tiZANidine HCl 6 MG Oral Capsule
DRUG INTERACTIONS
7 7.1 Fluvoxamine Concomitant use of fluvoxamine and tizanidine is contraindicated.
Changes in pharmacokinetics of tizanidine when administered with fluvoxamine resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment [see Contraindications (4) and Clinical Pharmacology (12.3) ].
7.2 Ciprofloxacin Concomitant use of ciprofloxacin and tizanidine is contraindicated.
Changes in pharmacokinetics of tizanidine when administered with ciprofloxacin resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment [see Contraindications (4) and Clinical Pharmacology (12.3) ] .
7.3 CYP1A2 Inhibitors other than Fluvoxamine and Ciprofloxacin Because of potential drug interactions, concomitant use of tizanidine with other CYP1A2 inhibitors, such as zileuton, fluoroquinolones other than strong CYP1A2 inhibitors (which are contraindicated), antiarrythmics (amiodarone, mexiletine, propafenone, and verapamil), cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine) should be avoided.
If their use is clinically necessary, therapy should be initiated with 2 mg (base) dose and increased in 2 mg (base) to 4 mg (base) steps daily based on patient response to therapy.
If adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue tizanidine therapy [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3) ] .
7.4 Oral Contraceptives Concomitant use of tizanidine with oral contraceptives is not recommended.
However, if concomitant use is clinically necessary, initiate tizanidine with a single 2 mg (base) dose and increase in 2 mg (base) to 4 mg (base) steps daily based on patient response to therapy.
If adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue tizanidine therapy [see Clinical Pharmacology (12.3) ] .
7.5 Alcohol Alcohol increases the overall amount of drug in the bloodstream after a dose of tizanidine.
This was associated with an increase in adverse reactions of tizanidine.
The CNS depressant effects of tizanidine and alcohol are additive [see Clinical Pharmacology (12.3) ] .
7.6 Other CNS Depressants The sedative effects of tizanidine with CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive.
Monitor patients who take tizanidine with another CNS depressant for symptoms of excess sedation [see Clinical Pharmacology (12.3) ] .
7.7 α 2 -adrenergic Agonists Because hypotensive effects may be cumulative, it is not recommended that tizanidine be used with other α 2 -adrenergic agonists [see Warnings and Precautions (5.1) ] .
OVERDOSAGE
10 A review of the safety surveillance database revealed cases of intentional and accidental tizanidine overdose.
Some of the cases resulted in fatality and many of the intentional overdoses were with multiple drugs including CNS depressants.
The clinical manifestations of tizanidine overdose were consistent with its known pharmacology.
In the majority of cases a decrease in sensorium was observed including lethargy, somnolence, confusion and coma.
Depressed cardiac function is also observed including most often bradycardia and hypotension.
Respiratory depression is another common feature of tizanidine overdose.
Should overdose occur, basic steps to ensure the adequacy of an airway and the monitoring of cardiovascular and respiratory systems should be undertaken.
Tizanidine is a lipid-soluble drug, which is only slightly soluble in water and methanol.
Therefore, dialysis is not likely to be an efficient method of removing drug from the body.
In general, symptoms resolve within one to three days following discontinuation of tizanidine and administration of appropriate therapy.
Due to the similar mechanism of action, symptoms and management of tizanidine overdose are similar to that following clonidine overdose.
For the most recent information concerning the management of overdose, contact a poison control center.
DESCRIPTION
11 Tizanidine hydrochloride capsules are a central alpha 2 -adrenergic agonist.
Tizanidine hydrochloride, USP is an almost white to slightly yellow crystalline powder, which is odorless or with a faint characteristic odor.
Tizanidine is slightly soluble in water and methanol; solubility in water decreases as the pH increases.
Its chemical name is 5-Chloro- N -(4,5-dihydro-1 H -imidazol-2yl)-2,1,3-benzothiadiazol-4-amine hydrochloride.
Tizanidine’s molecular formula is C 9 H 8 ClN 5 S•HCl, its molecular weight is 290.2 and its structural formula is: Tizanidine hydrochloride capsules are supplied as 2 mg, 4 mg, and 6 mg capsules for oral administration.
Tizanidine hydrochloride capsules contain the active ingredient, tizanidine hydrochloride, USP (2.29 mg equivalent to 2 mg tizanidine base, 4.58 mg equivalent to 4 mg tizanidine base, and 6.87 mg equivalent to 6 mg tizanidine base), and the inactive ingredients anhydrous lactose, colloidal silicon dioxide, hypromellose, microcrystalline cellulose and talc.
In addition, each of the empty hard gelatin capsules contain the following: gelatin, red iron oxide, titanium dioxide and yellow iron oxide.
The imprinting ink contains the following: black iron oxide, potassium hydroxide, propylene glycol, shellac and strong ammonia solution.
Tizanidine Hydrochloride Structural Formula
CLINICAL STUDIES
14 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 (base) or 16 mg (base) 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 mg (base) and 16 mg (base) 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 (base) produced a larger effect, adverse events including hypotension were more common and more severe than in the 8 mg (base) 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) 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 (base) daily given in three unequal doses (e.g., 10 mg (base) given in the morning and afternoon and 16 mg (base) 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 to 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 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: Seven Week Study – Mean Change in Muscle Tone 0.5 to 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)
HOW SUPPLIED
16 /STORAGE AND HANDLING 16.1 Tizanidine Hydrochloride Capsules Tizanidine Hydrochloride Capsules are available containing tizanidine hydrochloride, USP equivalent to 2 mg, 4 mg, or 6 mg of tizanidine base.
The 2 mg capsule is a hard-shell gelatin capsule with an orange opaque cap and an orange opaque body filled with light yellow to yellow granular powder.
The capsule is axially printed with MYLAN over TE 2 in black ink on both the cap and the body.
They are available as follows: NDC 0378-1665-19 bottles of 150 capsules The 4 mg capsule is a hard-shell gelatin capsule with an orange opaque cap and a white opaque body filled with light yellow to yellow granular powder.
The capsule is axially printed with MYLAN over TE 4 in black ink on both the cap and the body.
They are available as follows: NDC 0378-1666-19 bottles of 150 capsules The 6 mg capsule is a hard-shell gelatin capsule with an orange opaque cap and a peach opaque body filled with light yellow to yellow granular powder.
The capsule is axially printed with MYLAN over TE 6 in black ink on both the cap and the body.
They are available as follows: NDC 0378-1667-19 bottles of 150 capsules Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
GERIATRIC USE
8.5 Geriatric Use Tizanidine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Clinical studies of tizanidine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects.
Cross-study comparison of pharmacokinetic data following single dose administration of 6 mg (base) tizanidine showed that younger subjects cleared the drug four times faster than the elderly subjects.
In elderly patients with renal insufficiency (creatinine clearance < 25 mL/min), tizanidine clearance is reduced by more than 50% compared to healthy elderly subjects; this would be expected to lead to a longer duration of clinical effect.
During titration, the individual doses should be reduced.
If higher doses are required, individual doses rather than dosing frequency should be increased.
Monitor elderly patients because they may have an increased risk for adverse reactions associated with tizanidine.
DOSAGE FORMS AND STRENGTHS
3 Tizanidine Hydrochloride Capsules are available containing tizanidine hydrochloride, USP equivalent to 2 mg, 4 mg, or 6 mg of tizanidine base.
Capsules: • 2 mg: A hard-shell gelatin capsule with an orange opaque cap and an orange opaque body filled with light yellow to yellow granular powder.
The capsule is axially printed with MYLAN over TE 2 in black ink on both the cap and the body.
• 4 mg: A hard-shell gelatin capsule with an orange opaque cap and a white opaque body filled with light yellow to yellow granular powder.
The capsule is axially printed with MYLAN over TE 4 in black ink on both the cap and the body.
• 6 mg: A hard-shell gelatin capsule with an orange opaque cap and a peach opaque body filled with light yellow to yellow granular powder.
The capsule is axially printed with MYLAN over TE 6 in black ink on both the cap and the body.
• Capsules: 2 mg, 4 mg or 6 mg ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action Tizanidine is a central alpha-2-adrenergic receptor agonist and presumably reduces spasticity by increasing presynaptic inhibition of motor neurons.
The effects of tizanidine are greatest on polysynaptic pathways.
The overall effect of these actions is thought to reduce facilitation of spinal motor neurons.
INDICATIONS AND USAGE
1 Tizanidine hydrochloride capsules are a central alpha-2-adrenergic agonist indicated for the management of spasticity.
Because of the short duration of therapeutic effect, treatment with tizanidine hydrochloride capsules should be reserved for those daily activities and times when relief of spasticity is most important [see Dosage and Administration (2.1) ] .
Tizanidine hydrochloride capsules are a central alpha-2-adrenergic agonist indicated for the management of spasticity.
Because of the short duration of therapeutic effect, treatment with tizanidine hydrochloride capsules should be reserved for those daily activities and times when relief of spasticity is most important.
( 1 )
PEDIATRIC USE
8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.
PREGNANCY
8.1 Pregnancy Teratogenic Effects Pregnancy Category C Tizanidine has not been studied in pregnant women.
Tizanidine should be given to pregnant women only if the benefit outweighs the risk to the unborn fetus.
Reproduction studies performed in rats at a dose of 3 mg (base)/kg, equal to the maximum recommended human dose on a mg/m 2 basis, and in rabbits at 30 mg (base)/kg, 16 times the maximum recommended human dose on a mg/m 2 basis, did not show evidence of teratogenicity.
Tizanidine at doses that are equal to and up to 8 times the maximum recommended human dose on a mg/m 2 basis increased gestation duration in rats.
Prenatal and postnatal pup loss was increased and developmental retardation occurred.
Post-implantation loss was increased in rabbits at doses of 1 mg (base)/kg or greater, equal to or greater than 0.5 times the maximum recommended human dose on a mg/m 2 basis.
NUSRING MOTHERS
8.3 Nursing Mothers It is not known whether this drug is excreted in human milk.
Because many drugs are excreted in human milk, caution should be exercised when tizanidine is administered to a nursing woman.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS • Hypotension: monitor for signs and symptoms of hypotension, in particular in patients receiving concurrent antihypertensives; tizanidine should not be used with other α 2 -adrenergic agonists ( 5.1 , 7.7 ) • Risk of liver injury: monitor ALTs; discontinue tizanidine if liver injury occurs ( 5.2 ) • Sedation: Tizanidine may interfere with everyday activities; sedative effects of tizanidine, alcohol, and other CNS depressants are additive ( 5.3 , 7.5 , 7.6 ) • Hallucinations: consider discontinuation of tizanidine ( 5.4 ) • Less potent inhibitors of CYP1A2: may cause hypotension, bradycardia, or excessive drowsiness, use caution if tizanidine is used with less potent inhibitors of CYP1A2, e.g., zileuton, other fluoroquinolones, antiarrythmics, cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine ( 5.5 , 7.3 , 12.3 ) • Renal impairment (creatinine clearance < 25 mL/min): use tizanidine with caution, and monitor closely for dry mouth, somnolence, asthenia and dizziness as indicators of potential overdose ( 5.7 ) 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 is used in patients receiving concurrent antihypertensive therapy.
It is not recommended that tizanidine 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 (base) of tizanidine.
Therefore, concomitant use of tizanidine with fluvoxamine or with ciprofloxacin, potent inhibitors of CYP1A2, is contraindicated [see Contraindications (4) and Drug Interactions (7.1 , 7.2) ] .
5.2 Risk of Liver Injury Tizanidine may cause hepatocellular liver injury.
Tizanidine 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 (2.3) and Use in Specific Populations (8.7) ] .
5.3 Sedation Tizanidine 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 with alcohol and other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive.
Monitor patients who take tizanidine with another CNS depressant for symptoms of excess sedation [see Drug Interactions (7.5 , 7.6) ] .
5.4 Hallucinosis/Psychotic-Like Symptoms Tizanidine 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 in patients who develop hallucinations.
5.5 Interaction with CYP1A2 Inhibitors Because of potential drug interactions, tizanidine 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 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 therapy is clinically evident.
In such a case, use with caution [see Drug Interactions (7.3) and Clinical Pharmacology (12.3) ] .
5.6 Hypersensitivity Reactions Tizanidine 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 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 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 (2.2) 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 mg (base) to 28 mg (base) 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 mg (base) to 4 mg (base) per day) [see Dosage and Administration (2.2) ] .
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Serious Drug Interactions: Advise patients they should not take tizanidine hydrochloride capsules 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 hydrochloride capsules and other medicines.
Tizanidine Hydrochloride Capsules Dosing: Tell patients to take tizanidine hydrochloride capsules 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 hydrochloride capsules than prescribed because of the risk of adverse events at single doses greater than 8 mg (base) or total daily doses greater than 36 mg (base).
Tell patients that they should not suddenly discontinue tizanidine hydrochloride capsules, because rebound hypertension and tachycardia may occur.
Effects of Tizanidine Hydrochloride Capsules: 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 hydrochloride capsules 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 hydrochloride capsules are 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 hydrochloride capsules decrease spasticity and caution should be used.
Manufactured for: Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.
Manufactured by: Mylan Laboratories Limited Hyderabad — 500 034, India Code No.: MH/DRUGS/25/NKD/89 75059379 Revised: 8/2016 MX:TZNDC:R4
DOSAGE AND ADMINISTRATION
2 • Recommended starting dose: 2 mg (base); dose can be repeated at 6 to 8 hour intervals, up to a maximum of 3 doses in 24 hours ( 2.1 ) • Dosage can be increased by 2 mg (base) to 4 mg (base) per dose, with 1 to 4 days between increases; total daily dose should not exceed 36 mg (base) ( 2.1 ) • Tizanidine pharmacokinetics differs between tablets and capsules, and when taken with or without food.
These differences could result in a change in tolerability and control of symptoms ( 2.1 , 12.3 ) • To discontinue tizanidine hydrochloride capsules, decrease dose slowly to minimize the risk of withdrawal and rebound hypertension, tachycardia, and hypertonia ( 2.2 ) 2.1 Dosing Information Tizanidine hydrochloride capsules may be prescribed with or without food.
Once the formulation has been selected and the decision to take with or without food has been made, this regimen should not be altered.
Food has complex effects on tizanidine pharmacokinetics, which differ with the different formulations.
Tizanidine hydrochloride capsules and tizanidine tablets are bioequivalent to each other under fasting conditions (more than 3 hours after a meal), but not under fed conditions (within 30 minutes of a meal).
These pharmacokinetic differences may result in clinically significant differences when switching administration of tablet and capsules and when switching administration between the fed or fasted state.
These changes may result in increased adverse events, or delayed or more rapid onset of activity, depending upon the nature of the switch.
For this reason, the prescriber should be thoroughly familiar with the changes in kinetics associated with these different conditions [see Clinical Pharmacology (12.3) ].
The recommended starting dose is 2 mg (base).
Because the effect of tizanidine hydrochloride capsules peaks at approximately 1 to 2 hours post-dose and dissipates between 3 to 6 hours post-dose, treatment can be repeated at 6 to 8 hour intervals, as needed, to a maximum of three doses in 24 hours.
Dosage can be gradually increased by 2 mg (base) to 4 mg (base) at each dose, with 1 to 4 days between dosage increases, until a satisfactory reduction of muscle tone is achieved.
The total daily dose should not exceed 36 mg (base).
Single doses greater than 16 mg (base) have not been studied.
2.2 Dosing in Patients with Renal Impairment Tizanidine hydrochloride capsules 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 [see Warnings and Precautions (5.7) ] .
2.3 Dosing in Patients with Hepatic Impairment Tizanidine hydrochloride capsules should be used with caution in patients with any hepatic impairment.
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.
Monitoring of aminotransferase levels is recommended for baseline and 1 month after maximum dose is achieved, or if hepatic injury is suspected [see Use in Specific Populations (8.7) ] .
2.4 Drug Discontinuation If therapy needs to be discontinued, particularly in patients who have been receiving high doses (20 mg (base) to 36 mg (base) daily) for long periods (9 weeks or more) or who may be on concomitant treatment with narcotics, the dose should be decreased slowly (2 mg (base) to 4 mg (base) per day) to minimize the risk of withdrawal and rebound hypertension, tachycardia, and hypertonia [see Drug Abuse and Dependence (9.3) ].