Clonidine Hydrochloride

1 INDICATIONS AND USAGE 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 C linical 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 )

2 DOSAGE AND ADMINISTRATION • 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 extended-release tablets are 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 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.

3 DOSAGE FORMS AND STRENGTHS Clonidine hydrochloride extended-release tablets are available in one strength, 0.1 mg as an extended-release formulation. The 0.1 mg tablets are white, non-scored, standard convex with no debossing on both sides. The 0.1 mg tablets are round. Clonidine hydrochloride extended-release tablets must be swallowed whole and never crushed, cut or chewed. Extended-release tablets: 0.1 mg, not scored. ( 3 )

4 CONTRAINDICATIONS Clonidine hydrochloride extended-release tablets are contraindicated in patients with a history of a hypersensitivity reaction to clonidine. Reactions have included generalized rash, urticaria, and angioedema [see Adverse Reactions (6) ] . History of a hypersensitivity reaction to clonidine. Reactions have included generalized rash, urticaria, angioedema. ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are described in greater detail elsewhere in labeling: Hypotension/bradycardia [see Warnings and Precautions ( 5.1 )] Sedation and somnolence [see Warnings and Precautions ( 5.2 )] Rebound hypertension [see Warnings and Precautions ( 5.3 )] Allergic reactions [see Warnings and Precautions ( 5.4 )] Cardiac Conduction Abnormalities [see Warnings and Precautions ( 5.5 )] Most common adverse reactions (incidence at least 5% and twice the rate of placebo) as monotherapy in ADHD: somnolence, fatigue, irritability, nightmare, insomnia, constipation, dry mouth. ( 6.1 ) Most common adverse reactions (incidence at least 5% and twice the rate of placebo) as adjunct therapy to psychostimulant in ADHD: somnolence, fatigue, decreased appetite, dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ajanta Pharma USA Inc. at 1-855-664-7744 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials 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 extended-release tablets 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 extended-release tablets ADHD clinical study (Study 3, SHN KAP-401) evaluated 135 children and adolescents in a 40- week placebo-controlled randomized-withdrawal study. Study 1: Fixed-dose Clonidine Hydrochloride Extended-Release Tablets Monotherapy Study 1 (CLON-301) was a short-term, multi-center, randomized, double-blind, placebo-controlled study of two fixed doses (0.2 mg/day or 0.4 mg/day) of clonidine hydrochloride extended-release tablets in children and adolescents (6 to 17 years of age) who met DSM-IV criteria for ADHD hyperactive or combined inattentive/hyperactive subtypes. Most Common Adverse Reactions (incidence of greater than or equal to 5% and at least twice the rate of placebo): somnolence, fatigue, irritability, insomnia, nightmare, constipation, dry mouth. Adverse Events Leading to Discontinuation of clonidine hydrochloride extended-release tablets –Five patients (7%) in the low dose group (0.2 mg), 15 patients (20%) in the high dose group (0.4 mg), and 1 patient in the placebo group (1%) reported adverse reactions that led to discontinuation. The most common adverse reactions that led to discontinuation were somnolence and fatigue. Commonly observed adverse reactions (incidence of greater than or equal to 2% in either active treatment group and greater than the rate on placebo) during the treatment period are listed in Table 2. Table 2: Common Adverse Reactions in the Fixed-Dose Monotherapy Trial- Treatment Period (Study 1) * Somnolence includes the terms "somnolence" and "sedation". † Fatigue includes the terms "fatigue" and "lethargy". Percentage of Patients Reporting Event Preferred Term Clonidine Hydrochloride Extended-Release Tablets 0.2 mg/day N=76 Clonidine Hydrochloride Extended-Release Tablets 0.4 mg/day N=78 Placebo (N=76) PSYCHIATRIC DISORDERS Somnolence* 38% 31% 4% Nightmare 4% 9% 0% Emotional Disorder 4% 4% 1% Aggression 3% 1% 0% Tearfulness 1% 3% 0% Enuresis 0% 4% 0% Sleep Terror 3% 0% 0% Poor Quality Sleep 0% 3% 1% NERVOUS SYSTEM DISORDERS Headache 20% 13% 16% Insomnia 5% 6% 1% Tremor 1% 4% 0% Abnormal Sleep-Related Event 3% 1% 0% GASTROINTESTINAL DISORDERS Upper Abdominal Pain 15% 10% 12% Nausea 4% 5% 3% Constipation 1% 6% 0% Dry Mouth 0% 5% 1% GENERAL DISORDERS Fatigue† Irritability 16% 9% 13% 5% 1% 4% CARDIAC DISORDERS Dizziness Bradycardia 7% 0% 3% 4% 5% 0% INVESTIGATIONS Increased Heart Rate 0% 3% 0% METABOLISM AND NUTRITION DISORDERS Decreased Appetite 3% 4% 4% Commonly observed adverse reactions (incidence of greater than or equal to 2% in either …

7 DRUG INTERACTIONS 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 c lonidine hydrochloride extended-release tablets. ( 7 )

8 USE IN SPECIFIC POPULATIONS Renal Impairment: The dosage of clonidine hydrochloride extended-release tablets must be adjusted according to the degree of impairment, and patients should be carefully monitored. ( 8.6 , 12.3 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including clonidine hydrochloride extended-release tablets, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visiting https://womensmentalhealth.org/research/pregnancyregistry/adhd-medications/ . Risk Summary Prolonged experience with clonidine in pregnant women over several decades, based on published literature, including controlled trials, a retrospective cohort study and case reports, have not identified a drug associated risk of major birth defects, miscarriage, and adverse maternal or fetal outcomes. In animal embryofetal studies, increased resorptions were seen in rats and mice administered oral clonidine hydrochloride from implantation through organogenesis at 10 and 5 times, respectively, the maximum recommended human dose (MRHD) given to adolescents on a mg/m 2 basis. No developmental effects were seen in rabbits administered oral clonidine hydrochloride during organogenesis at doses up to 3 times the MRHD (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Oral administration of clonidine hydrochloride to pregnant rabbits during the period of embryo/fetal organogenesis at doses of up to 80 mcg/kg/day (approximately 3 times the oral maximum recommended daily dose [MRHD] of 0.4 mg/day given to adolescents on a mg/m 2 basis) produced no developmental effects. In pregnant rats, however, doses as low as 15 mcg/kg/day (1/3 the MRHD given to adolescents on a mg/m 2 basis) were associated with increased resorptions in a study in which dams were treated continuously from 2 months prior to mating and throughout gestation. Increased resorptions were not associated with treatment at the same or at higher dose levels (up to 3 times the MRHD) when treatment of the dams was restricted to gestation days 6 to 15. Increases in resorptions were observed in both rats and mice at 500 mcg/kg/day (10 and 5 times the MRHD in rats and mice, respectively) or higher when the animals were treated on gestation days 1 to 14; 500 mcg/kg/day was the lowest dose employed in this study. 8.2 Lactation Risk Summary Based on published lactation studies, clonidine hydrochloride is present in human milk at relative infant doses ranging from 4.1 to 8.4% of the maternal weight-adjusted dosage. Although in most cases, there were no reported adverse effects in breastfed infants exposed to clonidine, there is one case report of sedation, hypotonia, and apnea in an infant exposed to clonidine through breast milk. If an infant is exposed to clonidine hydrochloride through breastmilk, monitor for symptoms of hypotension and bradycardia, such as sedation, lethargy, tachypnea and poor feeding (see Clinical Considerations) . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for clonidine hydrochloride extended-release tablets and any potential adverse effects on the breastfed child from clonidine hydrochloride extended-release tablets or from the underlying maternal condition. Exercise caution when clonidine hydrochloride extended-release tablets are administered to a nursing woman. Clinical Considerations Monitor breastfeeding infants exposed to clonidine hydrochloride ext …

12.1 Mechanism of Action Clonidine stimulates alpha 2 -adrenergic receptors in the brain. Clonidine is not a central nervous system stimulant. The mechanism of action of clonidine in ADHD is not known.

11 DESCRIPTION Clonidine hydrochloride extended-release tablets USP are 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, hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The formulation is designed to delay the absorption of active drug in order to decrease peak to trough plasma concentration differences. Clonidine hydrochloride 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: C 9 H 9 Cl 2 N 3 •HCl Mol. Wt. 266.56 Clonidine hydrochloride is an odorless, bitter, white, crystalline substance soluble in water and alcohol. Clonidine hydrochloride extended-release tablets USP meet USP Dissolution Test 2. image-01

10 OVERDOSAGE 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.

16 HOW SUPPLIED/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