What are the FDA-approved and off-label uses of tizanidine. How does tizanidine work to reduce spasticity. What do clinical studies reveal about the efficacy of tizanidine compared to other anti-spastic medications. What are the potential side effects and precautions associated with tizanidine use.

Understanding Tizanidine: A Powerful Anti-Spastic Medication

Tizanidine is a centrally acting alpha-2 receptor agonist widely used in managing spasticity and other related conditions. This medication has gained significant attention in the medical community due to its effectiveness and versatility. Let’s explore the various aspects of tizanidine, including its uses, mechanism of action, and clinical efficacy.

FDA-Approved and Off-Label Uses of Tizanidine

Tizanidine has been approved by the FDA for specific indications, but it also finds application in various off-label uses. Understanding these applications can help healthcare providers make informed decisions about prescribing this medication.

FDA-Approved Indications

• Spasticity management due to multiple sclerosis
• Spinal cord injury
• Stroke
• Amyotrophic lateral sclerosis (ALS)
• Traumatic brain injury

Off-Label Uses

• Chronic neck and lower back pain
• Rebound headaches due to analgesic withdrawal
• Chronic migraine headaches
• Refractory insomnia in spastic quadriplegic patients
• Regional musculoskeletal pain syndromes

Can tizanidine be used for conditions other than spasticity. Yes, tizanidine has shown promise in managing various pain-related conditions and sleep disorders, although these uses are considered off-label and may require further research to establish their efficacy.

Mechanism of Action: How Tizanidine Works

To understand the effectiveness of tizanidine, it’s crucial to delve into its mechanism of action. Tizanidine’s unique properties contribute to its anti-spastic and pain-relieving effects.

Tizanidine is an imidazoline derivative that acts as a centrally acting alpha-2 receptor agonist. Its primary mechanism of action involves:

1. Inhibiting the release of excitatory amino acids (glutamate and aspartate) from spinal interneurons
2. Enhancing presynaptic inhibition of motor neurons
3. Reducing facilitation of spinal motor neurons
4. Inhibiting inter-neuronal activity, contributing to anti-nociceptive and anti-convulsant effects

How does tizanidine reduce spasticity. Tizanidine’s actions on spinal polysynaptic pathways lead to a decrease in muscle tone, spasm frequency, and clonus. This reduction in excessive muscle activity helps alleviate the symptoms of spasticity and improves patient mobility and comfort.

Clinical Efficacy: Comparing Tizanidine to Other Anti-Spastic Medications

Numerous clinical studies have evaluated the efficacy of tizanidine in managing spasticity and related conditions. These studies provide valuable insights into its performance compared to other commonly used medications.

Tizanidine vs. Placebo

Placebo-controlled studies have consistently demonstrated the significant efficacy of tizanidine in reducing spasticity, particularly in patients with spinal cord-induced spasticity. Research suggests that individuals with severe spasticity are more likely to benefit from tizanidine therapy.

Tizanidine vs. Baclofen and Diazepam

Several comparative studies have evaluated tizanidine against other anti-spastic medications, such as baclofen and diazepam. Key findings include:

• Similar efficacy in reducing excessive muscle tone in patients with multiple sclerosis or cerebrovascular lesions
• Comparable improvements in muscle strength, with tizanidine showing the most significant improvement in some studies
• No significant differences in overall anti-spastic effect
• Better tolerance profile for tizanidine compared to diazepam and baclofen

Is tizanidine more effective than other anti-spastic medications. While tizanidine has shown similar efficacy to baclofen and diazepam in managing spasticity, it often demonstrates a better tolerability profile, making it a preferred choice for many patients and healthcare providers.

Tizanidine in Pain Management and Other Applications

Beyond its primary use in spasticity management, tizanidine has shown promise in various pain-related conditions and other medical applications.

Chronic Pain Management

Tizanidine has demonstrated effectiveness in managing chronic neck and lower back pain, particularly when there is a myofascial component to the pain. Its muscle-relaxing properties, combined with its analgesic effects, make it a valuable option for patients suffering from regional musculoskeletal pain syndromes.

Headache Management

Research has shown that tizanidine can be beneficial in managing chronic migraine headaches and rebound headaches due to analgesic withdrawal. Its ability to modulate pain pathways and reduce muscle tension contributes to its efficacy in these conditions.

Neuropathic Pain

Animal studies have suggested that tizanidine may provide benefits in managing neuropathic pain, such as trigeminal neuralgia. These findings indicate potential applications in conditions involving nerve pain and dysfunction.

Opioid Withdrawal

Recent studies have explored the use of tizanidine and other alpha-2 agonists in medically supervised opioid withdrawal. This application highlights the potential role of tizanidine in addiction medicine and pain management strategies.

Guidelines and Recommendations for Tizanidine Use

Various medical organizations have provided guidelines and recommendations for the use of tizanidine in different clinical scenarios. Understanding these recommendations can help healthcare providers make informed decisions about prescribing tizanidine.

American Academy of Neurology Guidelines

The American Academy of Neurology has provided specific recommendations regarding the use of tizanidine in spasticity management:

• Tizanidine is recommended for generalized spasticity in cerebral palsy
• For segmental or localized spasticity, treatment with botulinum toxin-A is considered more effective

When should tizanidine be prescribed for spasticity. Tizanidine is most appropriate for cases of generalized spasticity, while localized spasticity may be better managed with targeted treatments like botulinum toxin injections.

Adverse Effects and Precautions Associated with Tizanidine Use

While tizanidine is generally well-tolerated, it’s essential to be aware of potential adverse effects and necessary precautions when prescribing this medication.

Common Side Effects

• Drowsiness and sedation
• Dizziness
• Dry mouth
• Weakness
• Hypotension

Precautions and Contraindications

Healthcare providers should exercise caution when prescribing tizanidine in the following situations:

• Patients with liver or kidney impairment
• Concurrent use with CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin)
• History of hypersensitivity to tizanidine or other alpha-2 agonists
• Patients with severe cardiovascular disease

What precautions should be taken when prescribing tizanidine. Healthcare providers should carefully assess the patient’s medical history, liver and kidney function, and potential drug interactions before initiating tizanidine therapy. Close monitoring during treatment is essential to ensure safety and efficacy.

Dosing and Administration of Tizanidine

Proper dosing and administration of tizanidine are crucial for maximizing its benefits while minimizing potential side effects. The following guidelines can help healthcare providers determine the appropriate dosing regimen for their patients.

Initial Dosing

• Starting dose: 2 mg orally every 6 to 8 hours as needed
• Gradually increase by 2 to 4 mg every 1 to 4 days
• Maximum recommended dose: 36 mg per day (usually divided into three or four doses)

Dosing Considerations

Several factors should be considered when determining the appropriate tizanidine dose:

• Severity of spasticity
• Patient’s response to treatment
• Tolerability of side effects
• Presence of liver or kidney impairment
• Concurrent medications

How should tizanidine dosing be adjusted. Tizanidine dosing should be individualized based on the patient’s response and tolerability. Gradual dose titration and close monitoring are essential to achieve optimal therapeutic effects while minimizing adverse reactions.

Drug Interactions and Pharmacokinetics of Tizanidine

Understanding the pharmacokinetics and potential drug interactions of tizanidine is crucial for safe and effective use of this medication. Healthcare providers should be aware of these factors when prescribing tizanidine alongside other medications.

Pharmacokinetics

• Rapid absorption after oral administration
• Peak plasma concentrations reached within 1 to 2 hours
• Metabolized primarily by the liver (CYP1A2 enzyme)
• Elimination half-life of approximately 2.5 hours

Significant Drug Interactions

Tizanidine has several important drug interactions that can affect its efficacy and safety:

• CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin): Can significantly increase tizanidine levels, leading to potentially dangerous side effects
• Oral contraceptives: May increase tizanidine concentrations
• Alcohol: Can enhance the sedative effects of tizanidine
• Other CNS depressants: May potentiate the sedative effects of tizanidine

What are the most important drug interactions to consider with tizanidine. The most critical interactions involve CYP1A2 inhibitors, which can dramatically increase tizanidine levels in the body. Concurrent use of these medications with tizanidine should be avoided or closely monitored.

Patient Education and Monitoring for Tizanidine Therapy

Effective patient education and ongoing monitoring are essential components of successful tizanidine therapy. Healthcare providers should ensure that patients understand the proper use of the medication and are aware of potential side effects and precautions.

Key Points for Patient Education

• Proper dosing schedule and importance of adherence
• Potential side effects and when to seek medical attention
• Avoiding alcohol and other CNS depressants while taking tizanidine
• Importance of regular follow-up appointments
• Gradual discontinuation to avoid withdrawal symptoms

Monitoring Parameters

Healthcare providers should regularly monitor patients on tizanidine therapy for:

• Efficacy in reducing spasticity or managing pain
• Occurrence and severity of side effects
• Changes in liver function
• Blood pressure and heart rate
• Drug interactions with new medications

How often should patients on tizanidine be monitored. The frequency of monitoring depends on individual patient factors, but generally, patients should be evaluated at least every 3 to 6 months for long-term therapy. More frequent monitoring may be necessary during dose titration or in patients with comorbidities.

Future Directions and Research in Tizanidine Use

As our understanding of tizanidine and its applications continues to evolve, ongoing research is exploring new potential uses and optimizing its current applications. Several areas of investigation hold promise for expanding the therapeutic potential of tizanidine.

Emerging Applications

• Neuropathic pain management: Further studies are needed to establish the efficacy of tizanidine in various neuropathic pain conditions
• Opioid withdrawal: Investigating the role of tizanidine in managing opioid withdrawal symptoms and supporting addiction treatment
• Fibromyalgia: Exploring the potential benefits of tizanidine in managing fibromyalgia symptoms
• Combination therapies: Evaluating the synergistic effects of tizanidine with other medications for enhanced pain management and spasticity control

Optimizing Current Use

Researchers are also focusing on improving the current applications of tizanidine:

• Developing extended-release formulations for improved dosing convenience and efficacy
• Investigating genetic factors that influence individual response to tizanidine
• Refining dosing strategies to maximize benefits while minimizing side effects
• Exploring the long-term effects of tizanidine use on muscle function and quality of life

What new applications of tizanidine are being explored. Researchers are investigating tizanidine’s potential in managing neuropathic pain, supporting opioid withdrawal, and treating fibromyalgia. Additionally, studies are focusing on optimizing current uses through improved formulations and personalized dosing strategies.

As research continues to uncover new applications and refine existing uses of tizanidine, healthcare providers can look forward to expanded treatment options and improved patient outcomes. The versatility of tizanidine in managing spasticity, pain, and related conditions makes it a valuable tool in the medical arsenal, with ongoing research promising to enhance its utility further.

Tizanidine – StatPearls – NCBI Bookshelf

Continuing Education Activity

Tizanidine is an FDA-approved drug for managing spasticity. It is a centrally acting alpha-2 receptor agonist. Tizanidine effectively works with spasticity caused by multiple sclerosis, an acquired brain injury, or a spinal cord injury. It has also been shown to be clinically effective in managing patients suffering from chronic neck and lumbosacral neuralgia with a myofascial component to their pain and regional musculoskeletal pain syndromes. It is also prescribed off-label for migraine headaches, insomnia, and as an anticonvulsant. Tizanidine can also be applied as part of a detoxification therapy regimen in patients exhibiting analgesic rebound headaches to assist with analgesic withdrawal. This activity outlines the indications, mechanism of action, methods of administration, significant adverse effects, toxicity, and monitoring, of tizanidine so providers can direct patient therapy as part of the inter-professional team.

Objectives:

• Explain the mechanism of action of tizanidine.

• Identify the clinical indications for tizanidine use.

• Review the adverse reaction profile of tizanidine.

• Summarize inter-professional team strategies for improving care, coordination, and communication for improving patient outcomes related to tizanidine therapy.

Access free multiple choice questions on this topic.

Indications

Tizanidine is a centrally acting alpha-2 agonist. Tizanidine is widely used as an anti-spastic agent for multiple medical conditions.

FDA-approved Indication

• Tizanidine is indicated for spasticity management due to multiple sclerosis, spinal cord injury, stroke, amyotrophic lateral sclerosis, and traumatic brain injury.[1][2][3]

Off-label Use

• Chronic neck and lower back pain[4]

• Rebound headaches due to analgesic withdrawal[5]

• Chronic migraine headaches[6]

• Refractory insomnia in spastic quadriplegic patients[7]

• Regional musculoskeletal pain syndromes[4]

Clinical Studies

• Placebo-controlled studies confirm the significant efficacy of tizanidine in reducing spasticity in patients with spinal cord-induced spasticity. Literature suggests that patients with severe spasticity are more likely to benefit from the therapy. Drug comparison studies have shown no differences in the efficacy of tizanidine compared with baclofen or diazepam. The tizanidine treatment group did not report increased weakness compared to the controls. Furthermore, patients given tizanidine experienced fewer adverse effects than those using controlled substances.[8]

• Studies exhibit that tizanidine, baclofen, and diazepam effectively decreased excessive muscle tone in patients with multiple sclerosis or cerebrovascular lesions. Muscle strength improved in all three treatment groups, but the improvement was most significant with tizanidine. Shakespeare et al. also reported similar findings showing no differences in efficacy between tizanidine, baclofen, and dantrolene compared to diazepam. However, diazepam was associated with more sedation.[9] 

• Another study by Lataste et al. showed no significant differences between tizanidine and baclofen or diazepam for muscle tone, muscle spasms, clonus, muscle strength, or overall anti-spastic effect. However, tizanidine tolerance is slightly better than diazepam and baclofen.[10]

• Groves et al. report no significant differences between tizanidine, baclofen, or diazepam for spasticity by Ashworth score. However, applying global tolerability to treatment favored tizanidine compared to baclofen and diazepam.[11] 

• Animal studies have shown that tizanidine provides benefits in the perioperative period and the management of neuropathic pain, such as trigeminal neuralgia, similar to the effects of clonidine under similar circumstances.

• A recent study indicates that tizanidine and other alpha-2 agonists can be used for medically supervised opioid withdrawal.[12]

• The American Academy of Neurology guidelines reports that tizanidine should be used for generalized spasticity in cerebral palsy, for segmental/localized spasticity treatment with botulinum toxin-A is more effective.[13]

Mechanism of Action

Tizanidine is an imidazoline derivative and a centrally acting alpha-2 receptor agonist. Tizanidine inhibits the release of excitatory amino acids like glutamate and aspartate from spinal interneurons. Consequently, tizanidine enhances the presynaptic inhibition of motor neurons. Tizanidine has significant action on spinal polysynaptic pathways.[14]

The overall effect of these actions is to reduce the facilitation of spinal motor neurons. Similarly, alpha-2 receptor-mediated inhibition of inter-neuronal activity appears to underlie tizanidine’s additional anti-nociceptive and anti-convulsant activities. Spasm frequency and clonus are also reduced by tizanidine.[15]

Tizanidine also has an affinity for the alpha-1 receptors but to a lesser degree, which may explain its mild and transitory effect on the cardiovascular system compared to clonidine despite their structural and biochemical similarity.[16]

Pharmacokinetics  

Absorption: Tizanidine has a significant, first-pass hepatic metabolism with an oral bioavailability of 20% to 34%. Tizanidine attains the steady-state concentration within 24 to 48 hours after administration. There is no noticeable change in its pharmacokinetic behavior with repeated intake.[17]

Distribution: Tizanidine has extensive tissue distribution; the volume of distribution is 2.4 L/kg. The plasma protein binding of tizanidine is approximately 30%.

Metabolism: Tizanidine is metabolized extensively in the liver by cytochrome P450-1A2 to inactive metabolites.

Excretion: Tizanidine has an elimination half-life of 2.5 hours, follows linear pharmacokinetics, and is excreted 60% through urine and 20% through feces.[18]

Administration

Tizanidine is administrated orally as 2 mg, 4 mg, and 6 mg capsules or as 2 mg and 4 mg tablets. Dosage starts with 2 mg orally and may repeat every 6 to 8 hours as needed. The dosage may gradually increase by 2 to 4 mg per dose for 1 to 4 days in between until there is a noticeably significant reduction of spasticity. Maximum dosing is three doses every 24 hours, up to 36 mg daily.

If tizanidine is used for more than nine weeks or given in high doses ranging from 20 mg to 36 mg daily, taper the dose gradually. The recommendation is to taper the dose to 2 to 4 mg daily to reduce the risk of tachycardia, rebound hypertension, and increased spasticity.[19]

The patient may open the capsule and sprinkle the contents into food. Patients can take tizanidine with food or on an empty stomach. It is important to note that the extent of absorption is greater when taken with food. The tablet and capsule dosage forms are not bioequivalent when administered with food. Hence, the clinician should counsel the patient to take tizanidine with or without food but be consistent to avoid fluctuations in concentration.[20] It is also important to recognize that smoking decreases tizanidine’s plasma concentration and exposure(AUC).[21]

Use in Specific Patient Population

Patients with Hepatic Impairment: The consequence of Hepatic impairment on the pharmacokinetics of tizanidine has not been evaluated. However, tizanidine is extensively metabolized by the liver; therefore, hepatic impairment would significantly influence the pharmacokinetics of tizanidine. Therefore, tizanidine should be avoided or used with extreme caution in patients with hepatic impairment.

Patients with Renal Impairment: Tizanidine should be used cautiously in patients with renal impairment (creatinine clearance < 25 mL/min), as clearance is decreased by more than 50%. Start with a low dose, evaluate the response to therapy, and if a higher dose is needed, the dose can be increased rather than increasing the frequency of administration. The clinician should monitor the patient closely for adverse drug reactions such as dry mouth, drowsiness, asthenia, and dizziness as indicators of toxicity.

Pregnancy Considerations: The use of tizanidine in managing spinal cord injury during pregnancy has been described in case reports.[22] However, it is important to note that tizanidine is a former FDA pregnancy category-C and should be used only if indicated after careful risk-benefit evaluation.

Breastfeeding Considerations: Tizanidine is a lipid-soluble drug; hypothetically, it may be present in breast milk; its use during lactation is not advised.

Adverse Effects

Tizanidine is generally well-tolerated. However, reports exist of potential adverse effects on several organs, such as cutaneous, gastrointestinal, neurologic, cardiovascular, endocrine, and respiratory systems.

Common Adverse Drug Reactions

• Drowsiness

• Blurred vision

• Asthenia

• Constipation

• Dyskinesia

• Nervousness

• Hallucination

• Rhinitis

• Xerostomia[15]

• Dizziness[23]

Severe Adverse Drug Reactions

• Severe hepatotoxicity and liver failure[24] 

• Anaphylaxis

• Exfoliative dermatitis

• Severe hypotension[25]

• QT interval prolongation[26]

• Severe bradycardia[27]

• Stevens-Johnson syndrome[28]

• Refractory hypokalemia and potassium wasting nephropathy[29]

Withdrawal Symptoms 

• Tachycardia

• Rebound hypertension

• Increased spasticity 

• Withdrawal symptoms are more likely to occur when discontinuing the drug abruptly. [19]

Drug Interactions

• Concomitant use of tizanidine with fluvoxamine or ciprofloxacin is contraindicated due to significant hypotension and increased psychomotor impairment.[30] A recent retrospective analysis of the WHO pharmacovigilance database identified severe cardiac and nervous system adverse drug reactions. The study concluded that the concomitant use of ciprofloxacin with tizanidine should be avoided.[31]

• Because of potential drug interactions, using tizanidine with other CYP1A2 inhibitors such as oral contraceptives containing Ethinyl estradiol and gestodene, dronedarone, pimozide, saquinavir, cimetidine, famotidine, acyclovir, and ticlopidine should be avoided due to decreased clearance of tizanidine.[32]

• If tizanidine is clinically necessary, therapy should be initiated with 2 mg and increased to 2 to 4 mg daily based on patient response to therapy.

• Adverse reactions such as hypotension, bradycardia, or excessive sedation require gradual dose reduction or stopping therapy.

• Tizanidine should be used cautiously in patients on other alpha-2 adrenergic receptor agonists.

• Patients should avoid alcohol and benzodiazepines with tizanidine as it can lead to excessive sedation and myocardial toxicity in rare instances.[33]

• Vemurafenib used in BRAF mutation-positive malignancy is an inhibitor of CYP1A2 and can increase plasma concentration of tizanidine, leading to potential toxicity.[34]

Contraindications

• Hypersensitivity to tizanidine or its ingredients is a contraindication to the use of tizanidine.

• Tizanidine use requires caution in patients with hepatic impairment. Review articles on tizanidine report cases of severe hepatotoxicity, acute liver failure, and death.[24]

• According to product labeling, tizanidine use requires caution in patients with renal impairment (creatinine clearance < 25 mL/min). In such patients, decrease the dose. If high doses are necessary, increase the individual dosage rather than the dosage frequency.

Monitoring

• Creatinine and liver function tests require measurement at baseline, then one month after the maintenance dose is achieved. Periodically monitor liver function tests in patients managed with tizanidine chronically and in higher doses.[24]

• Monitor blood pressure and heart rate before increasing the dosage because of the risk of severe hypotension associated with the higher dose.[25]

• Monitor the level of spasticity by Ashworth and modified Ashworth Scales.[35] 

• In patients with multiple sclerosis, monitor spasticity using MS Spasticity Scale(MSSS-88).[36]

Toxicity

• The maximum recommended dose of tizanidine is 36 mg/day.[37]

• In the retrospective review, which included 45 patients, the mean dose ingested was 72 mg (Above the maximum recommended dose).

Clinical Features

• Lethargy

• Bradycardia

• Hypotension

• Agitation

• Confusion

• Vomiting

• Drowsiness

• Coma

Management

• There is no antidote for tizanidine toxicity.

• Tizanidine overdose management is by close monitoring of airways, administration of intravenous fluid, and vasopressors as necessary.[25]

• The pediatric case report described an overdose of tizanidine in spastic quadriplegia and toxicity presented with multiple organ dysfunction in the absence of sepsis.[37]

• A recent case report described the altered mental status and hemodynamic instability due to tizanidine overdose, and naloxone 10 mg IV administration improved Richmond Agitation-Sedation Scale(RASS).[38] The study concluded that naloxone could be used in tizanidine overdose in emergency settings; however, naloxone does not reverse the hemodynamic parameters.[39]

Enhancing Healthcare Team Outcomes

Tizanidine is a centrally acting alpha-2 agonist prescribed to manage spasticity caused by multiple sclerosis, stroke, and spinal cord injury. Tizanidine is also used off-label for managing patients suffering from chronic neck and back pain and chronic migraines.  However, this drug can cause hypotension, bradycardia, and hepatotoxicity. Hence all healthcare providers need to understand indications, mechanisms, adverse effects, and their management. 

The clinician prescribes tizanidine for appropriate indication and should assess liver function tests at baseline and one month. In addition, the neurologist should evaluate the improvement in spasticity related to neurological disorders such as multiple sclerosis, stroke, and spinal cord injury. Nurses can check compliance, monitor for adverse events, and counsel patients for adherence to therapy. The pharmacist should verify the dosing regimen, perform medication reconciliation for drug interactions, and counsel the patient on adverse drug reactions. In addition, patients need to be warned not to combine it with antihypertensive medications. In the overdose of tizanidine, triage nurses should admit the patient, and the emergency department physicians should monitor blood pressure and heart rate and obtain 12 lead EKG. Additionally, a liver function test is required to assess for hepatotoxicity. The critical care physician should manage severe overdose, which requires vasopressors and fluids during the ICU stay.

As depicted above, there are multiple healthcare providers, including clinicians (MDs, DOs, NPs, PAs), specialists, pharmacists, and nurses, involved in taking care of the patient. Tizanidine can be an effective therapeutic agent, but it requires the entire interprofessional healthcare team to collaborate and communicate for therapy to be successful. In addition, a recent study noted that interprofessional care between clinicians, neurologists, pharmacists, nurses, physical therapists, speech and language therapists, and occupational therapists is crucial for providing patient-centered care in patients with multiple sclerosis.[40] [Level 5]

Review Questions

• Access free multiple choice questions on this topic.

• Comment on this article.

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Kaddar N, Vigneault P, Pilote S, Patoine D, Simard C, Drolet B. Tizanidine (Zanaflex): a muscle relaxant that may prolong the QT interval by blocking IKr. J Cardiovasc Pharmacol Ther. 2012 Mar;17(1):102-9. [PubMed: 21317414]

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Kitabata Y, Orita H, Kamimura M, Shiizaki K, Narukawa N, Abe T, Kobata H, Akizawa T. Symptomatic bradycardia probably due to tizanidine hydrochloride in a chronic hemodialysis patient. Ther Apher Dial. 2005 Feb;9(1):74-7. [PubMed: 15828911]

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Ishiguro A, Shibata T, Yanagishita T, Takama H, Uchida R, Ohshima Y, Watanabe D. A case of drug-induced Stevens-Johnson syndrome-like eruption predominating in mucosa: A case report. Clin Case Rep. 2020 Aug;8(8):1379-1381. [PMC free article: PMC7455421] [PubMed: 32884758]

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Brucculeri MJ, Garcia J. Potassium wasting nephropathy in the setting of tizanidine overdose: a case report. J Med Case Rep. 2021 May 01;15(1):250. [PMC free article: PMC8088014] [PubMed: 33931107]

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Granfors MT, Backman JT, Neuvonen M, Neuvonen PJ. Ciprofloxacin greatly increases concentrations and hypotensive effect of tizanidine by inhibiting its cytochrome P450 1A2-mediated presystemic metabolism. Clin Pharmacol Ther. 2004 Dec;76(6):598-606. [PubMed: 15592331]

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Rudolph A, Dahmke H, Kupferschmidt H, Burden A, Weiler S. Coadministration of tizanidine and ciprofloxacin: a retrospective analysis of the WHO pharmacovigilance database. Eur J Clin Pharmacol. 2021 Jun;77(6):895-902. [PMC free article: PMC8128801] [PubMed: 33404754]

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Chaugai S, Dickson AL, Shuey MM, Feng Q, Barker KA, Wei WQ, Luther JM, Stein CM, Chung CP. Co-Prescription of Strong CYP1A2 Inhibitors and the Risk of Tizanidine-Associated Hypotension: A Retrospective Cohort Study. Clin Pharmacol Ther. 2019 Mar;105(3):703-709. [PMC free article: PMC6379114] [PubMed: 30223305]

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Amino M, Yoshioka K, Ikari Y, Inokuchi S. Long-term myocardial toxicity in a patient with tizanidine and etizolam overdose. J Cardiol Cases. 2016 Mar;13(3):78-81. [PMC free article: PMC6280692] [PubMed: 30546611]

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Disclosure: Shirin Ghanavatian declares no relevant financial relationships with ineligible companies.

Disclosure: Armen Derian declares no relevant financial relationships with ineligible companies.

Side Effects, Dosage, Uses, and More

Highlights for tizanidine

1. Tizanidine oral tablet is available as both a generic and brand-name drug. Brand name: Zanaflex.
2. Tizanidine also comes as an oral capsule.
3. Tizanidine oral tablet is used to manage muscle spasms. It’s often used for people with multiple sclerosis, spinal cord injury, or muscle spasticity.

• Low blood pressure warning. Tizanidine can cause very low blood pressure that leads to dizziness or fainting. To help reduce this risk, your doctor may prescribe the lowest dose of this drug that works for you. If you already take medications that lower blood pressure, your doctor may check your blood pressure more often.
• Liver damage warning. Tizanidine can cause liver damage. If you have liver disease, talk with your doctor about whether this drug is safe for you. If you take this drug, your doctor may monitor you for changes in how well your liver works.
• Hallucinations or delusions warning. Tizanidine can cause visual hallucinations (seeing things that aren’t real). It can also cause delusions (believing things that aren’t real). If have either of these side effects, stop taking this drug and call your doctor right away.
• Sedation (drowsiness) warning. Tizanidine can cause sedation. Taking tizanidine with alcohol or certain drugs (benzodiazepines, opioids, or tricyclic antidepressants) can increase sedation. Tell your doctor or pharmacist about all medications, vitamins, or herbs you’re taking.

Tizanidine is a prescription drug that comes as an oral tablet and an oral capsule.

Tizanidine oral tablet is available as a brand-name drug Zanaflex. It’s also available as a generic drug. Generic drugs usually cost less than the brand-name version. In some cases, they may not be available in all strengths or forms as the brand-name drug.

Why it’s used

Tizanidine oral tablet is used to manage muscle spasms. Symptoms can include muscle tightness, pain, or stiffness. This drug is often used for people with multiple sclerosis, spinal cord injury, or muscle spasticity.

How it works

Tizanidine belongs to a class of drugs called alpha-2-adrenergic agonists. A class of drugs is a group of medications that work in a similar way. These drugs are often used to treat similar conditions.

Tizanidine reduces the activity of nerves in the spinal cord that control muscles. This helps to reduce muscle spasms.

Tizanidine oral tablet may cause drowsiness. It may also cause other side effects.

More common side effects

The more common side effects of tizanidine can include:

• dry mouth
• tiredness
• weakness
• dizziness
• urinary tract infection
• constipation
• vomiting
• trouble speaking
• runny nose
• sore throat
• vision problems

If these effects are mild, they may go away within a few days or a couple of weeks. If they’re more severe or don’t go away, talk with your doctor or pharmacist.

Serious side effects

Call your doctor right away if you have serious side effects. Call 911 if your symptoms feel life threatening or if you think you’re having a medical emergency. Serious side effects and their symptoms can include the following:

• Hallucinations. Symptoms can include:
  • seeing things that aren’t real
• Delusions. Symptoms can include:
  • believing things that aren’t real
• Extremely low blood pressure. Symptoms can include:
  • dizziness or lightheadedness, especially when standing after sitting or lying down
• Liver damage. Symptoms can include:
  • increased bleeding or bruising
  • yellowing of your skin or the whites of your eyes
• Sedation. Symptoms can include:
  • dizziness
  • weakness
  • fatigue and sleepiness

Disclaimer: Our goal is to provide you with the most relevant and current information. However, because drugs affect each person differently, we cannot guarantee that this information includes all possible side effects. This information is not a substitute for medical advice. Always discuss possible side effects with a healthcare professional who knows your medical history.

Tizanidine oral tablet can interact with other medications, vitamins, or herbs you may be taking. An interaction is when a substance changes the way a drug works. This can be harmful or prevent the drug from working well.

To help avoid interactions, your doctor should manage all of your medications carefully. Be sure to tell your doctor about all medications, vitamins, or herbs you’re taking. To find out how this drug might interact with something else you’re taking, talk with your doctor or pharmacist.

Examples of drugs that can cause interactions with tizanidine are listed below.

Drugs that should not be used with tizanidine

Do not take these drugs with tizanidine. When used with tizanidine, these drugs can cause dangerous effects in the body. Examples of these drugs include:

• Fluvoxamine and ciprofloxacin (Cipro). Using these drugs with tizanidine may cause very low blood pressure. It may also cause increased drowsiness or decreased muscle control.
• Other alpha-2 agonist medications such as clonidine, methyldopa, or guanfacine. Using these drugs with tizanidine can cause very low blood pressure.

Drugs that increase the risk of side effects from tizanidine

Taking tizanidine with certain medications raises your risk for side effects from tizanidine. This is because the amount of tizanidine in your body is increased. Avoid using these drugs with tizanidine if possible. Examples of these drugs include:

• Zileuton. Increased side effects can include decreased blood pressure, decreased heart rate, or extreme drowsiness.
• Certain antibiotics called fluoroquinolones (other than ciprofloxacin), such as levofloxacin, moxifloxacin, or gemifloxacin. Increased side effects can include decreased blood pressure, decreased heart rate, or extreme drowsiness.
• Certain heart rhythm drugs such as amiodarone, mexiletine, propafenone, or verapamil. Increased side effects can include decreased blood pressure, decreased heart rate, or extreme drowsiness.
• Antacids such as cimetidine or famotidine. Increased side effects can include decreased blood pressure, decreased heart rate, or extreme drowsiness.
• Oral contraceptives. Increased side effects can include decreased blood pressure, decreased heart rate, or extreme drowsiness.
• Acyclovir. Increased side effects can include decreased blood pressure, decreased heart rate, or extreme drowsiness.
• Ticlopidine. Increased side effects can include decreased blood pressure, decreased heart rate, or extreme drowsiness.

Using tizanidine with the following drugs can cause excessive sedation (drowsiness):

• benzodiazepines such as alprazolam, lorazepam, or diazepam.
• opioids such as morphine, methadone, or oxycodone.
• certain antidepressants such as amitriptyline, nortriptyline, or protriptyline.

Disclaimer: Our goal is to provide you with the most relevant and current information. However, because drugs interact differently in each person, we cannot guarantee that this information includes all possible interactions. This information is not a substitute for medical advice. Always speak with your healthcare professional about possible interactions with all prescription drugs, vitamins, herbs and supplements, and over-the-counter drugs that you are taking.

Tizanidine oral tablet comes with several warnings.

Allergy warning

Tizanidine can cause a severe allergic reaction. Symptoms can include:

• trouble breathing
• itching
• swelling of your throat or tongue

If you have an allergic reaction, call your doctor or local poison control center right away. If your symptoms are severe, call 911 or go to the nearest emergency room.

Don’t take this drug again if you’ve ever had an allergic reaction to it. Taking it again could be fatal (cause death).

Alcohol interaction warning

The use of drinks that contain alcohol increases the amount of tizanidine in your body. This can cause increased side effects from tizanidine.

Warnings for people with certain health conditions

For people with decreased liver function. Talk with your doctor about whether tizanidine is safe for you. If you take this drug, your doctor may give you a lower dose. Also, your doctor should check your liver function at the start of treatment. They may check it again 1 month after your maximum dose has been prescribed.

For people with decreased kidney function. Talk with your doctor about whether tizanidine is safe for you. If you take this drug, your doctor may give you a lower dose. Also, your doctor will watch for buildup of too much tizanidine in your body. Symptoms can include dry mouth, dizziness, or drowsiness.

Warnings for other groups

For pregnant women. Tizanidine is a category C pregnancy drug. That means two things:

1. Research in animals has shown adverse effects to the fetus when the mother takes the drug.
2. There haven’t been enough studies done in humans to be certain how the drug might affect the fetus.

Talk with your doctor if you’re pregnant or planning to become pregnant. This drug should only be used if the potential benefit justifies the potential risk to the fetus. Call your doctor if you become pregnant while taking this drug.

For women who are breastfeeding. It’s not known if tizanidine passes into breast milk and causes side effects in a child who is breastfed. Talk with your doctor if you breastfeed your child. You may need to decide whether to stop breastfeeding or stop taking this medication.

For seniors. The kidneys of older adults may not work as well as they used to. This can cause your body to process drugs more slowly. As a result, more of a drug stays in your body for a longer time. This raises your risk for side effects.

For children. This medication has not been studied in children. It should not be used in people younger than 18 years.

This dosage information is for tizanidine oral tablet. All possible dosages and drug forms may not be included here. Your dosage, drug form, and how often you take the drug will depend on:

• your age
• the condition being treated
• how severe your condition is
• other medical conditions you have
• how you react to the first dose

Forms and strengths

Generic: Tizanidine

• Form: oral tablet
• Strengths: 2 mg, 4 mg

Brand: Zanaflex

• Form: oral tablet
• Strengths: 4 mg

Dosage for muscle spasms

Adult dosage (ages 18 years and older)

• Typical starting dosage: 2 mg every 6–8 hours as needed.
• Dosage increases: Your doctor may increase your dosage by 2–4 mg until your symptoms are controlled. They will wait 1–4 days between any increases.
• Maximum dosage: 3 doses in 24 hours.

Child dosage (ages 0–17 years)

This medication has not been studied in children. It should not be used in people younger than 18 years.

Senior dosage (ages 65 years and older)

The kidneys of older adults may not work as well as they used to. This can cause your body to process drugs more slowly. As a result, more of a drug stays in your body for a longer time. This raises your risk for side effects. Your doctor may start you on a lowered dose or a different dosing schedule. This can help keep levels of this drug from building up too much in your body.

Disclaimer: Our goal is to provide you with the most relevant and current information. However, because drugs affect each person differently, we cannot guarantee that this list includes all possible dosages. This information is not a substitute for medical advice. Always speak with your doctor or pharmacist about dosages that are right for you.

Tizanidine oral tablet is used for long-term or short-term treatment. It comes with serious risks if you don’t take it as prescribed.

If you stop taking the drug suddenly or don’t take it at all: If you stop taking tizanidine suddenly, you are at risk for withdrawal symptoms. This risk is higher if you’ve been taking high doses of the drug or taking it for a long period of time.

Withdrawal symptoms can include high blood pressure, a fast heart rate, or worsened muscle spasms. If you decide to stop this drug, your doctor should slowly decrease your dosage by 2–4 mg per day.

If you don’t take this drug at all, your muscle spasms may not improve.

If you miss doses or don’t take the drug on schedule: Your medication may not work as well or may stop working completely. If you miss too many doses, you may have withdrawal symptoms.

If you take too much: You could have dangerous levels of the drug in your body. Symptoms of an overdose of this drug can include:

• extreme tiredness
• confusion
• coma
• decreased heart rate
• severe decrease in blood pressure
• slowed breathing

If you think you’ve taken too much of this drug, call your doctor or seek guidance from the American Association of Poison Control Centers at 800-222-1222 or through their online tool. But if your symptoms are severe, call 911 or go to the nearest emergency room right away.

What to do if you miss a dose: Take your dose as soon as you remember. But if you remember just a few hours before your next scheduled dose, take only one dose. Never try to catch up by taking two doses at once. This could result in dangerous side effects.

How to tell if the drug is working: You should have fewer symptoms of muscle spasms. These symptoms can include muscle tightness, pain, or stiffness.

Keep these considerations in mind if your doctor prescribes tizanidine oral tablet for you.

General

• You can take tizanidine with or without food. But you should be consistent. Take it the same way each time.
• You can cut or crush the tablet.

Storage

• Store tizanidine tablets at 77°F (25°C). You can store them for a short time at temperatures between 59°F and 86°F (15°C and 30°C).
• Don’t store this medication in moist or damp areas, such as bathrooms.

Refills

A prescription for this medication is refillable. You should not need a new prescription for this medication to be refilled. Your doctor will write the number of refills authorized on your prescription.

Travel

When traveling with your medication:

• Always carry your medication with you. When flying, never put it into a checked bag. Keep it in your carry-on bag.
• Don’t worry about airport X-ray machines. They can’t hurt your medication.
• You may need to show airport staff the pharmacy label for your medication. Always carry the original prescription-labeled container with you.
• Don’t put this medication in your car’s glove compartment or leave it in the car. Be sure to avoid doing this when the weather is very hot or very cold.

Clinical monitoring

You and your doctor should monitor certain health issues. This can help make sure you stay safe while you take tizanidine. These issues include:

• Kidney function. Blood tests can check how well your kidneys are working. If your kidneys aren’t working well, your doctor may lower your dosage of this drug.
• Liver function. Blood tests can check how well your liver is working. If your liver isn’t working well, your doctor may lower your dosage of this drug.
• Blood pressure. Your doctor may check your blood pressure to make sure that it does not get too low while you’re taking this drug.

Availability

Not every pharmacy stocks this drug. When filling your prescription, be sure to call ahead to make sure your pharmacy carries it.

Insurance

Many insurance companies require a prior authorization for this drug. This means your doctor may need to get approval from your insurance company before your insurance company will pay for the prescription.

There are other drugs available to treat your condition. Some may be better suited for you than others. Talk with your doctor about other drug options that may work for you.

Disclaimer: Healthline has made every effort to make certain that all information is factually correct, comprehensive, and up-to-date. However, this article should not be used as a substitute for the knowledge and expertise of a licensed healthcare professional. You should always consult your doctor or other healthcare professional before taking any medication. The drug information contained herein is subject to change and is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. The absence of warnings or other information for a given drug does not indicate that the drug or drug combination is safe, effective, or appropriate for all patients or all specific uses.

Tizanidine – description of the substance, pharmacology, use, contraindications, formula

Contents

• Structural formula

• Russian name

• English name

• Latin name

• chemical name

• Gross formula

• Pharmacological group of the substance Tizanidine

• Nosological classification

• CAS code

• pharmachologic effect

• Characteristic

• Pharmacology

• The use of the substance Tizanidin

• Contraindications

• Use during pregnancy and lactation

• Side effects of tizanidine

• Interaction

• Overdose

• Dosage and administration

• Precautionary measures

• Information sources

• Trade names with the active substance Tizanidine

Structural formula

Russian name

Tizanidin

English name

Tizanidine

Latin name

Tizanidinum ( born Tizanidini)

Chemical name

5-Chloro-N-(4,5-dihydro-1H-imidazole- 2-yl)-2,1,3-benzothiadiazol-4-amine (as hydrochloride)

Gross formula

C ₉ H ₈ ClN ₅ S

Pharmacological substance group Tizanidin

Alpha-agonists

Drugs affecting neuromuscular transmission

Nosological classification

ICD-10 code list

CAS code

51322-75-9

Pharmacological action

Pharmacological action –

muscle relaxant , central .

Characteristics

White or almost white crystalline powder, odorless or with a slight characteristic odor. Slightly soluble in water and methanol, solubility in water decreases with increasing pH.

Pharmacology

Excites alpha ₂ -adrenergic receptors, mainly at the level of the spinal cord; reduces the release of excitatory amino acids from the intermediate neurons of the spinal cord, selectively suppresses the polysynaptic mechanisms responsible for muscle hypertonicity. Relaxes skeletal muscles in chronic spastic conditions of spinal and cerebral origin, eliminates acute painful muscle spasms and clonic convulsions. Reduces muscle resistance during passive movements, increases the strength of voluntary muscle contractions.

After oral administration, it is rapidly and almost completely absorbed. Absolute bioavailability is approximately 40%. max “> C _max is achieved in 1-2 hours. Plasma protein binding is about 30%. Biotransformed in the liver with the participation of the CYP1A2 isoenzyme to inactive or inactive metabolites. Excreted by 70% in the urine. T _1/2 – 3-5 hours

Application of the substance Tizanidine

Painful muscle spasms in diseases of the spine (including osteochondrosis, spondylosis, syringomyelia, hemiplegia, cervical and lumbar syndromes), after surgery for a herniated disc or osteoarthritis of the hip, spasticity and pain caused by neurological diseases: multiple sclerosis, chronic myelopathy, degenerative diseases of the spinal cord, cerebrovascular accidents, stroke, traumatic brain injury, cerebral palsy, convulsions of central origin.

Contraindications

Hypersensitivity, severe liver and kidney failure, pregnancy, lactation, childhood.

Pregnancy and Lactation Use

FDA Fetal Category C.

Breastfeeding should be discontinued during treatment (it is unknown if tizanidine is excreted in breast milk).

Side effects of the substance Tizanidine

From the side of the nervous system and sensory organs: drowsiness, fatigue, dizziness or vertigo, muscle weakness, anxiety, sleep disturbances, hallucinations.

From the CCC and blood (hematopoiesis, hemostasis): slight decrease in blood pressure (at low doses) or arterial hypertension, bradycardia.

From the gastrointestinal tract: dry mouth, nausea, gastrointestinal disorders, temporary increase in serum transaminase activity.

Interactions

Antihypertensive drugs, including diuretics, increase hypotension and bradycardia. Alcohol and sedatives deepen the depressive effect.

Overdose

Symptoms: nausea, vomiting, lowering blood pressure, dizziness, miosis, respiratory failure, coma.

Treatment: gastric lavage, activated charcoal, forced diuresis, maintenance of vital functions.

Dosage and administration

Inside. Dosing regimen should be selected individually. Tizanidine has a narrow therapeutic index and high variability in plasma levels of tizanidine in patients, so careful dose selection is required. Initial dose – 2-4 mg 3 times a day, in severe cases – an additional 2-4 mg at night. In case of neurologically caused spastic conditions, the initial dose should not exceed 6 mg per day in 3 doses with a gradual increase by 2-4 mg at intervals of 3-4 days – up to a week. The optimal therapeutic effect is usually achieved at a dose of 12-24 mg / day in 3-4 doses at regular intervals. Do not exceed a dose of 36 mg / day.

Precautions

Periodic monitoring of liver and kidney function is necessary and dose reduction if they worsen. A continuous increase in the activity of transaminases in the blood requires discontinuation. Due to possible drowsiness and weakness, it is recommended to limit the appointment to persons whose work requires a quick physical and mental reaction (operators, drivers of vehicles, etc. ).

Generalized materials www.grls.rosminzdrav.ru, 2014–2016.

Trade names with the active ingredient Tizanidine

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Dosage
All dosages 2 mg 250-1000 g 4 mg 6 mg No dosage

Manufacturer
All manufacturers Avexima Sibir LLC Berezovsky Pharmaceutical Plant CJSC (CJSC “BFZ”) Veropharm JSC Veropharm JSC J.P.En. Pharma Pvt. Irbit Chemical and Pharmaceutical Plant Novartis Neva OJSC Novartis Saglik LLC Gida ve Tarim Yuryunleri Sanayi ve Ticaret A.S. Novartis Pharmaceutical Ozone LLC Sun Pharmaceutical Industries Ltd. North Star NAO Simpeks Pharma Teva Pharmaceutical Plant JSC Teva Pharmaceutical Plant Private Co. Ltd Farmak

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Sirdalud: instruction, price, analogues | Sandoz tablets

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• Pharmacological properties
• Indications Sirdalud
• Application Sirdalud
• Contraindications
• Side effects
• Special instructions
• Interactions
• Overdose
• Storage conditions
• Diagnosis
• Recommended alternatives
• Trade names

pharmacodynamics. Tizanidine is a centrally acting skeletal muscle relaxant. The main point of application of its influence is the spinal cord. By stimulating presynaptic α ₂ -adrenergic receptors, it inhibits the release of amino acids that stimulate N-methyl-D-aspartate receptors (NMDA receptors). As a result, polysynaptic signal transmission at the level of interneuronal connections in the spinal cord, which is responsible for excessive muscle tone, is suppressed, and muscle tone decreases. Sirdalud is effective both in acute painful muscle spasms and in chronic spasticity of spinal and cerebral origin. It reduces resistance to passive movement and suppresses spasm and clonic convulsions and improves the strength of active muscle contractions.

Pharmacokinetics

Suction and distribution . Tizanidine is rapidly absorbed. C _max in plasma is reached approximately 1 hour after application. The mean absolute bioavailability is 34% (CV 38%). The mean volume of distribution at steady state (Vss) after IV administration is 160 L. Plasma protein binding – 30%. Relatively low deviation of pharmacokinetic parameters among patients (C _max and AUC) facilitates a reliable preliminary assessment of plasma levels after oral administration.

Metabolism/excretion . The drug undergoes rapid and extensive metabolism in the liver. Tizanidine is metabolized in vitro predominantly by CYP 1A2. Metabolites are inactive. They are excreted mainly by the kidneys (70%). Elimination of total radioactivity (i.e., unchanged substance and metabolites) is biphasic, with a rapid initial phase (T _½ – 2. 5 hours) and a slower elimination phase (T _½ – 22 hours). Only a small amount of the substance in unchanged form (about 2.7%) is excreted by the kidneys. The average T _½ of the unchanged substance is 2-4 hours.

Linearity . The pharmacokinetics of tizanidine is linear at doses of 1 to 20 mg.

Pharmacokinetics in selected groups of patients . In patients with renal insufficiency (creatinine clearance <25 ml / min), the average value of C _max in blood plasma is twice that in healthy volunteers, and the final T _½ increases to approximately 14 hours, resulting in an average 6-fold increase in AUC.

Not studied in patients with hepatic impairment.

Tizanidine is metabolized by the CYP 1A2 isoenzyme in the liver. In patients with impaired liver function, higher plasma concentrations of the substance may occur.

Sirdalud is contraindicated in persons with severe hepatic impairment.

Pharmacokinetic data in elderly patients are limited.

Gender does not affect the pharmacokinetic properties of tizanidine.

The effect of ethnicity and race on the pharmacokinetics of tizanidine has not been studied.

The influence of food . Simultaneous food intake does not affect the pharmacokinetic profile of Sirdalud tablets. Although the value of C _max increases by a third, this is not clinically significant. There was no significant effect on absorption.

painful muscle spasm. Spasticity due to multiple sclerosis. Spasticity due to spinal cord injury. Spasticity due to brain damage.

Sirdalud has a narrow therapeutic window and high variability in plasma levels of tizanidine in different patients. Therefore, it is important to use it in optimal doses according to the needs of the patient. Treatment should be started with a low dose of 2 mg, which makes the risk of adverse effects from taking the drug minimal. If necessary, the dose of the drug can be gradually increased in compliance with all required precautions.

Adults

Relief of painful muscle spasms . Apply 2-4 mg 3 times a day. In severe cases, an additional dose of 2 or 4 mg may be taken at bedtime.

Spasticity in neurological disorders . The dose should be selected individually for each patient.

The initial daily dose should not exceed 6 mg divided into 3 divided doses. It can be increased gradually to 2-4 mg 2 times at intervals of 3-7 days. Usually the optimal therapeutic effect is achieved with a daily dose of 12-24 mg, divided into 3 or 4 doses. Do not exceed a total daily dose of 36 mg.

Special patient populations

Use in children and adolescents . The experience of using Sirdalud in children and adolescents is limited, therefore it is not recommended for use in this category of patients.

Use in the elderly . The experience of using the drug in elderly patients is limited, so care should be taken when using the drug Sirdalud in this category of patients. It is recommended to start treatment with a minimum dose and gradually, with caution, increase it in “small steps” until an optimal ratio of individual tolerability and therapeutic efficacy of the drug is reached.

Use in patients with impaired renal function . For patients with impaired renal function (creatinine clearance <25 ml / min), the recommended initial single daily therapeutic dose is 2 mg. Increasing the dose occurs gradually and with caution, "small steps", until the optimal ratio of individual tolerability and therapeutic efficacy of the drug is reached. In order to increase therapeutic efficacy, you should first increase the single dose before moving on to more frequent use of the drug during the day.

Use in patients with hepatic impairment . Treatment of persons with severely impaired liver function is contraindicated. Sirdalud is largely metabolized in the liver. There are limited data on the use of the drug Sirdalud in patients with impaired liver function (see Pharmacokinetics ). The use of the drug Sirdalud is associated with reversible abnormalities in liver function tests (see SPECIAL INSTRUCTIONS and SIDE EFFECTS). Sirdalud should be used with caution in the treatment of patients with moderate hepatic impairment. Treatment is required to start with a minimum dose, a possible increase in dose should be carried out with caution and taking into account the individual patient tolerance of the drug Sirdalud.

Treatment interruption . If it is necessary to interrupt treatment, the dose should be reduced slowly and gradually. This is especially true for patients who have used the drug at an increased dose for a long time. Thus, the risk of developing a rebound increase in blood pressure and tachycardia is reduced.

hypersensitivity to tizanidine or any other component of the drug. Severe liver dysfunction. Co-administration of tizanidine with potent CYP1A2 inhibitors such as fluvoxamine or ciprofloxacin.

Adverse reactions – such as drowsiness, fatigue, dizziness, dry mouth, decreased blood pressure, nausea, gastrointestinal disturbances and elevated plasma transaminase levels – are usually mild and transient in patients using the drug at low doses, recommended to relieve painful muscle spasm.

When taken at higher than recommended doses to relieve spasticity, the above adverse reactions occur more frequently and are more severe, but are rarely severe enough to warrant discontinuation of treatment. The following adverse reactions may also occur: arterial hypotension, bradycardia, muscle weakness, sleep disturbance, hallucinations and hepatitis.

The occurrence of such symptoms has been reported after abrupt discontinuation of tizanidine, especially after long-term treatment and/or high daily doses and/or concomitant therapy with antihypertensive drugs. Under such circumstances, patients may develop hypertension and tachycardia. In some cases, such rebound hypertension can cause a stroke. Therefore, treatment with tizanidine should not be stopped abruptly, but only by gradual dose reduction (see SPECIAL INDICATIONS and INTERACTIONS).

To assess the frequency of occurrence of various adverse reactions, the following classification was used: very often (≥1/10), often (≥1/100, <1/10), infrequently (≥1/1000, <1/100), rarely ( ≥1/10,000, <1/1000), very rare (<1/10,000), including isolated reports.

Mental disorders: often – insomnia, sleep disturbance.

From the side of the central nervous system: very often – drowsiness, weakness, dizziness.

From the side of the heart: infrequently – bradycardia

From the vascular system: often – hypertension, a slight decrease in blood pressure.

From the digestive tract: very often – dry mouth, gastrointestinal disorders; often nausea.

Hepatobiliary disorders: often – elevated plasma transaminase levels.

From the musculoskeletal system: very often – muscle weakness.

General disorders: very common – fatigue.

Post-marketing studies

Additional adverse drug reactions have been reported in post-marketing studies.

These adverse reactions have been reported in an indefinite number of patients, so it is not possible to reliably estimate their frequency.

From the immune system: hypersensitivity reactions (including anaphylaxis, angioedema, dyspnea and urticaria).

Mental disorders: hallucinations, confusion.

From the side of the central nervous system: vertigo.

From the side of the cardiovascular system: syncope.

On the part of the organ of vision: blurred vision.

Hepatobiliary disorders: hepatitis, liver failure.

Skin and subcutaneous tissue disorders: rash, erythema, pruritus, dermatitis.

General disorders: asthenia, withdrawal syndrome.

Co-administration of moderate CYP1A2 inhibitors with tizanidine is not recommended (see INTERACTIONS AND CONTRAINDICATIONS).

After sudden discontinuation of the drug, especially after prolonged use or rapid dose reduction and / or the use of high daily doses and / or with the simultaneous use of antihypertensive drugs, patients may experience a rebound phenomenon. Under such circumstances, patients may develop hypertension and tachycardia. In some cases, such rebound hypertension can cause a stroke. Tizanidine treatment should not be discontinued abruptly, but only by gradual dose reduction (see INTERACTIONS and SIDE EFFECTS).

In patients with renal insufficiency (creatinine clearance <25 ml/min), systemic exposure to tizanidine may be up to 6 times higher, so the recommended starting dose is 2 mg once daily (see APPLICATIONS). The dose should be increased sequentially based on efficacy and tolerability. To achieve a more pronounced effect, it is recommended to first increase the dose, which is used once a day, and then increase the frequency of administration.

Tizanidine-associated hepatic impairment has been reported, but rarely in patients receiving daily doses up to 12 mg. In this regard, it is recommended to monitor liver function once a month during the first 4 months of therapy in those patients who use tizanidine at a dose of 12 mg or higher and in patients with clinical symptoms suggestive of liver failure (such as nausea, loss of appetite or increased fatigue of unknown etiology). The use of the drug Sirdalud should be discontinued if the level of ALT or AST in the blood serum exceeds the upper limit of the norm by 3 times or more for a long period.

Hypersensitivity reactions including anaphylaxis, angioedema, dyspnea, dermatitis, rash, urticaria, pruritus and erythema have been reported with tizanidine. Careful monitoring of the condition of patients is recommended for 1 or 2 days after taking the first dose of tizanidine. In case of development of anaphylaxis or angioedema with anaphylactic shock or shortness of breath, the use of Sirdalud should be stopped immediately and the patient should be prescribed the necessary treatment.

Arterial hypotension may occur with the use of tizanidine, as well as as a result of drug interactions with CYP 1A2 inhibitors and / or antihypertensive drugs (see INTERACTIONS and SIDE EFFECTS). Severe manifestations of arterial hypotension, such as loss of consciousness and circulatory collapse, have been reported.

Caution should be exercised when using this drug concomitantly with agents that prolong the QT interval (such as cisapride, amitriptyline, azithromycin) (see Interactions).

Caution required in patients with CAD and/or heart failure. ECG monitoring should be carried out regularly at the beginning of the use of the drug Sirdalud in such patients. Before using this drug in patients with myasthenia gravis, the risk/benefit ratio should be carefully evaluated.

Experience in children and adolescents is limited, so the use of the drug Sirdalud is not recommended in this category of patients.

Caution should be exercised when using the drug in elderly patients.

Sirdalud tablets contain lactose. Patients with rare hereditary diseases – galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption syndrome – Sirdalud tablets are not recommended.

Use during pregnancy or lactation. Women of reproductive age who are sexually active should have a pregnancy test before starting treatment with Sirdalud.

Women of reproductive age should be advised that animal studies indicate that Sirdalud is harmful to the fetus. Women of reproductive age who are sexually active should use effective contraceptive methods (methods that allow pregnancy in less than 1% of cases) during the entire period of treatment with Sirdalud and within one day after stopping treatment with Sirdalud.

Pregnancy . Data on the use of the drug Sirdalud in pregnant women are limited, so it should not be prescribed during pregnancy, except in cases where the potential benefit to the mother outweighs the possible risk to the fetus. Sirdalud is not teratogenic in rats and rabbits, but causes obstructed labor, increased prenatal and postnatal mortality, and fetal growth retardation in rats.

Breastfeeding . When using tizanidine in rats and rabbits, no teratogenic effect was detected. Consideration should be given to the risk to the child who is being breastfed. Animal studies have shown that tizanidine passes into breast milk in small quantities. Therefore, women who are breastfeeding should not be prescribed the drug.

Fertility . There was no violation of fertility in male rats, which used the drug at a dose of 10 mg/kg/day, and in female rats, which used the drug at a dose of 3 mg/kg/day. Reduced fertility was observed in male rats treated with the drug at a dose of 30 mg/kg/day, and in female rats treated with the drug at a dose of 10 mg/kg/day. Sedation, weight loss and ataxia have also been reported at these doses.

The ability to influence the reaction rate when driving vehicles or operating other mechanisms . Even when prescribed as directed, tizanidine may cause drowsiness, dizziness and/or hypotension, thus impairing the patient’s ability to drive and use machines. The risks increase with the simultaneous use of alcohol. Therefore, you should refrain from activities that require a high concentration of attention and quick reaction, such as driving vehicles or working with other mechanisms.

Children . Experience with the use of the drug in pediatrics is limited. It is not recommended to prescribe Sirdalud to children.

Concomitant use of known inhibitors of CYP 1A2 may increase plasma levels of tizanidine. An increase in plasma levels of tizanidine can lead to symptoms of overdose, such as prolongation of the Q-T interval .

Co-administration of known CYP 1A2 inducers may reduce plasma levels of tizanidine. A decrease in the level of tizanidine in the blood plasma can lead to a decrease in the therapeutic effect of Sirdalud.

Co-administration of strong CYP1A2 inhibitors such as fluvoxamine or ciprofloxacin with tizanidine is contraindicated. The simultaneous use of tizanidine with fluvoxamine increases the AUC of tizanidine by 33 times, while the simultaneous use of tizanidine with ciprofloxacin increases the AUC of tizanidine by 10 times. This can lead to a clinically significant and long-term decrease in blood pressure, accompanied by drowsiness, dizziness, and reduced psychomotor performance.

Co-administration of tizanidine with other CYP1A2 inhibitors such as antiarrhythmic drugs (amiodarone, mexiletine, propafenone), cimetidine, certain fluoroquinolones (enoxacin, pefloxacin, norfloxacin), rofecoxib, oral contraceptives and ticlopidine is not recommended.

Elevated plasma levels of tizanidine may cause symptoms of overdose, including prolongation of the Q-T interval .

Simultaneous use of the drug Sirdalud with antihypertensive drugs, including diuretics, can sometimes cause arterial hypotension and bradycardia. In some patients who used concomitant treatment with antihypertensive drugs, rebound hypertension and rebound tachycardia were noted with abrupt withdrawal of tizanidine. In some cases, rebound hypertension can cause a stroke (See SPECIAL INDICATIONS and SIDE EFFECTS).

Caution should be exercised when using the drug Sirdalud with drugs that prolong the interval QT .

Co-administration of Sirdalud with rifampicin may result in a 50% reduction in tizanidine concentrations. Thus, the therapeutic effect may be reduced when using rifampicin during therapy with Sirdalud, which may be clinically significant for some patients. Long-term simultaneous use should be avoided, and if necessary, the dose must be adjusted very carefully. Careful dose adjustment (increase) is necessary in case of planned long-term combined treatment.

The use of the drug Sirdalud leads to a 30% reduction in the systemic exposure of tizanidine in smokers (more than 10 cigarettes per day). Long-term use of the drug in patients who smoke a lot requires the use of the drug in higher doses.

Simultaneous use of Sirdalud and other centrally acting drugs (for example, sedatives and hypnotics (benzodiazepine or baclofen), some antihistamines, general anesthetics and analgesics, psychotropic drugs, narcotic drugs) may increase the severity of the effects of each of the drugs and increase the hypnotic effect Sirdaluda. This applies, in particular, to the simultaneous use of alcohol, which can unpredictably change or enhance the effect of Sirdalud and increase the risk of adverse reactions, so you should refrain from drinking alcohol. The inhibitory effect of alcohol on the central nervous system may be enhanced by the drug Sirdalud.

The use of the drug Sirdalud simultaneously with α ₂ -adrenergic agonists (eg clonidine) should be avoided due to their potential additive hypotensive effect.

Very few reports of overdose of Sirdalud have been received. In all patients who have recorded isolated cases of an overdose of this drug, including 1 patient who took 400 mg of Sirdalud, recovery was uneventful.

Symptoms: nausea, vomiting, arterial hypotension, bradycardia, prolongation of the QT interval , dizziness, miosis, respiratory distress, coma, restlessness, drowsiness.

Treatment. To remove the drug from the body, repeated use of activated charcoal in high doses is recommended. Forced diuresis may accelerate the elimination of the drug. In the future, symptomatic treatment should be carried out.

at a temperature not exceeding 25 °C, out of the reach of children.

4-45-ANP-REC-0721

Information for healthcare professionals.

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