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).

Doses of clonidine hydrochloride higher than 0.4 mg/day (0.2 mg twice daily) were not evaluated in clinical trials for ADHD and are not recommended.

When clonidine hydrochloride extended-release tablets are 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.

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+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 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 tablets 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 tablets 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.

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Two clonidine hydrochloride ADHD clinical studies (Study 1, CLON-301 and Study 2, CLON-302) evaluated 256 patients in two 8-week placebo-controlled studies.

A third clonidine hydrochloride ADHD clinical study (Study 3, SHN-KAP-401) evaluated 135 children and adolescents in a 40-week placebo-controlled randomized-withdrawal study.

6.2 Post-marketing Experience

The following adverse reactions have been identified during post-approval use of clonidine hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events exclude those already mentioned in 6.1:

Psychiatric: hallucinations

Cardiovascular: Q-T prolongation

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and efficacy of clonidine hydrochloride in the treatment of ADHD have been established in pediatric patients 6 to 17 years of age. Use of clonidine hydrochloride in pediatric patients 6 to 17 years of age is supported by three adequate and well-controlled studies; a short-term, placebo-controlled monotherapy trial, a short-term adjunctive therapy trial and a longer-term randomized monotherapy trial [see Clinical Studies (14)]. Safety and efficacy in pediatric patients below the age of 6 years has not been established.

8.6 Renal Impairment

The impact of renal impairment on the pharmacokinetics of clonidine in children has not been assessed. The initial dosage of clonidine hydrochloride extended-release tablets should be based on degree of impairment. Monitor patients carefully for hypotension and bradycardia, and titrate to higher doses cautiously. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental clonidine hydrochloride extended-release tablets following dialysis.

9.1 Controlled Substance

Clonidine hydrochloride is not a controlled substance and has no known potential for abuse or dependence.

Symptoms

Treatment

Consult with a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice.

12.1 Mechanism of Action

Clonidine stimulates alpha2-adrenergic receptors in the brain. Clonidine is not a central nervous system stimulant. The mechanism of action of clonidine in ADHD is not known.

12.2 Pharmacodynamics

Clonidine is a known antihypertensive agent. By stimulating alpha2-adrenergic receptors in the brain stem, clonidine reduces sympathetic outflow from the central nervous system and decreases peripheral resistance, renal vascular resistance, heart rate, and blood pressure.

12.3 Pharmacokinetics

Single-dose Pharmacokinetics in Adults

Immediate-release clonidine hydrochloride and clonidine hydrochloride extended-release have different pharmacokinetic characteristics; dose substitution on a milligram for milligram basis will result in differences in exposure. A comparison across studies suggests that the Cmax is 50% lower for clonidine hydrochloride extended-release compared to immediate-release clonidine hydrochloride.

Following oral administration of an immediate release formulation, plasma clonidine concentration peaks in approximately 3 to 5 hours and the plasma half-life ranges from 12 to 16 hours. The half-life increases up to 41 hours in patients with severe impairment of renal function. Following oral administration about 40% to 60% of the absorbed dose is recovered in the urine as unchanged drug in 24 hours.

About 50% of the absorbed dose is metabolized in the liver. Although studies of the effect of renal impairment and studies of clonidine excretion have not been performed with clonidine hydrochloride extended-release, results are likely to be similar to those of the immediate release formulation.

The pharmacokinetic profile of clonidine hydrochloride extended-release administration was evaluated in an open-label, three-period, randomized, crossover study of 15 healthy adult subjects who received three single-dose regimens of clonidine: 0.1 mg of clonidine hydrochloride extended-release under fasted conditions, 0.1 mg of clonidine hydrochloride extended-release following a high fat meal, and 0.1 mg of clonidine immediate-release (Catapres®) under fasted conditions. Treatments were separated by one-week washout periods.

Mean concentration-time data from the 3 treatments are shown in Table 7 and Figure 1. After administration of clonidine hydrochloride extended-release, maximum clonidine concentrations were approximately 50% of the Catapres maximum concentrations and occurred approximately 5 hours later relative to Catapres. Similar elimination half-lives were observed and total systemic bioavailability following clonidine hydrochloride extended-release was approximately 89% of that following Catapres.

Food had no effect on plasma concentrations, bioavailability, or elimination half-life.

Table 7 Pharmacokinetic Parameters of Clonidine in Healthy Adult Volunteers

	CATAPRES-Fasted n=15		Clonidine Hydrochloride Extended-Release-Fed n=15		Clonidine Hydrochloride Extended-Release-Fasted n=14
Parameter	Mean	SD	Mean	SD	Mean	SD
Cmax (pg/mL)	443	59.6	235	34.7	258	33.3
AUCinf (hr*pg/mL)	7313	1812	6505	1728	6729	1650
hTmax (hr)	2.07	0.5	6.80	3.61	6.50	1.23
T1/2 (hr)	12.57	3.11	12.67	3.76	12.65	3.56

Figure 1 Mean Clonidine Concentration-Time Profiles after Single Dose Administration

13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility

Short-term Monotherapy and Adjunctive Therapy to Psychostimulant Studies for ADHD

The efficacy of clonidine hydrochloride 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 (CLON) 0.2 mg/day (N=78), clonidine hydrochloride 0.4 mg/day (N=80), or placebo (N=78). Dosing for the clonidine hydrochloride 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-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 adjunct to a psychostimulant (N=102) or psychostimulant alone (N=96). The clonidine hydrochloride 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 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).

Maintenance Monotherapy for ADHD

Study 3 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 (N=68) and Placebo (N=67), to evaluate the long-term efficacy of maintenance dose of clonidine hydrochloride 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 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.

Figure 2: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Treatment Failure (Study 3)

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 during pregnancy [see Use in Specific Populations (8.1)].

Lactation

Advise breastfeeding women using clonidine hydrochloride 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 may impair fertility [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].