Onyda Drug Information

is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to central nervous system (CNS) stimulant medications in pediatric patients 6 years of age and older. ONYDA XR is a centrally acting alpha 2 -adrenergic agonist indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy or as adjunctive therapy to central nervous system (CNS) stimulant medications in pediatric patients 6 years of age and older.

Recommended Dosage

The starting dosage of ONYDA XR is 0.1 mg orally once daily at bedtime with or without food . Titrate the dose of ONYDA XR in increments of 0.1 mg per day at weekly intervals depending on clinical response up to the maximum recommended dosage of 0.4 mg once daily at bedtime. Doses of ONYDA XR higher than 0.4 mg once daily were not evaluated in clinical trials for ADHD and are not recommended. When ONYDA XR is added to a CNS stimulant, adjust the dose of the CNS stimulant depending on the clinical response to ONYDA XR.

Administration Instructions Instruct patients to read the “Instructions for Use” for complete

administration instructions. Use the oral dosing dispenser and bottle adapter provided with ONYDA XR. Ensure that the bottle adapter is firmly inserted into the bottle before first use and keep the adapter in place for the duration of the usage of the bottle. Gently shake ONYDA XR with a smooth up and down motion (to avoid foaming) for at least 10 seconds before each administration.

For the bottles of 30 mL and 60 mL, discard any unused ONYDA XR 30 days after first opening the bottle. For the 120 mL bottle, discard any unused ONYDA XR 60 days after first opening the bottle.

Switching from Other Clonidine Products For patients switching from another clonidine product

discontinue that treatment, and titrate with ONYDA XR using the titration schedule . Do not substitute for other clonidine products on a milligram-per-milligram basis because of differing pharmacokinetic profiles.

Discontinuation

When discontinuing ONYDA XR, taper the total daily dose in decrements of no more than 0.1 mg every 3 to 7 days to avoid rebound hypertension.

Missed Doses

If a dose of ONYDA XR is missed, skip that dose and take the next dose as scheduled. Do not take more than the prescribed total daily amount of ONYDA XR in any 24-hour period.

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. The safety of ONYDA XR for the treatment of ADHD in pediatric patients 6 years and older is based upon adequate and well-controlled studies of clonidine hydrochloride extended-release tablets (referred to as “clonidine hydrochloride extended-release” in this section). The safety results of these adequate and well-controlled studies of clonidine hydrochloride extended-release tablets are presented below. Two clonidine hydrochloride extended-release ADHD clinical studies (Study 1 and Study 2) evaluated 256 patients in two 8-week placebo-controlled studies.

A third clonidine hydrochloride extended-release ADHD clinical study (Study 3) evaluated 135 pediatric patients 6 to 17 years of age in a 40-week placebo-controlled randomized‑withdrawal study. Study 1: Fixed-dose clonidine hydrochloride extended-release Monotherapy Study 1 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 in pediatric patients 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 ≥ 5% and at least twice the rate of placebo): somnolence, fatigue, irritability, insomnia, nightmare, constipation, dry mouth.

Adverse Reactions Leading to Discontinuation of clonidine hydrochloride extended-release: 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 ≥2% in either active treatment group and greater than the rate on placebo) during the treatment period are listed in Table 1. Table 1: Common Adverse Reactions Occurring in ≥2%of Patients Treated with Clonidine Hydrochloride Extended-Release Tablets and Greater than the Rate of Placebo in the Fixed-Dose Monotherapy Trial -Treatment Period (Study 1) 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 * Nightmare Emotional Disorder Aggression Tearfulness Enuresis Sleep Terror Poor Quality Sleep 38 4 4 3 1 0 3 0 31 9 4 1 3 4 0 3 4 0 1 0 0 0 0 1 NERVOUS SYSTEM DISORDERS Headache Insomnia Tremor Abnormal Sleep-Related Event 20 5 1 3 13 6 4 1 16 1 0 0 GASTRO-INTESTINAL DISORDERS Upper Abdominal Pain Nausea Constipation Dry Mouth 15 4 1 0 10 5 6 5 12 3 0 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 * Somnolence includes the terms "somnolence" and "sedation". † Fatigue includes the terms "fatigue" and "lethargy". Commonly observed adverse reactions (incidence of ≥2% in either active treatment group and greater than the rate on placebo) during the taper period are listed in Table 2. Table 2: Common Adverse Reactions Occurring in ≥2% of Patients Treated with Clonidine Hydrochloride Extended-Release Tablets and Greater than the Rate of Placebo in the Fixed-Dose Monotherapy Trial -Taper Period* (Study 1) 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 (%) Abdominal Pain Upper 0 6 3 Headache 5 2 3 Gastrointestinal Viral 0 5 0 Somnolence 2 3 0 Heart Rate Increased 0 3 0 Otitis Media Acute 3 0 0 * Taper Period: 0.2 mg dose, week 8; 0.4 mg dose, weeks 6-8; Placebo dose, weeks 6-8 Study 2: Flexible-dose clonidine hydrochloride extended-release as Adjunctive Therapy to Psychostimulants Study 2 was a short-term, randomized, double-blind, placebo-controlled study of a flexible dose of clonidine hydrochloride extended-release as adjunctive therapy to a psychostimulant in pediatric patients 6 to 17 years of age who met DSM-IV criteria for ADHD hyperactive or combined inattentive/hyperactive subtypes, during which clonidine hydrochloride extended‑release was initiated at 0.1 mg/day and titrated up to 0.4 mg/day over a 3-week period.

Most clonidine hydrochloride extended-release treated patients (75.5%) were escalated to the maximum dose of 0.4 mg/day. Most Common Adverse Reactions (incidence of ≥ 5% and at least twice the rate of placebo): somnolence, fatigue, decreased appetite, dizziness. Adverse Reactions Leading to Discontinuation: There was one patient in the clonidine hydrochloride extended-release + stimulant (group (1%) who discontinued because of an adverse event (severe bradyphrenia, with severe fatigue). Commonly observed adverse reactions (incidence of ≥2% in the treatment group and greater than the rate on placebo) during the treatment period are listed in Table 3. Table 3: Common Adverse Reactions Occurring in ≥2% of Patients Treated with Clonidine Hydrochloride Extended-Release Tablets and Greater than the Rate of Placebo in the Flexible-Dose Adjunctive to Stimulant Therapy Trial -Treatment Period (Study 2) Preferred Term Clonidine hydrochloride extended-release tablets + Stimulant N=102 (%) PBO+Stimulant N=96 (%) PSYCHIATRIC DISORDERS Somnolence+ Aggression Affect Lability Emotional Disorder 19 2 2 2 7 1 1 0 GENERAL DISORDERS Fatigue† Irritability 14 2 4 7 NERVOUS SYSTEM DISORDERS Headache Insomnia 7 4 12 3 GASTRO-INTESTINAL DISORDERS Upper Abdominal Pain 7 4 RESPIRATORY DISORDERS Nasal Congestion 2 2 METABOLISM AND NUTRITION DISORDERS Decreased Appetite 6 3 CARDIAC DISORDERS Dizziness 5 1 + Somnolence includes the terms: "somnolence" and "sedation" † Fatigue includes the terms "fatigue" and "lethargy" Commonly observed adverse reactions (incidence of ≥2% in the treatment group and greater than the rate on placebo) during the taper period are listed in Table 4. Table 4: Common Adverse Reactions Occurring in ≥2% of Patients Treated with Clonidine Hydrochloride Extended-Release Tablets and Greater than the Rate of Placebo in the Flexible-Dose Adjunctive to Stimulant Therapy Trial -Taper Period + (Study 2) Preferred Term Clonidine hydrochloride extended-release tablets + Stimulant N=102 (%) Placebo+Stimulant N=96 (%) Nasal Congestion 4 2 Headache 3 1 Irritability 3 2 Throat Pain 3 1 Gastroenteritis Viral 2 0 Rash 2 0 + Taper Period: weeks 6-8 Adverse Reactions Leading to Discontinuation Thirteen percent (13%) of patients receiving clonidine hydrochloride extended-release discontinued from the pediatric monotherapy study due to adverse reactions, compared to 1% in the placebo group.

The most common adverse reactions leading to discontinuation of clonidine hydrochloride extended-release monotherapy treated patients were somnolence/sedation (5%) and fatigue (4%). Effect on Blood Pressure and Heart Rate In patients that completed 5 weeks of treatment in a controlled, fixed-dose monotherapy study in pediatric patients, during the treatment period the maximum placebo-subtracted mean change in systolic blood pressure was -4.0 mmHg on clonidine hydrochloride extended-release 0.2 mg/day and -8.8 mmHg on clonidine hydrochloride extended-release 0.4 mg/day. The maximum placebo-subtracted mean change in diastolic blood pressure was -4.0 mmHg on clonidine hydrochloride extended-release 0.2 mg/day and -7.3 mmHg on clonidine hydrochloride extended-release 0.4 mg/day. The maximum placebo-subtracted mean change in heart rate was ‑4.0 beats per minute on clonidine hydrochloride extended-release 0.2 mg/day and -7.7 beats per minute on clonidine hydrochloride extended-release 0.4 mg/day.

During the taper period of the fixed-dose monotherapy study the maximum placebo-subtracted mean change in systolic blood pressure was +3.4 mmHg on clonidine hydrochloride extended‑release 0.2 mg/day and -5.6 mmHg on clonidine hydrochloride extended-release 0.4 mg/day. The maximum placebo-subtracted mean change in diastolic blood pressure was +3.3 mmHg on clonidine hydrochloride extended-release 0.2 mg/day and -5.4 mmHg on clonidine hydrochloride extended-release 0.4 mg/day. The maximum placebo-subtracted mean change in heart rate was -0.6 beats per minute on clonidine hydrochloride extended-release 0.2 mg/day and -3.0 beats per minute on clonidine hydrochloride extended-release 0.4 mg/day.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of clonidine hydrochloride extended-release tablets (and excludes those already mentioned in Section 6.1 ). 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. Psychiatric: hallucinations Cardiovascular: Q-T prolongation

The interactions of ONYDA XR with co-administration of other drugs have not been studied. The drug interaction data provided in this section is based on oral immediate-release clonidine formulations. Table 5 displays clinically important drug interactions with ONYDA XR. Table 5: Clinically Important Drug Interactions with ONYDA XR Antihypertensive drugs Clinical Implication Concomitant use of antihypertensive drugs with clonidine potentiates the hypotensive effects of clonidine.

Intervention Monitor blood pressure and heart rate, and adjust dosage of ONYDA XR accordingly in patients treated concomitantly with antihypertensives . CNS depressants Clinical Implication Concomitant use of CNS depressants with clonidine potentiates the sedating effects . Intervention Avoid concomitant use of CNS depressants with ONYDA XR. Drugs that affect sinus node function or AV node conduction (e.g., digitalis, calcium channel blockers, beta blockers) Clinical Implication Concomitant use of drugs that affect sinus node function or AV node conduction with clonidine potentiate bradycardia and risk of AV block . Intervention Avoid concomitant use of drugs that affect sinus node function or AV node conduction with ONYDA XR. Tricyclic antidepressants Clinical Implication Concomitant use of tricyclic antidepressants with clonidine can increase blood pressure and may counteract the hypotensive effects of clonidine. Intervention Monitor blood pressure and adjust dosage of ONYDA XR as needed. CNS Depressants: Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs.

Tricyclic Antidepressants: May reduce the hypotensive effect of clonidine. Drugs Known to Affect Sinus Node Function or AV Nodal Conduction: Avoid use of ONYDA XR 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. Antihypertensive drugs: Use caution when coadministered with ONYDA XR.

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including ONYDA XR, during pregnancy. Healthcare providers are encouraged to advise patients to register by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/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 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 6-15. 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 1-14; 500 mcg/kg/day was the lowest dose employed in this study.

Pediatric Use The safety and efficacy of clonidine hydrochloride extended-release in the treatment of ADHD have been established in pediatric patients 6 to 17 years of age. Use of clonidine hydrochloride extended-release 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. Safety and efficacy in pediatric patients below the age of 6 years has not been established.

Juvenile Animal Data In studies in juvenile rats, clonidine hydrochloride alone or in combination with methylphenidate had an effect on bone growth at clinically relevant doses and produced a slight delay in sexual maturation in males at 3 times the maximum recommended human dose (MRHD) for clonidine and methylphenidate. In a study where juvenile rats were treated orally with clonidine hydrochloride from day 21 of age to adulthood, a slight delay in onset of preputial separation (delayed sexual maturation) was seen in males treated with 300 mcg/kg/day, which is approximately 3 times the MRHD of 0.4 mg/day on a mg/m 2 basis. The no-effect dose was 100 mcg/kg/day, which is approximately equal to the MRHD. There was no drug effects on fertility or on other measures of sexual or neurobehavioral development.

In a study where juvenile rats were treated with clonidine alone (300 mcg/kg/day) or in combination with methylphenidate (10 mg/kg/day in females and 50/30 mg/kg/day in males; the dose was lowered from 50 to 30 mg/kg/day in males due to self-injurious behavior during the first week of treatment) from day 21 of age to adulthood, decreases in bone mineral density and mineral content were observed in males treated with 300 mcg/kg/day clonidine alone and in combination with 50/30 mg/kg/day methylphenidate and a decrease in femur length was observed in males treated with the combination at the end of the treatment period. These doses are approximately 3 times the MRHD of 0.4 mg/day clonidine and 54 mg/day methylphenidate on a mg/m 2 basis. All these effects in male were not reversed at the end of a 4-week recovery period.

In addition, similar findings were seen in males treated with a lower dose of clonidine (30 mcg/kg/day) in combination with 50 mg/kg/day of methylphenidate and a decrease in femur length was observed in females treated with clonidine alone at the end of the recovery period. These effects were accompanied by a decrease in body weight gain in treated animals during the treatment period but the effect was reversed at the end of the recovery period. A delay in preputial separation (sexual maturation) was observed in males treated with the combination treatment of 300 mcg/kg/day clonidine and 50/30 mg/kg/day methylphenidate.

There was no effect on reproduction or sperm analysis in these males.

is contraindicated in patients with a history of a hypersensitivity reaction to clonidine. Reactions have included generalized rash, urticaria, and angioedema. History of a hypersensitivity reaction to clonidine.

Reactions have included generalized rash, urticaria, angioedema.

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 pediatric patients 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. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.