KAPVAY SIDE EFFECTS
SIDE EFFECTS
The following serious adverse reactions are described in greater detail elsewhere in labeling:
- Hypotension/bradycardia
- Sedation and somnolence
- Rebound hypertension
- Allergic reactions
- Cardiac Conduction Abnormalities
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 KAPVAY ADHD clinical studies (Study 1, CLON-301 and Study 2, CLON-302) evaluated 256 patients in two 8-week placebo-controlled studies.
A third KAPVAY 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 KAPVAY 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 KAPVAY 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 KAPVAY –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 in the Fixed-Dose Monotherapy Trial- Treatment Period (Study 1)
| Preferred Term | Percentage of Patients Reporting Event | ||
| KAPVAY 0.2 mg/day N=76 |
KAPVAY 0.4 mg/day N=78 |
Placebo (N=76) |
|
| PSYCHIATRIC DISORDERS | |||
| Somnolence* | 38% | 31% | 4% |
| Nightmare | 4% | 9% | 0% |
| Emotional Disorder | 4% | 4% | 1% |
| Aggression | 3% | 1% | 0% |
| Tearfulness | 1% | 3% | 0% |
| Enuresis | 0% | 4% | 0% |
| Sleep Terror | 3% | 0% | 0% |
| Poor Quality Sleep | 0% | 3% | 1% |
| NERVOUS SYSTEM DISORDERS | |||
| Headache | 20% | 13% | 16% |
| Insomnia | 5% | 6% | 1% |
| Tremor | 1% | 4% | 0% |
| Abnormal Sleep-Related Event | 3% | 1% | 0% |
| GASTROINTESTINAL DISORDERS | |||
| Upper Abdominal Pain | 15% | 10% | 12% |
| Nausea | 4% | 5% | 3% |
| Constipation | 1% | 6% | 0% |
| Dry Mouth | 0% | 5% | 1% |
| GENERAL DISORDERS | |||
| Fatigue† | 16% | 13% | 1% |
| Irritability | 9% | 5% | 4% |
| CARDIAC DISORDERS | |||
| Dizziness | 7% | 3% | 5% |
| Bradycardia | 0% | 4% | 0% |
| INVESTIGATIONS | |||
| Increased Heart Rate | 0% | 3% | 0% |
| METABOLISM AND NUTRITION DISORDERS | |||
| Decreased Appetite | 3% | 4% | 4% |
| * Somnolence includes the terms “somnolence” and “sedation”. † Fatigue includes the terms “fatigue” and “lethargy”. |
|||
Commonly observed adverse reactions (incidence of ≥ 2% in either active treatment group and greater than the rate on placebo) during the taper period are listed in Table 2.
Table 2 : Common Adverse Reactions in the Fixed-Dose Monotherapy Trial- Taper Period* (Study 1)
| Preferred Term | Percentage of Patients Reporting Event | ||
| KAPVAY 0.2 mg/day N=76 |
KAPVAY 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 | 1 3% | 1 0% | 1 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 KAPVAY as Adjunctive Therapy to Psychostimulants
Study 2 (CLON-302) was a short-term, randomized, double-blind, placebo-controlled study of a flexible dose of KAPVAY 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 KAPVAY was initiated at 0.1 mg/day and titrated up to 0.4 mg/day over a 3-week period. Most KAPVAY 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 3.
Table 3 : Common Adverse Reactions in the Flexible-Dose Adjunctive to Stimulant Therapy Trial- Treatment Period (Study 2)
| Preferred Term | Percentage of Patients Reporting Event | |
| KAPVAY+STM (N=102) |
PBO+STM (N=96) |
|
| PSYCHIATRIC DISORDERS | ||
| Somnolence* | 19% | 7% |
| Aggression | 2% | 1% |
| Affect Lability | 2% | 1% |
| Emotional Disorder | 2% | 0% |
| GENERAL DISORDERS | ||
| Fatigue† | 14% | 4% |
| Irritability | 2% | 7% |
| NERVOUS SYSTEM DISORDERS | ||
| Headache | 7% | 12% |
| Insomnia | 4% | 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 4.
Table 4: Common Adverse Reactions in the Flexible-Dose Adjunctive to Stimulant Therapy Trial- Taper Period* (Study 2)
| Preferred Term | Percentage of Patients Reporting Event | |
| KAPVAY+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 KAPVAY 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 KAPVAY 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 KAPVAY 0.2 mg/day and -8.8 mmHg on KAPVAY 0.4 mg/day. The maximum placebo-subtracted mean change in diastolic blood pressure was -4.0 mmHg on KAPVAY 0.2 mg/day and -7.3 mmHg on KAPVAY 0.4 mg/day. The maximum placebo-subtracted mean change in heart rate was -4.0 beats per minute on KAPVAY 0.2 mg/day and -7.7 beats per minute on KAPVAY 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 KAPVAY 0.2 mg/day and -5.6 mmHg on KAPVAY 0.4 mg/day. The maximum placebo-subtracted mean change in diastolic blood pressure was +3.3 mmHg on KAPVAY 0.2 mg/day and -5.4 mmHg on KAPVAY 0.4 mg/day. The maximum placebo-subtracted mean change in heart rate was -0.6 beats per minute on KAPVAY 0.2 mg/day and -3.0 beats per minute on KAPVAY 0.4 mg/day.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of KAPVAY. 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
SRC: NLM .