Tizanidine Hcl

Tizanidin Hcl ist ein zentraler alpha-2-adrenerger Agonist, der für die Behandlung von Spastik angezeigt ist. Aufgrund der kurzen Dauer der therapeutischen Wirkung sollte die Behandlung mit Tizanidin Hcl für die täglichen Aktivitäten und Zeiten reserviert werden, in denen eine Linderung der Spastik am wichtigsten ist.

Dosierungsinformationen

Tizanidin-Hcl-Kapseln®- oder Tizanidin-Hcl®-Tabletten können mit oder ohne Nahrung verschrieben werden. Sobald die Formulierung ausgewählt und die Entscheidung getroffen wurde, mit oder ohne Nahrung einzunehmen, sollte dieses Regime nicht geändert werden.

Lebensmittel haben komplexe Auswirkungen auf die Pharmakokinetik von Tizanidin, die sich von den verschiedenen Formulierungen unterscheiden. Tizanidin-Hcl-Kapseln und Tizanidin-Hcl-Tabletten sind unter Fastenbedingungen (mehr als 3 Stunden nach einer Mahlzeit) bioäquivalent zueinander, jedoch nicht unter gefütterten Bedingungen (innerhalb von 30 Minuten nach einer Mahlzeit). Diese pharmakokinetischen Unterschiede können zu klinisch signifikanten Unterschieden beim Wechsel der Verabreichung von Tabletten und Kapseln und beim Wechsel der Verabreichung zwischen dem gefütterten oder dem nüchternen Zustand führen. Diese Änderungen können je nach Art des Schalters zu erhöhten unerwünschten Ereignissen oder zu einem verzögerten oder schnelleren Einsetzen der Aktivität führen. Aus diesem Grund sollte der verschreibende Arzt mit den Änderungen der Kinetik, die mit diesen unterschiedlichen Bedingungen verbunden sind, gründlich vertraut sein.

Die empfohlene Anfangsdosis beträgt 2 mg. Da die Wirkung von Tizanidin-Hcl ungefähr 1 bis 2 Stunden nach der Dosis ihren Peak erreicht und sich zwischen 3 und 6 Stunden nach der Dosis auflöst, kann die Behandlung bei Bedarf in Intervallen von 6 bis 8 Stunden bis maximal drei Dosen in 24 Stunden wiederholt werden .

Die Dosierung kann bei jeder Dosis schrittweise um 2 mg bis 4 mg erhöht werden, wobei zwischen den Dosierungen 1 bis 4 Tage liegen, bis eine zufriedenstellende Verringerung des Muskeltonus erreicht ist. Die tägliche Gesamtdosis sollte 36 mg nicht überschreiten. Einzeldosen über 16 mg wurden nicht untersucht.

Dosierung bei Patienten mit Nierenfunktionsstörung

Tizanidin Hcl sollte bei Patienten mit Niereninsuffizienz (Kreatinin-Clearance <25 ml / min) mit Vorsicht angewendet werden, da die Clearance um mehr als 50% verringert ist. Bei diesen Patienten sollten während der Titration die Einzeldosen reduziert werden. Wenn höhere Dosen erforderlich sind, sollten die Einzeldosen anstelle der Dosierungshäufigkeit erhöht werden.

Dosierung bei Patienten mit Leberfunktionsstörung

Tizanidin Hcl sollte bei Patienten mit Leberfunktionsstörungen mit Vorsicht angewendet werden. Bei diesen Patienten sollten während der Titration die Einzeldosen reduziert werden. Wenn höhere Dosen erforderlich sind, sollten die Einzeldosen anstelle der Dosierungshäufigkeit erhöht werden. Die Überwachung der Aminotransferase-Spiegel wird für den Ausgangswert und 1 Monat nach Erreichen der Maximaldosis oder bei Verdacht auf Leberschäden empfohlen.

Drogenabbruch

Wenn die Therapie abgebrochen werden muss, insbesondere bei Patienten, die hohe Dosen erhalten haben (20 mg bis 36 mg täglich) für lange Zeiträume (9 Wochen oder länger) oder wer gleichzeitig mit Betäubungsmitteln behandelt werden kann, Die Dosis sollte langsam verringert werden (2 mg bis 4 mg pro Tag) um das Risiko eines Entzugs und einer Rückprallhypertonie zu minimieren, Tachykardie, und Hypertonie.

Tizanidin Hcl ist bei patentenstäubenden wirksamen CYP1A2-Inhibitoren wie Fluvoxamin oder Ciprofloxacin kontraindiziert.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hypotension

Tizanidine is an α2-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.

Monitor for hypotension when Tizanidine Hcl is used in patients receiving concurrent antihypertensive therapy. It is not recommended that Tizanidine Hcl be used with other α2- adrenergic agonists. Clinically significant hypotension (decreases in both systolic and diastolic pressure) has been reported with concomitant administration of either fluvoxamine or ciprofloxacin and single doses of 4 mg of Tizanidine Hcl. Therefore, concomitant use of Tizanidine Hcl with fluvoxamine or with ciprofloxacin, potent inhibitors of CYP1A2, is contraindicated.

Risk of Liver Injury

Tizanidine Hcl may cause hepatocellular liver injury. Tizanidine Hcl should be used with caution in patients with any hepatic impairment.. Monitoring of aminotransferase levels is recommended for baseline and 1 month after maximum dose is achieved, or if hepatic injury is suspected.

Sedation

Tizanidine Hcl can cause sedation, which may interfere with everyday activity. In the multiple dose studies, 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. The CNS depressant effects of Tizanidine Hcl with alcohol and other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive. Monitor patients who take Tizanidine Hcl with another CNS depressant for symptoms of excess sedation.

Hallucinosis/Psychotic-Like Symptoms

Tizanidine Hcl use has been associated with hallucinations. Formed, visual hallucinations or delusions have been 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. Consider discontinuing Tizanidine Hcl in patients who develop hallucinations.

Interaction with CYP1A2 Inhibitors

Because of potential drug interactions, Tizanidine Hcl is contraindicated in patients taking potent CYP1A2 inhibitors, such as fluvoxamine or ciprofloxacin. Adverse reactions such as hypotension, bradycardia, or excessive drowsiness can occur when Tizanidine Hcl is taken with other CYP1A2 inhibitors, such as zileuton, fluoroquinolones other than ciprofloxacin (which is contraindicated), antiarrythmics (amiodarone, mexiletine, propafenone), cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine ). Concomitant use should be avoided unless the necessity for Tizanidine Hcl therapy is clinically evident. In such a case, use with caution.

Hypersensitivity Reactions

Tizanidine Hcl can cause anaphylaxis. Signs and symptoms including respiratory compromise, urticaria, and angioedema of the throat and tongue have been reported. Patients should be informed of the signs and symptoms of severe allergic reactions and instructed to discontinue Tizanidine Hcl and seek immediate medical care should these signs and symptoms occur.

Increased Risk of Adverse Reactions in Patients with Renal Impairment

Tizanidine Hcl should be used with caution in patients with renal insufficiency (creatinine clearance < 25 mL/min), as clearance is reduced by more than 50%. In these patients, during titration, the individual doses should be reduced. If higher doses are required, individual doses rather than dosing frequency should be increased. These patients should be monitored closely for the onset or increase in severity of the common adverse events (dry mouth, somnolence, asthenia and dizziness) as indicators of potential overdose.

Withdrawal Adverse Reactions

Withdrawal adverse reactions include rebound hypertension, tachycardia, and hypertonia. To minimize the risk of these reactions, particularly in patients who have been receiving high doses (20 to 28 mg daily) for long periods of time (9 weeks or more) or who may be on concomitant treatment with narcotics, the dose should be decreased slowly (2 to 4 mg per day).

Nonclinical Toxicology

Carcinogenesis, mutagenesis, impairment of fertility

Carcinogenesis

Tizanidine was administered to mice for 78 weeks at oral doses up to 16 mg/kg/day, which is 2 times the maximum recommended human dose (MRHD) on a mg/m² basis. Tizanidine was administered to rats for 104 weeks at oral doses up to 9 mg/kg/day, which is 2.5 times the MRHD on a mg/m² basis. There was no increase in tumors in either species.

Mutagenesis

Tizanidine was negative in in vitro (bacterial reverse mutation [Ames] , mammalian gene mutation, and chromosomal aberration test in mammalian cells) and in vivo (bone marrow micronucleus, and cytogenetics) assay.

Impairment of fertility

Oral administration of tizanidine resulted in reduced fertility in male and female rats following doses of 30 and 10 mg/kg/day, respectively. No effect on fertility was observed at doses of 10 (male) and 3 (female) mg/kg/day, which are approximately 8 and 3 times, respectively, the MRHD on a mg/m² basis).

Use In Specific Populations

Pregnancy

Pregnancy Category C

Tizanidine Hcl has not been studied in pregnant women. Tizanidine Hcl should be given to pregnant women only if the benefit outweighs the risk to the unborn fetus. Reproduction studies performed in rats at a dose of 3 mg/kg, equal to the maximum recommended human dose on a mg/m² basis, and in rabbits at 30 mg/kg, 16 times the maximum recommended human dose on a mg/m² 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/m² 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/m² basis.

Nursing mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Tizanidine Hcl is administered to a nursing woman.

Pediatric use

Safety and effectiveness in pediatric patients have not been established.

Geriatric use

Tizanidine Hcl is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Clinical studies of Tizanidine Hcl did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Crossstudy comparison of pharmacokinetic data following single dose administration of 6 mg Tizanidine Hcl showed that younger subjects cleared the drug four times faster than the elderly subjects. In elderly patients with renal insufficiency (creatinine clearance < 25 mL/min), tizanidine clearance is reduced by more than 50% compared to healthy elderly subjects; this would be expected to lead to a longer duration of clinical effect. During titration, the individual doses should be reduced. If higher doses are required, individual doses rather than dosing frequency should be increased. Monitor elderly patients because they may have an increased risk for adverse reactions associated with Tizanidine Hcl.

Impaired Renal Function

Tizanidine Hcl is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. In patients with renal insufficiency (creatinine clearance < 25 mL/min) clearance was reduced by more than 50%. In these patients, during titration, the individual doses should be reduced. If higher doses are required, individual doses rather than dosing frequency should be increased. These patients should be monitored closely for the onset or increase in severity of the common adverse events (dry mouth, somnolence, asthenia and dizziness) as indicators of potential overdose.

Impaired Hepatic Function

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..

The following adverse reactions are described elsewhere in other sections of the prescribing information:

• Hypotension
• Liver Injury
• Sedation
• Hallucinosis/Psychotic-Like Symptoms
• Hypersensitivity Reactions

Clinical 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 Hcl where the frequency in the Tizanidine Hcl 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 Hcl Tablets Incidence is Greater than Placebo

In the single dose, placebo-controlled study involving 142 patients with spasticity due to multiple sclerosis (Study 1) , 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

Post-Marketing Experience

The following adverse reactions have been identified during post approval use of Tizanidine Hcl. 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 Hcl. Based on the information provided regarding these reactions, a causal relationship with Tizanidine Hcl 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

A review of the safety surveillance database revealed cases of intentional and accidental Tizanidine Hcl 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 is 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. Tizanidine is a lipid-soluble drug, which is only slightly soluble in water and methanol. Therefore, dialysis is not likely to be an efficient method of removing drug from the body. 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 that following clonidine overdose. For the most recent information concerning the management of overdose, contact a poison control center.

Absorption und Verteilung

Nach oraler Verabreichung wird Tizanidin im Wesentlichen vollständig resorbiert. Die absolute orale Bioverfügbarkeit von Tizanidin beträgt aufgrund des umfassenden Leberstoffwechsels im ersten Durchgang ungefähr 40% (CV = 24%). Tizanidin ist nach intravenöser Verabreichung bei gesunden erwachsenen Freiwilligen im ganzen Körper mit einem mittleren Steady-State-Verteilungsvolumen von 2,4 l / kg (CV = 21%) weit verbreitet. Tizanidin ist zu ungefähr 30% an Plasmaproteine gebunden.

Unterschiede zwischen Tizanidin-Hcl-Kapseln® und Tizanidin-Hcl®-Tabletten

Tizanidin-Hcl-Kapseln®- und Tizanidin-Hcl®-Tabletten sind unter Fastenbedingungen bioäquivalent zueinander, jedoch nicht unter gefütterten Bedingungen. Eine Einzeldosis von entweder zwei 4-mg-Tabletten oder zwei 4-mg-Kapseln wurde unter Fütterungs- und Fastenbedingungen in einer offenen, vierperiodischen, randomisierten Crossover-Studie an 96 menschlichen Freiwilligen verabreicht, von denen 81 für die statistische Analyse in Frage kamen. Nach oraler Verabreichung der Tablette oder Kapsel (im nüchternen Zustand) traten 1,0 Stunden nach Dosierung mit einer Halbwertszeit von ungefähr 2 Stunden maximale Plasmakonzentrationen von Tizanidin auf. Wenn zwei 4-mg-Tabletten zusammen mit einer Nahrung verabreicht wurden, war die mittlere maximale Plasmakonzentration um ungefähr 30% erhöht, und die mittlere Zeit bis zur maximalen Plasmakonzentration war um 25 Minuten auf 1 Stunde und 25 Minuten erhöht. Im Gegensatz dazu war bei Verabreichung von zwei 4-mg-Kapseln mit einer Nahrung die mittlere maximale Plasmakonzentration um 20% verringert, die mittlere Zeit bis zur maximalen Plasmakonzentration um 2 bis 3 Stunden erhöht. Folglich beträgt der mittlere Cmax für die Kapsel bei Verabreichung mit einer Nahrung ungefähr 66% der Cmax für die Tablette, wenn sie mit einer Nahrung verabreicht wird.

Lebensmittel erhöhten auch das Absorptionsgrad sowohl für die Tabletten als auch für die Kapseln. Der Anstieg mit der Tablette (~ 30%) war signifikant größer als mit der Kapsel (~ 10%). Folglich betrug die von der Kapsel absorbierte Menge bei jeder Verabreichung mit einer Nahrung etwa 80% der von der Tablette absorbierten Menge. Die Verabreichung des auf Apfelmus gestreuten Kapselinhalts war nicht bioäquivalent zur Verabreichung einer intakten Kapsel unter Fastenbedingungen. Die Verabreichung des Kapselgehalts an Apfelmus führte zu einem Anstieg der Cmax und AUC von Tizanidin um 15% bis 20% und zu einer Verringerung der mittleren Verzögerungszeit und -zeit bis zur Spitzenkonzentration um 15 Minuten im Vergleich zur Verabreichung einer intakten Kapsel während des Fastens.

Abbildung 1: Mittlere Tizanidinkonzentration vs. Zeitprofile für Tizanidin-Hcl-Tabletten und -Kapseln (2 - 4 mg) unter fastenden und gefütterten Bedingungen

Stoffwechsel und Ausscheidung

Tizanidin hat eine lineare Pharmakokinetik über die in der klinischen Entwicklung untersuchten Dosen (1–20 mg). Tizanidin hat eine Halbwertszeit von ungefähr 2,5 Stunden (CV = 33%). Ungefähr 95% einer verabreichten Dosis werden metabolisiert. Das primäre Cytochrom P450-Isoenzym, das am Tizanidin-Metabolismus beteiligt ist, ist CYP1A2. Es ist nicht bekannt, dass Tizanidin-Metaboliten aktiv sind. Ihre Halbwertszeiten reichen von 20 bis 40 Stunden.

Nach einmaliger und mehrfacher oraler Dosierung von ¹⁴C-Tizanidin, durchschnittlich 60% und 20% der gesamten Radioaktivität, wurde im Urin bzw. im Kot zurückgewonnen.