ONYDA XR 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 [see Clinical Studies (14)].

{ "type": "p", "children": [], "text": "ONYDA XR 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 [see Clinical Studies (14)].\n" }

The starting dosage of ONYDA XR is 0.1 mg orally once daily at bedtime with or without food [see Clinical Pharmacology (12.3)]. 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.

Instruct patients to read the “Instructions for Use” for complete administration instructions.

For patients switching from another clonidine product, discontinue that treatment, and titrate with ONYDA XR using the titration schedule [see Dosage and Administration (2.1)]. Do not substitute for other clonidine products on a milligram-per-milligram basis because of differing pharmacokinetic profiles [see Clinical Pharmacology (12.3)].

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 [see Warnings and Precautions (5.3)].

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.

Extended-release oral suspension: Light beige to tan viscous suspension containing 0.1 mg clonidine hydrochloride per mL.

{ "type": "p", "children": [], "text": "Extended-release oral suspension: Light beige to tan viscous suspension containing 0.1 mg clonidine hydrochloride per mL. " }

ONYDA XR is contraindicated in patients with a history of a hypersensitivity reaction to clonidine. Reactions have included generalized rash, urticaria, and angioedema [see Warnings and Precautions (5.4) and Adverse Reactions (6)].

{ "type": "p", "children": [], "text": "ONYDA XR is contraindicated in patients with a history of a hypersensitivity reaction to clonidine. Reactions have included generalized rash, urticaria, and angioedema [see Warnings and Precautions (5.4) and Adverse Reactions (6)].\n" }

Treatment with ONYDA XR 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 ONYDA XR 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 [see Drug Interactions (7)].

Somnolence and sedation were commonly reported adverse reactions in clinical studies with clonidine hydrochloride extended-release tablets. 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 reaction. 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 plus a stimulant versus 7% treated with placebo plus a stimulant reported somnolence.

Before using ONYDA XR with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), consider the potential for additive sedative effects [see Drug Interactions (7)]. Caution patients against operating heavy equipment or driving until they know how they respond to treatment with ONYDA XR. Advise patients to avoid use with alcohol.

Abrupt discontinuation of ONYDA XR can cause rebound hypertension. In adults with hypertension, sudden cessation of clonidine extended-release formulation treatment in the 0.2 to 0.6 mg per 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. Pediatric patients with gastrointestinal illnesses that lead to vomiting may result in missed doses of ONYDA XR, increasing the risk for rebound hypertension.

No studies evaluating abrupt discontinuation of clonidine hydrochloride extended-release tablets in pediatric patients with ADHD have been conducted; however, to minimize the risk of rebound hypertension, gradually reduce the dose of ONYDA XR in decrements of no more than 0.1 mg every 3 to 7 days. Patients should be instructed not to discontinue ONYDA XR therapy without consulting their physician due to the potential risk of withdrawal effects.

In patients who have developed localized contact sensitization to clonidine transdermal system, continuation of clonidine transdermal system or use of oral ONYDA XR therapy may be associated with the development of a generalized skin rash.

In patients who develop an allergic reaction from clonidine transdermal system, use of ONYDA XR may also elicit an allergic reaction (including generalized rash, urticaria, or angioedema).

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 intravenous (IV) atropine, IV isoproterenol, and temporary cardiac pacing while taking clonidine. Titrate ONYDA XR slowly and monitor vital signs frequently in patients with cardiac conduction abnormalities or patients concomitantly treated with other sympatholytic drugs.

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)

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <col width="199.45pt"/> <col width="97.15pt"/> <col width="99pt"/> <col width="71.6pt"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Preferred Term</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Clonidine hydrochloride extended-release tablets</span> </p> <p> <span class="Bold">0.2 mg/day</span> </p> <p> <span class="Bold">N=76</span> </p> <p> <span class="Bold">(%)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Clonidine hydrochloride extended-release tablets</span> </p> <p> <span class="Bold">0.4 mg/day</span> </p> <p> <span class="Bold">N=78</span> </p> <p> <span class="Bold">(%)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Placebo N=76</span> </p> <p> <span class="Bold">(%)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">PSYCHIATRIC DISORDERS</p> <p>Somnolence<span class="Sup">*</span> </p> <p>Nightmare</p> <p>Emotional Disorder</p> <p>Aggression</p> <p>Tearfulness</p> <p>Enuresis</p> <p>Sleep Terror</p> <p>Poor Quality Sleep</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">38</p> <p>4</p> <p>4</p> <p>3</p> <p>1</p> <p>0</p> <p>3</p> <p>0</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">31</p> <p>9</p> <p>4</p> <p>1</p> <p>3</p> <p>4</p> <p>0</p> <p>3</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> <p>0</p> <p>1</p> <p>0</p> <p>0</p> <p>0</p> <p>0</p> <p>1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">NERVOUS SYSTEM DISORDERS</p> <p>Headache</p> <p>Insomnia</p> <p>Tremor</p> <p>Abnormal Sleep-Related Event</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">20</p> <p>5</p> <p>1</p> <p>3</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">13</p> <p>6</p> <p>4</p> <p>1</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">16</p> <p>1</p> <p>0</p> <p>0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">GASTRO-INTESTINAL DISORDERS</p> <p>Upper Abdominal Pain</p> <p>Nausea</p> <p>Constipation</p> <p>Dry Mouth</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">15</p> <p>4</p> <p>1</p> <p>0</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">10</p> <p>5</p> <p>6</p> <p>5</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">12</p> <p>3</p> <p>0</p> <p>1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">GENERAL DISORDERS</p> <p>Fatigue<span class="Sup">†</span> </p> <p>Irritability</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">16</p> <p>9</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">13</p> <p>5</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> <p>4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">CARDIAC DISORDERS</p> <p>Dizziness</p> <p>Bradycardia</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">7</p> <p>0</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> <p>4</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">5</p> <p>0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">INVESTIGATIONS</p> <p>Increased Heart Rate</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First">METABOLISM AND NUTRITION DISORDERS</p> <p>Decreased Appetite</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td> </tr> </tbody> </table></div>

* 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)

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <col width="116.8pt"/> <col width="116.8pt"/> <col width="116.8pt"/> <col width="116.8pt"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Preferred Term</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Clonidine hydrochloride extended-release tablets</span> </p> <p> <span class="Bold">0.2 mg/day</span> </p> <p> <span class="Bold">N=76</span> </p> <p> <span class="Bold">(%)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Clonidine hydrochloride extended-release tablets</span> </p> <p> <span class="Bold">0.4 mg/day</span> </p> <p> <span class="Bold">N=78</span> </p> <p> <span class="Bold">(%)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Placebo </span> </p> <p> <span class="Bold">N=76</span> </p> <p> <span class="Bold">(%)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Abdominal Pain Upper</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Headache</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">5</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Gastrointestinal Viral</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">5</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Somnolence</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Heart Rate Increased</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Otitis Media Acute</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> </tbody> </table></div>

* 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)

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <col width="193.5pt"/> <col width="148.9pt"/> <col width="134.6pt"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Preferred Term</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Clonidine hydrochloride extended-release tablets + Stimulant</span> </p> <p> <span class="Bold">N=102</span> </p> <p> <span class="Bold">(%)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">PBO+Stimulant</span> </p> <p> <span class="Bold">N=96</span> </p> <p> <span class="Bold">(%)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">PSYCHIATRIC DISORDERS</p> <p>Somnolence+</p> <p>Aggression</p> <p>Affect Lability</p> <p>Emotional Disorder</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">19</p> <p>2</p> <p>2</p> <p>2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">7</p> <p>1</p> <p>1</p> <p>0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">GENERAL DISORDERS</p> <p>Fatigue†</p> <p>Irritability</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">14</p> <p>2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> <p>7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">NERVOUS SYSTEM DISORDERS</p> <p>Headache</p> <p>Insomnia</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">7</p> <p>4</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">12</p> <p>3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">GASTRO-INTESTINAL DISORDERS</p> <p>Upper Abdominal Pain</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">7</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">RESPIRATORY DISORDERS</p> <p>Nasal Congestion</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">METABOLISM AND NUTRITION DISORDERS</p> <p>Decreased Appetite</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First">CARDIAC DISORDERS</p> <p>Dizziness</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">5</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td> </tr> </tbody> </table></div>

 +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)

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <col width="155.7pt"/> <col width="155.75pt"/> <col width="155.75pt"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Preferred Term</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Clonidine hydrochloride extended-release tablets + Stimulant</span> </p> <p> <span class="Bold">N=102</span> </p> <p> <span class="Bold">(%)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Placebo+Stimulant</span> </p> <p> <span class="Bold">N=96</span> </p> <p> <span class="Bold">(%)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Nasal Congestion</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Headache</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Irritability</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Throat Pain</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Gastroenteritis Viral</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Rash</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> </tbody> </table></div>

+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.

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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "\nTable 5 displays clinically important drug interactions with ONYDA XR." }

Table 5:  Clinically Important Drug Interactions with ONYDA XR

{ "type": "p", "children": [], "text": "\nTable 5:  Clinically Important Drug Interactions with ONYDA XR\n" }

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <col width="467.75pt"/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="2"> <p class="First"> <span class="Bold">Antihypertensive drugs</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Italics">Clinical Implication</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Concomitant use of antihypertensive drugs with clonidine potentiates the hypotensive effects of clonidine.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Italics">Intervention</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Monitor blood pressure and heart rate, and adjust dosage of ONYDA XR accordingly in patients treated concomitantly with antihypertensives <span class="Italics">[see Warnings and Precautions (</span><span class="Italics"><a href="#LINK_794d58dd-1009-43be-89d1-d8121df31c75">5.1</a></span><span class="Italics">)]</span>.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"> <p class="First"> <span class="Bold">CNS depressants</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Italics">Clinical Implication</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Concomitant use of CNS depressants with clonidine potentiates the sedating effects <span class="Italics">[see Warnings and Precautions (</span><span class="Italics"><a href="#LINK_056b2f92-dc45-4728-bddd-a19ecd9b17f6">5.2</a></span><span class="Italics">)]</span>.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Italics">Intervention</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Avoid concomitant use of CNS depressants with ONYDA XR.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"> <p class="First"> <span class="Bold">Drugs that affect sinus node function or AV node conduction (e.g., digitalis, calcium channel blockers, beta blockers)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Italics">Clinical Implication</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Concomitant use of drugs that affect sinus node function or AV node conduction with clonidine potentiate bradycardia and risk of AV block <span class="Italics">[see Warnings and Precautions (</span><span class="Italics"><a href="#LINK_583d00c2-f47d-45ff-a1ba-2e80d2cb397e">5.5</a></span><span class="Italics">)]</span>.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Italics">Intervention</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Avoid concomitant use of drugs that affect sinus node function or AV node conduction with ONYDA XR.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"> <p class="First"> <span class="Bold">Tricyclic antidepressants</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Italics">Clinical Implication</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Concomitant use of tricyclic antidepressants with clonidine can increase blood pressure and may counteract the hypotensive effects of clonidine.</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Italics">Intervention</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Monitor blood pressure and adjust dosage of ONYDA XR as needed.</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table border=\"1\" cellpadding=\"0\" cellspacing=\"0\">\n<col width=\"467.75pt\"/>\n<col/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Antihypertensive drugs</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Implication</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Concomitant use of antihypertensive drugs with clonidine potentiates the hypotensive effects of clonidine.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Monitor blood pressure and heart rate, and adjust dosage of ONYDA XR accordingly in patients treated concomitantly with antihypertensives <span class=\"Italics\">[see Warnings and Precautions (</span><span class=\"Italics\"><a href=\"#LINK_794d58dd-1009-43be-89d1-d8121df31c75\">5.1</a></span><span class=\"Italics\">)]</span>.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">CNS depressants</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Implication</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Concomitant use of CNS depressants with clonidine potentiates the sedating effects <span class=\"Italics\">[see Warnings and Precautions (</span><span class=\"Italics\"><a href=\"#LINK_056b2f92-dc45-4728-bddd-a19ecd9b17f6\">5.2</a></span><span class=\"Italics\">)]</span>.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Avoid concomitant use of CNS depressants with ONYDA XR.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Drugs that affect sinus node function or AV node conduction (e.g., digitalis, calcium channel blockers, beta blockers)</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Implication</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Concomitant use of drugs that affect sinus node function or AV node conduction with clonidine potentiate bradycardia and risk of AV block <span class=\"Italics\">[see Warnings and Precautions (</span><span class=\"Italics\"><a href=\"#LINK_583d00c2-f47d-45ff-a1ba-2e80d2cb397e\">5.5</a></span><span class=\"Italics\">)]</span>.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Avoid concomitant use of drugs that affect sinus node function or AV node conduction with ONYDA XR.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Tricyclic antidepressants</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Implication</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Concomitant use of tricyclic antidepressants with clonidine can increase blood pressure and may counteract the hypotensive effects of clonidine.</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Monitor blood pressure and adjust dosage of ONYDA XR as needed.</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

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/m2 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/m2 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/m2 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.

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 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 ONYDA XR and any potential adverse effects on the breastfed child from ONYDA XR or from the underlying maternal condition. Exercise caution when ONYDA XR is administered to a nursing woman.

Clinical Considerations

Monitor breastfeeding infants exposed to ONYDA XR through breast milk for symptoms of hypotension and/or bradycardia such as sedation, lethargy, tachypnea, and poor feeding.

Infertility

Findings in animal studies revealed that ONYDA XR may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)].

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 [see Clinical Studies (14)]. 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/m2 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/m2 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.

The impact of renal impairment on the pharmacokinetics of clonidine in pediatric patients has not been assessed. The initial dosage of ONYDA XR 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 ONYDA XR following dialysis.

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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations." }

ONYDA XR contains clonidine hydrochloride, a centrally acting alpha2-adrenergic agonist. Clonidine hydrochloride is an imidazoline derivative and exists as a mesomeric compound. The chemical name is 2-[(2,6-dichlorophenyl)imino]imidazolidine hydrochloride. The following is the structural formula:

{ "type": "p", "children": [], "text": "ONYDA XR contains clonidine hydrochloride, a centrally acting alpha2-adrenergic agonist. Clonidine hydrochloride is an imidazoline derivative and exists as a mesomeric compound. The chemical name is 2-[(2,6-dichlorophenyl)imino]imidazolidine hydrochloride. The following is the structural formula:" }

The molecular formula of clonidine hydrochloride is C9H9Cl2N3•HCl and the molecular weight is 266.5. The pKa is 8.05.

{ "type": "p", "children": [], "text": "The molecular formula of clonidine hydrochloride is C9H9Cl2N3•HCl and the molecular weight is 266.5. The pKa is 8.05." }

Clonidine hydrochloride is an odorless, bitter, white to almost white, crystalline powder soluble in water and alcohol. The pH of a 5% solution in water is between 3.5 and 5.5.

{ "type": "p", "children": [], "text": "Clonidine hydrochloride is an odorless, bitter, white to almost white, crystalline powder soluble in water and alcohol. The pH of a 5% solution in water is between 3.5 and 5.5. " }

ONYDA XR is an extended-release suspension for oral administration. Each mL of ONYDA XR contains 0.09 mg clonidine equivalent to 0.1 mg clonidine hydrochloride (0.095 mg clonidine hydrochloride complexed with sodium polystyrene sulfonate and 0.005 mg clonidine hydrochloride). The pH of ONYDA XR is between 2.8 and 4.

{ "type": "p", "children": [], "text": "ONYDA XR is an extended-release suspension for oral administration. Each mL of ONYDA XR contains 0.09 mg clonidine equivalent to 0.1 mg clonidine hydrochloride (0.095 mg clonidine hydrochloride complexed with sodium polystyrene sulfonate and 0.005 mg clonidine hydrochloride). The pH of ONYDA XR is between 2.8 and 4." }

The inactive ingredients are anhydrous citric acid, edetate disodium, glycerin, modified starch, methylparaben, orange flavor, polyvinyl acetate dispersion 30%, povidone, polysorbate 80, propylparaben, purified water, sucrose, sodium polystyrene sulfonate, triacetin, xanthan gum.

{ "type": "p", "children": [], "text": "The inactive ingredients are anhydrous citric acid, edetate disodium, glycerin, modified starch, methylparaben, orange flavor, polyvinyl acetate dispersion 30%, povidone, polysorbate 80, propylparaben, purified water, sucrose, sodium polystyrene sulfonate, triacetin, xanthan gum." }

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.

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.

Immediate-release clonidine hydrochloride, extended-release clonidine hydrochloride tablets, and ONYDA XR have different pharmacokinetic characteristics. Dose substitution on a milligram for milligram basis will result in differences in exposures [see Dosage and Administration (2.3)].

Absorption

Following a single 0.2 mg dose of ONYDA XR in 20 healthy adult subjects under fasting conditions in a crossover study, the median (range) time to peak plasma concentrations (Tmax) for clonidine was 7.50 (4 –17) hours after dosing. Peak concentration (Cmax) was 95.6% of the Cmax of clonidine extended-release tablet 0.1 mg administered at 0 and 12 hours under fasting conditions. The relative bioavailability of ONYDA XR compared with an equal dose of clonidine extended-release tablet was 96.1%.

After oral administration of 0.2 mg of ONYDA XR once daily over 5 days under fasted conditions in healthy adult subjects, the peak steady state plasma concentration (Cmax.ss) was 107.9%, and steady state relative bioavailability (AUCt, ss) was 97.7% compared with 0.1 mg of clonidine extended-release tablet administered twice daily under fasting conditions. The minimum concentration at steady state (Cmin,ss) of ONYDA XR was about 26% lower than that of the equal dose of clonidine extended-release tablet.

Following oral administration of an immediate release formulation in healthy adult subjects, plasma clonidine concentration peaks in approximately 3 to 5 hours.

A comparison across studies suggests that the Cmax is 50% lower for clonidine hydrochloride extended-release tablets compared to immediate-release clonidine hydrochloride.

Effect of Food

Food had no effect on plasma exposures of clonidine after administration of ONYDA XR (see Figure 1).

Figure 1:       Mean Clonidine Concentration-Time Profiles After Single Dose Administration

Elimination

The plasma half-life of immediate-release clonidine ranges from 12 to 16 hours. The half-life increases up to 41 hours in patients with severe impairment of renal function.

Metabolism

About 50% of the absorbed dose is metabolized in the liver.

Excretion

Following oral administration about 40% to 60% of the absorbed dose is recovered in the urine as unchanged drug in 24 hours. Although studies of the effect of renal impairment and studies of clonidine excretion have not been performed with ONYDA XR, results are expected to be similar to those of the immediate-release formulation.

Specific Populations

Pediatric patients                                                                                   

Plasma clonidine concentrations in pediatric patients 6 to 17 years (0.1 mg twice daily and 0.2 mg twice daily of clonidine hydrochloride extended-release tablets) with ADHD are greater than those of adults with hypertension, with pediatric patients 6 to 17 years receiving higher doses on a mg/kg basis. Body weight normalized clearance (CL/F) in pediatric patients aged 6 to 17 years was higher than CL/F observed in adults with hypertension. Clonidine concentrations in plasma increased with increases in dose over the dose range of 0.2 to 0.4 mg/day. Clonidine CL/F was independent of dose administered over the 0.2 to 0.4 mg/day dose range. Clonidine CL/F appeared to decrease slightly with increases in age over the range of 6 to 17 years, and females had a 23% lower CL/F than males. The incidence of "sedation-like" events (somnolence and fatigue) appeared to be independent of clonidine dose or concentration within the studied dose range in the titration study. Results from the add-on study showed that clonidine CL/F was 11% higher in patients who were receiving methylphenidate and 44% lower in those receiving amphetamine compared to subjects not on adjunctive therapy.

Drug Interaction Studies

Alcohol: In an in vitro alcohol-induced dose dumping study, a significantly faster and more variable ONYDA XR drug release was observed in the presence of 20% alcohol, but not with 5% or 10% alcohol, when compared to 0% alcohol.

Carcinogenesis

Clonidine hydrochloride was not carcinogenic when administered in the diet of rats (for up to 132 weeks) or mice (for up to 78 weeks) at doses of up to 1,620 (male rats), 2,040 (female rats), or 2,500 (mice) mcg/kg/day. These doses are approximately 20, 25, and 15 times, respectively, the maximum recommended human dose (MRHD) of 0.4 mg/day on a mg/m2 basis.

Mutagenesis

There was no evidence of genotoxicity in the Ames test for mutagenicity or mouse micronucleus test for clastogenicity.

Impairment of Fertility

In a reproduction study fertility of female rats appeared to be adversely affected at dose levels of 500 and 2,000 mcg/kg/day (10 and 40 times the MRHD on a mg/m2 basis). Lower doses have not been adequately evaluated and a no adverse effect level could not be established.

The efficacy of ONYDA XR for the treatment of ADHD in pediatric patients 6 years of age 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 efficacy results of these adequate and well-controlled studies of clonidine hydrochloride extended-release tablets are presented below.

{ "type": "p", "children": [], "text": "The efficacy of ONYDA XR for the treatment of ADHD in pediatric patients 6 years of age 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 efficacy results of these adequate and well-controlled studies of clonidine hydrochloride extended-release tablets are presented below." }

Efficacy of clonidine hydrochloride extended-release in the treatment of ADHD was established in pediatric patients 6 to 17 years in:

{ "type": "p", "children": [], "text": "Efficacy of clonidine hydrochloride extended-release in the treatment of ADHD was established in pediatric patients 6 to 17 years in:" }

{ "type": "ul", "children": [ "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)" ], "text": "" }

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

{ "type": "p", "children": [], "text": "\nShort-term Monotherapy and Adjunctive Therapy to Psychostimulant Studies for ADHD \n" }

The efficacy of clonidine hydrochloride extended-release 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 years, 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 was an 8-week randomized, double-blind, placebo-controlled, fixed dose study of pediatric patients 6 to 17 years (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 0.2 mg/day (N=78), clonidine hydrochloride extended-release 0.4 mg/day (N=80), or placebo (N=78). Dosing for the clonidine hydrochloride extended-release 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-treated patients compared with placebo-treated patients at the end of 5 weeks as measured by the ADHDRS-IV total score (Table 6). Study 2 was an 8-week randomized, double-blind, placebo-controlled, flexible dose study in pediatric patients 6 to 17 years (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 adjunct to a psychostimulant (N=102) or psychostimulant alone (N=96). The clonidine hydrochloride extended-release 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 plus stimulant group compared with the stimulant alone group at the end of 5 weeks as measured by the ADHDRS-IV total score (Table 6).

{ "type": "p", "children": [], "text": "The efficacy of clonidine hydrochloride extended-release 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 years, 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 was an 8-week randomized, double-blind, placebo-controlled, fixed dose study of pediatric patients 6 to 17 years (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 0.2 mg/day (N=78), clonidine hydrochloride extended-release 0.4 mg/day (N=80), or placebo (N=78). Dosing for the clonidine hydrochloride extended-release 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-treated patients compared with placebo-treated patients at the end of 5 weeks as measured by the ADHDRS-IV total score (Table 6). Study 2 was an 8-week randomized, double-blind, placebo-controlled, flexible dose study in pediatric patients 6 to 17 years (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 adjunct to a psychostimulant (N=102) or psychostimulant alone (N=96). The clonidine hydrochloride extended-release 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 plus stimulant group compared with the stimulant alone group at the end of 5 weeks as measured by the ADHDRS-IV total score (Table 6)." }

Table 6:          Short-Term Trials

{ "type": "p", "children": [], "text": "\nTable 6:          Short-Term Trials\n" }

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <col width="76.1pt"/> <col width="117pt"/> <col width="297pt"/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" rowspan="2"> <p class="First"> <span class="Bold">Study Number</span> </p> </td><td class="Botrule Lrule Rrule Toprule" rowspan="2"> <p class="First"> <span class="Bold">Treatment Group</span> </p> </td><td class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Bold">Primary Efficacy Measure: ADHDRS-IV Total Score</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Mean Baseline Score (SD)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">LS Mean Change from Baseline (SE)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Placebo-subtracted Difference<span class="Sup">a</span> (95% CI)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" rowspan="3"> <p class="First">Study 1</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Clonidine hydrochloride extended-release tablets </p> <p>(0.2 mg/day)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">43.8 (7.47)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">-15.0 (1.38)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">-8.5 (-12.2, -4.8)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Clonidine hydrochloride extended-release tablets (0.4 mg/day)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">44.6 (7.73)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">-15.6 (1.33)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">-9.1 (-12.8, -5.5)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Placebo</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">45.0 (8.53)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">-6.5 (1.35)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">----------</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Study 2</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Clonidine hydrochloride extended-release tablets (0.4 mg/day) + Psychostimulant</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">38.9 (6.95)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">-15.8 (1.18)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">-4.5 (-7.8, -1.1)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Psychostimulant alone</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">39.0 (7.68)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">-11.3 (1.24)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">----------</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table border=\"1\" cellpadding=\"0\" cellspacing=\"0\">\n<col width=\"76.1pt\"/>\n<col width=\"117pt\"/>\n<col width=\"297pt\"/>\n<col/>\n<col/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" rowspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Study Number</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" rowspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Treatment Group</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\">\n<p class=\"First\">\n<span class=\"Bold\">Primary Efficacy Measure: ADHDRS-IV Total Score</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">Mean Baseline Score (SD)</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">LS Mean Change from Baseline (SE)</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">Placebo-subtracted Difference<span class=\"Sup\">a</span> (95% CI)</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" rowspan=\"3\">\n<p class=\"First\">Study 1</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Clonidine hydrochloride extended-release tablets </p>\n<p>(0.2 mg/day)</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">43.8 (7.47)</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">-15.0 (1.38)</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">-8.5 (-12.2, -4.8)</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Clonidine hydrochloride extended-release tablets (0.4 mg/day)</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">44.6 (7.73)</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">-15.6 (1.33)</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">-9.1 (-12.8, -5.5)</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Placebo</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">45.0 (8.53)</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">-6.5 (1.35)</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">----------</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Study 2</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Clonidine hydrochloride extended-release tablets (0.4 mg/day) + Psychostimulant</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">38.9 (6.95)</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">-15.8 (1.18)</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">-4.5 (-7.8, -1.1)</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\"></td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Psychostimulant alone</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">39.0 (7.68)</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">-11.3 (1.24)</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">----------</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

a Difference (drug minus placebo) in least-squares mean change from baseline. SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.

{ "type": "p", "children": [], "text": "\na Difference (drug minus placebo) in least-squares mean change from baseline. SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval." }

Maintenance Monotherapy for ADHD

{ "type": "p", "children": [], "text": "\nMaintenance Monotherapy for ADHD\n" }

Study 3 was a double-blind, placebo-controlled, randomized-withdrawal study in pediatric patients 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 (N=68) and Placebo (N=67), to evaluate the long-term efficacy of maintenance dose of clonidine hydrochloride extended-release 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 group and 42 patients (62.7%) in the placebo group, with a statistically significant difference in the primary endpoint favoring clonidine (Table 7). The cumulative proportion of patients with treatment failure over time during the double-blind phase is displayed in Figure 2.

{ "type": "p", "children": [], "text": "Study 3 was a double-blind, placebo-controlled, randomized-withdrawal study in pediatric patients 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 (N=68) and Placebo (N=67), to evaluate the long-term efficacy of maintenance dose of clonidine hydrochloride extended-release 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 group and 42 patients (62.7%) in the placebo group, with a statistically significant difference in the primary endpoint favoring clonidine (Table 7). The cumulative proportion of patients with treatment failure over time during the double-blind phase is displayed in Figure 2." }

Table 7:          Treatment Failure: Double-Blind Full Analysis Set (Study 3)

{ "type": "p", "children": [], "text": "\nTable 7:          Treatment Failure: Double-Blind Full Analysis Set (Study 3)\n" }

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <col width="2in"/> <col width="4in"/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" rowspan="2"> <p class="First"> <span class="Bold">Study 3</span> </p> </td><td class="Botrule Lrule Rrule Toprule" colspan="2"> <p class="First"> <span class="Bold">Double-Blind Full Analysis Set</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Clonidine Hydrochloride Extended-Release Tablets</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Placebo</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Number of patients</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">68</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">67</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Number of treatment failures</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">31 (45.6%)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">42 (62.7%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First">Basis of Treatment Failure</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Clinical criteria<span class="Sup">a,b</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">11 (16.2%)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">9 (13.4%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Lack of efficacy<span class="Sup">c</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1 (1.5%)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3 (4.5%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Withdrawal of informed assent/consent</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4 (5.9%)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">20 (29.9%)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Other early terminations</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">15 (22.1%)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">10 (14.9%)</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table border=\"1\" cellpadding=\"0\" cellspacing=\"0\">\n<col width=\"2in\"/>\n<col width=\"4in\"/>\n<col/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" rowspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Study 3</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Double-Blind Full Analysis Set</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">Clonidine Hydrochloride Extended-Release Tablets</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">Placebo</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Number of patients</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">68</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">67</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Number of treatment failures</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">31 (45.6%)</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">42 (62.7%)</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\">\n<p class=\"First\">Basis of Treatment Failure</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Clinical criteria<span class=\"Sup\">a,b</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">11 (16.2%)</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">9 (13.4%)</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Lack of efficacy<span class=\"Sup\">c</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">1 (1.5%)</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">3 (4.5%)</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Withdrawal of informed assent/consent</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">4 (5.9%)</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">20 (29.9%)</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Other early terminations</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">15 (22.1%)</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">10 (14.9%)</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

 ADHD-RS-IV = Attention Deficit Hyperactivity Disorder-Rating Scale-4th edition; CGI-S = Clinical Global Impression-Severity

{ "type": "p", "children": [], "text": "\n ADHD-RS-IV = Attention Deficit Hyperactivity Disorder-Rating Scale-4th 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.

{ "type": "p", "children": [], "text": "   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." }

     bTwo patients (1 placebo and 1 clonidine hydrochloride extended-release tablets) withdrew consent, but met the clinical criteria for treatment failure.

{ "type": "p", "children": [], "text": "\n     bTwo patients (1 placebo and 1 clonidine hydrochloride extended-release tablets) withdrew consent, but met the clinical criteria for treatment failure." }

   cThree patients (all placebo) discontinued the study due to treatment failure, but met only the criterion for ADHD-RS-IV.

{ "type": "p", "children": [], "text": "   cThree patients (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 Pediatric Patients (6 to 17 Years) with Treatment Failure (Study 3)

{ "type": "p", "children": [], "text": "\nFigure 2:       Kaplan-Meier Estimation of Cumulative Proportion of Pediatric Patients (6 to 17 Years) with Treatment Failure (Study 3)\n" }

Figure 2

{ "type": "p", "children": [], "text": "\nFigure 2\n\n" }

How Supplied

{ "type": "p", "children": [], "text": "\nHow Supplied\n" }

ONYDA XR (clonidine hydrochloride) extended-release oral suspension 0.1 mg/mL is a light beige to tan viscous suspension.

{ "type": "p", "children": [], "text": "ONYDA XR (clonidine hydrochloride) extended-release oral suspension 0.1 mg/mL is a light beige to tan viscous suspension." }

ONYDA XR is supplied in a carton. Each carton contains one bottle with a child resistant closure, an oral dosing dispenser(s), and a press in bottle adapter(s). 

{ "type": "p", "children": [], "text": "ONYDA XR is supplied in a carton. Each carton contains one bottle with a child resistant closure, an oral dosing dispenser(s), and a press in bottle adapter(s). " }

<div class="scrollingtable"><table> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule">Bottle of 30 mL </td><td class="Botrule Lrule Rrule Toprule">NDC 24478-148-03 </td><td class="Botrule Lrule Rrule Toprule">One (1) oral dosing dispenser and one (1) press in bottle adapter </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Bottle of 60 mL</td><td class="Botrule Lrule Rrule Toprule">NDC 24478-148-04</td><td class="Botrule Lrule Rrule Toprule">One (1) oral dosing dispenser and one (1) press in bottle adapter</td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule">Bottle of 120 mL</td><td class="Botrule Lrule Rrule Toprule">NDC 24478-148-02</td><td class="Botrule Lrule Rrule Toprule">Two (2) oral dosing dispensers and two (2) press in bottle adapters</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col/>\n<col/>\n<col/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\">Bottle of 30 mL </td><td class=\"Botrule Lrule Rrule Toprule\">NDC 24478-148-03 </td><td class=\"Botrule Lrule Rrule Toprule\">One (1) oral dosing dispenser and one (1) press in bottle adapter </td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">Bottle of 60 mL</td><td class=\"Botrule Lrule Rrule Toprule\">NDC 24478-148-04</td><td class=\"Botrule Lrule Rrule Toprule\">One (1) oral dosing dispenser and one (1) press in bottle adapter</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\">Bottle of 120 mL</td><td class=\"Botrule Lrule Rrule Toprule\">NDC 24478-148-02</td><td class=\"Botrule Lrule Rrule Toprule\">Two (2) oral dosing dispensers and two (2) press in bottle adapters</td>\n</tr>\n</tbody>\n</table></div>" }

Storage and Handling

{ "type": "p", "children": [], "text": "\nStorage and Handling\n" }

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light.

{ "type": "p", "children": [], "text": "Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light. " }

Store and dispense ONYDA XR in the original bottle. Dispense with bottle adapter and oral dosing dispenser supplied in the carton.

{ "type": "p", "children": [], "text": "Store and dispense ONYDA XR in the original bottle. Dispense with bottle adapter and oral dosing dispenser supplied in the carton. " }

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

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "For the 120 mL bottle, discard any unused ONYDA XR 60 days after first opening the bottle." }

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use)." }

Dosage and Administration

{ "type": "p", "children": [], "text": "\nDosage and Administration\n" }

Advise patients that ONYDA XR may be taken with or without food. When initiating treatment, provide titration instructions [see Dosage and Administration (2.1)].

{ "type": "p", "children": [], "text": "Advise patients that ONYDA XR may be taken with or without food. When initiating treatment, provide titration instructions [see Dosage and Administration (2.1)].\n" }

Administration Instructions

{ "type": "p", "children": [], "text": "\nAdministration Instructions\n" }

Instruct patients to read the “Instructions for Use” for complete administration instructions [see Dosage and Administration (2.2)].

{ "type": "p", "children": [], "text": "Instruct patients to read the “Instructions for Use” for complete administration instructions [see Dosage and Administration (2.2)]. " }

Advise patients to:

{ "type": "p", "children": [], "text": "Advise patients to:" }

{ "type": "ul", "children": [ "firmly insert the bottle adapter into the bottle and do not remove the bottle adapter once inserted. Use the oral dispenser provided with ONYDA XR.", "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." ], "text": "" }

Missed Dose

{ "type": "p", "children": [], "text": "\nMissed Dose\n" }

If patients miss a dose of ONYDA XR, 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 ONYDA XR in any 24‑hour period [see Dosage and Administration (2.5)].

{ "type": "p", "children": [], "text": "If patients miss a dose of ONYDA XR, 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 ONYDA XR in any 24‑hour period [see Dosage and Administration (2.5)].\n" }

Hypotension/Bradycardia

{ "type": "p", "children": [], "text": "\nHypotension/Bradycardia\n" }

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)].

{ "type": "p", "children": [], "text": "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)].\n" }

Sedation and Somnolence

{ "type": "p", "children": [], "text": "\nSedation and Somnolence\n" }

Instruct patients to use caution when driving a car or operating heavy equipment until they know how they will respond to treatment with ONYDA XR. Also advise patients to avoid the use of ONYDA XR with other centrally active depressants and with alcohol [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Instruct patients to use caution when driving a car or operating heavy equipment until they know how they will respond to treatment with ONYDA XR. Also advise patients to avoid the use of ONYDA XR with other centrally active depressants and with alcohol [see Warnings and Precautions (5.2)].\n" }

Rebound Hypertension

{ "type": "p", "children": [], "text": "\nRebound Hypertension\n" }

Advise patients not to discontinue ONYDA XR abruptly. Inform patients and caregivers that pediatric patients with gastrointestinal illnesses that lead to vomiting may be at increased risk for rebound hypertension [see Warnings and Precautions (5.3)].

{ "type": "p", "children": [], "text": "Advise patients not to discontinue ONYDA XR abruptly. Inform patients and caregivers that pediatric patients with gastrointestinal illnesses that lead to vomiting may be at increased risk for rebound hypertension [see Warnings and Precautions (5.3)].\n" }

Allergic Reactions

{ "type": "p", "children": [], "text": "\nAllergic Reactions\n" }

Advise patients to discontinue ONYDA XR 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)].

{ "type": "p", "children": [], "text": "Advise patients to discontinue ONYDA XR 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)].\n" }

Pregnancy Registry

{ "type": "p", "children": [], "text": "\nPregnancy Registry\n" }

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to ONYDA XR during pregnancy [see Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to ONYDA XR during pregnancy [see Use in Specific Populations (8.1)].\n" }

Lactation

{ "type": "p", "children": [], "text": "\nLactation\n" }

Advise breastfeeding women using ONYDA XR 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)].

{ "type": "p", "children": [], "text": "Advise breastfeeding women using ONYDA XR 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)].\n" }

Fertility

{ "type": "p", "children": [], "text": "\nFertility\n" }

Advise females and males of reproductive potential that ONYDA XR may impair fertility [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].

{ "type": "p", "children": [], "text": "Advise females and males of reproductive potential that ONYDA XR may impair fertility [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].\n" }

Manufactured by/Distributed by:

{ "type": "p", "children": [], "text": "Manufactured by/Distributed by:" }

Tris Pharma, Inc.

{ "type": "p", "children": [], "text": "\nTris Pharma, Inc.\n" }

Monmouth Junction, NJ 08852

{ "type": "p", "children": [], "text": "Monmouth Junction, NJ 08852" }

www.trispharma.com

{ "type": "p", "children": [], "text": "\nwww.trispharma.com\n" }

LB8735

{ "type": "p", "children": [], "text": "LB8735" }

Rev. 05

{ "type": "p", "children": [], "text": "Rev. 05" }

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0" width="909.818px"> <col width="549pt"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">ONYDA<span class="Sup">TM</span> XR (oh-nee-dah)</span> </p> <p> <span class="Bold">(clonidine hydrochloride)</span> </p> <p> <span class="Bold">extended-release oral suspension</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">What is ONYDA XR?</span> </p> <p>ONYDA XR is a prescription medicine used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) alone or with certain other ADHD medicines in children 6 years of age and older. </p> <p>It is not known if ONYDA XR is safe and effective in children under 6 years of age.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Who should not take ONYDA XR?</span> </p> <p> <span class="Bold">Do not take ONYDA XR if you </span>are allergic to clonidine. See the end of this Patient Information for a complete list of ingredients in ONYDA XR.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Before taking ONYDA XR, tell your healthcare provider about all of your medical conditions, including if you:</span> </p> <ul class="Disc"> <li>have kidney problems</li> <li>have low or high blood pressure</li> <li>have a history of passing out (syncope)</li> <li>have heart problems, including slow heart rate or other heart rhythm problems</li> <li>had a stroke or have stroke symptoms</li> <li>had an allergic reaction after taking clonidine through your skin in a transdermal system (patch)</li> </ul> <ul class="Disc"> <li>are pregnant or plan to become pregnant. It is not known if ONYDA XR will harm the unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant. <ul class="Circle"> <li>There is a pregnancy registry for females who are exposed to ADHD medications, including ONYDA XR, during pregnancy. The purpose of the registry is to collect information about the health of females exposed to ONYDA XR and their baby. If you become pregnant during treatment with ONYDA XR, talk to your healthcare provider about registering with the National Pregnancy Registry of ADHD Medications at 1-866-961-2388 or visit online at <a href="https://womensmentalhealth.org/adhdmedications/">https://womensmentalhealth.org/adhdmedications/</a> </li> </ul> </li> <li>are breastfeeding or plan to breastfeed. ONYDA XR passes into the breast milk. Babies who are breastfed during treatment with ONYDA XR may become very sleepy, develop relaxed or floppy muscles, and develop trouble breathing. Call the baby’s healthcare provider if the baby is breastfed during treatment with ONYDA XR and develops any of these symptoms. Talk to your healthcare provider about the best way to feed your baby if you take ONYDA XR.</li> </ul> <p> <span class="Bold">Tell your healthcare provider about all of the medicines that you take,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements.</p> <p>ONYDA XR and certain other medicines may affect each other causing serious side effects. <span class="Bold">Especially tell your healthcare provider if you take:</span> </p> <p>• anti-depression medicines     • other medicines for ADHD<br/> • heart or blood pressure medicines    • medicines that cause sleepiness (sedation)<br/> • other medicines that contain clonidine</p> <p>Ask your healthcare provider or pharmacist if you are not sure if your medicine is listed above.</p> <p>Know the medicines that you take. Keep a list of your medicines with you to show your healthcare provider and pharmacist when you get a new medicine.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">How should I take ONYDA XR?</span> </p> <ul class="Disc"> <li>Take ONYDA XR 1 time daily at bedtime with or without food.</li> </ul> <ul class="Disc"> <li>Take ONYDA XR exactly as your healthcare provider tells you.</li> </ul> <ul class="Disc"> <li>Your healthcare provider may change your dose of ONYDA XR. Do not change your dose of ONYDA XR without talking to your healthcare provider.</li> </ul> <ul class="Disc"> <li> <span class="Bold">If you are taking another clonidine medicine</span>, <span class="Bold">stop taking it</span> before you start treatment with ONYDA XR.</li> <li> <span class="Bold">The dose of ONYDA XR is not the same as other clonidine medicines. Do not</span> change between ONYDA XR and other clonidine medicines unless your healthcare provider tells you.</li> <li> <span class="Bold">Do not</span> stop taking ONYDA XR without talking to your healthcare provider.</li> <li>If you miss a dose of ONYDA XR, skip the missed dose and take the next dose at their regular scheduled time. Do not take more ONYDA XR in a 24-hour period than your healthcare provider prescribed for your daily dose.</li> <li>For the bottles of 30 mL and 60 mL, throw away (discard of) any remaining ONYDA XR if you have not used it 30 days after first opening the bottle. </li> <li>For the 120 mL bottle, throw away (discard of) any remaining ONYDA XR if you have not used it 60 days after first opening the bottle. </li> <li> <span class="Bold">See the detailed Instructions for Use for information on how to take a dose of ONYDA XR.</span> </li> </ul> <p>If you take too much ONYDA XR, call your healthcare provider or Poison Help line at 1-800-222-1222, or go to the nearest hospital emergency room right away.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">What should I avoid while taking ONYDA XR?</span> </p> <ul class="Disc"> <li> <span class="Bold">Do not</span> become dehydrated or too hot (overheated) to decrease your chance of passing out during treatment with ONYDA XR.</li> <li> <span class="Bold">Do not</span> drive, operate heavy machinery, or do other dangerous activities until you know how ONYDA XR affects you because ONYDA XR can cause sleepiness and tiredness that could cause slow reaction times.</li> <li> <span class="Bold">Do not</span> drink alcohol or take other medicines that make you sleepy or dizzy during treatment with ONYDA XR until you talk with your healthcare provider. Taking ONYDA XR with alcohol or medicines that cause sleepiness or dizziness may make your sleepiness or dizziness worse.</li> <li> <span class="Bold">Do not</span> suddenly stop ONYDA XR. Tell your healthcare provider if you have been vomiting and cannot take ONYDA XR, you may be at risk for rebound hypertension.</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">What are possible side effects of ONYDA XR?</span> </p> <p> <span class="Bold">ONYDA XR may cause serious side effects, including:</span> </p> <ul class="Disc"> <li> <span class="Bold">Decreased blood pressure and heart rate.</span> ONYDA XR can decrease your blood pressure and heart rate, which can increase your chance of passing out (syncope). If you have a history of passing out or have other medical problems or take other medicines that increase your risk of passing out, your risk is higher. Your healthcare provider should check your heart rate and blood pressure before starting treatment and regularly during treatment with ONYDA XR. See “<span class="Bold">What should I avoid while taking ONYDA XR?</span>”</li> <li> <span class="Bold">Sleepiness and tiredness that could cause slow reaction times (sedation and somnolence).</span> See “<span class="Bold">What should I avoid while taking ONYDA XR?</span>”</li> <li> <span class="Bold">Rebound high blood pressure (hypertension). </span>Suddenly stopping ONYDA XR can cause high blood pressure to return if you have a history of high blood pressure.<span class="Bold"> Suddenly stopping ONYDA XR may also cause withdrawal symptoms</span> including headache, increased heart rate, nausea, flushing or warm feeling, lightheadedness, tightness in your chest and nervousness or anxiety. <span class="Bold">Do not suddenly stop ONYDA XR treatment without first talking to your healthcare provider.</span> </li> </ul> <ul class="Disc"> <li> <span class="Bold">Allergic reactions.</span> You may develop an allergic reaction to ONYDA XR if you had an allergic reaction to clonidine taken through your skin in a patch. Stop taking ONYDA XR and call your healthcare provider right away or go to the nearest emergency room if you develop any signs or symptoms of an allergic reaction, including:</li> </ul> <p>              o skin rash            o hives                     o swelling of the eyes, face, lips, or tongue</p> <p> <span class="Bold">The most common side effects of ONYDA XR when used alone include:</span> </p> <p>• falling asleep or sleepiness and tiredness that could cause slow reaction times             • nightmare            • constipation<br/> • irritability                                                                                                                           • trouble sleeping   • dry mouth</p> <p> <span class="Bold">The most common side effects of ONYDA XR when used with other ADHD medicines include:</span> </p> <p>• falling asleep or sleepiness and tiredness that could cause slow reaction times              • decreased appetite       • dizziness</p> <p>ONYDA XR may cause fertility problems in females and males, which may affect your ability to have a child. Talk to your healthcare provider if this is a concern for you.</p> <p>These are not all of the possible side effects of ONYDA XR. </p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">How should I store ONYDA XR?</span> </p> <ul class="Disc"> <li>Store ONYDA XR at room temperature between 68°F to 77°F (20°C to 25°C).</li> <li>Protect from light and keep ONYDA XR in the original container. Tightly close the child-resistant cap.</li> <li>For the bottles of 30 mL and 60 mL, throw away (discard of) any remaining ONYDA XR if you have not used it 30 days after first opening the bottle. </li> <li>For the 120 mL bottle, throw away (discard of) any remaining ONYDA XR if you have not used it 60 days after first opening the bottle. </li> </ul> <p> <span class="Bold">Keep ONYDA XR and all medicines out of the reach of children.</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">General information about the safe and effective use of ONYDA XR.</span> </p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ONYDA XR for a condition for which it was not prescribed. Do not give ONYDA XR to other people, even if they have the same symptoms that you have. It may harm them. You can also ask your pharmacist or healthcare provider for information about ONYDA XR that is written for health professionals.</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">What are the ingredients in ONYDA XR?</span> </p> <p> <span class="Bold">Active Ingredient:</span> clonidine hydrochloride</p> <p> <span class="Bold">Inactive Ingredients:</span> anhydrous citric acid, edetate disodium, glycerin, modified starch, methylparaben, orange flavor, polyvinyl acetate dispersion 30%, povidone, polysorbate 80, propylparaben, purified water, sucrose, sodium polystyrene sulfonate, triacetin, and xanthan gum</p> <p>Manufactured by/Distributed by:</p> <p> <span class="Bold">Tris Pharma, Inc.</span> </p> <p>Monmouth Junction, NJ 08852</p> <p> <a href="http://www.trispharma.com/">www.trispharma.com</a> </p> <p>For more information about ONYDA XR call 1-732-940-0358.</p> <p>Rev. 04</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"909.818px\">\n<col width=\"549pt\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">ONYDA<span class=\"Sup\">TM</span> XR (oh-nee-dah)</span>\n</p>\n<p>\n<span class=\"Bold\">(clonidine hydrochloride)</span>\n</p>\n<p>\n<span class=\"Bold\">extended-release oral suspension</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">What is ONYDA XR?</span>\n</p>\n<p>ONYDA XR is a prescription medicine used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) alone or with certain other ADHD medicines in children 6 years of age and older. </p>\n<p>It is not known if ONYDA XR is safe and effective in children under 6 years of age.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">Who should not take ONYDA XR?</span>\n</p>\n<p>\n<span class=\"Bold\">Do not take ONYDA XR if you </span>are allergic to clonidine. See the end of this Patient Information for a complete list of ingredients in ONYDA XR.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">Before taking ONYDA XR, tell your healthcare provider about all of your medical conditions, including if you:</span>\n</p>\n<ul class=\"Disc\">\n<li>have kidney problems</li>\n<li>have low or high blood pressure</li>\n<li>have a history of passing out (syncope)</li>\n<li>have heart problems, including slow heart rate or other heart rhythm problems</li>\n<li>had a stroke or have stroke symptoms</li>\n<li>had an allergic reaction after taking clonidine through your skin in a transdermal system (patch)</li>\n</ul>\n<ul class=\"Disc\">\n<li>are pregnant or plan to become pregnant. It is not known if ONYDA XR will harm the unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant.\n <ul class=\"Circle\">\n<li>There is a pregnancy registry for females who are exposed to ADHD medications, including ONYDA XR, during pregnancy. The purpose of the registry is to collect information about the health of females exposed to ONYDA XR and their baby. If you become pregnant during treatment with ONYDA XR, talk to your healthcare provider about registering with the National Pregnancy Registry of ADHD Medications at 1-866-961-2388 or visit online at <a href=\"https://womensmentalhealth.org/adhdmedications/\">https://womensmentalhealth.org/adhdmedications/</a>\n</li>\n</ul>\n</li>\n<li>are breastfeeding or plan to breastfeed. ONYDA XR passes into the breast milk. Babies who are breastfed during treatment with ONYDA XR may become very sleepy, develop relaxed or floppy muscles, and develop trouble breathing. Call the baby’s healthcare provider if the baby is breastfed during treatment with ONYDA XR and develops any of these symptoms. Talk to your healthcare provider about the best way to feed your baby if you take ONYDA XR.</li>\n</ul>\n<p>\n<span class=\"Bold\">Tell your healthcare provider about all of the medicines that you take,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements.</p>\n<p>ONYDA XR and certain other medicines may affect each other causing serious side effects. <span class=\"Bold\">Especially tell your healthcare provider if you take:</span>\n</p>\n<p>• anti-depression medicines     • other medicines for ADHD<br/>\n • heart or blood pressure medicines    • medicines that cause sleepiness (sedation)<br/>\n • other medicines that contain clonidine</p>\n<p>Ask your healthcare provider or pharmacist if you are not sure if your medicine is listed above.</p>\n<p>Know the medicines that you take. Keep a list of your medicines with you to show your healthcare provider and pharmacist when you get a new medicine.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">How should I take ONYDA XR?</span>\n</p>\n<ul class=\"Disc\">\n<li>Take ONYDA XR 1 time daily at bedtime with or without food.</li>\n</ul>\n<ul class=\"Disc\">\n<li>Take ONYDA XR exactly as your healthcare provider tells you.</li>\n</ul>\n<ul class=\"Disc\">\n<li>Your healthcare provider may change your dose of ONYDA XR. Do not change your dose of ONYDA XR without talking to your healthcare provider.</li>\n</ul>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">If you are taking another clonidine medicine</span>, <span class=\"Bold\">stop taking it</span> before you start treatment with ONYDA XR.</li>\n<li>\n<span class=\"Bold\">The dose of ONYDA XR is not the same as other clonidine medicines. Do not</span> change between ONYDA XR and other clonidine medicines unless your healthcare provider tells you.</li>\n<li>\n<span class=\"Bold\">Do not</span> stop taking ONYDA XR without talking to your healthcare provider.</li>\n<li>If you miss a dose of ONYDA XR, skip the missed dose and take the next dose at their regular scheduled time. Do not take more ONYDA XR in a 24-hour period than your healthcare provider prescribed for your daily dose.</li>\n<li>For the bottles of 30 mL and 60 mL, throw away (discard of) any remaining ONYDA XR if you have not used it 30 days after first opening the bottle. </li>\n<li>For the 120 mL bottle, throw away (discard of) any remaining ONYDA XR if you have not used it 60 days after first opening the bottle. </li>\n<li>\n<span class=\"Bold\">See the detailed Instructions for Use for information on how to take a dose of ONYDA XR.</span>\n</li>\n</ul>\n<p>If you take too much ONYDA XR, call your healthcare provider or Poison Help line at 1-800-222-1222, or go to the nearest hospital emergency room right away.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">What should I avoid while taking ONYDA XR?</span>\n</p>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Do not</span> become dehydrated or too hot (overheated) to decrease your chance of passing out during treatment with ONYDA XR.</li>\n<li>\n<span class=\"Bold\">Do not</span> drive, operate heavy machinery, or do other dangerous activities until you know how ONYDA XR affects you because ONYDA XR can cause sleepiness and tiredness that could cause slow reaction times.</li>\n<li>\n<span class=\"Bold\">Do not</span> drink alcohol or take other medicines that make you sleepy or dizzy during treatment with ONYDA XR until you talk with your healthcare provider. Taking ONYDA XR with alcohol or medicines that cause sleepiness or dizziness may make your sleepiness or dizziness worse.</li>\n<li>\n<span class=\"Bold\">Do not</span> suddenly stop ONYDA XR. Tell your healthcare provider if you have been vomiting and cannot take ONYDA XR, you may be at risk for rebound hypertension.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">What are possible side effects of ONYDA XR?</span>\n</p>\n<p>\n<span class=\"Bold\">ONYDA XR may cause serious side effects, including:</span>\n</p>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Decreased blood pressure and heart rate.</span> ONYDA XR can decrease your blood pressure and heart rate, which can increase your chance of passing out (syncope). If you have a history of passing out or have other medical problems or take other medicines that increase your risk of passing out, your risk is higher. Your healthcare provider should check your heart rate and blood pressure before starting treatment and regularly during treatment with ONYDA XR. See “<span class=\"Bold\">What should I avoid while taking ONYDA XR?</span>”</li>\n<li>\n<span class=\"Bold\">Sleepiness and tiredness that could cause slow reaction times (sedation and somnolence).</span> See “<span class=\"Bold\">What should I avoid while taking ONYDA XR?</span>”</li>\n<li>\n<span class=\"Bold\">Rebound high blood pressure (hypertension). </span>Suddenly stopping ONYDA XR can cause high blood pressure to return if you have a history of high blood pressure.<span class=\"Bold\"> Suddenly stopping ONYDA XR may also cause withdrawal symptoms</span> including headache, increased heart rate, nausea, flushing or warm feeling, lightheadedness, tightness in your chest and nervousness or anxiety. <span class=\"Bold\">Do not suddenly stop ONYDA XR treatment without first talking to your healthcare provider.</span>\n</li>\n</ul>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Allergic reactions.</span> You may develop an allergic reaction to ONYDA XR if you had an allergic reaction to clonidine taken through your skin in a patch. Stop taking ONYDA XR and call your healthcare provider right away or go to the nearest emergency room if you develop any signs or symptoms of an allergic reaction, including:</li>\n</ul>\n<p>              o skin rash            o hives                     o swelling of the eyes, face, lips, or tongue</p>\n<p>\n<span class=\"Bold\">The most common side effects of ONYDA XR when used alone include:</span>\n</p>\n<p>• falling asleep or sleepiness and tiredness that could cause slow reaction times             • nightmare            • constipation<br/>\n • irritability                                                                                                                           • trouble sleeping   • dry mouth</p>\n<p>\n<span class=\"Bold\">The most common side effects of ONYDA XR when used with other ADHD medicines include:</span>\n</p>\n<p>• falling asleep or sleepiness and tiredness that could cause slow reaction times              • decreased appetite       • dizziness</p>\n<p>ONYDA XR may cause fertility problems in females and males, which may affect your ability to have a child. Talk to your healthcare provider if this is a concern for you.</p>\n<p>These are not all of the possible side effects of ONYDA XR. </p>\n<p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">How should I store ONYDA XR?</span>\n</p>\n<ul class=\"Disc\">\n<li>Store ONYDA XR at room temperature between 68°F to 77°F (20°C to 25°C).</li>\n<li>Protect from light and keep ONYDA XR in the original container. Tightly close the child-resistant cap.</li>\n<li>For the bottles of 30 mL and 60 mL, throw away (discard of) any remaining ONYDA XR if you have not used it 30 days after first opening the bottle. </li>\n<li>For the 120 mL bottle, throw away (discard of) any remaining ONYDA XR if you have not used it 60 days after first opening the bottle. </li>\n</ul>\n<p>\n<span class=\"Bold\">Keep ONYDA XR and all medicines out of the reach of children.</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">General information about the safe and effective use of ONYDA XR.</span>\n</p>\n<p>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ONYDA XR for a condition for which it was not prescribed. Do not give ONYDA XR to other people, even if they have the same symptoms that you have. It may harm them. You can also ask your pharmacist or healthcare provider for information about ONYDA XR that is written for health professionals.</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">What are the ingredients in ONYDA XR?</span>\n</p>\n<p>\n<span class=\"Bold\">Active Ingredient:</span> clonidine hydrochloride</p>\n<p>\n<span class=\"Bold\">Inactive Ingredients:</span> anhydrous citric acid, edetate disodium, glycerin, modified starch, methylparaben, orange flavor, polyvinyl acetate dispersion 30%, povidone, polysorbate 80, propylparaben, purified water, sucrose, sodium polystyrene sulfonate, triacetin, and xanthan gum</p>\n<p>Manufactured by/Distributed by:</p>\n<p>\n<span class=\"Bold\">Tris Pharma, Inc.</span>\n</p>\n<p>Monmouth Junction, NJ 08852</p>\n<p>\n<a href=\"http://www.trispharma.com/\">www.trispharma.com</a>\n</p>\n<p>For more information about ONYDA XR call 1-732-940-0358.</p>\n<p>Rev. 04</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

This Patient Information has been approved by the U.S. Food and Drug Administration.                                                                      Revised:04/2025

{ "type": "p", "children": [], "text": "This Patient Information has been approved by the U.S. Food and Drug Administration.                                                                      Revised:04/2025" }

ONYDATM XR (oh-nee-dah)

{ "type": "p", "children": [], "text": "\nONYDATM XR (oh-nee-dah)\n" }

(clonidine hydrochloride)

{ "type": "p", "children": [], "text": "\n(clonidine hydrochloride)\n" }

extended-release oral suspension

{ "type": "p", "children": [], "text": "\nextended-release oral suspension\n" }

This Instructions for Use contains information on how to take ONYDA XR.

{ "type": "p", "children": [], "text": "This Instructions for Use contains information on how to take ONYDA XR." }

Important Information You Need to Know Before Taking ONYDA XR:

{ "type": "p", "children": [], "text": "\nImportant Information You Need to Know Before Taking ONYDA XR:\n" }

{ "type": "ul", "children": [ "ONYDA XR is for oral use only (taken by mouth).", "Take ONYDA XR with or without food.", "Use only the oral dosing syringe and bottle adapter that come with ONYDA XR to measure and take a dose of ONYDA XR.", "Shake the ONYDA XR bottle gently.", "Check the expiration date (EXP) on the carton label. Do not take ONYDA XR after the expiration date has passed. Call your healthcare provider or pharmacist if your medicine is expired.", "For the bottles of 30 mL and 60 mL, throw away (discard of) any remaining ONYDA XR if you have not used it 30 days after first opening the bottle. ", "For the 120 mL bottle, throw away (discard of) any remaining ONYDA XR if you have not used it 60 days after first opening the bottle." ], "text": "" }

Supplies included in the ONYDA XR carton:

{ "type": "p", "children": [], "text": "\nSupplies included in the ONYDA XR carton:\n" }

<div class="scrollingtable"><table> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"> <span class="Bold">1 bottle of ONYDA XR</span></td><td class="Botrule Lrule Rrule Toprule"><span class="Bold">Dosing Syringe(s) </span></td><td class="Botrule Lrule Rrule Toprule"><span class="Bold"> Bottle Adapter(s)</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> 30 mL bottle</td><td class="Botrule Lrule Rrule Toprule"> 1</td><td class="Botrule Lrule Rrule Toprule"> 1</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> 60 mL bottle</td><td class="Botrule Lrule Rrule Toprule"> 1</td><td class="Botrule Lrule Rrule Toprule"> 1</td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> 120 mL bottle</td><td class="Botrule Lrule Rrule Toprule"> 2</td><td class="Botrule Lrule Rrule Toprule"> 2</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col/>\n<col/>\n<col/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\"> <span class=\"Bold\">1 bottle of ONYDA XR</span></td><td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Bold\">Dosing Syringe(s) </span></td><td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Bold\"> Bottle Adapter(s)</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"> 30 mL bottle</td><td class=\"Botrule Lrule Rrule Toprule\"> 1</td><td class=\"Botrule Lrule Rrule Toprule\"> 1</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"> 60 mL bottle</td><td class=\"Botrule Lrule Rrule Toprule\"> 1</td><td class=\"Botrule Lrule Rrule Toprule\"> 1</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\"> 120 mL bottle</td><td class=\"Botrule Lrule Rrule Toprule\"> 2</td><td class=\"Botrule Lrule Rrule Toprule\"> 2</td>\n</tr>\n</tbody>\n</table></div>" }

Figure A

{ "type": "p", "children": [], "text": "Figure A" }

{ "type": "", "children": [], "text": "" }

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0" width="876.364px"> <col width="256.5pt"/> <col width="3.25in"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Step 1: </span> </p> <p> <span class="Bold">Preparing to take ONYDA XR:</span> </p> <ul class="Disc"> <li>Wash and dry your hands (see Figure B).</li> <li>Remove the ONYDA XR bottle, 1 oral dosing syringe, and 1 bottle adapter from the carton. </li> </ul> <p>Tell your pharmacist right away if you are missing any supplies from the carton.</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"><img alt="Figure B" src="/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--5.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7"/><p class="MultiMediaCaptionNotCentered">Figure B</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Step 2:</span> </p> <ul class="Disc"> <li>Place the ONYDA XR bottle on a flat surface like a table or countertop and remove the child resistant cap by pressing down and turning counterclockwise (see Figure C). <p class="First"> <span class="Bold">Insert the bottle adapter </span>(first time use only).</p> </li> <li>Hold the bottle firmly and insert the ridged end of the bottle adapter into the neck of the bottle.</li> <li>Firmly push the bottle adapter all the way down with your thumb until the top of the adapter is aligned and flat (flush) with the top of the bottle (See Figure D).</li> <li>Do not remove the bottle adapter once it has been inserted into the bottle.</li> </ul> </td><td align="right" class="Botrule Lrule Rrule Toprule"><img alt="Figure C" src="/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--6.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7"/><p class="MultiMediaCaptionNotCentered">Figure C</p> <img alt="Figure D" src="/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--7.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7"/><p class="MultiMediaCaptionNotCentered">Figure D</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Step 3: </span> </p> <ul class="Disc"> <li>Put the cap back on the bottle and close it tightly by turning the cap clockwise (see Figure E).</li> <li>Shake the bottle gently with a smooth up and down motion to avoid foaming (see Figure F). </li> <li>Shake the bottle gently for at least 10 seconds before you take each dose.</li> </ul> </td><td align="right" class="Botrule Lrule Rrule Toprule"> <p class="First"> <img alt="Figure E" src="/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--8.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7"/></p><p class="MultiMediaCaptionNotCentered">Figure E</p> <img alt="Figure F" src="/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--9.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7"/><p class="MultiMediaCaptionNotCentered">Figure F</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Step 4: </span> </p> <p>Place the ONYDA XR bottle upright on the table or countertop. Open the cap again by pressing down and turn counterclockwise to remove the cap (see Figure G). </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"><img alt="Figure G" src="/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--10.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7"/><p class="MultiMediaCaptionNotCentered">Figure G</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Step 5: </span> </p> <ul class="Disc"> <li>Check the ONYDA XR oral dosing syringe to find the right dose in milliliters (mL) that has been prescribed by the healthcare provider (see Figure H).</li> <li>Make sure the oral dosing syringe is dry. </li> </ul> </td><td align="center" class="Botrule Lrule Rrule Toprule"><img alt="Figure H" src="/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--11.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7"/><p class="MultiMediaCaptionNotCentered">Figure H</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Step 6:</span> </p> <ul class="Disc"> <li>Insert the tip of the oral dosing syringe through the adapter into the bottle (see Figure I).</li> <li>Push the plunger all the way down (see Figure J).</li> </ul> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <img alt="Figure I" src="/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--12.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7"/></p><p class="MultiMediaCaptionNotCentered">Figure I</p> <img alt="Figure J" src="/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--13.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7"/><p class="MultiMediaCaptionNotCentered">Figure J</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Step 7: </span> </p> <p> <span class="Bold">Measuring the dose of ONYDA XR:</span> </p> <ul class="Disc"> <li>With the tip of the oral dosing syringe in place in the adapter, hold the ONYDA XR bottle with 1 hand and turn the bottle upside down. Pull the plunger down until the white end of the plunger reaches the number of mL you need for the prescribed dose (see Figure K). </li> <li>Push and pull the plunger a few times to make sure that there are no air bubbles.</li> <li>Tap the barrel of the oral dosing syringe if needed to get rid of any air bubbles (see Figure L).</li> </ul> </td><td align="right" class="Botrule Lrule Rrule Toprule"><img alt="Figure K" src="/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--14.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7"/><p class="MultiMediaCaptionNotCentered">Figure K</p> <img alt="Figure L" src="/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--15.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7"/><p class="MultiMediaCaptionNotCentered">Figure L</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Step 8: </span> </p> <ul class="Disc"> <li>Turn the bottle over and place it upright on a table or countertop, then remove the oral dosing syringe from the bottle adapter (see Figure M).</li> </ul> </td><td align="center" class="Botrule Lrule Rrule Toprule"><img alt="Figure M" src="/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--16.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7"/><p class="MultiMediaCaptionNotCentered">Figure M</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Step 9:</span> </p> <ul class="Disc"> <li>Check that the correct dose in mL was pulled up into the oral dosing syringe (see Figure N).</li> <li>If the dose is not correct:</li> </ul> <ul class="Circle"> <li>Insert the oral syringe tip back into the bottle and fully push in the plunger to the bottom of the syringe barrel so that all of the oral suspension flows back into the bottle.</li> <li>Repeat Steps 6 through 8.</li> </ul> </td><td align="right" class="Botrule Lrule Rrule Toprule"><img alt="Figure N" src="/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--17.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7"/><p class="MultiMediaCaptionNotCentered">Figure N</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Step 10: </span> </p> <p> <span class="Bold">Taking the dose of ONYDA XR:</span> </p> <ul class="Disc"> <li>The child should be in a seated position before taking ONYDA XR.</li> <li>Tilt the head slightly upwards.</li> <li>Place the oral dosing syringe into the mouth and point it toward the cheek (see Figure O). <ul class="Disc"> <li>Close the mouth tightly around the oral dosing syringe and slowly push the plunger all the way down to give the ONYDA XR dose (see Figure P).</li> </ul> </li> <li>After all the medication has been taken, remove the oral dosing syringe from the mouth.</li> </ul> </td><td align="center" class="Botrule Lrule Rrule Toprule"><img alt="Figure O" src="/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--18.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7"/><p class="MultiMediaCaptionNotCentered">Figure O</p> <img alt="Figure P" src="/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--19.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7"/><p class="MultiMediaCaptionNotCentered">Figure P</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Step 11:</span> </p> <p> <span class="Bold">Closing the bottle:</span> </p> <ul class="Disc"> <li>Put the ONYDA XR cap back on the bottle and close the cap tightly by turning the cap clockwise (see Figure Q). </li> </ul> </td><td align="center" class="Botrule Lrule Rrule Toprule"><img alt="Figure Q" src="/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--20.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7"/><p class="MultiMediaCaptionNotCentered">Figure Q</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Step 12: </span> </p> <p> <span class="Bold">Cleaning up:</span> </p> <ul class="Disc"> <li>Clean the oral dosing syringe after each use by rinsing with tap water (see Figure R). </li> <li>Allow the oral dosing syringe to dry and keep it in a safe place for the next use.</li> <li>Wash and dry your hands.</li> </ul> </td><td class="Botrule Lrule Rrule Toprule"><img alt="Figure R" src="/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--21.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7"/><p class="MultiMediaCaptionNotCentered">Figure R</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"876.364px\">\n<col width=\"256.5pt\"/>\n<col width=\"3.25in\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">Step 1: </span>\n</p>\n<p>\n<span class=\"Bold\">Preparing to take ONYDA XR:</span>\n</p>\n<ul class=\"Disc\">\n<li>Wash and dry your hands (see Figure B).</li>\n<li>Remove the ONYDA XR bottle, 1 oral dosing syringe, and 1 bottle adapter from the carton. </li>\n</ul>\n<p>Tell your pharmacist right away if you are missing any supplies from the carton.</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"><img alt=\"Figure B\" src=\"/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--5.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7\"/><p class=\"MultiMediaCaptionNotCentered\">Figure B</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">Step 2:</span>\n</p>\n<ul class=\"Disc\">\n<li>Place the ONYDA XR bottle on a flat surface like a table or countertop and remove the child resistant cap by pressing down and turning counterclockwise (see Figure C).\n <p class=\"First\">\n<span class=\"Bold\">Insert the bottle adapter </span>(first time use only).</p>\n</li>\n<li>Hold the bottle firmly and insert the ridged end of the bottle adapter into the neck of the bottle.</li>\n<li>Firmly push the bottle adapter all the way down with your thumb until the top of the adapter is aligned and flat (flush) with the top of the bottle (See Figure D).</li>\n<li>Do not remove the bottle adapter once it has been inserted into the bottle.</li>\n</ul>\n</td><td align=\"right\" class=\"Botrule Lrule Rrule Toprule\"><img alt=\"Figure C\" src=\"/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--6.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7\"/><p class=\"MultiMediaCaptionNotCentered\">Figure C</p>\n<img alt=\"Figure D\" src=\"/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--7.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7\"/><p class=\"MultiMediaCaptionNotCentered\">Figure D</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">Step 3: </span>\n</p>\n<ul class=\"Disc\">\n<li>Put the cap back on the bottle and close it tightly by turning the cap clockwise (see Figure E).</li>\n<li>Shake the bottle gently with a smooth up and down motion to avoid foaming (see Figure F).\n </li>\n<li>Shake the bottle gently for at least 10 seconds before you take each dose.</li>\n</ul>\n</td><td align=\"right\" class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<img alt=\"Figure E\" src=\"/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--8.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7\"/></p><p class=\"MultiMediaCaptionNotCentered\">Figure E</p>\n<img alt=\"Figure F\" src=\"/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--9.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7\"/><p class=\"MultiMediaCaptionNotCentered\">Figure F</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">Step 4: </span>\n</p>\n<p>Place the ONYDA XR bottle upright on the table or countertop. Open the cap again by pressing down and turn counterclockwise to remove the cap (see Figure G). </p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"><img alt=\"Figure G\" src=\"/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--10.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7\"/><p class=\"MultiMediaCaptionNotCentered\">Figure G</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">Step 5: </span>\n</p>\n<ul class=\"Disc\">\n<li>Check the ONYDA XR oral dosing syringe to find the right dose in milliliters (mL) that has been prescribed by the healthcare provider (see Figure H).</li>\n<li>Make sure the oral dosing syringe is dry. </li>\n</ul>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"><img alt=\"Figure H\" src=\"/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--11.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7\"/><p class=\"MultiMediaCaptionNotCentered\">Figure H</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">Step 6:</span>\n</p>\n<ul class=\"Disc\">\n<li>Insert the tip of the oral dosing syringe through the adapter into the bottle (see Figure I).</li>\n<li>Push the plunger all the way down (see Figure J).</li>\n</ul>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<img alt=\"Figure I\" src=\"/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--12.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7\"/></p><p class=\"MultiMediaCaptionNotCentered\">Figure I</p>\n<img alt=\"Figure J\" src=\"/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--13.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7\"/><p class=\"MultiMediaCaptionNotCentered\">Figure J</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">Step 7: </span>\n</p>\n<p>\n<span class=\"Bold\">Measuring the dose of ONYDA XR:</span>\n</p>\n<ul class=\"Disc\">\n<li>With the tip of the oral dosing syringe in place in the adapter, hold the ONYDA XR bottle with 1 hand and turn the bottle upside down. Pull the plunger down until the white end of the plunger reaches the number of mL you need for the prescribed dose (see Figure K). </li>\n<li>Push and pull the plunger a few times to make sure that there are no air bubbles.</li>\n<li>Tap the barrel of the oral dosing syringe if needed to get rid of any air bubbles (see Figure L).</li>\n</ul>\n</td><td align=\"right\" class=\"Botrule Lrule Rrule Toprule\"><img alt=\"Figure K\" src=\"/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--14.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7\"/><p class=\"MultiMediaCaptionNotCentered\">Figure K</p>\n<img alt=\"Figure L\" src=\"/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--15.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7\"/><p class=\"MultiMediaCaptionNotCentered\">Figure L</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">Step 8: </span>\n</p>\n<ul class=\"Disc\">\n<li>Turn the bottle over and place it upright on a table or countertop, then remove the oral dosing syringe from the bottle adapter (see Figure M).</li>\n</ul>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"><img alt=\"Figure M\" src=\"/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--16.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7\"/><p class=\"MultiMediaCaptionNotCentered\">Figure M</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">Step 9:</span>\n</p>\n<ul class=\"Disc\">\n<li>Check that the correct dose in mL was pulled up into the oral dosing syringe (see Figure N).</li>\n<li>If the dose is not correct:</li>\n</ul>\n<ul class=\"Circle\">\n<li>Insert the oral syringe tip back into the bottle and fully push in the plunger to the bottom of the syringe barrel so that all of the oral suspension flows back into the bottle.</li>\n<li>Repeat Steps 6 through 8.</li>\n</ul>\n</td><td align=\"right\" class=\"Botrule Lrule Rrule Toprule\"><img alt=\"Figure N\" src=\"/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--17.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7\"/><p class=\"MultiMediaCaptionNotCentered\">Figure N</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">Step 10: </span>\n</p>\n<p>\n<span class=\"Bold\">Taking the dose of ONYDA XR:</span>\n</p>\n<ul class=\"Disc\">\n<li>The child should be in a seated position before taking ONYDA XR.</li>\n<li>Tilt the head slightly upwards.</li>\n<li>Place the oral dosing syringe into the mouth and point it toward the cheek (see Figure O).\n <ul class=\"Disc\">\n<li>Close the mouth tightly around the oral dosing syringe and slowly push the plunger all the way down to give the ONYDA XR dose (see Figure P).</li>\n</ul>\n</li>\n<li>After all the medication has been taken, remove the oral dosing syringe from the mouth.</li>\n</ul>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"><img alt=\"Figure O\" src=\"/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--18.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7\"/><p class=\"MultiMediaCaptionNotCentered\">Figure O</p>\n<img alt=\"Figure P\" src=\"/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--19.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7\"/><p class=\"MultiMediaCaptionNotCentered\">Figure P</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">Step 11:</span>\n</p>\n<p>\n<span class=\"Bold\">Closing the bottle:</span>\n</p>\n<ul class=\"Disc\">\n<li>Put the ONYDA XR cap back on the bottle and close the cap tightly by turning the cap clockwise (see Figure Q). </li>\n</ul>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"><img alt=\"Figure Q\" src=\"/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--20.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7\"/><p class=\"MultiMediaCaptionNotCentered\">Figure Q</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">Step 12: </span>\n</p>\n<p>\n<span class=\"Bold\">Cleaning up:</span>\n</p>\n<ul class=\"Disc\">\n<li>Clean the oral dosing syringe after each use by rinsing with tap water (see Figure R). </li>\n<li>Allow the oral dosing syringe to dry and keep it in a safe place for the next use.</li>\n<li>Wash and dry your hands.</li>\n</ul>\n</td><td class=\"Botrule Lrule Rrule Toprule\"><img alt=\"Figure R\" src=\"/dailymed/image.cfm?name=onyda-xr-clonidine-hydrochloride-extended-release--21.jpg&amp;setid=4a15c850-9da5-4bdc-a34d-7f740a6149b7\"/><p class=\"MultiMediaCaptionNotCentered\">Figure R</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

 Disposing of ONYDA XR:

{ "type": "p", "children": [], "text": "\n Disposing of ONYDA XR:\n" }

{ "type": "ul", "children": [ "Throw away any unused or expired ONYDA XR in your household trash.", "For the bottles of 30 mL and 60 mL, throw away (discard of) any remaining ONYDA XR if you have not used it 30 days after first opening the bottle. ", "For the 120 mL bottle, throw away (discard of) any remaining ONYDA XR if you have not used it 60 days after first opening the bottle." ], "text": "" }

Storing ONYDA XR:

{ "type": "p", "children": [], "text": "\nStoring ONYDA XR:\n" }

{ "type": "ul", "children": [ "Store ONYDA XR at room temperature between 68°F to 77°F (20°C to 25°C).", "Protect from light and keep ONYDA XR in the original container. Tightly close the child-resistant cap." ], "text": "" }

Keep ONYDA XR and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep ONYDA XR and all medicines out of the reach of children.\n" }

Manufactured by/Distributed by:

{ "type": "p", "children": [], "text": "Manufactured by/Distributed by:" }

Tris Pharma, Inc.

{ "type": "p", "children": [], "text": "\nTris Pharma, Inc.\n" }

Monmouth Junction, NJ 08852

{ "type": "p", "children": [], "text": "Monmouth Junction, NJ 08852" }

LB8730  Rev. 03

{ "type": "p", "children": [], "text": "LB8730  Rev. 03" }

This Instructions for Use has been approved by the U.S. Food and Drug Administration                                                       

{ "type": "p", "children": [], "text": "This Instructions for Use has been approved by the U.S. Food and Drug Administration                                                        " }

Revised: 02/2025

{ "type": "p", "children": [], "text": "Revised: 02/2025" }

NDC 24478-148-01 ONYDATM XR 

{ "type": "p", "children": [], "text": "\nNDC 24478-148-01\n\nONYDATM XR \n" }

 (clonidine hydrochloride) extended-release oral suspension

{ "type": "p", "children": [], "text": "\n (clonidine hydrochloride) extended-release oral suspension\n" }

0.1 mg    Shake Gently Before Use

{ "type": "p", "children": [], "text": "\n0.1 mg   \n\nShake Gently Before Use\n" }

7 mL    Rx only

{ "type": "p", "children": [], "text": "\n\n7 mL    Rx only\n" }

NDC 24478-148-01 ONYDATM XR 

{ "type": "p", "children": [], "text": "\nNDC 24478-148-01\n\nONYDATM XR \n" }

(clonidine hydrochloride) extended-release oral suspension

{ "type": "p", "children": [], "text": "\n(clonidine hydrochloride) extended-release oral suspension\n" }

0.1 mg    Shake Gently Before Use 7 mL    Rx only

{ "type": "p", "children": [], "text": "\n0.1 mg   \n\nShake Gently Before Use\n\n\n7 mL    Rx only\n" }

NDC 24478-148-03 ONYDATM XR 

{ "type": "p", "children": [], "text": "\nNDC 24478-148-03\n\nONYDATM XR \n" }

(clonidine hydrochloride) extended-release oral suspension

{ "type": "p", "children": [], "text": "\n(clonidine hydrochloride) extended-release oral suspension\n" }

0.1 mg    Shake Gently Before Use 30 mL    Rx only

{ "type": "p", "children": [], "text": "\n0.1 mg   \n\nShake Gently Before Use\n\n30 mL    Rx only\n" }

NDC 24478-148-03 ONYDATM XR 

{ "type": "p", "children": [], "text": "\nNDC 24478-148-03\n\nONYDATM XR \n" }

(clonidine hydrochloride) extended-release oral suspension

{ "type": "p", "children": [], "text": "\n(clonidine hydrochloride) extended-release oral suspension\n" }

0.1 mg    Shake Gently Before Use 30 mL    Rx only

{ "type": "p", "children": [], "text": "\n0.1 mg   \n\nShake Gently Before Use\n\n\n30 mL    Rx only\n" }

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)].

{ "type": "p", "children": [], "text": "\nClonidine 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)].\n" }

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)].

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).

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span> Table 1 Clonidine Hydrochloride Extended-Release Tablets Dosing Guidance </span> </caption> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Total Daily Dose<br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> Morning Dose<br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> Bedtime Dose<br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> 0.1 mg/day<br/> </td><td class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> 0.1 mg<br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> 0.2 mg/day<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0.1 mg<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0.1 mg<br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> 0.3 mg/day<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0.1 mg<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0.2 mg<br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> 0.4 mg/day<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0.2 mg<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0.2 mg<br/> </td> </tr> </tbody> </table></div>

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.

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)].

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.

Clonidine hydrochloride extended-release tablets are available in a 0.1 mg strength formulation. The 0.1 mg tablets are white to off-white round, biconvex tablets with debossing: "U" on one side and "77" on the other side. Clonidine hydrochloride extended-release tablets must be swallowed whole and never crushed, cut or chewed.

{ "type": "p", "children": [], "text": "\nClonidine hydrochloride extended-release tablets are available in a 0.1 mg strength formulation. The 0.1 mg tablets are white to off-white round, biconvex tablets with debossing: \"U\" on one side and \"77\" on the other side. Clonidine hydrochloride extended-release tablets must be swallowed whole and never crushed, cut or chewed." }

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)].

{ "type": "p", "children": [], "text": "\nClonidine 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)].\n" }

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.

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.

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.

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).

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.

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.

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 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 ≥ 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 – 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 2.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span> Table 2 Common Adverse Reactions in the Fixed-Dose Monotherapy Trial – Treatment Period (Study 1) </span> </caption> <col width="25%"/> <col width="25%"/> <col width="25%"/> <col width="25%"/> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Somnolence includes the terms "somnolence" and "sedation".</dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>Fatigue includes the terms "fatigue" and "lethargy".</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="3" valign="top"><span class="Bold"> Percentage of Patients Reporting Event</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="bottom"><span class="Bold"> Preferred Term</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> Clonidine Hydrochloride</span> <br/> <span class="Bold"> 0.2 mg/day</span> <br/> <span class="Bold"> N=76</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> Clonidine Hydrochloride</span> <br/> <span class="Bold"> 0.4 mg/day</span> <br/> <span class="Bold"> N=78</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> Placebo</span> <br/> <span class="Bold"> (N=76)</span> <br/> </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> PSYCHIATRIC DISORDERS<br/> </td><td class="Rrule" valign="top"></td><td class="Rrule" valign="top"></td><td class="Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> Somnolence<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a> <br/> </td><td align="center" class="Rrule" valign="top"> 38%<br/> </td><td align="center" class="Rrule" valign="top"> 31%<br/> </td><td align="center" class="Rrule" valign="top"> 4%<br/> </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> Nightmare<br/> </td><td align="center" class="Rrule" valign="top"> 4%<br/> </td><td align="center" class="Rrule" valign="top"> 9%<br/> </td><td align="center" class="Rrule" valign="top"> 0%<br/> </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> Emotional Disorder<br/> </td><td align="center" class="Rrule" valign="top"> 4%<br/> </td><td align="center" class="Rrule" valign="top"> 4%<br/> </td><td align="center" class="Rrule" valign="top"> 1%<br/> </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> Aggression<br/> </td><td align="center" class="Rrule" valign="top"> 3%<br/> </td><td align="center" class="Rrule" valign="top"> 1%<br/> </td><td align="center" class="Rrule" valign="top"> 0%<br/> </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> Tearfulness<br/> </td><td align="center" class="Rrule" valign="top"> 1%<br/> </td><td align="center" class="Rrule" valign="top"> 3%<br/> </td><td align="center" class="Rrule" valign="top"> 0%<br/> </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> Enuresis<br/> </td><td align="center" class="Rrule" valign="top"> 0%<br/> </td><td align="center" class="Rrule" valign="top"> 4%<br/> </td><td align="center" class="Rrule" valign="top"> 0%<br/> </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> Sleep Terror<br/> </td><td align="center" class="Rrule" valign="top"> 3%<br/> </td><td align="center" class="Rrule" valign="top"> 0%<br/> </td><td align="center" class="Rrule" valign="top"> 0%<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Poor Quality Sleep<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1%<br/> </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> NERVOUS SYSTEM DISORDERS<br/> </td><td class="Rrule" valign="top"></td><td class="Rrule" valign="top"></td><td class="Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> Headache<br/> </td><td align="center" class="Rrule" valign="top"> 20%<br/> </td><td align="center" class="Rrule" valign="top"> 13%<br/> </td><td align="center" class="Rrule" valign="top"> 16%<br/> </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> Insomnia<br/> </td><td align="center" class="Rrule" valign="top"> 5%<br/> </td><td align="center" class="Rrule" valign="top"> 6%<br/> </td><td align="center" class="Rrule" valign="top"> 1%<br/> </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> Tremor<br/> </td><td align="center" class="Rrule" valign="top"> 1%<br/> </td><td align="center" class="Rrule" valign="top"> 4%<br/> </td><td align="center" class="Rrule" valign="top"> 0%<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Abnormal Sleep-Related Event<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0%<br/> </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> GASTROINTESTINAL DISORDERS<br/> </td><td class="Rrule" valign="top"></td><td class="Rrule" valign="top"></td><td class="Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> Upper Abdominal Pain<br/> </td><td align="center" class="Rrule" valign="top"> 15%<br/> </td><td align="center" class="Rrule" valign="top"> 10%<br/> </td><td align="center" class="Rrule" valign="top"> 12%<br/> </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> Nausea<br/> </td><td align="center" class="Rrule" valign="top"> 4%<br/> </td><td align="center" class="Rrule" valign="top"> 5%<br/> </td><td align="center" class="Rrule" valign="top"> 3%<br/> </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> Constipation<br/> </td><td align="center" class="Rrule" valign="top"> 1%<br/> </td><td align="center" class="Rrule" valign="top"> 6%<br/> </td><td align="center" class="Rrule" valign="top"> 0%<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Dry Mouth<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1%<br/> </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> GENERAL DISORDERS<br/> </td><td class="Rrule" valign="top"></td><td class="Rrule" valign="top"></td><td class="Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> Fatigue<a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a> <br/> </td><td align="center" class="Rrule" valign="top"> 16%<br/> </td><td align="center" class="Rrule" valign="top"> 13%<br/> </td><td align="center" class="Rrule" valign="top"> 1%<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Irritability<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 9%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 4%<br/> </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> CARDIAC DISORDERS<br/> </td><td class="Rrule" valign="top"></td><td class="Rrule" valign="top"></td><td class="Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> Dizziness<br/> </td><td align="center" class="Rrule" valign="top"> 7%<br/> </td><td align="center" class="Rrule" valign="top"> 3%<br/> </td><td align="center" class="Rrule" valign="top"> 5%<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Bradycardia<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 4%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0%<br/> </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> INVESTIGATIONS<br/> </td><td class="Rrule" valign="top"></td><td class="Rrule" valign="top"></td><td class="Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Increased Heart Rate<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0%<br/> </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> METABOLISM AND NUTRITION DISORDERS<br/> </td><td class="Rrule" valign="top"></td><td class="Rrule" valign="top"></td><td class="Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Decreased Appetite<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 4%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 4%<br/> </td> </tr> </tbody> </table></div>

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 3.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span> Table 3 Common Adverse Reactions in the Fixed-Dose Monotherapy Trial – Taper Period<a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a> (Study 1) </span> </caption> <col width="25%"/> <col width="25%"/> <col width="25%"/> <col width="25%"/> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>Taper Period: 0.2 mg dose, week 8; 0.4 mg dose, weeks 6 to 8; Placebo dose, weeks 6 to 8</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="3" valign="top"><span class="Bold"> Percentage of Patients Reporting Event</span> <br/> </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="bottom"><span class="Bold"> Preferred Term</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold"> Clonidine Hydrochloride</span> <br/> <span class="Bold"> 0.2 mg/day</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold"> Clonidine Hydrochloride</span> <br/> <span class="Bold"> 0.4 mg/day</span> <br/> </td><td align="center" class="Botrule Rrule" rowspan="2"><span class="Bold"> Placebo</span> <br/> <span class="Bold"> (N=76)</span> <br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> N=76</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> N=78</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Abdominal Pain Upper<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 6%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3%<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Headache<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3%<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Gastrointestinal Viral<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0%<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Somnolence<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0%<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Heart Rate Increased<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0%<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Otitis Media Acute<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0%<br/> </td> </tr> </tbody> </table></div>

Study 2: Flexible-dose Clonidine Hydrochloride Extended-Release Tablets as Adjunctive Therapy to Psychostimulants

Study 2 (CLON-302) was a short-term, randomized, double-blind, placebo-controlled study of a flexible dose of clonidine hydrochloride as adjunctive therapy to a psychostimulant in children and adolescents (6 to 17 years) who met DSM-IV criteria for ADHD hyperactive or combined inattentive/hyperactive subtypes during which clonidine hydrochloride was initiated at 0.1 mg/day and titrated up to 0.4 mg/day over a 3-week period. Most clonidine hydrochloride 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 Events Leading to Discontinuation – There was one patient in the CLON+STM 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 4.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span> Table 4 Common Adverse Reactions in the Flexible-Dose Adjunctive to Stimulant Therapy Trial – Treatment Period (Study 2) </span> </caption> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-4" name="footnote-4">*</a> </dt> <dd>Somnolence includes the terms: "somnolence" and "sedation".</dd> <dt> <a href="#footnote-reference-5" name="footnote-5">†</a> </dt> <dd>Fatigue includes the terms "fatigue" and "lethargy".</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td class="Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold"> Percentage of Patients Reporting Event</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold"> Preferred Term</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> Clonidine Hydrochloride+STM</span> <br/> <span class="Bold"> (N=102)</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> PBO+STM</span> <br/> <span class="Bold"> (N=96)</span> <br/> </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> PSYCHIATRIC DISORDERS<br/> </td><td class="Rrule" valign="top"></td><td class="Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> Somnolence<a class="Sup" href="#footnote-4" name="footnote-reference-4">*</a> <br/> </td><td align="center" class="Rrule" valign="top"> 19%<br/> </td><td align="center" class="Rrule" valign="top"> 7%<br/> </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> Aggression<br/> </td><td align="center" class="Rrule" valign="top"> 2%<br/> </td><td align="center" class="Rrule" valign="top"> 1%<br/> </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> Affect Lability<br/> </td><td align="center" class="Rrule" valign="top"> 2%<br/> </td><td align="center" class="Rrule" valign="top"> 1%<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Emotional Disorder<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0%<br/> </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> GENERAL DISORDERS<br/> </td><td class="Rrule" valign="top"></td><td class="Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> Fatigue<a class="Sup" href="#footnote-5" name="footnote-reference-5">†</a> <br/> </td><td align="center" class="Rrule" valign="top"> 14%<br/> </td><td align="center" class="Rrule" valign="top"> 4%<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Irritability<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 7%<br/> </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> NERVOUS SYSTEM DISORDERS<br/> </td><td class="Rrule" valign="top"></td><td class="Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> Headache<br/> </td><td align="center" class="Rrule" valign="top"> 7%<br/> </td><td align="center" class="Rrule" valign="top"> 12%<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Insomnia<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 4%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3%<br/> </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> GASTROINTESTINAL DISORDERS<br/> </td><td class="Rrule" valign="top"></td><td class="Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Upper Abdominal Pain<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 7%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 4%<br/> </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> RESPIRATORY DISORDERS<br/> </td><td class="Rrule" valign="top"></td><td class="Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Nasal Congestion<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2%<br/> </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> METABOLISM AND NUTRITION DISORDERS<br/> </td><td class="Rrule" valign="top"></td><td class="Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Decreased Appetite<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 6%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3%<br/> </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"> CARDIAC DISORDERS<br/> </td><td class="Rrule" valign="top"></td><td class="Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Dizziness<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1%<br/> </td> </tr> </tbody> </table></div>

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 5.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span> Table 5 Common Adverse Reactions in the Flexible-Dose Adjunctive to Stimulant Therapy Trial – Taper Period<a class="Sup" href="#footnote-6" name="footnote-reference-6">*</a> (Study 2) </span> </caption> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-6" name="footnote-6">*</a> </dt> <dd>Taper Period: weeks 6 to 8</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Lrule Rrule Toprule" valign="top"> <br/> </td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold"> Percentage of Patients Reporting Event</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold"> Preferred Term</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> Clonidine</span> <br/> <span class="Bold"> Hydrochloride+STM</span> <br/> <span class="Bold"> (N=102)</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> PBO+STM</span> <br/> <span class="Bold"> (N=96)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Nasal Congestion<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 4%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2%<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Headache<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1%<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Irritability<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2%<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Throat Pain<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1%<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Gastroenteritis Viral<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0%<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Rash<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2%<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0%<br/> </td> </tr> </tbody> </table></div>

Adverse Reactions Leading to Discontinuation

Thirteen percent (13%) of patients receiving clonidine hydrochloride discontinued from the pediatric monotherapy study due to adverse events, compared to 1% in the placebo group. The most common adverse reactions leading to discontinuation of clonidine hydrochloride monotherapy treated patients were from 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 0.2 mg/day and -8.8 mmHg on clonidine hydrochloride 0.4 mg/day. The maximum placebo-subtracted mean change in diastolic blood pressure was -4.0 mmHg on clonidine hydrochloride 0.2 mg/day and -7.3 mmHg on clonidine hydrochloride 0.4 mg/day. The maximum placebo-subtracted mean change in heart rate was -4.0 beats per minute on clonidine hydrochloride 0.2 mg/day and -7.7 beats per minute on clonidine hydrochloride 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 0.2 mg/day and -5.6 mmHg on clonidine hydrochloride 0.4 mg/day. The maximum placebo-subtracted mean change in diastolic blood pressure was +3.3 mmHg on clonidine hydrochloride 0.2 mg/day and -5.4 mmHg on clonidine hydrochloride 0.4 mg/day. The maximum placebo-subtracted mean change in heart rate was -0.6 beats per minute on clonidine hydrochloride 0.2 mg/day and -3.0 beats per minute on clonidine hydrochloride 0.4 mg/day.

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

The following have been reported with other oral immediate release formulations of clonidine:

{ "type": "p", "children": [], "text": "\nThe following have been reported with other oral immediate release formulations of clonidine:" }

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span> Table 6 Clinically Important Drug Interactions </span> </caption> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold"> Concomitant Drug Name or Drug Class</span> <br/> </td><td align="left" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Clinical Rationale</span> <br/> </td><td align="left" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Clinical Recommendation</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Tricyclic antidepressants<br/> </td><td align="left" class="Botrule Rrule" valign="top"> Increase blood pressure and may counteract clonidine's hypotensive effects<br/> </td><td align="left" class="Botrule Rrule" valign="top"> Monitor blood pressure and adjust as needed<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Antihypertensive drugs<br/> </td><td align="left" class="Botrule Rrule" valign="top"> Potentiate clonidine's hypotensive effects<br/> </td><td align="left" class="Botrule Rrule" valign="top"> Monitor blood pressure and adjust as needed<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> CNS depressants<br/> </td><td align="left" class="Botrule Rrule" valign="top"> Potentiate sedating effects<br/> </td><td align="left" class="Botrule Rrule" valign="top"> Avoid use<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Drugs that affect sinus node function or AV node conduction (e.g., digitalis, calcium channel blockers, beta blockers)<br/> </td><td align="left" class="Botrule Rrule" valign="top"> Potentiate bradycardia and risk of AV block<br/> </td><td align="left" class="Botrule Rrule" valign="top"> Avoid use<br/> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<caption>\n<span> Table 6 Clinically Important Drug Interactions </span>\n</caption>\n<col width=\"33%\"/>\n<col width=\"33%\"/>\n<col width=\"33%\"/>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Bold\"> Concomitant Drug Name or Drug Class</span>\n<br/>\n</td><td align=\"left\" class=\"Botrule Rrule Toprule\" valign=\"top\"><span class=\"Bold\"> Clinical Rationale</span>\n<br/>\n</td><td align=\"left\" class=\"Botrule Rrule Toprule\" valign=\"top\"><span class=\"Bold\"> Clinical Recommendation</span>\n<br/>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"> Tricyclic antidepressants<br/>\n</td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\"> Increase blood pressure and may counteract clonidine's hypotensive effects<br/>\n</td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\"> Monitor blood pressure and adjust as needed<br/>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"> Antihypertensive drugs<br/>\n</td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\"> Potentiate clonidine's hypotensive effects<br/>\n</td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\"> Monitor blood pressure and adjust as needed<br/>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"> CNS depressants<br/>\n</td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\"> Potentiate sedating effects<br/>\n</td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\"> Avoid use<br/>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"> Drugs that affect sinus node function or AV node conduction (e.g., digitalis, calcium channel blockers, beta blockers)<br/>\n</td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\"> Potentiate bradycardia and risk of AV block<br/>\n</td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\"> Avoid use<br/>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including clonidine hydrochloride, 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/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/m2 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/m2 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/m2 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.

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 and any potential adverse effects on the breastfed child from clonidine hydrochloride or from the underlying maternal condition. Exercise caution when clonidine hydrochloride is administered to a nursing woman.

Clinical Considerations

Monitor breastfeeding infants exposed to clonidine hydrochloride through breast milk for symptoms of hypotension and/or bradycardia such as sedation, lethargy, tachypnea, and poor feeding.

Infertility

Based on findings in Animal studies revealed that clonidine hydrochloride may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)].

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.

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/m2 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/m2 basis. All these effects in males 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.

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.

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

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.

Clonidine hydrochloride extended-release tablets are a centrally acting alpha2-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.

{ "type": "p", "children": [], "text": "\nClonidine hydrochloride extended-release tablets are a centrally acting alpha2-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 sodium lauryl sulfate, lactose monohydrate, hypromellose, pregelatinized starch, colloidal silicon dioxide, and magnesium stearate. 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:

{ "type": "p", "children": [], "text": "The inactive ingredients are sodium lauryl sulfate, lactose monohydrate, hypromellose, pregelatinized starch, colloidal silicon dioxide, and magnesium stearate. 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:" }

C9H9Cl2N3∙HClMol. Wt. 266.56

{ "type": "p", "children": [], "text": "C9H9Cl2N3∙HClMol. Wt. 266.56" }

Clonidine hydrochloride, USP is an odorless, bitter, white, crystalline substance soluble in water and alcohol.

{ "type": "p", "children": [], "text": "\nClonidine hydrochloride, USP is an odorless, bitter, white, crystalline substance soluble in water and alcohol." }

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.

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.

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.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span> Table 7 Pharmacokinetic Parameters of Clonidine in Healthy Adult Volunteers </span> </caption> <col width="14%"/> <col width="14%"/> <col width="14%"/> <col width="14%"/> <col width="14%"/> <col width="14%"/> <col width="14%"/> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <br/> </td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold"> CATAPRES-Fasted</span> <br/> <span class="Bold"> n=15</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold"> Clonidine Hydrochloride Extended-Release-Fed</span> <br/> <span class="Bold"> n=15</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold"> Clonidine Hydrochloride Extended-Release-Fasted</span> <br/> <span class="Bold"> n=14</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Parameter</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> Mean</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> SD</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> Mean</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> SD</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> Mean</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> SD</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> C<span class="Sub">max</span> (pg/mL)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 443<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 59.6<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 235<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 34.7<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 258<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 33.3<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> AUC<span class="Sub">inf</span> (hr*pg/mL)<br/> </td><td align="center" class="Botrule Rrule"> 7313<br/> </td><td align="center" class="Botrule Rrule"> 1812<br/> </td><td align="center" class="Botrule Rrule"> 6505<br/> </td><td align="center" class="Botrule Rrule"> 1728<br/> </td><td align="center" class="Botrule Rrule"> 6729<br/> </td><td align="center" class="Botrule Rrule"> 1650<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> hT<span class="Sub">max</span> (hr)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 2.07<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 0.5<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 6.80<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3.61<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 6.50<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1.23<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> T<span class="Sub">1/2</span> (hr)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 12.57<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3.11<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 12.67<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3.76<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 12.65<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3.56<br/> </td> </tr> </tbody> </table></div>

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

Multiple-dose Pharmacokinetics in Children and Adolescents

Plasma clonidine concentrations in children and adolescents (0.1 mg bid and 0.2 mg bid) with ADHD are greater than those of adults with hypertension with children and adolescents receiving higher doses on a mg/kg basis. Body weight normalized clearance (CL/F) in children and adolescents was higher than CL/F observed in adults with hypertension. Clonidine concentrations in plasma increased with increases in dose over the dose range of 0.2 to 0.4 mg/day. Clonidine CL/F was independent of dose administered over the 0.2 to 0.4 mg/day dose range. Clonidine CL/F appeared to decrease slightly with increases in age over the range of 6 to 17 years, and females had a 23% lower CL/F than males. The incidence of "sedation-like" AEs (somnolence and fatigue) appeared to be independent of clonidine dose or concentration within the studied dose range in the titration study. Results from the add-on study showed that clonidine CL/F was 11% higher in patients who were receiving methylphenidate and 44% lower in those receiving amphetamine compared to subjects not on adjunctive therapy.

Carcinogenesis

Clonidine hydrochloride was not carcinogenic when administered in the diet of rats (for up to 132 weeks) or mice (for up to 78 weeks) at doses of up to 1620 (male rats), 2040 (female rats), or 2500 (mice) mcg/kg/day. These doses are approximately 20, 25, and 15 times, respectively, the maximum recommended human dose (MRHD) of 0.4 mg/day on a mg/m2 basis.

Mutagenesis

There was no evidence of genotoxicity in the Ames test for mutagenicity or mouse micronucleus test for clastogenicity.

Impairment of Fertility

In a reproduction study, fertility of female rats appeared to be adversely affected at dose levels of 500 and 2000 mcg/kg/day (10 and 40 times the MRHD on a mg/ m2 basis). Lower doses have not been adequately evaluated and a no adverse effect level could not be established.

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).

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span> Table 8 Short-Term Trials </span> </caption> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <tfoot> <tr> <td align="left" colspan="5"> <p class="First Footnote">SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.</p> </td> </tr> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-7" name="footnote-7">*</a> </dt> <dd>Difference (drug minus placebo) in least-squares mean change from baseline.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Botrule Toprule" rowspan="2" valign="top"><span class="Bold"> Study Number</span> <br/> </td><td align="left" class="Botrule Toprule" rowspan="2" valign="top"><span class="Bold"> Treatment Group</span> <br/> </td><td align="left" class="Botrule Toprule" colspan="3" valign="top"><span class="Bold"> Primary Efficacy Measure: ADHDRS-IV Total Score</span> <br/> </td> </tr> <tr> <td align="center" class="Botrule" valign="top"><span class="Bold"> Mean Baseline Score (SD)</span> <br/> </td><td align="center" class="Botrule Toprule" valign="top"><span class="Bold"> LS Mean Change from Baseline (SE)</span> <br/> </td><td align="left" class="Botrule Toprule" valign="top"><span class="Bold"> Placebo-subtracted Difference</span><a class="Sup" href="#footnote-7" name="footnote-reference-7">*</a><span class="Bold"> (95% CI)</span> <br/> </td> </tr> <tr> <td align="left" valign="top"> Study 1<br/> </td><td align="left" valign="top"> Clonidine HCl (0.2 mg/day)<br/> </td><td align="left" valign="top"> 43.8 (7.47)<br/> </td><td align="left" valign="top"> -15.0 (1.38)<br/> </td><td align="left" valign="top"> -8.5 (-12.2, -4.8)<br/> </td> </tr> <tr> <td valign="top"></td><td align="left" valign="top"> Clonidine HCl (0.4 mg/day)<br/> </td><td align="left" valign="top"> 44.6 (7.73)<br/> </td><td align="left" valign="top"> -15.6 (1.33)<br/> </td><td align="left" valign="top"> -9.1 (-12.8, -5.5)<br/> </td> </tr> <tr> <td class="Botrule" valign="top"></td><td align="left" class="Botrule" valign="top"> Placebo<br/> </td><td align="left" class="Botrule" valign="top"> 45.0 (8.53)<br/> </td><td align="left" class="Botrule" valign="top"> -6.5 (1.35)<br/> </td><td align="left" class="Botrule" valign="top"> --<br/> </td> </tr> <tr> <td align="left" valign="top"> Study 2<br/> </td><td align="left" valign="top"> Clonidine HCl (0.4 mg/day) + Psychostimulant<br/> </td><td align="left"> 38.9 (6.95)<br/> </td><td align="left"> -15.8 (1.18)<br/> </td><td align="left"> -4.5 (-7.8, -1.1)<br/> </td> </tr> <tr> <td class="Botrule" valign="top"></td><td align="left" class="Botrule" valign="top"> Psychostimulant alone<br/> </td><td align="left" class="Botrule" valign="top"> 39.0 (7.68)<br/> </td><td align="left" class="Botrule" valign="top"> -11.3 (1.24)<br/> </td><td align="left" class="Botrule" valign="top"> --<br/> </td> </tr> </tbody> </table></div>

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.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span> Table 9 Treatment Failure: Double-Blind Full Analysis Set (Study 3) </span> </caption> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tfoot> <tr> <td align="left" colspan="3"> <p class="First Footnote">ADHD-RS-IV = Attention Deficit Hyperactivity Disorder-Rating Scale-4<span class="Sup">th</span> edition; CGI-S = Clinical Global Impression-Severity</p> </td> </tr> <tr> <td align="left" colspan="3"> <p class="First Footnote"> <span class="Sup">a</span>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.</p> </td> </tr> <tr> <td align="left" colspan="3"> <p class="First Footnote"> <span class="Sup">b</span>Two subjects (1 placebo and 1 clonidine hydrochloride) withdrew consent, but met the clinical criteria for treatment failure.</p> </td> </tr> <tr> <td align="left" colspan="3"> <p class="First Footnote"> <span class="Sup">c</span>Three subjects (all placebo) discontinued the study due to treatment failure, but met only the criterion for ADHD-RS-IV.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" rowspan="2"><span class="Bold"> Study 3</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold"> Double-Blind Full Analysis Set</span> <br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> Clonidine Hydrochloride</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Placebo</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Number of subjects<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 68<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 67<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Number of treatment failures<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 31 (45.6%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 42 (62.7%)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="3" valign="top"> Basis of Treatment Failure<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Clinical criteria<span class="Sup">a ,b</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 11 (16.2%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 9 (13.4%)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Lack of efficacy<span class="Sup">c</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 1 (1.5%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 3 (4.5%)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Withdrawal of informed assent/consent<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 4 (5.9%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 20 (29.9%)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Other early terminations<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 15 (22.1%)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 10 (14.9%)<br/> </td> </tr> </tbody> </table></div>

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

Clonidine hydrochloride extended-release tablet 0.1 mg is a white to off-white round, biconvex tablets with debossing: "U" on one side and "77" on the other side and supplied as follows.

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Bottles of 60 tablets with child-resistant closure, NDC 70069-044-01

{ "type": "p", "children": [], "text": "Bottles of 60 tablets with child-resistant closure, NDC 70069-044-01 " }

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].

{ "type": "p", "children": [], "text": "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]." }

Dispense in a tight container as defined in the USP.

{ "type": "p", "children": [], "text": "Dispense in a tight container as defined in the USP." }

Keep clonidine hydrochloride extended-release tablets and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "Keep clonidine hydrochloride extended-release tablets and all medicines out of the reach of children." }

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)].

Manufactured for:

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Somerset Therapeutics, LLC

{ "type": "p", "children": [], "text": "Somerset Therapeutics, LLC" }

Somerset, NJ 08873

{ "type": "p", "children": [], "text": "Somerset, NJ 08873" }

Made in Portugal

{ "type": "p", "children": [], "text": "Made in Portugal" }

All trademarks are property of their respective owners.

{ "type": "p", "children": [], "text": "All trademarks are property of their respective owners." }

Revised: 10/2024

{ "type": "p", "children": [], "text": "Revised: 10/2024" }

Patient Information Clonidine Hydrochloride (kloe' ni deen hye'' droe klor' ide) Extended-Release Tablets

{ "type": "p", "children": [], "text": "\nPatient Information Clonidine Hydrochloride (kloe' ni deen hye'' droe klor' ide) Extended-Release Tablets\n" }

Read the Patient Information that comes with clonidine hydrochloride extended-release tablets before you start taking it and each time you get a refill. There may be new information. This Patient Information leaflet does not take the place of talking to your doctor about your medical condition or treatment.

{ "type": "p", "children": [], "text": "Read the Patient Information that comes with clonidine hydrochloride extended-release tablets before you start taking it and each time you get a refill. There may be new information. This Patient Information leaflet does not take the place of talking to your doctor about your medical condition or treatment." }

What are clonidine hydrochloride extended-release tablets?

{ "type": "p", "children": [], "text": "\nWhat are clonidine hydrochloride extended-release tablets?\n" }

Clonidine hydrochloride extended-release tablets are a prescription medicine used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). Your doctor may prescribe clonidine hydrochloride extended-release tablets alone or together with certain other ADHD medicines.

{ "type": "p", "children": [], "text": "Clonidine hydrochloride extended-release tablets are a prescription medicine used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). Your doctor may prescribe clonidine hydrochloride extended-release tablets alone or together with certain other ADHD medicines." }

{ "type": "ul", "children": [ "Clonidine hydrochloride extended-release tablets are not a central nervous system (CNS) stimulant.", "Clonidine hydrochloride extended-release tablets should be used as part of a total treatment program for ADHD that may include counseling or other therapies." ], "text": "" }

Who should not take clonidine hydrochloride extended-release tablets?

{ "type": "p", "children": [], "text": "\nWho should not take clonidine hydrochloride extended-release tablets?\n" }

{ "type": "ul", "children": [ "Do not take clonidine hydrochloride extended-release tablets if you are allergic to clonidine in clonidine hydrochloride extended-release tablets. See the end of this leaflet for a complete list of ingredients in clonidine hydrochloride extended-release tablets." ], "text": "" }

What should I tell my doctor before taking clonidine hydrochloride extended-release tablets?

{ "type": "p", "children": [], "text": "\nWhat should I tell my doctor before taking clonidine hydrochloride extended-release tablets?\n" }

Before you take clonidine hydrochloride extended-release tablets, tell your doctor if you:

{ "type": "p", "children": [], "text": "Before you take clonidine hydrochloride extended-release tablets, tell your doctor if you:" }

{ "type": "ul", "children": [ "have kidney problems", "have low or high blood pressure", "have a history of passing out (syncope)", "have heart problems, including history of heart attack", "have had a stroke or have stroke symptoms", "had a skin reaction (such as a rash) after taking clonidine in a transdermal form (skin patch)", "have any other medical conditions", "are pregnant or plan to become pregnant. It is not known if clonidine hydrochloride extended-release tablets will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.\nThere is a pregnancy registry for females who are exposed to ADHD medications, including clonidine hydrochloride extended-release tablets, during pregnancy. The purpose of the registry is to collect information about the health of females exposed to clonidine hydrochloride extended-release tablets and their baby. If you or your child becomes pregnant during treatment with clonidine hydrochloride extended-release tablets, talk to your healthcare provider about registering with the National Pregnancy Registry of ADHD Medications at 1-866-961-2388 or visit online at https://womensmentalhealth.org/adhdmedications/.\n\n", "are breastfeeding or plan to breastfeed. Clonidine hydrochloride extended-release tablets can pass into your breast milk. Talk to your doctor about the best way to feed your baby if you take clonidine hydrochloride extended-release tablets." ], "text": "" }

Tell your doctor about all of the medicines that you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

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Clonidine hydrochloride extended-release tablets and certain other medicines may affect each other causing serious side effects. Sometimes the doses of other medicines may need to be changed while taking clonidine hydrochloride extended-release tablets.

{ "type": "p", "children": [], "text": "Clonidine hydrochloride extended-release tablets and certain other medicines may affect each other causing serious side effects. Sometimes the doses of other medicines may need to be changed while taking clonidine hydrochloride extended-release tablets." }

Especially tell your doctor if you take:

{ "type": "p", "children": [], "text": "\nEspecially tell your doctor if you take:\n" }

{ "type": "ul", "children": [ "anti-depression medicines", "heart or blood pressure medicine", "other medicines that contain clonidine", "a medicine that makes you sleepy (sedation)" ], "text": "" }

Ask your doctor or pharmacist for a list of these medicines, if you are not sure if your medicine is listed above.

{ "type": "p", "children": [], "text": "\nAsk your doctor or pharmacist for a list of these medicines, if you are not sure if your medicine is listed above." }

Know the medicines that you take. Keep a list of your medicines with you to show your doctor and pharmacist when you get a new medicine.

{ "type": "p", "children": [], "text": "Know the medicines that you take. Keep a list of your medicines with you to show your doctor and pharmacist when you get a new medicine." }

How should I take clonidine hydrochloride extended-release tablets?

{ "type": "p", "children": [], "text": "\nHow should I take clonidine hydrochloride extended-release tablets?\n" }

{ "type": "ul", "children": [ "Take clonidine hydrochloride extended-release tablets exactly as your doctor tells you to take it.", "Your doctor will tell you how many clonidine hydrochloride extended-release tablets to take and when to take them. Your doctor may change your dose of clonidine hydrochloride extended-release tablets. Do not change your dose of clonidine hydrochloride extended-release tablets without talking to your doctor.", "Do not stop taking clonidine hydrochloride extended-release tablets without talking to your doctor.", "Clonidine hydrochloride extended-release tablets can be taken with or without food.", "Clonidine hydrochloride extended-release tablets should be taken 2 times a day (in the morning and at bedtime).", "If you miss a dose of clonidine hydrochloride extended-release tablets, skip the missed dose. Just take the next dose at your regular time. Do not take two doses at the same time.", "Take clonidine hydrochloride extended-release tablets whole. Do not chew, crush or break clonidine hydrochloride extended-release tablets. Tell your doctor if you cannot swallow clonidine hydrochloride extended-release tablets whole. You may need a different medicine.", "If you take too much clonidine hydrochloride extended-release tablets, call your Poison Control Center or go to the nearest hospital emergency room right away." ], "text": "" }

What should I avoid while taking clonidine hydrochloride extended-release tablets?

{ "type": "p", "children": [], "text": "\nWhat should I avoid while taking clonidine hydrochloride extended-release tablets?\n" }

{ "type": "ul", "children": [ "Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking clonidine hydrochloride extended-release tablets until you talk with your doctor. Clonidine hydrochloride extended-release tablets taken with alcohol or medicines that cause sleepiness or dizziness may make your sleepiness or dizziness worse.", "Do not drive, operate heavy machinery or do other dangerous activities until you know how clonidine hydrochloride extended-release tablets will affect you.", "Avoid becoming dehydrated or overheated." ], "text": "" }

What are possible side effects of clonidine hydrochloride extended-release tablets?

{ "type": "p", "children": [], "text": "\nWhat are possible side effects of clonidine hydrochloride extended-release tablets?\n" }

Clonidine hydrochloride extended-release tablets may cause serious side effects, including:

{ "type": "p", "children": [], "text": "\nClonidine hydrochloride extended-release tablets may cause serious side effects, including:\n" }

{ "type": "ul", "children": [ "\nLow blood pressure and low heart rate. Your doctor should check your heart rate and blood pressure before starting treatment and regularly during treatment with clonidine hydrochloride extended-release tablets.", "Sleepiness.", "Withdrawal symptoms. Suddenly stopping clonidine hydrochloride extended-release tablets may cause withdrawal symptoms including: increased blood pressure, headache, increased heart rate, lightheadedness, tightness in your chest and nervousness." ], "text": "" }

The most common side effects of clonidine hydrochloride extended-release tablets include:

{ "type": "p", "children": [], "text": "\nThe most common side effects of clonidine hydrochloride extended-release tablets include:" }

{ "type": "ul", "children": [ "sleepiness", "tiredness", "irritability", "trouble sleeping (insomnia)", "nightmare", "constipation", "dry mouth", "decreased appetite", "dizziness" ], "text": "" }

Tell your doctor if you have any side effects that bother you or that does not go away.

{ "type": "p", "children": [], "text": "\nTell your doctor if you have any side effects that bother you or that does not go away." }

These are not all of the possible side effects of clonidine hydrochloride extended-release tablets. For more information, ask your doctor or pharmacist.

{ "type": "p", "children": [], "text": "These are not all of the possible side effects of clonidine hydrochloride extended-release tablets. For more information, ask your doctor or pharmacist." }

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

{ "type": "p", "children": [], "text": "Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088." }

How should I store clonidine hydrochloride extended-release tablets?

{ "type": "p", "children": [], "text": "\nHow should I store clonidine hydrochloride extended-release tablets?\n" }

{ "type": "ul", "children": [ "Store clonidine hydrochloride extended-release tablets between 68° to 77°F (20° to 25°C).", "Keep clonidine hydrochloride extended-release tablets in a tightly closed container.", "Clonidine hydrochloride extended-release tablets come in a child-resistant package." ], "text": "" }

Keep clonidine hydrochloride extended-release tablets and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep clonidine hydrochloride extended-release tablets and all medicines out of the reach of children.\n" }

General information about the safe and effective use of clonidine hydrochloride extended-release tablets

{ "type": "p", "children": [], "text": "\nGeneral information about the safe and effective use of clonidine hydrochloride extended-release tablets\n" }

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use clonidine hydrochloride extended-release tablets for a condition for which it was not prescribed.

{ "type": "p", "children": [], "text": "Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use clonidine hydrochloride extended-release tablets for a condition for which it was not prescribed." }

Do not give clonidine hydrochloride extended-release tablets to other people, even if they have the same symptoms that you have. It may harm them.

{ "type": "p", "children": [], "text": "Do not give clonidine hydrochloride extended-release tablets to other people, even if they have the same symptoms that you have. It may harm them." }

This Patient Information leaflet summarizes the most important information about clonidine hydrochloride extended-release tablets. If you would like more information, talk with your doctor. You can also ask your doctor or pharmacist for information about clonidine hydrochloride extended-release tablets that is written for healthcare professionals.

{ "type": "p", "children": [], "text": "This Patient Information leaflet summarizes the most important information about clonidine hydrochloride extended-release tablets. If you would like more information, talk with your doctor. You can also ask your doctor or pharmacist for information about clonidine hydrochloride extended-release tablets that is written for healthcare professionals." }

For more information about clonidine hydrochloride extended-release tablets contact Somerset Therapeutics, LLC at 1-800-417-9175.

{ "type": "p", "children": [], "text": "For more information about clonidine hydrochloride extended-release tablets contact Somerset Therapeutics, LLC at 1-800-417-9175." }

What are the ingredients in clonidine hydrochloride extended-release tablets?

{ "type": "p", "children": [], "text": "\nWhat are the ingredients in clonidine hydrochloride extended-release tablets?\n" }

{ "type": "ul", "children": [ "Active Ingredient: clonidine hydrochloride", "Inactive Ingredients: sodium lauryl sulfate, lactose monohydrate, hypromellose, pregelatinized starch, colloidal silicon dioxide, and magnesium stearate" ], "text": "" }

Manufactured for:

{ "type": "p", "children": [], "text": "\nManufactured for:" }

Somerset Therapeutics, LLC

{ "type": "p", "children": [], "text": "Somerset Therapeutics, LLC" }

Somerset, NJ 08873

{ "type": "p", "children": [], "text": "Somerset, NJ 08873" }

Made in Portugal

{ "type": "p", "children": [], "text": "Made in Portugal" }

Revised: 10/2024

{ "type": "p", "children": [], "text": "Revised: 10/2024" }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

NDC 70069-044-01

{ "type": "p", "children": [], "text": "NDC 70069-044-01" }

Clonidine Hydrochloride

{ "type": "p", "children": [], "text": "\nClonidine Hydrochloride\n" }

Extended-Release

{ "type": "p", "children": [], "text": "\nExtended-Release\n" }

Tablets

{ "type": "p", "children": [], "text": "\nTablets\n" }

0.1 mg

{ "type": "p", "children": [], "text": "\n0.1 mg\n" }

60 Tablets

{ "type": "p", "children": [], "text": "60 Tablets" }