Disclaimer:
Medidex is not a provider of medical services and all information is provided for the convenience of the user. No medical decisions should be made based on the information provided on this website without first consulting a licensed healthcare provider.This website is intended for persons 18 years or older. No person under 18 should consult this website without the permission of a parent or guardian.
Tizanidine
Overview
What is Tizanidine?
Tizanidine tablets USP, is supplied as 2 mg and 4 mg tablets for oral administration. Tizanidine tablets USP, are composed of the active ingredient, tizanidine hydrochloride USP (2.29 mg equivalent to 2 mg tizanidine base and 4.58 mg equivalent to 4 mg tizanidine base), and the inactive ingredients, anhydrous lactose, microcrystalline cellulose, colloidal silicon dioxide and stearic acid.
What does Tizanidine look like?
What are the available doses of Tizanidine?
Sorry No records found.
What should I talk to my health care provider before I take Tizanidine?
Sorry No records found
How should I use Tizanidine?
Tizanidine tablets are a short-acting drug for the management of spasticity. Because of the short duration of effect, treatment with tizanidine should be reserved for those daily activities and times when relief of spasticity is most important (see ).
A single dose of 8 mg of tizanidine reduces muscle tone in patients with spasticity for a period of several hours. The effect peaks at approximately 1 to 2 hours and dissipates between 3 to 6 hours. Effects are dose-related.
Although single doses of less than 8 mg have not been demonstrated to be effective in controlled clinical studies, the dose-related nature of tizanidine’s common adverse events make it prudent to begin treatment with single oral doses of 4 mg. Increase the dose gradually (2 to 4 mg steps) to optimum effect (satisfactory reduction of muscle tone at a tolerated dose).
The dose can be repeated at 6 to 8 hour intervals, as needed, to a maximum of three doses in 24 hours. The total daily dose should not exceed 36 mg.
Experience with single doses exceeding 8 mg and daily doses exceeding 24 mg is limited. There is essentially no experience with repeated, single, daytime doses greater than 12 mg or total daily doses greater than 36 mg (see ).
Food has complex effects on tizanidine pharmacokinetics, which differ with the different formulations. These pharmacokinetic differences may result in clinically significant differences when switching administration of the tablet between the fed or fasted state. These changes may result in increased adverse events or delayed/more rapid onset of activity, depending upon the nature of the switch. For this reason, the prescriber should be thoroughly familiar with the changes in kinetics associated with these different conditions (see ).
What interacts with Tizanidine?
Concomitant use of tizanidine with fluvoxamine or with ciprofloxacin, potent inhibitors of CYP1A2, is contraindicated. Significant alterations of pharmacokinetic parameters of tizanidine including increased AUC, t Cmax, increased oral bioavailability and decreased plasma clearance have been observed with concomitant administration of either fluvoxamine or ciprofloxacin. This pharmacokinetic interaction can result in potentially serious adverse events (See and ). Tizanidine tablets are contraindicated in patients with known hypersensitivity to tizanidine or its ingredients.
What are the warnings of Tizanidine?
After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate-to-severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against colitis.
Hypotension
Risk Of Liver Injury
Monitoring of aminotransferase levels is recommended during the first 6 months of treatment (e.g., baseline, 1, 3 and 6 months) and periodically thereafter, based on clinical status. Because of the potential toxic hepatic effect of tizanidine, the drug should be used only with extreme caution in patients with impaired hepatic function.
Sedation
Hallucinosis/Psychotic-Like Symptoms
In a pharmacokinetic study, tizanidine serum concentration was significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with ciprofloxacin. Potentiated hypotensive and sedative effects were observed. Ciprofloxacin and tizanidine should not be used together (See and ).
What are the precautions of Tizanidine?
Cardiovascular
Ophthalmic
Dose-related retinal degeneration and corneal opacities have been found in animal studies at doses equivalent to approximately the maximum recommended dose on a mg/m basis. There have been no reports of corneal opacities or retinal degeneration in the clinical studies.
Use in Renally Impaired Patients
Array
Use in Women Taking Oral Contraceptives
Discontinuing Therapy
Information For Patients
Because of the possibility of tizanidine lowering blood pressure, patients should be warned about the risk of clinically significant orthostatic hypotension (see ).
Because of the possibility of sedation, patients should be warned about performing activities requiring alertness, such as driving a vehicle or operating machinery (see ).
Patients should also be instructed that the sedation may be additive when tizanidine is taken in conjunction with drugs (baclofen, benzodiazepines) or substances (e.g., alcohol) that act as CNS depressants. Patients should be advised of the change in the absorption profile of tizanidine if taken with food and the potential changes in efficacy and adverse effect profiles that may result (see ).
Patients should be advised not to stop tizanidine suddenly as rebound hypertension and tachycardia may occur (see ).
Tizanidine should be used with caution where spasticity is utilized to sustain posture and balance in locomotion or whenever spasticity is utilized to obtain increased function.
Because of the potential for the increased risk of serious adverse reactions including severe lowering of blood pressure and sedation when tizanidine and either fluvoxamine or ciprofloxacin are used together, tizanidine should not be used with either fluvoxamine or ciprofloxacin. Because of the potential for interaction with other CYP1A2 inhibitors, patients should be instructed to inform their physicians and pharmacists when any medication is added or removed from their regimen.
Drug Interactions
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. Fluvoxamine The effect of fluvoxamine on the pharmacokinetics of a single 4 mg dose of tizanidine was studied in 10 healthy subjects. The Cmax, AUC, and half-life of tizanidine increased by 12-fold, 33-fold, and 3-fold, respectively. These changes resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment. (See and ).
Array
The effect of ciprofloxacin on the pharmacokinetics of a single 4 mg dose of tizanidine was studied in 10 healthy subjects. The Cmax and AUC of tizanidine increased by 7-fold and 10-fold, respectively. These changes resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment. (See and ).
Array
The interaction between tizanidine and either fluvoxamine or ciprofloxacin is most likely due to inhibition of CYP1A2 by fluvoxamine or ciprofloxacin. Although there have been no clinical studies evaluating the effects of other CYP1A2 inhibitors on tizanidine, other CYP1A2 inhibitors, including zileuton, other fluroquinolones, antiarrythmics (amiodarone, mexiletine, propafenone, and verapamil), cimetidine and famotidine, oral contraceptives, acyclovir, and ticlopidine may also lead to substantial increases in tizanidine blood concentrations. Concomitant use of tizanidine with CYP1A2 inhibitors should ordinarily be avoided. If their use is clinically necessary, they should be used with caution (see ).
Acetaminophen
Tizanidine delayed the Tmax 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 Cmax by approximately 15%. This was associated with an increase in side effects of tizanidine. The CNS depressant effects of tizanidine and alcohol are additive.
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 that women not on oral contraceptives.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence for carcinogenicity was seen in two dietary studies in rodents. Tizanidine was administered to mice for 78 weeks at doses up to 16 mg/kg, which is equivalent to 2 times the maximum recommended human dose on a mg/m basis. Tizanidine was also administered to rats for 104 weeks at doses up to 9 mg/kg, which is equivalent to 2.5 times the maximum recommended human dose on a mg/m basis. There was no statistically significant increase in tumors in either species.
Tizanidine was not mutagenic or clastogenic in the following in vitro assays: the bacterial Ames test and the mammalian gene mutation test and chromosomal aberration test in Chinese hamster cells. It was also negative in the following in vivo assays: the bone marrow micronucleus test in mice, the bone marrow micronucleus and cytogenicity test in Chinese hamsters, the dominant lethal mutagenicity test in mice, and the unscheduled DNA synthesis (UDS) test in mice.
Tizanidine did not affect fertility in male rats at doses of 10 mg/kg, approximately 2.7 times the maximum recommended human dose on a mg/m basis, and in females at doses of 3 mg/kg, approximately equal to the maximum recommended human dose on a mg/m basis; fertility was reduced in males receiving 30 mg/kg (8 times the maximum recommended human dose on a mg/m basis) and in females receiving 10 mg/kg (2.7 times the maximum recommended human dose on a mg/m basis). At these doses, maternal behavioral effects and clinical signs were observed including marked sedation, weight loss, and ataxia.
Pregnancy Category C
Reproduction studies performed in rats at a dose of 3 mg/kg, equal to the maximum recommended human dose on a mg/m basis, and in rabbits at 30 mg/kg, 16 times the maximum recommended human dose on a mg/m basis, did not show evidence of teratogenicity. Tizanidine at doses that are equal to and up to 8 times the maximum recommended human dose on a mg/m basis increased gestation duration in rats. Prenatal and postnatal pup loss was increased and developmental retardation occurred. Post-implantation loss was increased in rabbits at doses of 1 mg/kg or greater, equal to or greater than 0.5 times the maximum recommended human dose on a mg/m basis.
Tizanidine has not been studied in pregnant women. Tizanidine should be given to pregnant women only if clearly needed.
LABOR AND DELIVERY SECTION
The effect of tizanidine on labor and delivery in humans is unknown.
Nursing Mothers
It is not known whether tizanidine is excreted in human milk, although as a lipid soluble drug, it might be expected to pass into breast milk.
Geriatric Use
Tizanidine should be used with caution in elderly patients because clearance is decreased four-fold.
PEDIATRIC USE SECTION
There are no adequate and well-controlled studies to document the safety and efficacy of tizanidine in children.
What are the side effects of Tizanidine?
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.
Common Adverse Events Leading To Discontinuation
Most Frequent Adverse Clinical Events Seen In Association With The Use Of Tizanidine
Adverse Events Reported In Controlled Studies
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.
TABLE 1:
* (weakness, fatigue, and/or tiredness)
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 effects are summarized in Table 2. Other events were, in general, reported at a rate of 2% or less.
Table 2:
* (weakness, fatigue and/or tiredness)
Other Adverse Events Observed During The Evaluation Of Tizanidine
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 1385 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, rare adverse events are those occurring in fewer than 1/1000 patients.
Body as a Whole
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
| Event | Placebo N =261 % | Tizanidine Tablet N =264 % | |
| Dry Mouth | 10 | 49 | |
| Somnolence | 10 | 48 | |
| Asthenia* | 16 | 41 | |
| Dizziness | 4 | 16 | |
| UTI | 7 | 10 | |
| Infection | 5 | 6 | |
| Constipation | 1 | 4 | |
| Liver function tests abnormal | <1 | 3 | |
| Vomiting | 0 | 3 | |
| Speech disorder | 0 | 3 | |
| Amblyopia (blurred vision) | <1 | 3 | |
| Urinary frequency | 2 | 3 | |
| Flu symptom | 2 | 3 | |
| SGPT/ALT increased | <1 | 3 | |
| Dyskinesia | 0 | 3 | |
| Nervousness | <1 | 3 | |
| Pharyngitis | 1 | 3 | |
| Rhinitis | 2 | 3 | |
| Event | Placebo N =48 % | Tizanidine Tablet, 8 mg, N =45 % | Tizanidine Tablet, 16 mg, N =49 % |
| Somnolence | 31 | 78 | 92 |
| Dry mouth | 35 | 76 | 88 |
| Asthenia * | 40 | 67 | 78 |
| Dizziness | 4 | 22 | 45 |
| Hypotension | 0 | 16 | 33 |
| Bradycardia | 0 | 2 | 10 |
DRUG ABUSE AND DEPENDENCE SECTION
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/m basis. These transient withdrawal signs (increased locomotion, body twitching, and aversive behavior toward the observer) were not reversed by naloxone administration.
Tizanidine is closely related to clonidine, which is often abused in combination with narcotics and is known to cause symptoms of rebound upon abrupt withdrawal. Three cases of rebound symptoms on sudden withdrawal of tizanidine have been reported. The case reports suggest that these patients were also misusing narcotics. Withdrawal symptoms included hypertension, tachycardia, hypertonia, tremor, and anxiety. As with clonidine, withdrawal is expected to be more likely in cases where high doses are used, especially for prolonged periods.
What should I look out for while using Tizanidine?
Concomitant use of tizanidine with fluvoxamine or with ciprofloxacin, potent inhibitors of CYP1A2, is contraindicated. Significant alterations of pharmacokinetic parameters of tizanidine including increased AUC, t Cmax, increased oral bioavailability and decreased plasma clearance have been observed with concomitant administration of either fluvoxamine or ciprofloxacin. This pharmacokinetic interaction can result in potentially serious adverse events (See and ). Tizanidine tablets are contraindicated in patients with known hypersensitivity to tizanidine or its ingredients.
Limited Data Base For Chronic Use Of Single Doses Above 8 Mg And Multiple Doses Above 24 Mg Per Day
DOSAGE AND ADMINISTRATION
AND
Hypotension
Risk Of Liver Injury
Monitoring of aminotransferase levels is recommended during the first 6 months of treatment (e.g., baseline, 1, 3 and 6 months) and periodically thereafter, based on clinical status. Because of the potential toxic hepatic effect of tizanidine, the drug should be used only with extreme caution in patients with impaired hepatic function.
Sedation
Hallucinosis/Psychotic-Like Symptoms
Use in Patients With Hepatic Impairment
Risk Of Liver Injury
Potential Interaction With Fluvoxamine Or Ciprofloxacin
In a pharmacokinetic study, tizanidine serum concentration was significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with ciprofloxacin. Potentiated hypotensive and sedative effects were observed. Ciprofloxacin and tizanidine should not be used together (See and ).
Possible Interaction With Other Cyp1A2 Inhibitors
What might happen if I take too much Tizanidine?
A review of the safety surveillance database revealed cases of intentional and accidental tizanidine overdose. Some of the cases resulted in fatality and many of the intentional overdoses were with multiple drugs including CNS depressants. The clinical manifestations of tizanidine overdose were consistent with its known pharmacology. In the majority of cases a decrease in sensorium was observed including lethargy, somnolence, confusion and coma. Depressed cardiac function are also observed including most often bradycardia and hypotension. Respiratory depression is another common feature of tizanidine overdose.
Should overdose occur, basic steps to ensure the adequacy of an airway and the monitoring of cardiovascular and respiratory systems should be undertaken. In general, symptoms resolve within one to three days following discontinuation of tizanidine and administration of appropriate therapy. Due to the similar mechanism of action, symptoms and management of tizanidine overdose are similar to those following clonidine overdose. For the most recent information concerning the management of overdose, contact a poison control center.
How should I store and handle Tizanidine?
Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].Dispense in a tight, light-resistant container as defined in the USP/NF with a child-resistant closure.A Schedule CIII Narcotic.Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].Dispense in a tight, light-resistant container as defined in the USP/NF with a child-resistant closure.A Schedule CIII Narcotic.Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].Dispense in a tight, light-resistant container as defined in the USP/NF with a child-resistant closure.A Schedule CIII Narcotic.Tizanidine Tablets USP, 2 mgare white to off white, oval, flat, beveled edged tablets embossed with “R179” on one side and “bisecting score” on other side.They are supplied by as follows:Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Dispense in containers with child resistant closure.Rx OnlyManufactured by:Dr. Reddy’s Laboratories LimitedRevised: 0510This Product was Repackaged By:Altura Pharmaceuticals, Inc.Tizanidine Tablets USP, 2 mgare white to off white, oval, flat, beveled edged tablets embossed with “R179” on one side and “bisecting score” on other side.They are supplied by as follows:Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Dispense in containers with child resistant closure.Rx OnlyManufactured by:Dr. Reddy’s Laboratories LimitedRevised: 0510This Product was Repackaged By:Altura Pharmaceuticals, Inc.Tizanidine Tablets USP, 2 mgare white to off white, oval, flat, beveled edged tablets embossed with “R179” on one side and “bisecting score” on other side.They are supplied by as follows:Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Dispense in containers with child resistant closure.Rx OnlyManufactured by:Dr. Reddy’s Laboratories LimitedRevised: 0510This Product was Repackaged By:Altura Pharmaceuticals, Inc.Tizanidine Tablets USP, 2 mgare white to off white, oval, flat, beveled edged tablets embossed with “R179” on one side and “bisecting score” on other side.They are supplied by as follows:Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Dispense in containers with child resistant closure.Rx OnlyManufactured by:Dr. Reddy’s Laboratories LimitedRevised: 0510This Product was Repackaged By:Altura Pharmaceuticals, Inc.Tizanidine Tablets USP, 2 mgare white to off white, oval, flat, beveled edged tablets embossed with “R179” on one side and “bisecting score” on other side.They are supplied by as follows:Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Dispense in containers with child resistant closure.Rx OnlyManufactured by:Dr. Reddy’s Laboratories LimitedRevised: 0510This Product was Repackaged By:Altura Pharmaceuticals, Inc.Tizanidine Tablets USP, 2 mgare white to off white, oval, flat, beveled edged tablets embossed with “R179” on one side and “bisecting score” on other side.They are supplied by as follows:Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Dispense in containers with child resistant closure.Rx OnlyManufactured by:Dr. Reddy’s Laboratories LimitedRevised: 0510This Product was Repackaged By:Altura Pharmaceuticals, Inc.Tizanidine Tablets USP, 2 mgare white to off white, oval, flat, beveled edged tablets embossed with “R179” on one side and “bisecting score” on other side.They are supplied by as follows:Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Dispense in containers with child resistant closure.Rx OnlyManufactured by:Dr. Reddy’s Laboratories LimitedRevised: 0510This Product was Repackaged By:Altura Pharmaceuticals, Inc.Tizanidine Tablets USP, 2 mgare white to off white, oval, flat, beveled edged tablets embossed with “R179” on one side and “bisecting score” on other side.They are supplied by as follows:Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Dispense in containers with child resistant closure.Rx OnlyManufactured by:Dr. Reddy’s Laboratories LimitedRevised: 0510This Product was Repackaged By:Altura Pharmaceuticals, Inc.Tizanidine Tablets USP, 2 mgare white to off white, oval, flat, beveled edged tablets embossed with “R179” on one side and “bisecting score” on other side.They are supplied by as follows:Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Dispense in containers with child resistant closure.Rx OnlyManufactured by:Dr. Reddy’s Laboratories LimitedRevised: 0510This Product was Repackaged By:Altura Pharmaceuticals, Inc.
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
Absorption and Distribution
Following oral administration, tizanidine is essentially completely absorbed. The absolute oral bioavailability of tizanidine is approximately 40% (CV = 24%), due to extensive first-pass hepatic metabolism. Tizanidine is extensively distributed throughout the body with a mean steady state volume of distribution of 2.4 L/kg (CV = 21%) following intravenous administration in healthy adult volunteers. Tizanidine is approximately 30% bound to plasma proteins.
Pharmacokinetics, Metabolism and Excretion
Tizanidine has linear pharmacokinetics over a dose of 1 to 20 mg. Tizanidine has a half-life of approximately 2.5 hours (CV=33%). Approximately 95% of an administered dose is metabolized. The primary cytochrome P450 isoenzyme involved in tizanidine metabolism is CYP1A2. Tizanidine metabolites are not known to be active; their half-lives range from 20 to 40 hours. Following single and multiple oral dosing of C-tizanidine, an average of 60% and 20% of total radioactivity was recovered in the urine and feces, respectively.
Special Populations
No specific pharmacokinetic study was conducted to investigate age effects. Cross study comparison of pharmacokinetic data following single dose administration of 6 mg tizanidine showed that younger subjects cleared the drug four times faster than the elderly subjects. Tizanidine has not been evaluated in children (see
).
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. Tizanidine should ordinarily be avoided or used with extreme caution in this patient population (see ).
Renal Impairment
Tizanidine clearance is reduced by more than 50% in elderly patients with renal insufficiency (creatinine clearance < 25 mL/min) compared to healthy elderly subjects; this would be expected to lead to a longer duration of clinical effect. Tizanidine should be used with caution in renally impaired patients (see ).
Gender Effects
No specific pharmacokinetic study was conducted to investigate gender effects. Retrospective analysis of pharmacokinetic data, however, following single and multiple doseadministration of 4 mg tizanidine showed that gender had no effect on the pharmacokinetics of tizanidine.
Race Effects
Pharmacokinetic differences due to race have not been studied.
Non-Clinical Toxicology
Concomitant use of tizanidine with fluvoxamine or with ciprofloxacin, potent inhibitors of CYP1A2, is contraindicated. Significant alterations of pharmacokinetic parameters of tizanidine including increased AUC, t Cmax, increased oral bioavailability and decreased plasma clearance have been observed with concomitant administration of either fluvoxamine or ciprofloxacin. This pharmacokinetic interaction can result in potentially serious adverse events (See and ). Tizanidine tablets are contraindicated in patients with known hypersensitivity to tizanidine or its ingredients.Limited Data Base For Chronic Use Of Single Doses Above 8 Mg And Multiple Doses Above 24 Mg Per Day
DOSAGE AND ADMINISTRATION
AND
Hypotension
Risk Of Liver Injury
Monitoring of aminotransferase levels is recommended during the first 6 months of treatment (e.g., baseline, 1, 3 and 6 months) and periodically thereafter, based on clinical status. Because of the potential toxic hepatic effect of tizanidine, the drug should be used only with extreme caution in patients with impaired hepatic function.
Sedation
Hallucinosis/Psychotic-Like Symptoms
Use in Patients With Hepatic Impairment
Risk Of Liver Injury
Potential Interaction With Fluvoxamine Or Ciprofloxacin
In a pharmacokinetic study, tizanidine serum concentration was significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with ciprofloxacin. Potentiated hypotensive and sedative effects were observed. Ciprofloxacin and tizanidine should not be used together (See and ).
Possible Interaction With Other Cyp1A2 Inhibitors
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. Fluvoxamine The effect of fluvoxamine on the pharmacokinetics of a single 4 mg dose of tizanidine was studied in 10 healthy subjects. The Cmax, AUC, and half-life of tizanidine increased by 12-fold, 33-fold, and 3-fold, respectively. These changes resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment. (See and ).
The effect of ciprofloxacin on the pharmacokinetics of a single 4 mg dose of tizanidine was studied in 10 healthy subjects. The Cmax and AUC of tizanidine increased by 7-fold and 10-fold, respectively. These changes resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment. (See and ).
The interaction between tizanidine and either fluvoxamine or ciprofloxacin is most likely due to inhibition of CYP1A2 by fluvoxamine or ciprofloxacin. Although there have been no clinical studies evaluating the effects of other CYP1A2 inhibitors on tizanidine, other CYP1A2 inhibitors, including zileuton, other fluroquinolones, antiarrythmics (amiodarone, mexiletine, propafenone, and verapamil), cimetidine and famotidine, oral contraceptives, acyclovir, and ticlopidine may also lead to substantial increases in tizanidine blood concentrations. Concomitant use of tizanidine with CYP1A2 inhibitors should ordinarily be avoided. If their use is clinically necessary, they should be used with caution (see ).
Acetaminophen
Tizanidine delayed the Tmax 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 Cmax by approximately 15%. This was associated with an increase in side effects of tizanidine. The CNS depressant effects of tizanidine and alcohol are additive.
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 that women not on oral contraceptives.
Cardiovascular
Ophthalmic
Dose-related retinal degeneration and corneal opacities have been found in animal studies at doses equivalent to approximately the maximum recommended dose on a mg/m basis. There have been no reports of corneal opacities or retinal degeneration in the clinical studies.
Use in Renally Impaired Patients
Use in Women Taking Oral Contraceptives
Discontinuing Therapy
Information For Patients
Because of the possibility of tizanidine lowering blood pressure, patients should be warned about the risk of clinically significant orthostatic hypotension (see ).
Because of the possibility of sedation, patients should be warned about performing activities requiring alertness, such as driving a vehicle or operating machinery (see ).
Patients should also be instructed that the sedation may be additive when tizanidine is taken in conjunction with drugs (baclofen, benzodiazepines) or substances (e.g., alcohol) that act as CNS depressants. Patients should be advised of the change in the absorption profile of tizanidine if taken with food and the potential changes in efficacy and adverse effect profiles that may result (see ).
Patients should be advised not to stop tizanidine suddenly as rebound hypertension and tachycardia may occur (see ).
Tizanidine should be used with caution where spasticity is utilized to sustain posture and balance in locomotion or whenever spasticity is utilized to obtain increased function.
Because of the potential for the increased risk of serious adverse reactions including severe lowering of blood pressure and sedation when tizanidine and either fluvoxamine or ciprofloxacin are used together, tizanidine should not be used with either fluvoxamine or ciprofloxacin. Because of the potential for interaction with other CYP1A2 inhibitors, patients should be instructed to inform their physicians and pharmacists when any medication is added or removed from their regimen.
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.
Common Adverse Events Leading To Discontinuation
Most Frequent Adverse Clinical Events Seen In Association With The Use Of Tizanidine
Adverse Events Reported In Controlled Studies
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.
TABLE 1:
* (weakness, fatigue, and/or tiredness)
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 effects are summarized in Table 2. Other events were, in general, reported at a rate of 2% or less.
Table 2:
* (weakness, fatigue and/or tiredness)
Other Adverse Events Observed During The Evaluation Of Tizanidine
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 1385 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, rare adverse events are those occurring in fewer than 1/1000 patients.
Body as a Whole
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
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
While we update our database periodically, we cannot guarantee it is always updated to the latest version.
Review
Read user comments about the side effects, benefits, and effectiveness of losartan oral.
Overall User Ratings
514Total User Reviews
User Reviews
Learn about
User Reviews
Professional
Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
Tips
Interactions
Interactions
A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).