Approved Drug Label (PDF)
4
Contraindications
Additions and/or
revisions underlined:
Zanaflex is contraindicated in patients:
taking strong CYP1A2 inhibitors [see Drug Interactions (7.1)].
with a history
of hypersensitivity to tizanidine or the ingredients in Zanaflex. Symptoms
have included anaphylaxis and angioedema [see
Warnings and Precautions (5.5)].
5
Warnings and Precautions
5.1 Hypotension
Additions and/or
revisions underlined:
Zanaflex is an ?2-adrenergic agonist
that can produce hypotension [see Adverse
Reactions (6.1) and Drug Interactions (7.5)]. Syncope has been reported in patients treated
with tizanidine in
the postmarketing setting. The risk of hypotension may be
minimized by dose titration; monitoring for signs and symptoms of
hypotension prior to dosage increase may minimize the risks associated with hypotension. In addition, patients
moving from a supine to fixed upright
position may be at increased risk for hypotension and orthostatic
effects.
Monitor for hypotension when Zanaflex is used in patients receiving concurrent antihypertensive
therapy. It is
not recommended that Zanaflex be used with other ?2-adrenergic agonists.
Clinically significant hypotension (decreases in both systolic
and diastolic pressure)
has been reported with
concomitant administration of tizanidine and strong CYP1A2 inhibitors [see Clinical Pharmacology (12.3)]. Therefore, concomitant use of Zanaflex with strong CYP1A2 inhibitors is contraindicated [see Contraindications (4) and Drug
Interactions (7.1)].
5.2 Liver Injury
Subsection title revised
Additions and/or
revisions underlined:
Zanaflex
may cause hepatocellular liver injury. Liver function test abnormality and
hepatotoxicity have been observed with
Zanaflex [see Adverse Reactions (6.1, 6.2)]. Monitoring
of aminotransferase levels is recommended at baseline and 1 month after
maximum dose is achieved, or if hepatic injury is suspected [see Dosage and Administration (2.1) and Use
in Specific Populations (8.7)].
5.3 Sedation
Additions and/or
revisions underlined:
Zanaflex
can cause sedation, which may interfere with everyday activity. In the multiple
dose studies of Zanaflex, the prevalence of patients with sedation
peaked following the first week of titration and then remained stable for the
duration of the maintenance phase of the study [see Adverse Reactions (6.1)]. The CNS depressant effects of
Zanaflex with alcohol and other CNS depressants (e.g., benzodiazepines, opioids,
tricyclic antidepressants) may be additive
[see Drug Interactions (7.4)]. Monitor patients who take Zanaflex
with another CNS depressant for symptoms of excess sedation.
5.4
Hallucinosis/Psychotic-Like Symptoms
Additions and/or
revisions underlined:
Zanaflex
use has been associated with hallucinations.
Formed, visual hallucinations or delusions were reported in 5 of 170
patients (3%) in two North American controlled clinical studies. Most of the
patients were aware that the events were unreal. One patient developed
psychosis in association with the
hallucinations. One patient among
these 5 continued to have problems
for at least 2 weeks following discontinuation of tizanidine. Hallucinations
have also been reported with tizanidine use in the postmarketing setting. Consider discontinuing Zanaflex
in patients who develop hallucinations.
5.5
Hypersensitivity Reactions
Additions and/or
revisions underlined:
Zanaflex
can cause anaphylaxis. Signs and symptoms of hypersensitivity, including
respiratory compromise, urticaria, and angioedema of the throat
and tongue, have been reported. Zanaflex is
contraindicated in patients with a history of hypersensitivity
reactions to tizanidine [see
Contraindications (4)].
5.6
Withdrawal Adverse Reactions
Additions and/or
revisions underlined:
Zanaflex
can cause
withdrawal adverse reactions, which include rebound hypertension,
tachycardia, and hypertonia. To minimize the risk of these reactions,
particularly in patients who have been receiving
high doses of Zanaflex (20 to 28 mg daily) for long periods of time (9 weeks
or more) or who may be on concomitant treatment with narcotics, the Zanaflex dosage should be
decreased slowly [see Dosage and
Administration (2.5)].
6
Adverse Reactions
Addition of the following to the bulleted line listing:
6.1 Clinical
Trials Experience
Additions and/or
revisions underlined:
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.
The safety of Zanaflex
has been evaluated
in three double-blind, randomized, placebo-controlled
clinical studies [see Clinical
Studies (14)]. 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 period.
In all, 264 patients received tizanidine and 261 patients received placebo.
Across the three studies approximately 51% of patients were women, and
the median dose during the plateau phase ranged from 20 to 28 mg/day.
The most common adverse
reactions (>10% of patients treated with Zanaflex) 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 reactions as
mild to moderate and one-quarter of the patients rated the reactions as
being severe. These adverse reactions appeared to be dose related.
Table 1 lists adverse reactions that were reported in greater than 2% of patients in three multiple dose, placebo-controlled studies
who received Zanaflex where the frequency in the Zanaflex group was greater
than the placebo group.
…
6.2 Postmarketing
Experience
Additions and/or
revisions underlined:
The
following adverse reactions have been identified during post approval use of
Zanaflex. 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.
Cardiac Disorders: Ventricular tachycardia, decreased blood pressure
Hepatobiliary Disorders: Hepatotoxicity [see Warnings and Precautions (5.2)], hepatitis
Musculoskeletal and
Connective Tissue Disorders: arthralgia
Nervous System Disorders: Convulsion, paresthesia, tremor,
muscle spasms
Psychiatric Disorders: Hallucinations [see Warnings
and Precautions (5.4)],
depression
Skin and Subcutaneous Tissue Disorders: Stevens Johnson
Syndrome, anaphylactic reaction
[see Warnings and Precautions
(5.5)], exfoliative dermatitis, rash
7
Drug Interactions
7.1
Strong CYP1A2 Inhibitors
Subsection
title revised
Additions and/or
revisions underlined:
Concomitant
use of Zanaflex with strong cytochrome P450 1A2 (CYP1A2) inhibitors (e.g.,
fluvoxamine, ciprofloxacin) is contraindicated. Changes
in pharmacokinetics of tizanidine when administered with a strong CYP1A2
inhibitor resulted in significantly decreased blood pressure,
increased drowsiness, and increased psychomotor impairment [see Contraindications (4) and Clinical Pharmacology (12.3)].
7.2
Moderate or Weak CYP1A2 Inhibitors
Subsection
title revised
Additions and/or
revisions underlined:
Concomitant
use of Zanaflex with moderate or weak CYP1A2 inhibitors (e.g., zileuton, antiarrhythmics [amiodarone,
mexiletine, propafenone, and verapamil], cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine) should be avoided.
If concomitant use
is clinically necessary, and
adverse reactions such as hypotension, bradycardia, or excessive drowsiness
occur, reduce Zanaflex dosage or discontinue Zanaflex therapy [see Clinical Pharmacology (12.3)].
7.3 Oral Contraceptives
Additions and/or
revisions underlined:
Concomitant
use of Zanaflex with oral contraceptives is not recommended. However, if
concomitant use is clinically necessary
and adverse reactions
such as hypotension, bradycardia,
or excessive drowsiness occur, reduce or discontinue Zanaflex therapy [see Clinical Pharmacology (12.3)].
7.4
Alcohol and Other CNS Depressants
Subsection
title revised
Additions and/or revisions underlined:
Alcohol increases
the exposure of
tizanidine after administration of Zanaflex. This was
associated with an increase in adverse reactions of Zanaflex. Concomitant use
of Zanaflex with CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) may cause additive CNS
depressant effects, including sedation. Monitor patients who take Zanaflex with another CNS depressant for symptoms of excess
sedation [see Clinical Pharmacology
(12.3)].
7.6
Antihypertensive Medications
Newly added
subsection:
Concomitant use of Zanaflex
with antihypertensive medications may cause additive
hypotensive effects [see Warnings
and Precautions (5.1)]. Monitor
patients who take Zanaflex with antihypertensive medications for hypotension.
8
Use in Specific Populations
8.4 Pediatric Use
Additions and/or
revisions underlined:
Safety and effectiveness in pediatric patients
have not been established.
Juvenile
Animal Toxicity Data
Oral administration of tizanidine
(0, 1, 3, and 10 mg/kg/day) to juvenile rats from postnatal day (PND) 7 through
PND 70 resulted in delayed sexual maturation in males at all doses, reduced
body weight gain, delayed sexual
maturation in females,
and bilateral corneal
crystals at the mid
and high doses. Corneal crystals
were still observed
at the mid and high doses after a three-week recovery period.
Neurobehavioral deficits were observed on a learning and memory task at the
high dose. A no-effect dose for adverse effects on postnatal development not
identified.
8.6
Renal Impairment
Subsection title revised
Additions and/or
revisions underlined:
In
patients with renal insufficiency (creatinine clearance < 25 mL/min),
clearance of tizanidine was reduced [see
Clinical Pharmacology (12.3)]. In these patients, dosage reduction is recommended
[see Dosage and Administration (2.3)].
Because the risk of adverse reactions to Zanaflex may be greater in patients with
impaired renal function, monitor
these patients closely for the onset or increase
in severity of common adverse
reactions [see Adverse Reactions (6.1)].
8.7
Hepatic Impairment
Subsection title
revised
Additions and/or
revisions underlined:
Zanaflex
should be used with caution in patients with hepatic impairment. The
influence of hepatic impairment on the pharmacokinetics of tizanidine has not
been evaluated. Because tizanidine is extensively metabolized in the liver, hepatic
impairment would be expected to have
significant effects on pharmacokinetics of tizanidine [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. In
patients with hepatic impairment, dosage reduction is recommended [see Dosage and Administration (2.4)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions and/or
revisions underlined:
…
Hypotension
Warn patients
that they may experience hypotension and to be careful when changing from a
lying or sitting to a standing position [see
Warnings and Precautions (5.1)].
Sedation
Tell patients that Zanaflex may
cause them to become sedated or somnolent and they should be careful when
performing activities that require alertness, such as driving a vehicle or
operating machinery [see Warnings and Precautions (5.3)]. Tell patients that the sedation
may be additive when Zanaflex is taken in conjunction with drugs
(baclofen, benzodiazepines) or substances (e.g., alcohol) that act as CNS
depressants.
Remind patients that if they depend
on their spasticity to sustain posture and balance in locomotion, or whenever spasticity is utilized to obtain increased function, that Zanaflex decreases spasticity and caution
should be used.
Hypersensitivity Reactions
Inform patients of the signs and
symptoms of severe allergic reactions and instruct them to discontinue Zanaflex
and seek immediate medical care should
these signs and symptoms occur [see
Warnings and Precautions (5.5)].