Tizanidine

M03B - Muscle relaxants, centrally acting agents ATC M03BX02 Small molecule approved 1996 Oral Natural product

JFDA label: SIRDALUD Tab

Mechanism of Action

An alpha2-adrenergic agonist agent which decreases spasticity by increasing presynaptic inhibition; effects are greatest on polysynaptic pathways; overall effect is to reduce facilitation of spinal motor neurons.

Indications

Approved

Muscle spasticity

Off-label

Acute low back pain
Spasticity associated with cerebral palsy

Contraindications

Source: Lexicomp

Concomitant therapy with ciprofloxacin or fluvoxamine (potent CYP1A2 inhibitors) Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (2)

Very Common Hypotension

Common Bradycardia

Nervous system disorders (10)

Very Common dizziness · Drowsiness

Common anxiety · delusions · depression · myasthenia · Nervousness · paresthesia · speech disturbance · visual hallucination

Hepatobiliary disorders (1)

Common Increased liver enzymes

Renal and urinary disorders (2)

Common urinary frequency · Urinary tract infection

Gastrointestinal disorders (6)

Very Common Xerostomia

Common abdominal pain · Constipation · diarrhea · dyspepsia · vomiting

Skin and subcutaneous tissue disorders (3)

Common Dermal ulcer · diaphoresis · skin rash

Musculoskeletal and connective tissue disorders (3)

Very Common Weakness

Common back pain · Dyskinesia

Eye disorders (1)

Common Blurred vision

Infections and infestations (1)

Common Infection

General disorders and administration site conditions (1)

Common Fever

Respiratory, thoracic and mediastinal disorders (3)

Common Flu-like symptoms · pharyngitis · rhinitis

Dosing

Source: Lexicomp

Spasticity: Oral: Initial: 2 mg up to 3 times daily (at 6- to 8-hour intervals) as needed; may titrate to optimal effect in 2-4 mg increments per dose (with a minimum of 1-4 days between dose increases); maximum: 36 mg daily. Note: Single doses >16 mg have not been studied. Discontinuation of therapy: Gradually taper dose by 2-4 mg daily.

(For additional information see "Tizanidine: Pediatric drug information") Spasticity associated with cerebral palsy: Limited data available (Dai 2008; Dai 2016; Kliegman 2016; Patel 2005): Dosing based on small open label trials and clinical experience; tizanidine was used in combination with adjunct botulinum toxin therapy Initial dose: Children 2 to Children ≥10 years and Adolescents: Oral: 2 mg at bedtime, titrate as needed Titration and maintenance dose: Children ≥2 years and Adolescents: Oral: Titrate initial dose upward to reported effective range of: 0.3 to 0.5 mg/kg/day in 3 to 4 divided doses; maximum daily dose: 24 mg/day. Discontinuation of therapy: Refer to adult dosing

Use with caution; clearance is decreased. Refer to adult dosing.

CrCl ≥25 mL/minute: No dosage adjustment provided in manufacturer’s labeling; however, caution may be needed as creatinine clearance decreases. CrCl 50%. During initial dose titration, use reduced doses. If higher doses are necessary, increase dose instead of increasing dosing frequency.

Avoid use in hepatic impairment; if used, reduce dose during initial dose titration. If higher doses are necessary, increase dose instead of increasing dosing frequency. Monitor aminotransferases.

Warnings & Precautions

Source: Lexicomp

Hepatic effects

Potential for hepatotoxicity; monitor aminotransferases prior to and during use or if hepatic injury is suspected.

Hypersensitivity reactions

Hypersensitivity reactions, including anaphylaxis, angioedema, respiratory compromise, and urticaria have been reported with use. Patients with signs and symptoms of allergic reactions should discontinue therapy.

Hypotension

Significant hypotension and syncope may occur; use with caution in patients at risk for severe hypotensive effects (eg, patients taking concurrent medications which may predispose to hypotension). Minimize effects by titrating dose and monitoring for signs and symptoms of hypotension prior to dose increase.

Sedation

Sedation may occur; use with caution in patients at risk for sedative effects (eg, patients taking concurrent CNS depressants); patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

Visual hallucinations

Use has been associated with visual hallucinations or delusions; use caution in patients with psychiatric disorders. Consider discontinuation of therapy if hallucinations occur. Disease-related concerns:

Hepatic impairment

Use not recommended in patients with hepatic impairment; potential for effects likely due to extensive hepatic metabolism of tizanidine.

Renal impairment

Use with caution in patients with renal impairment. Clearance decreased significantly in patients with severe impairment (CrCl Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Sedatives

Effects with other sedative drugs or ethanol may be potentiated. Special populations:

Elderly

Use with caution; clearance decreased fourfold in the elderly; may increase risk of adverse effects and/or duration of effects. Elderly with severe renal impairment (CrCl 50% compared to healthy elderly subjects. Other warnings/precautions:

Abrupt withdrawal

Withdrawal resulting in rebound hypertension, tachycardia, and hypertonia may occur upon discontinuation; doses should be decreased slowly, particularly in patients taking concomitant opioids or receiving high doses (20-28 mg daily) for prolonged periods (≥9 weeks).

Food

Food alters absorption profile relative to administration under fasting conditions. In addition, bioequivalence between capsules and tablets is altered by food; capsules and tablets are bioequivalent under fasting conditions, but not under nonfasting conditions.

Pregnancy & Lactation

Pregnancy

FDA category C

Adverse events were observed in some animal reproduction studies.

Lactation

Excretion in breast milk is unknown, but expected due to lipid solubility.

LactMed: monitor the infant.

Monitoring

Clinical pearl	Monitor liver function (aminotransferases) at baseline and 1 month after maximum dose achieved or if hepatic injury suspected; blood pressure; renal function

Chemistry & Properties

Formula	C9H8ClN5S
Molecular weight	253.72 g/mol
IUPAC name	5-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-2,1,3-benzothiadiazol-4-amine
CAS	51322-75-9
PubChem CID	5487
InChIKey	`XFYDIVBRZNQMJC-UHFFFAOYSA-N`
logP	1.72 (XLogP 1.1)
Polar surface area	62.2 Å²
H-bond acceptors / donors	6 / 2
Drug-likeness (QED)	0.81
Lipinski violations	0

SMILES

Clc1ccc2nsnc2c1NC1=NCCN1

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	Yes

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—
CYP2C19	Substrate	—
CYP2D6	Inhibitor	—
CYP2D6	Substrate	—
CYP3A4	Substrate	—

Receptor binding (top 7)

Target	Action	Affinity
α2B-adrenoceptor (ADRA2B)	Agonist	pIC50 7.8
α2A-adrenoceptor (ADRA2A)	Agonist	pIC50 7.6
Nischarin (NISCH)	Binding	pKi 7.5
α2B-adrenoceptor (ADRA2B)	Agonist	pEC50 7.0
α2A-adrenoceptor (ADRA2A)	Agonist	pKi 6.0
α2A-adrenoceptor (ADRA2A)	Agonist	pEC50 5.8
α2B-adrenoceptor (ADRA2B)	Agonist	pKi 5.8

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Acyclovir	major
Aldesleukin	major
Amyl Nitrite	major
Anagrelide	major
Arsenic trioxide	major
Cabozantinib	major
Caffeine	major
Ceritinib	major
Chloroquine	major
Cimetidine	major
Cisapride	major
Codeine	major
Crizotinib	major
Deferasirox	major
Diazoxide	major
Dolasetron	major
Epoprostenol	major
Ethinylestradiol	major
Famotidine	major
Fingolimod	major
Halofantrine	major
Hydrocodone	major
Hydroxychloroquine	major
Iloprost	major
Interferon alfa-2b	major
Ivosidenib	major
Leflunomide	major
Lumefantrine	major
Macimorelin	major
Methoxsalen	major
Minoxidil	major
Morphine	major
Morphine (liposomal)	major
Niclosamide	major
Nilotinib	major
Obeticholic acid	major
Osilodrostat	major
Ozanimod	major
Panobinostat	major
Papaverine	major

Showing 40 of 100+.

Registered Products (4)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Relezin	Tablet 2 mg	30 tab	UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN	1.750
SIRDALUD Tab	Tablet 2 mg	30 tab	Nabulsi Drug Store	2.130
Relezin	Tablet 4 mg	30 tab	UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN	4.350
SIRDALUD Tab	Tablet 4 mg	30 tab	Nabulsi Drug Store	7.300