cloNIDine HCl 0.2 MG 24HR Extended Release Oral Tablet
Generic Name: CLONIDINE HYDROCHLORIDE
Brand Name: Clonidine Hydrochloride
- Substance Name(s):
- CLONIDINE HYDROCHLORIDE
DRUG INTERACTIONS
7 The following have been reported with other oral immediate release formulations of clonidine: Table 6 Clinically Important Drug Interactions Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation Tricyclic antidepressants Increase blood pressure and may counteract clonidine’s hypotensive effects Monitor blood pressure and adjust as needed Antihypertensive drugs Potentiate clonidine’s hypotensive effects Monitor blood pressure and adjust as needed CNS depressants Potentiate sedating effects Avoid use Drugs that affect sinus node function or AV node conduction (e.g., digitalis, calcium channel blockers, beta blockers) Potentiate bradycardia and risk of AV block Avoid use Sedating Drugs: Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs.
( 7 ) Tricyclic Antidepressants: May reduce the hypotensive effect of clonidine.
( 7 ) Drugs Known to Affect Sinus Node Function or AV Nodal Conduction: Caution is warranted in patients receiving clonidine concomitantly with agents known to affect sinus node function or AV nodal conduction (e.g., digitalis, calcium channel blockers and beta-blockers) due to a potential for additive effects such as bradycardia and AV block.
( 7 ) Antihypertensive drugs: Use caution when coadministered with clonidine hydrochloride extended-release tablets.
( 7 )
OVERDOSAGE
10 Symptoms Clonidine overdose: hypertension may develop early and may be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased or absent reflexes, weakness, irritability and miosis.
The frequency of CNS depression may be higher in children than adults.
Large overdoses may result in reversible cardiac conduction defects or dysrhythmias, apnea, coma and seizures.
Signs and symptoms of overdose generally occur within 30 minutes to two hours after exposure.
Treatment Consult with a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice.
DESCRIPTION
11 Clonidine hydrochloride extended-release is a centrally acting alpha 2 -adrenergic agonist available as 0.1 mg extended-release tablets for oral administration.
Each 0.1 mg tablet is equivalent to 0.087 mg of the free base.
The inactive ingredients are colloidal silicon dioxide, hydroxyethyl cellulose, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, red iron oxide, sodium lauryl sulfate and titanium dioxide.
The formulation is designed to delay the absorption of active drug in order to decrease peak to trough plasma concentration differences.
Clonidine hydrochloride, USP is an imidazoline derivative and exists as a mesomeric compound.
The chemical name is 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride.
The following is the structural formula: Clonidine hydrochloride, USP is an odorless, bitter, white, crystalline substance soluble in water and alcohol.
Product meets Dissolution Test 4.
bceb3bbb-figure-03
CLINICAL STUDIES
14 Efficacy of clonidine hydrochloride extended-release tablets in the treatment of ADHD was established in children and adolescents (6 to 17 years) in: One short-term, placebo-controlled monotherapy trial (Study 1) One short-term adjunctive therapy to psychostimulants trial (Study 2) One randomized withdrawal trial as monotherapy (Study 3) Short-term Monotherapy and Adjunctive Therapy to Psychostimulant Studies for ADHD The efficacy of clonidine hydrochloride extended-release tablets in the treatment of ADHD was established in 2 (one monotherapy and one adjunctive therapy) placebo-controlled trials in pediatric patients aged 6 to 17, who met DSM-IV criteria of ADHD hyperactive or combined hyperactive/inattentive subtypes.
Signs and symptoms of ADHD were evaluated using the investigator administered and scored ADHD Rating Scale-IV-Parent Version (ADHDRS-IV) total score including hyperactive/impulsivity and inattentive subscales.
Study 1 (CLON-301), was an 8-week randomized, double-blind, placebo-controlled, fixed dose study of children and adolescents aged 6 to 17 (N=236) with a 5-week primary efficacy endpoint.
Patients were randomly assigned to one of the following three treatment groups: clonidine hydrochloride extended-release tablets (CLON) 0.2 mg/day (N=78), clonidine hydrochloride extended-release tablets 0.4 mg/day (N=80), or placebo (N=78).
Dosing for the clonidine hydrochloride extended-release tablets groups started at 0.1 mg/day and was titrated in increments of 0.1 mg/week to their respective dose (as divided doses).
Patients were maintained at their dose for a minimum of 2 weeks before being gradually tapered down to 0.1 mg/day at the last week of treatment.
At both doses, improvements in ADHD symptoms were statistically significantly superior in clonidine hydrochloride extended-release tablets-treated patients compared with placebo-treated patients at the end of 5 weeks as measured by the ADHDRS-IV total score (Table 8).
Study 2 (CLON-302) was an 8-week randomized, double-blind, placebo-controlled, flexible dose study in children and adolescents aged 6 to 17 (N=198) with a 5-week primary efficacy end point.
Patients had been treated with a psychostimulant (methylphenidate or amphetamine) for four weeks with inadequate response.
Patients were randomly assigned to one of two treatment groups: clonidine hydrochloride extended-release tablets adjunct to a psychostimulant (N=102) or psychostimulant alone (N=96).
The clonidine hydrochloride extended-release tablet dose was initiated at 0.1 mg/day and doses were titrated in increments of 0.1 mg/week up to 0.4 mg/day, as divided doses, over a 3-week period based on tolerability and clinical response.
The dose was maintained for a minimum of 2 weeks before being gradually tapered to 0.1 mg/day at the last week of treatment.
ADHD symptoms were statistically significantly improved in clonidine hydrochloride extended-release tablets plus stimulant group compared with the stimulant alone group at the end of 5 weeks as measured by the ADHDRS-IV total score (Table 8).
Table 8 Short-Term Trials Study Number Treatment Group Primary Efficacy Measure: ADHDRS-IV Total Score Mean Baseline Score LS Mean Change from Placebo-subtracted (SD) Baseline (SE) Difference a (95% CI) Study 1 Clonidine Hydrochloride Extended-Release Tablets (0.2 mg/day) 43.8 (7.47) -15.0 (1.38) -8.5 (-12.2, -4.8) Clonidine Hydrochloride Extended-Release Tablets (0.4 mg/day) 44.6 (7.73) -15.6 (1.33) -9.1 (-12.8, -5.5) Placebo 45.0 (8.53) -6.5 (1.35) -- Study 2 Clonidine Hydrochloride Extended-Release Tablets (0.4 mg/day) + Psychostimulant 38.9 (6.95) -15.8 (1.18) -4.5 (-7.8, -1.1) Psychostimulant alone 39.0 (7.68) -11.3 (1.24) -- SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.
a Difference (drug minus placebo) in least-squares mean change from baseline.
Maintenance Monotherapy for ADHD Study 3 (SHN-KAP-401), was a double-blind, placebo-controlled, randomized-withdrawal study in children and adolescents aged 6 to 17 years (n=253) with DSM-IV-TR diagnosis of ADHD.
The study consisted of a 10-week, open-label phase (4 weeks of dose optimization and 6 weeks of dose maintenance), a 26-week double-blind phase, and a 4-week taper-down and follow-up phase.
All patients were initiated at 0.1 mg/day and increased at weekly intervals in increments of 0.1 mg/day until reaching personalized optimal dose (0.1, 0.2, 0.3 or 0.4 mg/day, as divided doses).
Eligible patients had to demonstrate treatment response as defined by ≥30% reduction in ADHD-RS-IV total score and a Clinical Global Impression-Improvement score of 1 or 2 during the open label phase.
Patients who sustained treatment response (n=135) until the end of the open label phase were randomly assigned to one of the two treatment groups, clonidine hydrochloride extended-release tablets (N=68) and Placebo (N=67), to evaluate the long-term efficacy of maintenance dose of clonidine hydrochloride extended-release tablets in the double-blind phase.
The primary efficacy endpoint was the percentage of patients with treatment failure defined as a ≥30% increase(worsening) in ADHD-RS-IV total score and ≥2 points increase (worsening ) in Clinical Global Impression – Severity Scale in 2 consecutive visits or early termination for any reason.
A total of 73 patients experienced treatment failure in the double-blind phase: 31 patients (45.6%) in the clonidine hydrochloride extended-release tablets group and 42 patients (62.7%) in the placebo group, with a statistically significant difference in the primary endpoint favoring clonidine hydrochloride extended-release tablets (Table 9).
The cumulative proportion of patients with treatment failure over time during the double-blind phase is displayed in Figure 2.
Table 9 Treatment Failure: Double-Blind Full Analysis Set (Study 3) Double-Blind Full Analysis Set Study 3 Clonidine Hydrochloride Extended-Release Tablets Placebo Number of subjects 68 67 Number of treatment failures 31 (45.6%) 42 (62.7%) Basis of Treatment Failure Clinical criteria a,b 11 (16.2%) 9 (13.4%) Lack of efficacy c 1 (1.5%) 3 (4.5%) Withdrawal of informed assent/consent 4 (5.9%) 20 (29.9%) Other early termination 15 (22.1%) 10 (14.9%) ADHD-RS-IV = Attention Deficit Hyperactivity Disorder-Rating Scale-4 th edition; CGI-S = Clinical Global Impression-Severity a At the same 2 consecutive visits a (1) 30% or greater reduction in ADHD-RS-IV, and (2) 2-point or more increase in CGI-S.
b Two subjects (1 placebo and 1 Clonidine Hydrochloride Extended-Release Tablets) withdrew consent, but met the clinical criteria for treatment failure.
c Three subjects (all placebo) discontinued the study due to treatment failure, but met only the criterion for ADHD-RS-IV.
Figure 2: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Treatment Failure (Study 3) figure 2
HOW SUPPLIED
16 /STORAGE AND HANDLING Clonidine Hydrochloride Extended-Release Tablets, USP are supplied as follows: 0.1 mg — Each pink, round, unscored tablet debossed with on one side and 241 on the other side contains 0.1 mg of clonidine hydrochloride, USP.
Tablets are supplied in bottles of 60 (NDC 0228-4241-06).
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).
See USP Controlled Room Temperature.
Brands listed are the trademarks of their respective owners.
Dispense in a tight, light-resistant container as defined in the USP.
bceb3bbb-figure-05
DOSAGE FORMS AND STRENGTHS
3 Clonidine hydrochloride, USP is available as 0.1 mg strength extended-release tablets.
The 0.1 mg tablets are pink, unscored, round and debossed with on one side and 241 on the other side.
Clonidine hydrochloride extended-release tablets must be swallowed whole and never crushed, cut or chewed.
Extended-release tablets: 0.1 mg, not scored.
( 3 ) bceb3bbb-figure-02
INDICATIONS AND USAGE
1 Clonidine hydrochloride extended-release tablets are indicated for the treatment of attention deficit hyperactivity disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications [see Clinical Studies (14) ] .
Clonidine hydrochloride extended-release tablets are a centrally acting alpha 2 -adrenergic agonist indicated for the treatment of attention deficit hyperactivity disorder (ADHD) as monotherapy or as adjunctive therapy to stimulant medications.
( 1 )
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Hypotension/bradycardia/syncope: Titrate slowly and monitor vital signs frequently in patients at risk for hypotension, heart block, bradycardia, syncope, cardiovascular disease, vascular disease, cerebrovascular disease or chronic renal failure.
Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy.
Avoid concomitant use of drugs with additive effects unless clinically indicated.
Advise patients to avoid becoming dehydrated or overheated.
( 5.1 ) Somnolence/Sedation: Has been observed with clonidine hydrochloride extended-release tablets.
Consider the potential for additive sedative effects with CNS depressant drugs.
Caution patients against operating heavy equipment or driving until they know how they respond to clonidine hydrochloride extended-release tablets.
( 5.2 ) Cardiac Conduction Abnormalities: May worsen sinus node dysfunction and atrioventricular (AV) block, especially in patients taking other sympatholytic drugs.
Titrate slowly and monitor vital signs frequently.
( 5.5 ) 5.1 Hypotension/Bradycardia Treatment with clonidine hydrochloride extended-release tablets can cause dose-related decreases in blood pressure and heart rate [see Adverse Reactions (6.1) ] .
Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy.
Titrate clonidine hydrochloride extended-release tablets slowly in patients with a history of hypotension, and those with underlying conditions that may be worsened by hypotension and bradycardia; e.g., heart block, bradycardia, cardiovascular disease, vascular disease, cerebrovascular disease, or chronic renal failure.
In patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration, advise patients to avoid becoming dehydrated or overheated.
Monitor blood pressure and heart rate, and adjust dosages accordingly in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope.
5.2 Sedation and Somnolence Somnolence and sedation were commonly reported adverse reactions in clinical studies.
In patients that completed 5 weeks of therapy in a controlled, fixed dose pediatric monotherapy study, 31% of patients treated with 0.4 mg/day and 38% treated with 0.2 mg/day versus 4% of placebo treated patients reported somnolence as an adverse event.
In patients that completed 5 weeks of therapy in a controlled flexible dose pediatric adjunctive to stimulants study, 19% of patients treated with clonidine hydrochloride extended-release tablets+stimulant versus 7% treated with placebo+stimulant reported somnolence.
Before using clonidine hydrochloride extended-release tablets with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), consider the potential for additive sedative effects.
Caution patients against operating heavy equipment or driving until they know how they respond to treatment with clonidine hydrochloride extended-release tablets.
Advise patients to avoid use with alcohol.
5.3 Rebound Hypertension Abrupt discontinuation of clonidine hydrochloride extended-release tablets can cause rebound hypertension.
In adults with hypertension, sudden cessation of clonidine hydrochloride extended-release formulation treatment in the 0.2 to 0.6 mg/day range resulted in reports of headache, tachycardia, nausea, flushing, warm feeling, brief lightheadedness, tightness in chest, and anxiety.
In adults with hypertension, sudden cessation of treatment with immediate-release clonidine has, in some cases, resulted in symptoms such as nervousness, agitation, headache, and tremor accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma.
No studies evaluating abrupt discontinuation of clonidine hydrochloride extended-release tablets in children with ADHD have been conducted; however, to minimize the risk of rebound hypertension, gradually reduce the dose of clonidine hydrochloride extended-release tablets in decrements of no more than 0.1 mg every 3 to 7 days.
Patients should be instructed not to discontinue clonidine hydrochloride extended-release tablet therapy without consulting their physician due to the potential risk of withdrawal effects.
5.4 Allergic Reactions In patients who have developed localized contact sensitization to clonidine transdermal system, continuation of clonidine transdermal system or substitution of oral clonidine hydrochloride extended-release tablet therapy may be associated with the development of a generalized skin rash.
In patients who develop an allergic reaction from clonidine transdermal system, substitution of oral clonidine hydrochloride extended-release tablets may also elicit an allergic reaction (including generalized rash, urticaria, or angioedema).
5.5 Cardiac Conduction Abnormalities The sympatholytic action of clonidine may worsen sinus node dysfunction and atrioventricular (AV) block, especially in patients taking other sympatholytic drugs.
There have been post-marketing reports of patients with conduction abnormalities and/or taking other sympatholytic drugs who developed severe bradycardia requiring IV atropine, IV isoproterenol, and temporary cardiac pacing while taking clonidine.
Titrate clonidine hydrochloride extended-release tablets slowly and monitor vital signs frequently in patients with cardiac conduction abnormalities or patients concomitantly treated with other sympatholytic drugs.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved Patient Labeling ( Patient Information ) Dosage and Administration Advise patients that clonidine hydrochloride extended-release tablets must be swallowed whole, never crushed, cut, or chewed, and may be taken with or without food.
When initiating treatment, provide dosage escalation instructions [see Dosage and Administration (2.1) ] .
Missed Dose If patients miss a dose of clonidine hydrochloride extended-release tablets, advise them to skip the dose and take the next dose as scheduled and not to take more than the prescribed total daily amount of clonidine hydrochloride extended-release tablets in any 24-hour period [see Dosage and Administration (2.4) ] .
Hypotension/Bradycardia Advise patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration, to avoid becoming dehydrated or overheated [see Warnings and Precautions (5.1) ] .
Sedation and Somnolence Instruct patients to use caution when driving a car or operating hazardous machinery until they know how they will respond to treatment with clonidine hydrochloride extended-release tablets.
Also advise patients to avoid the use of clonidine hydrochloride extended-release tablets with other centrally active depressants and with alcohol [see Warnings and Precautions (5.2) ] .
Rebound Hypertension Advise patients not to discontinue clonidine hydrochloride extended-release tablets abruptly [see Warnings and Precautions (5.3) ] .
Allergic Reactions Advise patients to discontinue clonidine hydrochloride extended-release tablets and seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction occur, such as generalized rash, urticaria, or angioedema [see Warnings and Precautions (5.4) ] .
Pregnancy Registry Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to clonidine hydrochloride extended-release tablets during pregnancy [see Use in Specific Populations ( 8.1 )] .
Lactation Advise breastfeeding women using clonidine hydrochloride extended-release tablets to monitor infants for excess sedation, decreased muscle tone, and respiratory depression and to seek medical care if they notice these signs [see Use in Specific Populations ( 8.2 )] .
Fertility Advise females and males of reproductive potential that clonidine hydrochloride extended-release tablets may impair fertility [see Use in Specific Populations ( 8.3 ) and Nonclinical Toxicology ( 13.1 )] .
Dispense with Patient Package Insert available at: www.tevausa.com/PatientPI Manufactured For: Teva Pharmaceuticals Parsippany, NJ 07054 Rev.
B 6/2023
DOSAGE AND ADMINISTRATION
2 Start with one 0.1 mg tablet at bedtime for one week.
Increase daily dosage in increments of 0.1 mg/day at weekly intervals until the desired response is achieved.
Take twice a day, with either an equal or higher split dosage being given at bedtime, as depicted below ( 2.2 ) Total Daily Dose Morning Dose Bedtime Dose 0.1 mg/day 0.1 mg 0.2 mg/day 0.1 mg 0.1 mg 0.3 mg/day 0.1 mg 0.2 mg 0.4 mg/day 0.2 mg 0.2 mg Do not crush, chew or break tablet before swallowing.
( 2.1 ) Do not substitute for other clonidine products on a mg-per-mg basis, because of differing pharmacokinetic profiles.
( 2.1 ) When discontinuing, taper the dose in decrements of no more than 0.1 mg every 3 to 7 days to avoid rebound hypertension.
( 2.3 ) 2.1 General Dosing Information Clonidine hydrochloride is an extended-release tablet to be taken orally with or without food.
Swallow tablets whole.
Do not crush, chew, or break tablets because this will increase the rate of clonidine release.
Due to the lack of controlled clinical trial data and differing pharmacokinetic profiles, substitution of clonidine hydrochloride extended-release tablets for other clonidine products on a mg-per-mg basis is not recommended [see Clinical Pharmacology (12.3) ] .
2.2 Dose Selection The dose of clonidine hydrochloride extended-release tablets administered either as monotherapy or as adjunctive therapy to a psychostimulant, should be individualized according to the therapeutic needs and response of the patient.
Dosing should be initiated with one 0.1 mg tablet at bedtime, and the daily dosage should be adjusted in increments of 0.1 mg/day at weekly intervals until the desired response is achieved.
Doses should be taken twice a day, with either an equal or higher split dosage being given at bedtime (see Table 1).
Table 1 Clonidine Hydrochloride Extended-Release Tablets Dosing Guidance Total Daily Dose Morning Dose Bedtime Dose 0.1 mg/day 0.1 mg 0.2 mg/day 0.1 mg 0.1 mg 0.3 mg/day 0.1 mg 0.2 mg 0.4 mg/day 0.2 mg 0.2 mg Doses of clonidine hydrochloride extended-release tablets higher than 0.4 mg/day (0.2 mg twice daily) were not evaluated in clinical trials for ADHD and are not recommended.
When a clonidine hydrochloride extended-release tablet is being added-on to a psychostimulant, the dose of the psychostimulant can be adjusted depending on the patient’s response to clonidine hydrochloride extended-release tablets.
2.3 Discontinuation When discontinuing clonidine hydrochloride extended-release tablets, the total daily dose should be tapered in decrements of no more than 0.1 mg every 3 to 7 days to avoid rebound hypertension [see Warnings and Precautions (5.3) ] .
2.4 Missed Doses If patients miss a dose of clonidine hydrochloride extended-release tablets, they should skip that dose and take the next dose as scheduled.
Do not take more than the prescribed total daily amount of clonidine hydrochloride extended-release tablets in any 24-hour period.