Zanaflex Side Effects, and Drug Interactions - Tizanidine

Zanaflex Side Effects, and Drug Interactions - Tizanidine

SIDE EFFECTS

In multiple dose, placebo-controlled clinical studies, 264 patients were treated with tizanidine and 261 with placebo. Adverse events, including severe adverse events, were more frequently reported with tizanidine than with placebo.

Forty-five of 264 (17%) patients receiving tizanidine and 13 of 261 (5%) patients receiving placebo in three multiple dose, placebo-controlled clinical studies discontinued treatment for adverse events. When patients withdrew from the study, they frequently had more than one reason for discontinuing. The adverse events most frequently leading to withdrawal of tizanidine treated patients in the controlled clinical studies were asthenia (weakness, fatigue and/or tiredness) (3%), somnolence (3%), dry mouth (3%), increased spasm or tone (2%) and dizziness (2%).

In multiple dose, placebo-controlled clinical studies involving 264 patients with spasticity, the most frequent adverse events 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.

The events cited reflect experience gained under closely monitored conditions of clinical studies in a highly selected patient population. In actual clinical practice or in other clinical studies, these frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ. Table 1 lists treatment emergent 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 at least as common as in the placebo group. These events are not necessarily related to tizanidine treatment. For comparison purposes, the corresponding frequency of the event (per 100 patients) among placebo treated patients is also provided.

In the single dose, placebo-controlled study involving 142 patients with spasticity, the patients were specifically asked if they had experienced any of the four most common adverse events: dry mouth, somnolence (drowsiness), asthenia (weakness, fatigue and/or tiredness) and dizziness. In addition, hypotension and bradycardia were observed. The occurrence of these adverse events are summarized in Table 2. Other events were, in general, reported at a rate of 2% or less.

Tizanidine was administered to 1187 patients in additional clinical studies where adverse event information was available. The conditions and duration of exposure varied greatly, and included (in overlapping categories) double-blind and open-label studies, uncontrolled and controlled studies, inpatient and outpatient studies, and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.

In the tabulations that follow, reported adverse events were classified using a standard COSTART-based dictionary terminology. The frequencies presented, therefore, represent the proportion of the 1187 patients exposed to tizanidine who experienced an event of the type cited on at least one occasion while receiving tizanidine. All reported events are included except those already listed in Table 1. If the COSTART term for an event was so general as to be uninformative, it was replaced with a more informative term. It is important to emphasize that, although the events reported occurred during treatment with tizanidine, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled studies appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients.

BODY AS A WHOLE: Frequent: fever; Infrequent: allergic reaction, moniliasis, malaise, abscess, neck pain, sepsis, cellulitis, death, overdose; Rare: carcinoma, congenital anomaly, suicide attempt.

CARDIOVASCULAR SYSTEM: Infrequent: vasodilatation, postural hypotension, syncope, migraine, arrhythmia; Rare: angina pectoris, coronary artery disorder, heart failure, myocardial infarct, phlebitis, pulmonary embolus, ventricular extrasystoles, ventricular tachycardia.

DIGESTIVE SYSTEM: Frequent: abdomen pain, diarrhea, dyspepsia; Infrequent: dysphagia, cholelithiasis, fecal impaction, flatulence, gastrointestinal hemorrhage, hepatitis, melena; Rare: gastroenteritis, hematemesis, hepatoma, intestinal obstruction, liver damage.

HEMIC AND LYMPHATIC SYSTEM: Infrequent: ecchymosis, hypercholesteremia, anemia, hyperlipemia, leukopenia, leukocytosis, sepsis; Rare: petechia, purpura, thrombocythemia, thrombocytopenia.

METABOLIC AND NUTRITIONAL SYSTEM: Infrequent: edema, hypothyroidism, weight loss; Rare: adrenal cortex insufficiency, hyperglycemia, hypokalemia, hyponatremia, hypoproteinemia, respiratory acidosis.

MUSCULOSKELETAL SYSTEM: Frequent: myasthenia, back pain; Infrequent: pathological fracture, arthralgia, arthritis, bursitis.

NERVOUS SYSTEM: Frequent: depression, anxiety, paresthesia; Infrequent: tremor, emotional lability, convulsion, paralysis, thinking abnormal, vertigo, abnormal dreams, agitation, depersonalization, euphoria, migraine, stupor, dysautonomia, neuralgia; Rare: dementia, hemiplegia, neuropathy.

RESPIRATORY SYSTEM: Infrequent: sinusitis, pneumonia, bronchitis; Rare: asthma.

SKIN AND APPENDAGES: Frequent: rash, sweating, skin ulcer; Infrequent: pruritus, dry skin, acne, alopecia, urticaria; Rare: exfoliative dermatitis, herpes simplex, herpes zoster, skin carcinoma.

SPECIAL SENSES: Infrequent: ear pain, tinnitus, deafness, glaucoma, conjunctivitis, eye pain, optic neuritis, otitis media, retinal hemorrhage, visual field defect; Rare: iritis, keratitis, optic atrophy.

UROGENITAL SYSTEM: Infrequent: urinary urgency, cystitis, menorrhagia, pyelonephritis, urinary retention, kidney calculus, uterine fibroids enlarged, vaginal moniliasis, vaginitis; Rare: albuminuria, glycosuria, hematuria, metrorrhagia.

Post-marketing experience has reported bradycardia, dizziness, significant hypotension, and somnolence with concomitant administration of fluvoxamine (see CONTRAINDICATIONS, PRECAUTIONS, WARNINGS, DRUG INTERACTIONS).

Abuse potential was not evaluated in human studies. Rats were able to distinguish tizanidine from saline in a standard discrimination paradigm, after training, but failed to generalize the effects of morphine, cocaine, diazepam or phenobarbital to tizanidine. Monkeys were shown to self-administer tizanidine in a dose-dependent manner, and abrupt cessation of tizanidine produced transient signs of withdrawal at doses > 35 times the maximum recommended human dose on a mg/m² basis. These transient withdrawal signs (increased locomotion, body twitching, and aversive behavior toward the observer) were not reversed by naloxone administration.

In vitro studies of cytochrome P450 isoenzymes using human liver microsomes indicate that neither tizanidine nor the major metabolites are likely to affect the metabolism of other drugs metabolized by cytochrome P450 isoenzymes.

Acetaminophen: Tizanidine delayed the T_max of acetaminophen by 16 minutes. Acetaminophen did not affect the pharmacokinetics of tizanidine.

Alcohol: Alcohol increased the AUC of tizanidine by approximately 20% while also increasing its C_max by approximately 15%. This was associated with an increase in side effects of tizanidine. The CNS depressant effects of tizanidine and alcohol are additive.

Fluvoxamine: Clinically significant hypotension (decreases in both systolic and diastolic pressure) has been reported with concomitant administration of fluvoxamine following single doses of 4 mg (see DRUG INTERACTIONS, CONTRAINDICATIONS).

Caution is recommended when considering concomitant use of tizanidine with other inhibitors of CYP1A2, such as, antiarrhythmics (amiodarone, mexiletine, propafenone), cimetidine, fluoroquinolones (ciprofloxacin, norfloxacin), rofecoxib, oral contraceptives, and ticlopidine.

Oral Contraceptives: No specific pharmacokinetic study was conducted to investigate interaction between oral contraceptives and tizanidine, but retrospective analysis of population pharmacokinetic data following single and multiple dose administration of 4 mg tizanidine showed that women concurrently taking oral contraceptives had 50% lower clearance of tizanidine than women not on oral contraceptives.