1 INDICATIONS AND USAGE Clonidine hydrochloride extended-release tablets are indicated for the treatment of attention deficit hyperactivity disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications [see C linical Studies (14) ] .

• Clonidine hydrochloride extended-release tablets are a centrally acting alpha 2 -adrenergic agonist indicated for the treatment of attention deficit hyperactivity disorder (ADHD) as monotherapy or as adjunctive therapy to stimulant medications.

( 1 )

6 ADVERSE REACTIONS The following serious adverse reactions are described in greater detail elsewhere in labeling: Hypotension/bradycardia [see Warnings and Precautions (5.1) ] Sedation and somnolence [see Warnings and Precautions (5.2) ] Rebound hypertension [see Warnings and Precautions (5.3) ] Allergic reactions [see Warnings and Precautions (5.4) ] Cardiac Conduction Abnormalities [see Warnings and Precautions (5.5) ] Most common adverse reactions (incidence at least 5% and twice the rate of placebo) as monotherapy in ADHD: somnolence, fatigue, irritability, nightmare, insomnia, constipation, dry mouth.

( 6.1 ) Most common adverse reactions (incidence at least 5% and twice the rate of placebo) as adjunct therapy to psychostimulant in ADHD: somnolence, fatigue, decreased appetite, dizziness.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Xiamen LP Pharmaceutical Co,.

Ltd.

at 1-415-516-9498 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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

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

Additional pediatric use information for patients ages 6 to 17 years is approved for Concordia Pharmaceuticals Inc.’s KAPVAY (clonidine hydrochloride) extended-release tablets.

However, due to Concordia Pharmaceuticals Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Study 1: Fixed-dose Clonidine Hydrochloride Extended-Release Tablets Monotherapy Study 1 (CLON-301) was a short-term, multi-center, randomized, double-blind, placebo-controlled study of two fixed doses (0.2 mg/day or 0.4 mg/day) of clonidine hydrochloride extended-release tablets in children and adolescents (6 to 17 years of age) who met DSM-IV criteria for ADHD hyperactive or combined inattentive/hyperactive subtypes.

Most Common Adverse Reactions (incidence of ≥5% and at least twice the rate of placebo): somnolence, fatigue, irritability, insomnia, nightmare, constipation, dry mouth.

Adverse Events Leading to Discontinuation of Clonidine Hydrochloride Extended-Release Tablets –Five patients (7%) in the low dose group (0.2 mg), 15 patients (20%) in the high dose group (0.4 mg), and 1 patient in the placebo group (1%) reported adverse reactions that led to discontinuation.

The most common adverse reactions that led to discontinuation were somnolence and fatigue.

Commonly observed adverse reactions (incidence of ≥2% in either active treatment group and greater than the rate on placebo) during the treatment period are listed in Table 2.

Table 2 Common Adverse Reactions in the Fixed-Dose Monotherapy Trial - Treatment Period (Study 1) Percentage of Patients Reporting Event Preferred Term Clonidine Hydrochloride Extended-Release Tablets 0.2 mg/day N=76 Clonidine Hydrochloride Extended-Release Tablets 0.4 mg/day N=78 Placebo (N=76) PSYCHIATRIC DISORDERS Somnolence* Nightmare Emotional Disorder Aggression Tearfulness Enuresis Sleep Terror Poor Quality Sleep 38% 4% 4% 3% 1% 0% 3% 0% 31% 9% 4% 1% 3% 4% 0% 3% 4% 0% 1% 0% 0% 0% 0% 1% NERVOUS SYSTEM DISORDERS Headache Insomnia Tremor Abnormal Sleep-Related Event 20% 5% 1% 3% 13% 6% 4% 1% 16% 1% 0% 0% GASTROINTESTINAL DISORDERS Upper Abdominal Pain Nausea Constipation Dry Mouth 15% 4% 1% 0% 10% 5% 6% 5% 12% 3% 0% 1% GENERAL DISORDERS Fatigue† Irritability 16% 9% 13% 5% 1% 4% CARDIAC DISORDERS Dizziness Bradycardia 7% 0% 3% 4% 5% 0% INVESTIGATIONS Increased Heart Rate 0% 3% 0% METABOLISM AND NUTRITION DISORDERS Decreased Appetite 3% 4% 4% * Somnolence includes the terms "somnolence" and "sedation".

† Fatigue includes the terms "fatigue" and "lethargy".

Commonly observed adverse reactions (incidence of ≥2% in either active treatment group and greater than the rate on placebo) during the taper period are listed in Table 3.

Table 3 Common Adverse Reactions in the Fixed-Dose Monotherapy Trial - Taper Period* (Study 1) Percentage of Patients Reporting Event Preferred Term Clonidine Hydrochloride Extended-Release Tablets 0.2 mg/day N=76 Clonidine Hydrochloride Extended-Release Tablets 0.4 mg/day N=78 Placebo (N=76) Abdominal Pain Upper 0% 6% 3% Headache 5% 2% 3% Gastrointestinal Viral 0% 5% 0% Somnolence 2% 3% 0% Heart Rate Increased 0% 3% 0% Otitis Media Acute 3% 0% 0% * Taper Period: 0.2 mg dose, week 8; 0.4 mg dose, weeks 6-8; Placebo dose, weeks 6-8 Study 2: Flexible-dose Clonidine Hydrochloride Extended-Release 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 extended-release tablets 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 extended-release tablets were initiated at 0.1 mg/day and titrated up to 0.4 mg/day over a 3-week period.

Most clonidine hydrochloride extended-release tablets 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.

Table 4 Common Adverse Reactions in the Flexible-Dose Adjunctive to Stimulant Therapy Trial - Treatment Period (Study 2) Percentage of Patients Reporting Event Preferred Term Clonidine Hydrochloride Extended-Release Tablets+STM (N=102) PBO+STM (N=96) PSYCHIATRIC DISORDERS Somnolence* Aggression Affect Lability Emotional Disorder 19% 2% 2% 2% 7% 1% 1% 0% GENERAL DISORDERS Fatigue† Irritability 14% 2% 4% 7% NERVOUS SYSTEM DISORDERS Headache Insomnia 7% 4% 12% 3% GASTROINTESTINAL DISORDERS Upper Abdominal Pain 7% 4% RESPIRATORY DISORDERS Nasal Congestion 2% 2% METABOLISM AND NUTRITION DISORDERS Decreased Appetite 6% 3% CARDIAC DISORDERS Dizziness 5% 1% * Somnolence includes the terms: "somnolence" and "sedation".

† Fatigue includes the terms "fatigue" and "lethargy".

Commonly observed adverse reactions (incidence of ≥2% in the treatment group and greater than the rate on placebo) during the taper period are listed in Table 5.

Table 5 Common Adverse Reactions in the Flexible-Dose Adjunctive to Stimulant Therapy Trial - Taper Period* (Study 2) Percentage of Patients Reporting Event Preferred Term Clonidine Hydrochloride Extended-Release Tablets+STM (N=102) PBO+STM (N=96) Nasal Congestion 4% 2% Headache 3% 1% Irritability 3% 2% Throat Pain 3% 1% Gastroenteritis Viral 2% 0% Rash 2% 0% * Taper Period: weeks 6-8 Adverse Reactions Leading to Discontinuation Thirteen percent (13%) of patients receiving clonidine hydrochloride extended-release tablets 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 extended-release tablets 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 extended-release tablets 0.2 mg/day and -8.8 mmHg on clonidine hydrochloride extended-release tablets 0.4 mg/day.

The maximum placebo-subtracted mean change in diastolic blood pressure was -4.0 mmHg on clonidine hydrochloride extended-release tablets 0.2 mg/day and -7.3 mmHg on clonidine hydrochloride extended-release tablets 0.4 mg/day.

The maximum placebo-subtracted mean change in heart rate was -4.0 beats per minute on clonidine hydrochloride extended-release tablets 0.2 mg/day and -7.7 beats per minute on clonidine hydrochloride extended-release tablets 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 tablets 0.2 mg/day and -5.6 mmHg on clonidine hydrochloride extended-release tablets 0.4 mg/day.

The maximum placebo-subtracted mean change in diastolic blood pressure was +3.3 mmHg on clonidine hydrochloride extended-release tablets 0.2 mg/day and -5.4 mmHg on clonidine hydrochloride extended-release tablets 0.4 mg/day.

The maximum placebo-subtracted mean change in heart rate was -0.6 beats per minute on clonidine hydrochloride extended-release tablets 0.2 mg/day and -3.0 beats per minute on clonidine hydrochloride extended-release tablets 0.4 mg/day.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of clonidine hydrochloride extended-release tablets.

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