-adrenergic agonists.
• CNS depressants: Sedative effects may be potentiated when used with other CNS depressants.
• High potential for interactions: In general, avoid use in patients taking other CYP1A2 inhibitors; if taken concomitantly, use with caution and monitor for increased hypotensive and sedative effects of tizanidine.
Special populations:
• Elderly: Use with caution; clearance decreased fourfold in the elderly; may increase risk of adverse effects and/or duration of effects. Elderly with severe renal impairment (Clcr <25 mL/minute) may have clearance reduced by >50% compared to healthy elderly subjects.
Other warnings/precautions:
• Abrupt withdrawal: Withdrawal resulting in rebound hypertension, tachycardia, and hypertonia may occur upon discontinuation; doses should be decreased slowly, particularly in patients receiving high doses for prolonged periods.
• Food: Food alters absorption profile relative to administration under fasting conditions. In addition, bioequivalence between capsules and tablets altered by food; capsules and tablets bioequivalent under fasting conditions, but not under nonfasting conditions.
• Long-term use: Limited data exists for chronic use of single doses >8 mg and multiple doses >24 mg/day.
Metabolism/Transport Effects
Substrate of CYP1A2 (major)
Interactions
 
Abiraterone Acetate: May increase the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy
ACE Inhibitors: TiZANidine may enhance the hypotensive effect of ACE Inhibitors. Risk C: Monitor therapy
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Antidepressants (Alpha2-Antagonist): May diminish the hypotensive effect of Alpha2-Agonists. Risk D: Consider therapy modification
Beta-Blockers: May enhance the rebound hypertensive effect of Alpha2-Agonists. This effect can occur when the alpha2-agonist is abruptly withdrawn. Exceptions: Levobunolol; Metipranolol. Risk D: Consider therapy modification
Ciprofloxacin: May decrease the metabolism of TiZANidine. Risk X: Avoid combination
Ciprofloxacin (Systemic): May decrease the metabolism of TiZANidine. Risk X: Avoid combination
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Risk C: Monitor therapy
Contraceptives (Estrogens): May increase the serum concentration of TiZANidine. Risk C: Monitor therapy
CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy
CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 Substrates. Risk D: Consider therapy modification
Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy
Deferasirox: May increase the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
FluvoxaMINE: May decrease the metabolism of TiZANidine. Risk X: Avoid combination
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Hypotensive Agents: May enhance the adverse/toxic effect of other Hypotensive Agents. Risk C: Monitor therapy
Iobenguane I 123: Alpha2-Agonists may diminish the therapeutic effect of Iobenguane I 123. Risk X: Avoid combination
Lisinopril: TiZANidine may enhance the hypotensive effect of Lisinopril. Risk C: Monitor therapy
MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification
Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Risk C: Monitor therapy
Serotonin/Norepinephrine Reuptake Inhibitors: May diminish the antihypertensive effect of Alpha2-Agonists. Risk C: Monitor therapy
Tricyclic Antidepressants: May diminish the antihypertensive effect of Alpha2-Agonists. Risk D: Consider therapy modification
Pregnancy
 
C
Pregnancy Implications
Adverse events were observed in some animal reproduction studies.
Lactation
 
Excretion in breast milk unknown
Breast-Feeding Considerations
Excretion in breast milk is unknown, but expected due to lipid solubility.
Mechanism of Action
 
An alpha2-adrenergic agonist agent which decreases excitatory input to alpha motor neurons; an imidazole derivative chemically-related to clonidine, which acts as a centrally acting muscle relaxant with alpha2-adrenergic agonist properties; acts on the level of the spinal cord
Pharmacodynamics / Kinetics
 
Duration: 3-6 hours
Absorption: Tablets and capsules are bioequivalent under fasting conditions, but not under nonfasting conditions.
Tablets administered with food: Peak plasma concentration is increased by ~30%; time to peak increased by 25 minutes; extent of absorption increased by ~30%.
Distribution: 2.4 L/kg
Protein binding: ~30%
Metabolism: Extensively hepatic via CYP1A2 to inactive metabolites
Bioavailability: ~40% (extensive first-pass metabolism)
Half-life elimination: 2.5 hours
Time to peak, serum:
Fasting state: Capsule, tablet: 1 hour
Fed state: Capsule: 3-4 hours, Tablet: 1.5 hours
Excretion: Urine (60%); feces (20%)
 
   
 
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