Tizanidine (Page 5 of 5)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, mutagenesis, impairment of fertility

Carcinogenesis

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

Mutagenesis

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

Impairment of fertility

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

14 CLINICAL STUDIES

Tizanidine’s capacity to reduce increased muscle tone associated with spasticity was demonstrated in two adequate and well controlled studies in patients with multiple sclerosis or spinal cord injury (Studies 1 and 2).

Single-Dose Study in Patients with Multiple Sclerosis with Spasticity

In Study 1, patients with multiple sclerosis were randomized to receive single oral doses of drug or placebo. Patients and assessors were blind to treatment assignment and efforts were made to reduce the likelihood that assessors would become aware indirectly of treatment assignment (e.g., they did not provide direct care to patients and were prohibited from asking questions about side effects). In all, 140 patients received placebo, 8 mg or 16 mg of tizanidine.

Response was assessed by physical examination; muscle tone was rated on a 5 point scale (Ashworth score), with a score of 0 used to describe normal muscle tone. A score of 1 indicated a slight spastic catch while a score of 2 indicated more marked muscle resistance. A score of 3 was used to describe considerable increase in tone, making passive movement difficult. A muscle immobilized by spasticity was given a score of 4. Spasm counts were also collected.

Assessments were made at 1, 2, 3 and 6 hours after treatment. A statistically significant reduction of the Ashworth score for tizanidine compared to placebo was detected at 1, 2 and 3 hours after treatment. Figure 2 below shows a comparison of the mean change in muscle tone from baseline as measured by the Ashworth scale. The greatest reduction in muscle tone was 1 to 2 hours after treatment. By 6 hours after treatment, muscle tone in the 8 and 16 mg tizanidine groups was indistinguishable from muscle tone in placebo treated patients. Within a given patient, improvement in muscle tone was correlated with plasma concentration. Plasma concentrations were variable from patient to patient at a given dose. Although 16 mg produced a larger effect, adverse events including hypotension were more common and more severe than in the 8 mg group. There were no differences in the number of spasms occurring in each group.

Figure 2: Single Dose Study—Mean Change in Muscle Tone from Baseline as Measured by the Ashworth Scale ± 95% Confidence Interval (A Negative Ashworth Score Signifies an Improvement in Muscle Tone from Baseline)

Figure 3
(click image for full-size original)

Seven-Week Study in Patients with Spinal Cord Injury with Spasticity

In a 7-week study (Study 2), 118 patients with spasticity secondary to spinal cord injury were randomized to either placebo or tizanidine. Steps similar to those taken in the first study were employed to ensure the integrity of blinding.

Patients were titrated over 3 weeks up to a maximum tolerated dose or 36 mg daily given in three unequal doses (e.g., 10 mg given in the morning and afternoon and 16 mg given at night). Patients were then maintained on their maximally tolerated dose for 4 additional weeks (i.e., maintenance phase). Throughout the maintenance phase, muscle tone was assessed on the Ashworth scale within a period of 2.5 hours following either the morning or afternoon dose. The number of daytime spasms was recorded daily by patients.

At endpoint (the protocol-specified time of outcome assessment), there was a statistically significant reduction in muscle tone and frequency of spasms in the tizanidine treated group compared to placebo. The reduction in muscle tone was not associated with a reduction in muscle strength (a desirable outcome) but also did not lead to any consistent advantage of tizanidine treated patients on measures of activities of daily living. Figure 3 below shows a comparison of the mean change in muscle tone from baseline as measured by the Ashworth scale.

Figure 3: Seven Week Study—Mean Change in Muscle Tone 0.5–2.5 Hours After Dosing as Measured by the Ashworth Scale ± 95% Confidence Interval (A Negative Ashworth Score Signifies an Improvement in Muscle Tone from Baseline)

Figure 4
(click image for full-size original)

16 HOW SUPPLIED/STORAGE AND HANDLING

Product: 53002-1418

NDC: 53002-1418-3 30 TABLET in a BOTTLE

NDC: 53002-1418-5 15 TABLET in a BOTTLE

17 PATIENT COUNSELING INFORMATION

Serious Drug Interactions

Advise patients they should not take tizanidine if they are taking fluvoxamine or ciprofloxacin because of the increased risk of serious adverse reactions including severe lowering of blood pressure and sedation. Instruct patients to inform their physicians or pharmacists when they start or stop taking any medication because of the risks associated with interaction between tizanidine and other medicines.

Tizanidine Dosing

Tell patients to take tizanidine exactly as prescribed (consistently either with or without food) and not to switch between tablets and capsules. Inform patients that they should not take more tizanidine than prescribed because of the risk of adverse events at single doses greater than 8 mg or total daily doses greater than 36 mg. Tell patients that they should not suddenly discontinue tizanidine, because rebound hypertension and tachycardia may occur.

Effects of tizanidine

Warn patients that they may experience hypotension and to be careful when changing from a lying or sitting to a standing position. Tell patients that tizanidine may cause them to become sedated or somnolent and they should be careful when performing activities that require alertness, such as driving a vehicle or operating machinery. Tell patients that the sedation may be additive when tizanidine is taken in conjunction with drugs (baclofen, benzodiazepines) or substances (e.g., alcohol) that act as CNS depressants. Remind patients that if they depend on their spasticity to sustain posture and balance in locomotion, or whenever spasticity is utilized to obtain increased function, that tizanidine decreases spasticity and caution should be used.

Manufactured by:

UNICHEM LABORATORIES LTD.

Pilerne Ind. Estate,

Pilerne, Bardez, Goa 403511, India

Manufactured for:

logo

East Brunswick, NJ 08816

08-R-02/2022

13013805

Tizanidine HCl 2mg Tablets

Label Image
(click image for full-size original)
TIZANIDINE tizanidine tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:53002-1418(NDC:29300-168)
Route of Administration ORAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
TIZANIDINE HYDROCHLORIDE (TIZANIDINE) TIZANIDINE 2 mg
Inactive Ingredients
Ingredient Name Strength
ANHYDROUS LACTOSE
MICROCRYSTALLINE CELLULOSE
SILICON DIOXIDE
STEARIC ACID
Product Characteristics
Color WHITE (White to off white) Score 2 pieces
Shape ROUND Size 8mm
Flavor Imprint Code U;168
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:53002-1418-3 30 TABLET in 1 BOTTLE None
2 NDC:53002-1418-5 15 TABLET in 1 BOTTLE None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA091283 04/01/2013
Labeler — RPK Pharmaceuticals, Inc. (147096275)
Establishment
Name Address ID/FEI Operations
RPK Pharmaceuticals, Inc. 147096275 RELABEL (53002-1418), REPACK (53002-1418)

Revised: 06/2023 RPK Pharmaceuticals, Inc.

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