FDA

Tizanidine Hydrochloride

Approved 27 May 2020OralCapsule

The FDA lists this product in 60 strengths and forms.

Indications

Tizanidine hydrochloride is a central alpha-2-adrenergic agonist indicated for the management of spasticity. Because of the short duration of therapeutic effect, treatment with tizanidine hydrochloride capsules should be reserved for those daily activities and times when relief of spasticity is most important [see Dosage and Administration ( 2.1 )] . Tizanidine hydrochloride is a central alpha-2-adrenergic agonist indicated for the management of spasticity.

Because of the short duration of therapeutic effect, treatment with tizanidine hydrochloride capsules should be reserved for those daily activities and times when relief of spasticity is most important. ( 1 )

Contraindications

Tizanidine hydrochloride capsules is contraindicated in patients taking potent inhibitors of CYP1A2, such as fluvoxamine or ciprofloxacin [see Drug Interactions ( 7.1 , 7.2 )] . Concomitant use with potent inhibitors of CYP1A2, such as fluvoxamine or ciprofloxacin ( 4 , 5.5 , 7.1 , 7.2 )

Warnings and precautions

Hypotension: monitor for signs and symptoms of hypotension, in particular in patients receiving concurrent antihypertensives; tizanidine should not be used with other α 2 -adrenergic agonists ( 5.1 , 7.7 ) Risk of liver injury: monitor ALTs; discontinue tizanidine if liver injury occurs ( 5.2 ) Sedation: Tizanidine may interfere with everyday activities; sedative effects of tizanidine, alcohol, and other CNS depressants are additive ( 5.3 , 7.5 , 7.6 ) Hallucinations: consider discontinuation of tizanidine ( 5.4 ) Less potent inhibitors of CYP1A2: may cause hypotension, bradycardia, or excessive drowsiness, use caution if tizanidine is used with less potent inhibitors of CYP1A2, e.g., zileuton, other fluoroquinolones, antiarrythmics , cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine ( 5.5 , 7.3 , 12.3 ) Renal impairment (creatinine clearance < 25 mL/min): use tizanidine with caution, and monitor closely for dry mouth, somnolence, asthenia and dizziness as indicators of potential overdose ( 5.7 )

5.1Hypotension

Tizanidine is an α 2 -adrenergic agonist that can produce hypotension. Syncope has been reported in the post marketing setting. The chance of significant hypotension may possibly be minimized by titration of the dose and by focusing attention on signs and symptoms of hypotension prior to dose advancement. In addition, patients moving from a supine to fixed upright position may be at increased risk for hypotension and orthostatic effects.

At a glance

Brand name: Tizanidine Hydrochloride
Route: Oral
Dosage form: Capsule
Applicant: Rubicon Research
Status: Prescription
FDA approval: 27 May 2020
Application: ANDA213798-004

Indications

Warnings and precautions

5.1Hypotension

Interactions

7.1Fluvoxamine

Concomitant use of fluvoxamine and tizanidine is contraindicated. Changes in pharmacokinetics of tizanidine when administered with fluvoxamine resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment. [see Contraindications ( 4 ) and Clinical Pharmacology ( 12.3 )]

7.2Ciprofloxacin

Concomitant use of ciprofloxacin and tizanidine is contraindicated. Changes in pharmacokinetics of tizanidine when administered with ciprofloxacin resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment [see Contraindications ( 4 ) and Clinical Pharmacology ( 12.3 )] .

7.3CYP1A2

Inhibitors other than Fluvoxamine and Ciprofloxacin Because of potential drug interactions, concomitant use of tizanidine with other CYP1A2 inhibitors, such as zileuton, fluoroquinolones other than strong CYP1A2 inhibitors (which are contraindicated), antiarrythmics (amiodarone, mexiletine, propafenone, and verapamil), cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine) should be avoided. If their use is clinically necessary, therapy should be initiated with 2 mg dose and increased in 2–4 mg steps daily based on patient response to therapy.

If adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue tizanidine therapy. [see Warnings and Precautions ( 5.5 ) and Clinical Pharmacology ( 12.3 )]

7.4Oral Contraceptives

Concomitant use of tizanidine with oral contraceptives is not recommended. However, if concomitant use is clinically necessary, initiate tizanidine with a single 2 mg dose and increase in 2–4 mg steps daily based on patient response to therapy. If adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue tizanidine therapy. [see Clinical Pharmacology ( 12.3 )]

7.5Alcohol

Alcohol increases the overall amount of drug in the bloodstream after a dose of tizanidine. This was associated with an increase in adverse reactions of tizanidine. The CNS depressant effects of tizanidine and alcohol are additive. [see Clinical Pharmacology ( 12.3 )]

7.6Other CNS Depressants

The sedative effects of tizanidine with CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive. Monitor patients who take tizanidine with another CNS depressant for symptoms of excess sedation. [see Clinical Pharmacology ( 12.3 )] 7.7 α 2 -adrenergic agonists Because hypotensive effects may be cumulative, it is not recommended that tizanidine be used with other α 2 -adrenergic agonists. [see Warnings and Precautions ( 5.1 )]

Adverse reactions

The following adverse reactions are described elsewhere in other sections of the prescribing information: Hypotension [see Warnings and Precautions ( 5.1 )] Liver Injury [see Warnings and Precautions ( 5.2 )] Sedation [see Warnings and Precautions ( 5.3 )] Hallucinosis/Psychotic-Like Symptoms [see Warnings and Precautions ( 5.4 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.6 )] The most common adverse reactions (greater than 2% of 264 patients taking tizanidine and greater than in placebo-treated patients in three multiple dose, placebo-controlled studies) were dry mouth, somnolence, asthenia, dizziness, urinary tract infection, constipation, liver function tests abnormal, vomiting, speech disorder, amblyopia, urinary frequency, flu syndrome, SGPT/ALT increased, dyskinesia, nervousness, pharyngitis, and rhinitis ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Advagen Pharma Ltd, at 888-413-0949 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. Three double-blind, randomized, placebo-controlled clinical studies were conducted to evaluate the effect of tizanidine on spasticity control. Two studies were conducted in patients with multiple sclerosis and one in patients with spinal cord injury.

Each study had a 13-week active treatment period which included a 3-week titration phase to the maximum tolerated dose up to 36 mg/day in three divided doses, a 9-week plateau phase where the dose of tizanidine was held constant and a 1-week dose tapering. In all, 264 patients received tizanidine and 261 patients received placebo. Across the three studies patient ages ranged from 15–69 years and 51.4 percent were women.

The median dose during the plateau phase ranged from 20–28 mg/day. The most frequent adverse reactions reported in multiple dose, placebo-controlled clinical studies involving 264 patients with spasticity were dry mouth, somnolence/sedation, asthenia (weakness, fatigue and/or tiredness) and dizziness. Three-quarters of the patients rated the events as mild to moderate and one-quarter of the patients rated the events as being severe.

These events appeared to be dose related. Table 1 lists signs and symptoms that were reported in greater than 2% of patients in three multiple dose, placebo-controlled studies who received tizanidine where the frequency in the tizanidine group was greater than the placebo group. For comparison purposes, the corresponding frequency of the event (per 100 patients) among placebo treated patients is also provided. Table 1: Multiple Dose, Placebo-Controlled Studies - Frequent (>2%) Adverse Reactions Reported for Which Tizanidine Tablets Incidence is Greater than Placebo Event Placebo N = 261 % Tizanidine Tablet N = 264 % Dry mouth 10 49 Somnolence 10 48 Asthenia (weakness, fatigue, and/or tiredness) 16 41 Dizziness 4 16 UTI 7 10 Infection 5 6 Constipation 1 4 Liver test abnormality 2 6 Vomiting 0 3 Speech disorder 0 3 Amblyopia (blurred vision) <1 3 Urinary frequency 2 3 Flu syndrome 2 3 Dyskinesia 0 3 Nervousness <1 3 Pharyngitis 1 3 Rhinitis 2 3 In the single dose, placebo-controlled study involving 142 patients with spasticity due to multiple sclerosis (Study 1) [see Clinical Studies ( 14 )] , the patients were specifically asked if they had experienced any of the four most common adverse reactions: dry mouth, somnolence (drowsiness), asthenia (weakness, fatigue and/or tiredness) and dizziness.

In addition, hypotension and bradycardia were observed. The occurrence of these reactions is summarized in Table 2 . Other events were, in general, reported at a rate of 2% or less. Table 2: Single Dose, Placebo-Controlled Study - Common Adverse Reactions Reported Event Placebo N = 48 % Tizanidine Tablet, 8mg, N = 45 % Tizanidine Tablet, 16 mg, N = 49 % Somnolence 31 78 92 Dry mouth 35 76 88 Asthenia (weakness, fatigue, and/or tiredness) 40 67 78 Dizziness 4 22 45 Hypotension 0 16 33 Bradycardia 0 2 10

6.2Post-Marketing Experience

The following adverse reactions have been identified during post approval use of tizanidine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Certain events, such as somnolence, dry mouth, hypotension, decreased blood pressure, bradycardia, dizziness, weakness or asthenia, muscle spasms, hallucinations, fatigue, liver function test abnormality and hepatotoxicity, have been observed in post marketing and clinical trials and are discussed in previous sections of this document.

The following adverse reactions have been identified as occurring in the post marketing experience of tizanidine. Based on the information provided regarding these reactions, a causal relationship with tizanidine cannot be entirely excluded. The events are listed in order of decreasing clinical significance; severity in the post marketing setting is not reported. Stevens Johnson Syndrome Anaphylactic Reaction Exfoliative Dermatitis Ventricular Tachycardia Hepatitis Convulsion Depression Arthralgia Paresthesia Rash Tremor

Tizanidine Hydrochloride

Indications

Contraindications

Warnings and precautions

5.1Hypotension

At a glance

Two medicines in one question?

Tizanidine Hydrochloride

Indications

Contraindications

Warnings and precautions

5.1Hypotension

At a glance

Two medicines in one question?

5.2Risk of Liver Injury

5.3Sedation

5.4Hallucinosis/Psychotic-Like Symptoms

5.5Interaction with CYP1A2 Inhibitors Because

5.6Hypersensitivity Reactions

5.7Increased Risk of Adverse Reactions in Patients with Renal Impairment

5.8Withdrawal Adverse Reactions

Interactions

7.1Fluvoxamine

7.2Ciprofloxacin

7.3CYP1A2

7.4Oral Contraceptives

7.5Alcohol

7.6Other CNS Depressants

Pregnancy and breastfeeding

8.1Pregnancy Pregnancy Category C

Adverse reactions

6.1Clinical Trials Experience

6.2Post-Marketing Experience

Composition

Strengths and forms

Official product information