Methylphenidate Hydrochloride (Page 3 of 8)

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 the clinical trials of another drug and may not reflect the rates observed in practice.

The clinical program for methylphenidate hydrochloride extended-release capsules consisted of 6 studies: 2 controlled clinical studies conducted in children with ADHD aged 6 to 12 years and 4 clinical pharmacology studies conducted in healthy adult volunteers. These studies included a total of 256 subjects; 195 children with ADHD and 61 healthy adult volunteers. The subjects received methylphenidate hydrochloride extended-release capsules in doses of 10 to 40 mg per day. Safety of methylphenidate hydrochloride extended-release capsules was assessed by evaluating frequency and nature of adverse events, routine laboratory tests, vital signs, and body weight. A placebo-controlled, double-blind, parallel-group study was conducted to evaluate the efficacy and safety of methylphenidate hydrochloride extended-release capsules in children with ADHD aged 6 to 12 years. All subjects received methylphenidate hydrochloride extended-release capsules for up to 4 weeks, and had their dose optimally adjusted, prior to entering the double-blind phase of the trial. In the 2-week double-blind treatment phase of this study, patients received either placebo or methylphenidate hydrochloride extended-release capsules at their individually-titrated dose (range, 10 mg to 40 mg).

Adverse reactions with an incidence greater than 5% during the initial 4-week single-blind methylphenidate hydrochloride extended-release capsules titration period of this study were headache, insomnia, upper abdominal pain, appetite decreased, and anorexia.

Adverse reactions with an incidence greater than 2% among methylphenidate hydrochloride extended-release capsules-treated subjects, during the 2-week double-blind phase of the clinical study, are shown in Table 2.

Table 2: Adverse Reactions in Greater Than 2% Methylphenidate Hydrochloride Extended-Release Capsules -Treated Subjects in the 2-Week Double-Blind Phase

Preferred Term Methylphenidate Hydrochloride Extended-Release Capsules N = 65 N (%) Placebo N = 71 N (%)
Anorexia 2 (3.1) 0 (0.0)
Insomnia 2 (3.1) 0 (0.0)

Adverse Reactions Associated with Discontinuation of Treatment

In the 2-week double-blind treatment phase of a placebo-controlled parallel-group study in children with ADHD, one methylphenidate hydrochloride extended-release capsules-treated subject (1/65, 1.5%) discontinued due to an adverse event (depressed mood).

In the single-blind titration period of this study, subjects received methylphenidate hydrochloride extended-release capsules for up to 4 weeks. During this period a total of 6 subjects (6/161, 3.7%) discontinued due to adverse events. The adverse events leading to discontinuation were anger (2 patients), hypomania, anxiety, depressed mood, fatigue, migraine, and lethargy.

6.2 Postmarketing Experience

The following adverse reactions have been identified during the post approval use of methylphenidate products. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure.

Adverse Reactions Reported with Methylphenidate Hydrochloride Tablets and Methylphenidate Hydrochloride Extended-Release Capsules

Infections and Infestations: nasopharyngitis

Blood and the Lymphatic System Disorders: leukopenia, thrombocytopenia, anemia

Immune System Disorders: hypersensitivity reactions, including angioedema and anaphylaxis

Metabolism and Nutrition Disorders: decreased appetite, reduced weight gain, and suppression of growth during prolonged use in children

Psychiatric Disorders: insomnia, anxiety, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), depressed mood, depression

Nervous System Disorders: headache, dizziness, tremor, dyskinesia including choreoathetoid movements, drowsiness, convulsions, cerebrovascular disorders (including vasculitis, cerebral hemorrhages and cerebrovascular accidents), serotonin syndrome in combination with serotonergic drugs

Eye Disorders: blurred vision, difficulties in visual accommodation

Cardiac Disorders: tachycardia, palpitations, increased blood pressure, arrhythmias, angina pectoris

Respiratory, Thoracic, and Mediastinal Disorders: cough
Gastrointestinal Disorders: dry mouth, nausea, vomiting, abdominal pain, dyspepsia

Hepatobiliary Disorders: abnormal liver function, ranging from transaminase elevation to severe hepatic injury

Skin and Subcutaneous Tissue Disorders: hyperhidrosis, pruritus, urticaria, exfoliative dermatitis, scalp hair loss, erythema multiforme rash, thrombocytopenic purpura

Musculoskeletal and Connective Tissue Disorders: arthralgia, muscle cramps, rhabdomyolysis, trismus

Investigations: weight loss (adult ADHD patients)

Vascular Disorders: peripheral coldness, Raynaud’s phenomenon

Adverse Reactions Reported with Other Methylphenidate-Containing Products

The list below shows adverse reactions not listed with methylphenidate hydrochloride tablets, or methylphenidate hydrochloride extended-release capsules, formulations that have been reported with other methylphenidate-containing products.

Blood and Lymphatic Disorders: pancytopenia

Immune System Disorders: hypersensitivity reactions such as auricular swelling, bullous conditions, eruptions, exanthemas

Psychiatric Disorders: affect lability, mania, disorientation, libido changes,

Nervous System Disorders: migraine, motor and verbal tics

Eye Disorders: diplopia, increased intraocular pressure, mydriasis

Cardiac Disorders: sudden cardiac death, myocardial infarction, bradycardia, extrasystole

Respiratory, Thoracic, and Mediastinal Disorders: pharyngolaryngeal pain, dyspnea Gastrointestinal Disorders: diarrhea, constipation

Skin and Subcutaneous Tissue Disorders: angioneurotic edema, erythema, fixed drug eruption

Musculoskeletal, Connective Tissue, and Bone Disorders: myalgia, muscle twitching

Renal and Urinary Disorders: hematuria

Reproductive System and Breast Disorders: gynecomastia

General Disorders: fatigue, hyperpyrexia

Urogenital Disorders: priapism

7 DRUG INTERACTIONS

7.1 Clinically Important Drug Interactions with Methylphenidate Hydrochloride Extended-Release Capsules

Table 3 presents clinically important drug interactions with methylphenidate hydrochloride extended-release capsules

Table 3: Clinically Important Drug Interactions with Methylphenidate Hydrochloride Extended-Release Capsules

Monoamine Oxidase Inhibitors (MAOI)
Clinical impact Concomitant use of MAOIs and CNS stimulants, including methylphenidate hydrochloride extended-release capsules, can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure [see Contraindications (4)] .
Intervention Concomitant use of methylphenidate hydrochloride extended-release capsules with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated.
Antihypertensive Drugs
Clinical impact Methylphenidate hydrochloride extended-release capsules may decrease the effectiveness of drugs used to treat hypertension [see Warnings and Precautions (5.3)] .
Intervention Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed.
Halogenated Anesthetics
Clinical impact Concomitant use of halogenated anesthetics and methylphenidate hydrochloride extended-release capsules may increase the risk of sudden blood pressure and heart rate increase during surgery.
Intervention Avoid use of methylphenidate hydrochloride extended-release capsules in patients being treated with anesthetics on the day of surgery.
Risperidone
Clinical impact Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS)
Intervention Monitor for signs of EPS

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