Zanaflex Capsule (Oral)

A cápsula de Zanaflex (Oral) é um agonista alfa-2-adrenérgico central indicado para o gerenciamento da espasticidade. Devido à curta duração do efeito terapêutico, o tratamento com Zanaflex Capsule (Oral) deve ser reservado para as atividades diárias e momentos em que o alívio da espasticidade é mais importante.

Informações de dosagem

Os comprimidos de Cápsula Zanaflex (Oral) Capsules® ou Zanaflex Capsule (Oral) ® podem ser prescritos com ou sem alimentos. Depois que a formulação for selecionada e a decisão de tomar com ou sem alimentos for tomada, esse regime não deve ser alterado.

Os alimentos têm efeitos complexos na farmacocinética da tizanidina, que diferem nas diferentes formulações. Cápsulas Zanaflex (Oral) As cápsulas e os comprimidos da Cápsula Zanaflex (Oral) são bioequivalentes entre si em condições de jejum (mais de 3 horas após uma refeição), mas não em condições de alimentação (dentro de 30 minutos de uma refeição). Essas diferenças farmacocinéticas podem resultar em diferenças clinicamente significativas ao alternar a administração de comprimidos e cápsulas e ao alternar a administração entre o estado alimentado ou em jejum. Essas alterações podem resultar em eventos adversos aumentados ou atraso ou início mais rápido da atividade, dependendo da natureza do comutador. Por esse motivo, o prescritor deve estar completamente familiarizado com as mudanças na cinética associadas a essas diferentes condições.

A dose inicial recomendada é de 2 mg. Como o efeito da Cápsula Zanaflex (Oral) atinge um pico de aproximadamente 1 a 2 horas após a dose e se dissipa entre 3 a 6 horas após a dose, o tratamento pode ser repetido em intervalos de 6 a 8 horas, conforme necessário, até um máximo de três doses em 24 horas.

A dosagem pode ser aumentada gradualmente em 2 mg a 4 mg em cada dose, com 1 a 4 dias entre o aumento da dose, até que seja alcançada uma redução satisfatória do tônus muscular. A dose diária total não deve exceder 36 mg. Doses únicas superiores a 16 mg não foram estudadas.

Dosagem em pacientes com comprometimento renal

A cápsula de Zanaflex (Oral) deve ser usada com cautela em pacientes com insuficiência renal (depuração da creatinina <25 mL / min), pois a depuração é reduzida em mais de 50%. Nestes pacientes, durante a titulação, as doses individuais devem ser reduzidas. Se forem necessárias doses mais altas, as doses individuais, em vez da frequência de dosagem, devem ser aumentadas.

Dosagem em pacientes com comprometimento hepático

A cápsula de Zanaflex (Oral) deve ser usada com cautela em pacientes com qualquer insuficiência hepática. Nestes pacientes, durante a titulação, as doses individuais devem ser reduzidas. Se forem necessárias doses mais altas, as doses individuais, em vez da frequência de dosagem, devem ser aumentadas. O monitoramento dos níveis de aminotransferase é recomendado para a linha de base e 1 mês após a dose máxima ser alcançada ou se houver suspeita de lesão hepática.

Descontinuação de Drogas

Se a terapia precisar ser descontinuada, particularmente em pacientes que receberam altas doses (20 mg a 36 mg por dia) por longos períodos (9 semanas ou mais) ou que possam estar em tratamento concomitante com narcóticos, a dose deve ser diminuída lentamente (2 mg a 4 mg por dia) minimizar o risco de abstinência e hipertensão rebote, taquicardia, e hipertonia.

A cápsula de Zanaflex (Oral) está contra-indicada em inibidores potentes do CYP1A2, como fluvoxamina ou ciprofloxacina.

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 Zanaflex Capsule (Oral) is used in patients receiving concurrent antihypertensive therapy. It is not recommended that Zanaflex Capsule (Oral) 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 Zanaflex Capsule (Oral). Therefore, concomitant use of Zanaflex Capsule (Oral) with fluvoxamine or with ciprofloxacin, potent inhibitors of CYP1A2, is contraindicated.

Risk of Liver Injury

Zanaflex Capsule (Oral) may cause hepatocellular liver injury. Zanaflex Capsule (Oral) 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

Zanaflex Capsule (Oral) 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 Zanaflex Capsule (Oral) with alcohol and other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive. Monitor patients who take Zanaflex Capsule (Oral) with another CNS depressant for symptoms of excess sedation.

Hallucinosis/Psychotic-Like Symptoms

Zanaflex Capsule (Oral) 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 Zanaflex Capsule (Oral) in patients who develop hallucinations.

Interaction with CYP1A2 Inhibitors

Because of potential drug interactions, Zanaflex Capsule (Oral) 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 Zanaflex Capsule (Oral) 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 Zanaflex Capsule (Oral) therapy is clinically evident. In such a case, use with caution.

Hypersensitivity Reactions

Zanaflex Capsule (Oral) 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 Zanaflex Capsule (Oral) and seek immediate medical care should these signs and symptoms occur.

Increased Risk of Adverse Reactions in Patients with Renal Impairment

Zanaflex Capsule (Oral) 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

Zanaflex Capsule (Oral) has not been studied in pregnant women. Zanaflex Capsule (Oral) 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 Zanaflex Capsule (Oral) is administered to a nursing woman.

Pediatric use

Safety and effectiveness in pediatric patients have not been established.

Geriatric use

Zanaflex Capsule (Oral) 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 Zanaflex Capsule (Oral) 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 Zanaflex Capsule (Oral) 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 Zanaflex Capsule (Oral).

Impaired Renal Function

Zanaflex Capsule (Oral) 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..

As seguintes reações adversas são descritas em outras seções das informações de prescrição :

• Hipotensão
• Lesão hepática
• Sedação
• Alucinose / sintomas psicóticos
• Reações de hipersensibilidade

Experiência em ensaios clínicos

Como os estudos clínicos são realizados em condições muito variadas, as taxas de reação adversa observadas nos estudos clínicos de um medicamento não podem ser diretamente comparadas às taxas nos estudos clínicos de outro medicamento e podem não refletir as taxas observadas na prática clínica.

Três estudos clínicos randomizados, duplo-cegos e controlados por placebo foram realizados para avaliar o efeito da tizanidina no controle da espasticidade. Dois estudos foram realizados em pacientes com esclerose múltipla e um em pacientes com lesão medular. Cada estudo teve um período de tratamento ativo de 13 semanas, que incluiu uma fase de titulação de 3 semanas até a dose máxima tolerada de até 36 mg / dia em três doses divididas, uma fase de platô de 9 semanas em que a dose de tizanidina era mantida constante e uma redução da dose de 1 semana. Ao todo, 264 pacientes receberam tizanidina e 261 pacientes receberam placebo. Nos três estudos, a idade dos pacientes variou de 15 a 69 anos e 51,4% eram mulheres. A dose média durante a fase do platô variou de 20 a 28 mg / dia.

As reações adversas mais frequentes relatadas em doses múltiplas, estudos clínicos controlados por placebo envolvendo 264 pacientes com espasticidade foram boca seca, sonolência / sedação, astenia (fraqueza, fadiga e / ou cansaço) e tontura. Três quartos dos pacientes classificaram os eventos como leves a moderados e um quarto dos pacientes classificou os eventos como graves. Esses eventos pareciam estar relacionados à dose.

A Tabela 1 lista os sinais e sintomas relatados em mais de 2% dos pacientes em três estudos controlados por placebo e dose múltipla que receberam Zanaflex Capsule (Oral), onde a frequência no grupo Zanaflex Capsule (Oral) foi maior que o grupo placebo. Para fins de comparação, também é fornecida a frequência correspondente do evento (por 100 pacientes) entre os pacientes tratados com placebo.

Tabela 1: Dose múltipla, estudos controlados por placebo - reações adversas frequentes (> 2%) relatadas para as quais a incidência de comprimidos de cápsulas de Zanaflex (Oral) é maior que o placebo

Na dose única, estudo controlado por placebo envolvendo 142 pacientes com espasticidade devido à esclerose múltipla (Estudo 1), os pacientes foram perguntados especificamente se haviam experimentado alguma das quatro reações adversas mais comuns: boca seca, sonolência (sonolência), astenia (fraqueza, fadiga e / ou cansaço) e tontura. Além disso, hipotensão e bradicardia foram observadas. A ocorrência dessas reações está resumida na Tabela 2. Outros eventos foram, em geral, relatados a uma taxa de 2% ou menos.

Tabela 2: Estudo controlado por placebo de dose única - reações adversas comuns relatadas

Experiência pós-comercialização

As seguintes reações adversas foram identificadas durante o uso pós-aprovação da Zanaflex Capsule (Oral). Como essas reações são relatadas voluntariamente a partir de uma população de tamanho incerto, nem sempre é possível estimar com segurança sua frequência ou estabelecer uma relação causal com a exposição a medicamentos.

Certos eventos, como sonolência, boca seca, hipotensão, diminuição da pressão arterial, bradicardia, tontura, fraqueza ou astenia, espasmos musculares, alucinações, fadiga, anormalidade nos testes de função hepática e hepatotoxicidade, foram observados em ensaios clínicos e pós-marketing e são discutidos em seções anteriores deste documento.

As seguintes reações adversas foram identificadas como ocorrendo na experiência pós-comercialização da Zanaflex Capsule (Oral). Com base nas informações fornecidas sobre essas reações, uma relação causal com a Zanaflex Capsule (Oral) não pode ser totalmente excluída. Os eventos são listados em ordem decrescente de significância clínica; a gravidade na configuração pós-marketing não é relatada.

• Síndrome de Stevens Johnson
• Reação anafilática
• Dermatite esfoliativa
• Taquicardia ventricular
• Hepatite
• Convulsão
• Depressão
• Artralgia
• Parestesia
• Erupção cutânea
• Tremor

A review of the safety surveillance database revealed cases of intentional and accidental Zanaflex Capsule (Oral) 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 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.

Differences between Zanaflex Capsule (Oral) Capsules® and Zanaflex Capsule (Oral)® Tablets

Zanaflex Capsule (Oral) Capsules® and Zanaflex Capsule (Oral)® tablets are bioequivalent to each other under fasting conditions, but not under fed conditions. A single dose of either two 4 mg tablets or two 4 mg capsules was administered under fed and fasting conditions in an open label, four period, randomized crossover study in 96 human volunteers, of whom 81 were eligible for the statistical analysis. Following oral administration of either the tablet or capsule (in the fasted state), peak plasma concentrations of tizanidine occurred 1.0 hours after dosing with a half-life of approximately 2 hours. When two 4 mg tablets were administered with food, the mean maximal plasma concentration was increased by approximately 30%, and the median time to peak plasma concentration was increased by 25 minutes, to 1 hour and 25 minutes. In contrast, when two 4 mg capsules were administered with food, the mean maximal plasma concentration was decreased by 20%, the median time to peak plasma concentration was increased 2 to 3 hours. Consequently, the mean Cmax for the capsule when administered with food is approximately 66% the Cmax for the tablet when administered with food.

Food also increased the extent of absorption for both the tablets and capsules. The increase with the tablet (~30%) was significantly greater than with the capsule (~10%). Consequently when each was administered with food, the amount absorbed from the capsule was about 80% of the amount absorbed from the tablet. Administration of the capsule contents sprinkled on applesauce was not bioequivalent to administration of an intact capsule under fasting conditions. Administration of the capsule contents on applesauce resulted in a 15%–20% increase in Cmax and AUC of tizanidine and a 15 minute decrease in the median lag time and time to peak concentration compared to administration of an intact capsule while fasting.

Figure 1: Mean Tizanidine Concentration vs. Time Profiles For Zanaflex Capsule (Oral) Tablets and Capsules (2 × 4 mg) Under Fasted and Fed Conditions

Metabolism and Excretion

Tizanidine has linear pharmacokinetics over the doses studied in clinical development (1–20 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 ¹⁴C-tizanidine, an average of 60% and 20% of total radioactivity was recovered in the urine and feces, respectively.