ADVERSE REACTIONS
Clinical Trial Experience
Two clonidine hydrochloride extended-release tablets ADHD clinical studies evaluated 256 patients who received active therapy, in one of the two placebo-controlled studies (Studies 1 and 2) with primary efficacy end-points at 5-weeks.
Study 1: Fixed-dose Clonidine Hydrochloride Extended-Release Tablets Monotherapy
Study 1 was a multi-center, randomized, double-blind, placebo-controlled study with primary efficacy endpoint at 5 weeks, 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.
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
0.4 mg/day
N=78
|
Clonidine Hydrochloride Extended-Release Tablets
0.2 mg/day
N=76
|
Placebo
(N=76)
|
| Somnolence*
|
31% |
38% |
5% |
| Headache |
19% |
29% |
18% |
| Upper Abdominal Pain |
13% |
20% |
17% |
| Fatigue†
|
13% |
16% |
1% |
| Upper Respiratory Tract Infection |
6% |
11% |
4% |
| Irritability |
6% |
9% |
3% |
| Throat Pain |
6% |
8% |
3% |
| Nausea |
8% |
5% |
4% |
| Nightmare |
9% |
3% |
0 |
| Dizziness |
3% |
7% |
5% |
| Insomnia |
6% |
4% |
1% |
| Emotional Disorder |
5% |
4% |
1% |
| Constipation |
6% |
1% |
0 |
| Dry Mouth |
5% |
0 |
1% |
| Nasal Congestion |
5% |
3% |
1% |
| Body Temperature Increased |
1% |
5% |
3% |
| Gastrointestinal Viral |
0% |
7% |
4% |
| Diarrhea |
1% |
4% |
3% |
| Ear Pain |
0 |
5% |
1% |
| Nasopharyngitis |
3% |
3% |
1% |
| Abnormal Sleep-Related Event |
1% |
3% |
0 |
| Aggression |
1% |
3% |
1% |
| Asthma |
1% |
3% |
1% |
| Bradycardia |
4% |
0 |
0 |
| Enuresis |
4% |
0 |
0 |
| Influenza like Illness |
3% |
1% |
1% |
| Tearfulness |
3% |
1% |
0 |
| Thirst |
3% |
1% |
0 |
| Tremor |
3% |
1% |
0 |
| Epistaxis |
0 |
3% |
0 |
| Lower Respiratory Tract Infection |
0 |
3% |
1% |
| Pollakiuria |
0 |
3% |
0 |
| Sleep Terror |
0 |
3% |
0 |
* 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
0.4 mg/day
N=78
|
Clonidine Hydrochloride Extended-Release Tablets
0.2
mg/day
N=76
|
Placebo
(N=76)
|
| Abdominal Pain Upper |
6% |
0 |
3% |
| Headache |
2% |
5% |
3% |
| Gastrointestinal Viral |
5% |
0 |
0 |
| Somnolence |
3% |
2% |
0 |
| Heart Rate Increased |
3% |
0 |
0 |
| Otitis Media Acute |
0 |
3% |
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 was a multi-center, randomized, double-blind, placebo-controlled study, with primary efficacy endpoint at 5 weeks, 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. 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.
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)
|
| Somnolence*
|
19% |
8% |
| Fatigue†
|
16% |
4% |
| Abdominal Pain Upper |
12% |
7% |
| Nasal Congestion |
6% |
5% |
| Throat Pain |
6% |
3% |
| Decreased Appetite |
5% |
4% |
| Body Temperature Increased |
4% |
2% |
| Dizziness |
4% |
2% |
| Insomnia |
4% |
2% |
| Epistaxis |
3% |
0 |
| Rhinorrhea |
3% |
0 |
| Abdominal Pain |
2% |
1% |
| Anxiety |
2% |
0 |
| Pain in Extremity |
2% |
0 |
* 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
Most common adverse reactions, defined as events that were reported in at least 5% of drug-treated patients and at least twice the rate as in placebo patients, during the treatment period were somnolence, fatigue, upper respiratory tract infection, irritability, throat pain, insomnia, nightmares, emotional disorder, constipation, nasal congestion, increased body temperature, dry mouth, and ear pain. The most common adverse reactions that were reported during the taper phase were upper abdominal pain and gastrointestinal virus.
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%). Less common adverse reactions leading to discontinuation (occurring in approximately 1% of patients) included: formication, vomiting, prolonged QT, increased heart rate, and rash. In the pediatric adjunctive treatment to stimulants study, one patient discontinued from clonidine hydrochloride extended-release tablets + stimulant group because of bradyphrenia.
Effects on Laboratory Tests, Vital Signs, and Electrocardiograms
Clonidine hydrochloride extended-release tablets treatment was not associated with any clinically important effects on any laboratory parameters in either of the placebo-controlled studies.
Mean decreases in blood pressure and heart rate were seen [see Warnings and Precautions].
There were no changes on ECGs to suggest a drug-related effect.
Postmarketing Experience
Hallucinations and atrioventricular (AV) block have been identified during post approval use of clonidine hydrochloride extended-release tablets. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
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