RELEXXII (Page 3 of 9)
6 ADVERSE REACTIONS
The following are discussed in more detail in other sections of the labeling:
- Abuse, Misuse, and Addiction [see Box Warning, Warnings and Precautions (5.1), and Drug Abuse and Dependence (9.2, 9.3)]
- Known hypersensitivity to methylphenidate or other ingredients [see Contraindications (4)]
- Hypertensive crisis when used concomitantly with monoamine oxidase inhibitors [see Contraindications (4) and Drug Interactions (7.1)]
- Risks to Patients with Serious Cardiac Disease [see Warnings and Precautions (5.2)]
- Increased Blood Pressure and Heart Rate [see Warnings and Precautions (5.3)]
- Psychiatric Adverse Reactions [ see Warnings and Precautions (5.4)]
- Priapism [see Warnings and Precautions (5.5)]
- Peripheral Vasculopathy, including Raynaud’s Phenomenon [see Warnings and Precautions (5.6)]
- Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions (5.7)]
- Potential for Gastrointestinal Obstruction [see Warnings and Precautions (5.8)]
- Acute Angle Closure Glaucoma [see Warnings and Precautions (5.9)]
- Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions (5.10)]
- Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings and Precautions (5.11)]
6.1 Clinical Trials 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 clinical trials of another drug and may not reflect the rates observed in clinical practice.
The safety of RELEXXII for the treatment of ADHD is based on adequate and well-controlled studies of another formulation of methylphenidate hydrochloride extended-release tablets. Below is a display of adverse reactions from those adequate and well-controlled studies in ADHD.
Adults and pediatric patients 6 to 17 years with ADHD were evaluated in six controlled clinical studies and eleven open-label clinical studies (see Table 3). Safety was assessed by collecting adverse reactions, vital signs, weights, and electrocardiograms (ECGs), and by performing physical examinations and laboratory analyses. A total of 3,906 patients participated in the clinical trials.
Table 3. Exposure in Double-Blind and Open-Label Clinical Studies of Another Formulation of Methylphenidate Hydrochloride Extended-Release Tablets
Patient Population | N | Dosage Range |
Pediatric patients 6 to 12 years | 2216 | 18 mg to 54 mg once daily |
Pediatric patients 13 to 17 years | 502 | 18 mg to 72 mg once daily |
Adults | 1188 | 18 mg to 108 mg* once daily |
* 108 mg is 1.5 times the maximum recommended dosage of RELEXXII.
The most common adverse reactions in double-blind clinical trials (>5%) were:
- Pediatric patients 6 to 17 years: abdominal pain upper (see Table 4).
- Adults: decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, and hyperhidrosis (see Table 5).
The most common adverse reactions associated with discontinuation (≥1%) from either pediatric or adult clinical trials were anxiety, irritability, insomnia, and blood pressure increased.
Adverse reactions in either the pediatric or adult double-blind adverse reactions tables may be relevant for both patient populations.
Pediatric Patients 6 to 17 Years
Table 4 lists the adverse reactions reported in 1% or more of another formulation of methylphenidate hydrochloride extended-release tablet-treated pediatric patients (6 to 17 years) in four placebo-controlled, double-blind clinical trials.
Table 4. Adverse Reactions Reported by ≥1% of Pediatric Patients (6 to 17 years) Treated with Another Formulation of Methylphenidate Hydrochloride Extended-release Tablets in Four Placebo-Controlled, Double-Blind Clinical Trials
System/Organ Class Adverse Reaction | Another Formulation of Methylphenidate Hydrochloride Extended-release Tablets (n=321) % | Placebo (n=318) % |
Gastrointestinal Disorders | ||
Abdominal pain upper | 6.2 | 3.8 |
Vomiting | 2.8 | 1.6 |
General Disorders and Administration Site Conditions | ||
Pyrexia | 2.2 | 0.9 |
Infections and Infestations | ||
Nasopharyngitis | 2.8 | 2.2 |
Nervous System Disorders | ||
Dizziness | 1.9 | 0 |
Psychiatric Disorders | ||
Insomnia* | 2.8 | 0.3 |
Respiratory, Thoracic and Mediastinal Disorders | ||
Cough | 1.9 | 0.9 |
Oropharyngeal pain | 1.2 | 0.9 |
* Terms of Initial insomnia (methylphenidate hydrochloride extended-release tablets =0.6%) and Insomnia (methylphenidate hydrochloride extended-release tablets =2.2%) are combined into Insomnia. |
Adults
Table 5 lists the adverse reactions reported in 1% or more of adults treated with another formulation of methylphenidate hydrochloride extended-release tablets in two placebo-controlled, double-blind clinical trials.
Table 5. Adverse Reactions Reported by ≥1% of Adults Treated with Another Formulation of Methylphenidate Hydrochloride Extended-release Tablets in Two Placebo-Controlled, Double-Blind Clinical Trials*
System/Organ Class Adverse Reaction | Another Formulation of Methylphenidate Hydrochloride Extended-release Tablets (n=415) % | Placebo (n=212) % |
Cardiac Disorders | ||
Tachycardia | 4.8 | 0 |
Palpitations | 3.1 | 0.9 |
Ear and Labyrinth Disorders | ||
Vertigo | 1.7 | 0 |
Eye Disorders | ||
Vision blurred | 1.7 | 0.5 |
Gastrointestinal Disorders | ||
Dry mouth | 14.0 | 3.8 |
Nausea | 12.8 | 3.3 |
Dyspepsia | 2.2 | 0.9 |
Vomiting | 1.7 | 0.5 |
Constipation | 1.4 | 0.9 |
General Disorders and Administration Site Conditions | ||
Irritability | 5.8 | 1.4 |
Infections and Infestations | ||
Upper respiratory tract infection | 2.2 | 0.9 |
Investigations | ||
Weight decreased | 6.5 | 3.3 |
Metabolism and Nutrition Disorders | ||
Decreased appetite | 25.3 | 6.6 |
Anorexia | 1.7 | 0 |
Musculoskeletal and Connective Tissue Disorders | ||
Muscle tightness | 1.9 | 0 |
Nervous System Disorders | ||
Headache | 22.2 | 15.6 |
Dizziness | 6.7 | 5.2 |
Tremor | 2.7 | 0.5 |
Paresthesia | 1.2 | 0 |
Sedation | 1.2 | 0 |
Tension headache | 1.2 | 0.5 |
Psychiatric Disorders | ||
Insomnia | 12.3 | 6.1 |
Anxiety | 8.2 | 2.4 |
Initial insomnia | 4.3 | 2.8 |
Depressed mood | 3.9 | 1.4 |
Nervousness | 3.1 | 0.5 |
Restlessness | 3.1 | 0 |
Agitation | 2.2 | 0.5 |
Aggression | 1.7 | 0.5 |
Bruxism | 1.7 | 0.5 |
Depression | 1.7 | 0.9 |
Libido decreased | 1.7 | 0.5 |
Affect lability | 1.4 | 0.9 |
Confusional state | 1.2 | 0.5 |
Tension | 1.2 | 0.5 |
Respiratory, Thoracic and Mediastinal Disorders | ||
Oropharyngeal pain | 1.7 | 1.4 |
Skin and Subcutaneous Tissue Disorders | ||
Hyperhidrosis | 5.1 | 0.9 |
* Included doses up to 108 mg (1.5 times the maximum recommended dosage of RELEXXII). |
Adverse Reactions Observed in Clinical Trials with Another Formulation of Methylphenidate Hydrochloride Extended-release Tablets
This section includes adverse reactions reported with use of another formulation of methylphenidate hydrochloride extended-release tablets in double-blind trials that do not meet the criteria specified for Table 4 or Table 5 and all adverse reactions reported by the other formulation of methylphenidate hydrochloride extended-release tablets-treated patients who participated in open-label and postmarketing clinical trials.
Blood and Lymphatic System Disorders: Leukopenia
Eye Disorders: Accommodation disorder, Dry eye
Vascular Disorders: Hot flush
Gastrointestinal Disorders: Abdominal discomfort, Abdominal pain, Diarrhea
General Disorders and Administrative Site Conditions: Asthenia, Fatigue, Feeling jittery, Thirst
Infections and Infestations: Sinusitis
Investigations: Alanine aminotransferase increased, Blood pressure increased, Cardiac murmur, Heart rate increased
Musculoskeletal and Connective Tissue Disorders: Muscle spasms
Nervous System Disorders: Lethargy, Psychomotor hyperactivity, Somnolence
Psychiatric Disorders: Anger, Hypervigilance, Mood altered, Mood swings, Panic attack, Sleep disorder, Tearfulness, Tic
Reproductive System and Breast Disorders: Erectile dysfunction
Respiratory, Thoracic and Mediastinal Disorders: Dyspnea
Skin and Subcutaneous Tissue Disorders: Rash, Rash macular
Vascular Disorders: Hypertension
Discontinuation Due to Adverse Reactions
Adverse reactions in the four placebo-controlled studies of pediatric patients (6 to 17 years) leading to discontinuation occurred in 2 patients (0.6%) treated with another formulation of methylphenidate hydrochloride extended-release tablets including depressed mood (1, 0.3%) and headache and insomnia (1, 0.3%), and 6 placebo patients (1.9%) including headache and insomnia (1, 0.3%), irritability (2, 0.6%), headache (1, 0.3%), psychomotor hyperactivity (1, 0.3%), and tic (1, 0.3%).
In the two placebo-controlled studies of adults, 25 patients (6.0%) treated with another formulation of methylphenidate hydrochloride extended-release tablets and 6 placebo patients (2.8%) discontinued due to an adverse reaction. Incidence of >0.5% in patients treated with another formulation of methylphenidate hydrochloride extended-release tablets included anxiety (1.7%), irritability (1.4%), blood pressure increased (1.0%), and nervousness (0.7%). In placebo patients, blood pressure increased and depressed mood had an incidence of >0.5% (0.9%).
In the eleven open-label studies of pediatric patients and adults, 266 patients (7.0%) treated with another formulation of methylphenidate hydrochloride extended-release tablets discontinued due to an adverse reaction. Incidence of >0.5% included insomnia (1.2%), irritability (0.8%), anxiety (0.7%), decreased appetite (0.7%), and tic (0.6%).
Tics
In a long-term uncontrolled study (n=432 pediatric patients 6 to 12 years), the cumulative incidence of new onset of tics was 9% after 27 months of treatment with another formulation of methylphenidate hydrochloride extended-release tablets.
In a second uncontrolled study (n=682 pediatric patients 6 to 12 years) the cumulative incidence of new-onset tics was 1% (9/682). The treatment period was up to 9 months with mean treatment duration of 7.2 months.
Blood Pressure and Heart Rate Increases
In the laboratory classroom clinical trials in pediatric patients 6 to 12 years (Studies 1 and 2), both another formulation of methylphenidate hydrochloride extended-release tablets once daily and methylphenidate three times daily increased resting pulse by an average of 2 to 6 bpm and produced average increases of systolic and diastolic blood pressure of roughly 1 to 4 mm Hg during the day, relative to placebo. In the placebo-controlled trial in pediatric patients 13 to 17 years (Study 4), mean increases from baseline in resting pulse rate were observed with another formulation of methylphenidate hydrochloride extended-release tablets and placebo at the end of the double-blind phase (5 and 3 beats/minute, respectively). Mean increases from baseline in blood pressure at the end of the double-blind phase for another formulation of methylphenidate hydrochloride extended-release tablets and placebo-treated patients were 0.7 and 0.7 mm Hg (systolic) and 2.6 and 1.4 mm Hg (diastolic), respectively. In one placebo-controlled study in adults (Study 6), dose-dependent mean increases of 3.9 to 9.8 bpm from baseline in standing pulse rate were observed with another formulation of methylphenidate hydrochloride extended-release tablets at the end of the double-blind treatment vs. an increase of 2.7 beats/minute with placebo. Mean changes from baseline in standing blood pressure at the end of double-blind treatment ranged from 0.1 to 2.2 mm Hg (systolic) and -0.7 to 2.2 mm Hg (diastolic) for another formulation of methylphenidate hydrochloride extended-release tablets and was 1.1 mm Hg (systolic) and -1.8 mm Hg (diastolic) for placebo. In a second placebo-controlled study in adults (Study 5), mean changes from baseline in resting pulse rate were observed for another formulation of methylphenidate hydrochloride extended-release tablets and placebo at the end of the double-blind treatment (3.6 and –1.6 beats/minute, respectively). Mean changes from baseline in blood pressure at the end of the double–blind treatment for another formulation of methylphenidate hydrochloride extended-release tablets and placebo-treated patients were –1.2 and –0.5 mm Hg (systolic) and 1.1 and 0.4 mm Hg (diastolic), respectively [see Warnings and Precautions (5.3)].
All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.