TIZANIDINE Drug Interactions: What You Need to Know

DRUG INTERACTIONS SECTION Fluvoxamine The effect of fluvoxamine on the pharmacokinetics of tizanidine was studied in 10 healthy subjects.

The

Cmax, AUC, and half-life of tizanidine increased by 12-fold, 33-fold, and 3-fold, respectively. These changes resulted in significant decreases in blood pressure, increased drowsiness, and psychomotor impairment. (See CONTRAINDICATIONS and WARNINGS ).

Ciprofloxacin

The effect of ciprofloxacin on the pharmacokinetics of tizanidine was studied in 10 healthy subjects.

The

Cmax and AUC of tizanidine increased by 7-fold and 10-fold, respectively. These changes resulted in significant decreases in blood pressure, increased drowsiness, and psychomotor impairment. (See CONTRAINDICATIONS and WARNINGS ). CYP1A2 Inhibitors The interaction between tizanidine and either fluvoxamine or ciprofloxacin is most likely due to inhibition of CYP1A2 by fluvoxamine or ciprofloxacin. Although there have been no clinical studies evaluating the effects of other CYP1A2 inhibitors on tizanidine, other CYP1A2 inhibitors, such as zileuton, other fluoroquinolones, antiarrythmics (amiodarone, mexiletine, propafenone and verapamil), cimetidine, famotidine oral contraceptives, acyclovir and ticlopidine, may also lead to substantial increases in tizanidine blood concentrations. (See WARNINGS )

Oral

Contraceptives No specific pharmacokinetic study was conducted to investigate interaction between oral contraceptives and tizanidine. Retrospective analysis of population pharmacokinetic data following single and multiple dose administration of 4 mg tizanidine, however, showed that women concurrently taking oral contraceptives had 50% lower clearance of tizanidine compared to women not on oral contraceptives (see PRECAUTIONS ).

Drug

Interactions In vitro studies of cytochrome P450 isoenzymes using human liver microsomes indicate that neither tizanidine nor the major metabolites are likely to affect the metabolism of other drugs metabolized by cytochrome P450 isoenzymes.

Fluvoxamine

The effect of fluvoxamine on the pharmacokinetics of a single 4 mg dose of tizanidine was studied in 10 healthy subjects.

The

Cmax, AUC, and half-life of tizanidine increased by 12-fold, 33-fold, and 3-fold, respectively. These changes resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment. (See CONTRAINDICATIONS and WARNINGS ).

Ciprofloxacin

The effect of ciprofloxacin on the pharmacokinetics of a single 4 mg dose of tizanidine was studied in 10 healthy subjects.

The

Cmax and AUC of tizanidine increased by 7-fold and 10-fold, respectively. These changes resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment. (See CONTRAINDICATIONS and WARNINGS ). CYP1A2 inhibitors The interaction between tizanidine and either fluvoxamine or ciprofloxacin is most likely due to inhibition of CYP1A2 by fluvoxamine or ciprofloxacin. Although there have been no clinical studies evaluating the effects of other CYP1A2 inhibitors on tizanidine, other CYP1A2 inhibitors, including zileuton, other fluroquinolones, antiarrythmics (amiodarone, mexiletine, propafenone, and verapamil), cimetidine and famotidine, oral contraceptives, acyclovir, and ticlopidine may also lead to substantial increases in tizanidine blood concentrations. Concomitant use of tizanidine with CYP1A2 inhibitors should ordinarily be avoided. If their use is clinically necessary, they should be used with caution (see WARNINGS ).

Acetaminophen

Tizanidine delayed the Tmax of acetaminophen by 16 minutes. Acetaminophen did not affect the pharmacokinetics of tizanidine.

Alcohol

Alcohol increased the AUC of tizanidine by approximately 20%, while also increasing its Cmax by approximately 15%. This was associated with an increase in side effects of tizanidine. The CNS depressant effects of tizanidine and alcohol are additive.

Oral

Contraceptives No specific pharmacokinetic study was conducted to investigate interaction between oral contraceptives and tizanidine, but retrospective analysis of population pharmacokinetic data following single and multiple dose administration of 4 mg tizanidine showed that women concurrently taking oral contraceptives had 50% lower clearance of tizanidine that women not on oral contraceptives.

CONTRAINDICATIONS Concomitant use of tizanidine with fluvoxamine or with ciprofloxacin, potent inhibitors of CYP1A2, is contraindicated. Significant alterations of pharmacokinetic parameters of tizanidine including increased AUC, t1/2, C max , increased oral bioavailability and decreased plasma clearance have been observed with concomitant administration of either fluvoxamine or ciprofloxacin. This pharmacokinetic interaction can result in potentially serious adverse events (See WARNINGS and CLINICAL PHARMACOLOGY: Drug Interactions). Tizanidine tablets is contraindicated in patients with known hypersensitivity to Tizanidine tablets or its ingredients.

AND PRECAUTIONS

5.1 Hypotension Tizanidine is an α 2 -adrenergic agonist that can produce hypotension. Syncope has been reported in the post marketing setting. The chance of significant hypotension may possibly be minimized by titration of the dose and by focusing attention on signs and symptoms of hypotension prior to dose advancement. In addition, patients moving from a supine to fixed upright position may be at increased risk for hypotension and orthostatic effects. Monitor for hypotension when Tizanidine Tablets, USP is used in patients receiving concurrent antihypertensive therapy. It is not recommended that Tizanidine Tablets, USP be used with other α 2 -adrenergic agonists. Clinically significant hypotension (decreases in both systolic and diastolic pressure) has been reported with concomitant administration of either fluvoxamine or ciprofloxacin and single doses of 4 mg of Tizanidine Tablets, USP. Therefore, concomitant use of Tizanidine Tablets, USP with fluvoxamine or with ciprofloxacin, potent inhibitors of CYP1A2, is contraindicated [ see Contraindications (4) andDrug Interactions ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. ) ].

5.2 Risk of Liver Injury Tizanidine Tablets, USP may cause hepatocellular liver injury.

Tizanidine

Tablets, USP 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. [ see Dosage and Administration ( Error! Hyperlink reference not valid. ) and Use in Specific Populations ( 8.7 ) ]

5.3 Sedation Tizanidine Tablets, USP can cause sedation, which may interfere with everyday activity. In the multiple dose studies, the prevalence of patients with sedation peaked following the first week of titration and then remained stable for the duration of the maintenance phase of the study. The CNS depressant effects of Tizanidine Tablets, USP with alcohol and other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive. Monitor patients who take Tizanidine Tablets, USP with another CNS depressant for symptoms of excess sedation. [ see Drug Interactions ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. ) ]

5.4 Hallucinosis/Psychotic-Like Symptoms Tizanidine Tablets, USP use has been associated with hallucinations. Formed, visual hallucinations or delusions have been reported in 5 of 170 patients (3%) in two North American controlled clinical studies. Most of the patients were aware that the events were unreal. One patient developed psychosis in association with the hallucinations. One patient among these 5 continued to have problems for at least 2 weeks following discontinuation of tizanidine. Consider discontinuing Tizanidine Tablets, USP in patients who develop hallucinations.

5.5 Interaction with CYP1A2 Inhibitors Because of potential drug interactions, Tizanidine Tablets, USP is contraindicated in patients taking potent CYP1A2 inhibitors, such as fluvoxamine or ciprofloxacin. Adverse reactions such as hypotension, bradycardia, or excessive drowsiness can occur when Tizanidine Tablets, USP is taken with other CYP1A2 inhibitors, such as zileuton, fluoroquinolones other than ciprofloxacin (which is contraindicated), antiarrythmics (amiodarone, mexiletine, propafenone), cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine). Concomitant use should be avoided unless the necessity for Tizanidine Tablets, USP therapy is clinically evident. In such a case, use with caution. [ see Drug Interactions ( Error! Hyperlink reference not valid. ) and Clinical Pharmacology ( 12.3 ) ]

5.6 Hypersensitivity Reactions Tizanidine Tablets, USP can cause anaphylaxis. Signs and symptoms including respiratory compromise, urticaria, and angioedema of the throat and tongue have been reported. Patients should be informed of the signs and symptoms of severe allergic reactions and instructed to discontinue Tizanidine Tablets, USP and seek immediate medical care should these signs and symptoms occur. [ see Contraindications (4) ]

5.7 Increased Risk of Adverse Reactions in Patients with Renal Impairment Tizanidine Tablets, USP 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. [ see Dosage and Administration ( Error! Hyperlink reference not valid. ) and Use in Specific Populations ( 8.6 ) ]

5.8 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). <span class="opacity-50 text-xs">[see Dosage and Administration ( Error! Hyperlink reference not valid. )]</span>

• Hypotension: monitor for signs and symptoms of hypotension, in particular in patients receiving concurrent antihypertensives; Tizanidine Tablets, USP should not be used with other α 2 -adrenergic agonists ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. )
• Risk of liver injury: monitor ALTs; discontinue Tizanidine Tablets, USP if liver injury occurs ( Error! Hyperlink reference not valid. )
• Sedation: Tizanidine Tablets, USP may interfere with everyday activities; sedative effects of Tizanidine Tablets, USP, alcohol, and other CNS depressants are additive ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. )
• Hallucinations: consider discontinuation of Tizanidine Tablets, USP ( Error! Hyperlink reference not valid. )
• Less potent inhibitors of CYP1A2: may cause hypotension, bradycardia, or excessive drowsiness, use caution if Tizanidine Tablets, USP is used with less potent inhibitors of CYP1A2, e.g., zileuton, other fluoroquinolones, antiarrythmics, cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. , 12.3 )
• Renal impairment (creatinine clearance < 25 mL/min): use Tizanidine Tablets, USP with caution, and monitor closely for dry mouth, somnolence, asthenia and dizziness as indicators of potential overdose ( Error! Hyperlink reference not valid. )