Methylphenidate Hydrochloride
Generic: METHYLPHENIDATE HYDROCHLORIDE
Basic Information
Manufacturer
Actavis Pharma, Inc.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
85ef422d-af27-4126-9841-6892af1871d6
Indications & Usage
1 INDICATIONS AND USAGE Methylphenidate hydrochloride extended-release tablets are indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in patients aged 6 to 65 years old.
Limitations of Use The use of methylphenidate hydrochloride extended-release tablets are not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage [see Warnings and Precautions ( 5.7 ) and Use in Specific Populations ( 8.4 )].
Methylphenidate hydrochloride extended-release tablets are a CNS stimulant indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in patients aged 6 to 65 years old.
( 1 ) Limitations of Use The use of methylphenidate hydrochloride extended-release tablets are not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage ( 5.7 , 8.4 ).
Limitations of Use The use of methylphenidate hydrochloride extended-release tablets are not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage [see Warnings and Precautions ( 5.7 ) and Use in Specific Populations ( 8.4 )].
Methylphenidate hydrochloride extended-release tablets are a CNS stimulant indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in patients aged 6 to 65 years old.
( 1 ) Limitations of Use The use of methylphenidate hydrochloride extended-release tablets are not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage ( 5.7 , 8.4 ).
Adverse Reactions
6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Abuse, Misuse, and Addiction [see Boxed Warning, Warnings and Precautions ( 5.1 ), Drug Abuse and Dependence ( 9.2) ] Hypersensitivity Reactions [see Contraindications ( 4 )] Monoamine Oxidase Inhibitors [see Contraindications ( 4 ), Drug Interactions ( 7 )] 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 )] Risks of Gastrointestinal Obstruction in Patients with Gastrointestinal Narrowing [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 )] The most common adverse reactions (≥5%) in double-blind clinical trials were: Pediatric patients 6 to 17 years: upper abdominal pain.
( 6.1 ) Adults up to 65 years of age: decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, tachycardia, and hyperhidrosis.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 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 clinical trials of another drug and may not reflect the rates observed in clinical practice.
The data below is based on a total of 3,906 patients in clinical studies who received methylphenidate hydrochloride extended-release tablets.
Patients aged 6 up to 65 years old with ADHD were evaluated in 6 controlled clinical studies and 11 open-label clinical studies [see Table 3] .
Table 3.
Methylphenidate Hydrochloride Extended-Release Tablets-treated Patients in Double-Blind and Open-Label Clinical Studies Patient Population N Dosage Range Pediatric patients 6 to 12 years of age 2,216 18 to 54 mg once daily Adolescents 502 18 to 72 mg once daily Adults up to 65 years of age 1,188 18 to 108 mg once daily The most common adverse reactions (≥5%) in double-blind clinical trials were: Pediatric patients: upper abdominal pain [see Table 4] .
Adults: decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, tachycardia, and hyperhidrosis [see Table 5] .
The most common adverse reactions associated with methylphenidate hydrochloride extended-release tablets discontinuation (≥1%) from the pediatric and adult clinical trials were anxiety, irritability, insomnia, and increased blood pressure.
Most Common Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials: Adverse reactions in either the pediatric or adult double-blind adverse reactions tables may be relevant for both patient populations.
Adverse Reactions in Pediatric Patients Aged 6 years and Older Table 4 displays adverse reactions reported in 2% or more of methylphenidate hydrochloride extended-release tablets -treated pediatric patients ages 6 and older with ADHD in 4 placebo-controlled, double-blind clinical trials.
Table 4: Most Common Adverse Reactions 1 in Pediatric Patients 6 Years of Age and Older with ADHD in 4 Placebo-Controlled, Double-Blind Clinical Trials Methylphenidate Hydrochloride Extended-Release Tablets (n=321) Placebo (n=318) Upper abdominal pain 6% 4% Insomnia 2 3% 1% Nasopharyngitis 3% 2% Vomiting 3% 2% Pyrexia 2% 1% 1 Reported in ≥ 2% of Methylphenidate Hydrochloride Extended-Release Tablets-treated patients 2 Initial insomnia (Methylphenidate Hydrochloride Extended-Release Tablets=0.6%) and insomnia (Methylphenidate Hydrochloride Extended-Release Tablets=2.2%) terms were combined into Insomnia.
Adverse Reactions in Adults Table 5 lists the adverse reactions reported in 2% or more of Methylphenidate Hydrochloride Extended-Release Tablets-treated adults with ADHD in 2 placebo-controlled, double-blind clinical trials.
Table 5: Most Common Adverse Reactions 1 in Adults with ADHD in 2 Placebo- Controlled, Double-Blind Clinical Trials Methylphenidate Hydrochloride Extended-Release Tablets 2 (n=415) Placebo (n=212) Decreased appetite 25% 7% Headache 22% 16% Dry mouth 14% 4% Nausea 13% 3% Insomnia 12% 6% Anxiety 8% 2% Decreased weight 7% 3% Dizziness 7% 5% Irritability 6% 1% Tachycardia 5% 0% Hyperhidrosis 5% 1% Depressed mood 4% 1% Initial insomnia 4% 3% Restlessness 3% 0% Palpitations 3% 1% Nervousness 3% 1% Tremor 3% 1% Upper respiratory tract infection 2% 1% Agitation 2% 1% Dyspepsia 2% 1% 1 Reported in ≥ 2% of Methylphenidate Hydrochloride Extended-Release Tablets-treated patients 2 Included dosages up to 108 mg/day (1.5 times the maximum recommended dosage).
Other Adverse Reactions Observed in Clinical Trials of Methylphenidate Hydrochloride Extended-Release Tablets The following adverse reactions occurred in less than 2% of methylphenidate hydrochloride extended-release tablets-treated patients ages 6 to 65 years of age in the double-blind and open-label clinical ADHD trials.
Blood and Lymphatic System Disorders : Leukopenia Cardiac Disorders : Cardiac murmur, Hypertension, Heart rate increased Ear and Labyrinth Disorders : Vertigo Eye Disorders : Accommodation disorder, Dry eye, Vision blurred Gastrointestinal Disorders : Abdominal discomfort/pain, Constipation, Diarrhea, Vomiting General Disorders and Administration Site Conditions : Asthenia, Fatigue, Feeling jittery, Thirst Hepatobiliary Disorders : Hepatic enzymes increased Infections and Infestations : Sinusitis Metabolism and Nutrition Disorders : Anorexia Musculoskeletal and Connective Tissue Disorders: Muscle spasms, Muscle tightness Nervous System Disorders : Lethargy, Paresthesia, Psychomotor hyperactivity, Sedation, Somnolence, Tension headache Psychiatric Disorders : Affect lability, Aggression, Anger, Bruxism, Confusional state, Depression, Hypervigilance, decreased libido, Mood swings, Panic attack, Sleep disorder, Tearfulness, Tension, Tic Reproductive System and Breast Disorders : Erectile dysfunction Respiratory, Thoracic and Mediastinal Disorders : Cough, Dyspnea, Oropharyngeal pain Skin and Subcutaneous Tissue Disorders : Rash Vascular Disorders : Hot flush Discontinuation Due to Adverse Reactions In the 2 placebo-controlled studies in adults with ADHD, 25 (6%) methylphenidate hydrochloride extended-release tablets-treated patients and 6 (3%) placebo-treated patients discontinued due to an adverse reaction.
In the methylphenidate hydrochloride extended-release tablets group, adverse reactions leading to discontinuation with an incidence of >0.5% were anxiety (1.7%), irritability (1.4%), increased blood pressure (1%), and nervousness (0.7%).
In the placebo group, adverse reactions leading to discontinuation with an incidence of >0.5% were increased blood pressure (0.9%) and depressed mood (0.9%).
In the 11 open-label studies in patients 6 to 65 years of age with ADHD, 266 (7%) methylphenidate hydrochloride extended-release tablets-treated patients discontinued due to an adverse reaction including insomnia (1.2%), irritability (0.8%), anxiety (0.7%), decreased appetite (0.7%), and tic (0.6%).
Blood Pressure and Heart Rate Increases In the 1-week treatment, controlled trials in pediatric patients 6 to 12 years of age with ADHD (Studies 1 and 2) [see Clinical Studies ( 14.2 )] , both the methylphenidate hydrochloride extended-release tablets once daily group and the methylphenidate three times daily group increased resting pulse by an average of 2 to 6 beats per minute (bpm) and increased the average systolic and diastolic blood pressure roughly 1 to 4 mm Hg during the day, relative to placebo.
In the randomized withdrawal portion of the double-blind, placebo-controlled trial with pediatric patients 13 to 17 years of age with ADHD (Study 4) [see Clinical Studies ( 14.3 )] , mean increases from baseline in resting pulse rate were observed with methylphenidate hydrochloride extended-release tablets and placebo at the end of the double-blind phase (5 and 3 beats/minute (bpm), respectively).
At the end of four weeks of treatment, mean increases from baseline in blood pressure for 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 the 7-week dose-titration, placebo-controlled study in adults 18 to 65 years of age with ADHD (Study 5) [see Clinical Studies (1 4.4 )] , mean changes from baseline in resting pulse rate were 3.6 in methylphenidate hydrochloride extended-release tablets-treated patients and -1.6 for placebo-treated patients after 7 weeks of treatment.
Mean changes from baseline in blood pressure after 7 weeks of treatment in methylphenidate hydrochloride extended-release tablets-treated 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 )] .
In the 5-week fixed-dose, placebo-controlled trial in adults 18 to 65 years of age with ADHD (Study 5) [see Clinical Studies (14.4)] , dose-dependent mean increases of 3.9 to 9.8 bpm from baseline in standing pulse rate were observed with methylphenidate hydrochloride extended-release tablets-treated patients and 2.7 bpm with placebo-treated patients at the end of 5 weeks.
Mean changes from baseline in standing blood pressure after 5 weeks of treatment ranged from 0.1 to 2.2 mm Hg (systolic) and -0.7 to 2.2 mm Hg (diastolic) for methylphenidate hydrochloride extended-release tablets-treated patients and 1.1 mm Hg (systolic) and -1.8 mm Hg (diastolic) for placebo-treated patients.
6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of methylphenidate 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: Blood and Lymphatic System Disorders : Pancytopenia, Thrombocytopenia, Thrombocytopenic purpura Cardiac Disorders : Angina pectoris, Bradycardia, Supraventricular tachycardia, Ventricular extrasystoles Eye Disorders : Diplopia, Increased intraocular pressure, Mydriasis General Disorders and Administration Site Conditions : Chest pain, Drug effect decreased, Hyperpyrexia Hepatobiliary Disorders : Hepatocellular injury, Acute hepatic failure, Blood bilirubin increased Immune System Disorders : Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Exanthemas NEC Investigations : Blood alkaline phosphatase increased, Platelet count decreased, Musculoskeletal and Connective Tissue Disorders : Arthralgia, Myalgia, Muscle twitching, Rhabdomyolysis Nervous System Disorders : Convulsion, Grand mal convulsion, Stroke in pediatric patients, Dyskinesia, Serotonin syndrome in combination with serotonergic drugs, Motor and Verbal Tics Psychiatric Disorders : Disorientation, Hallucination, Mania, Logorrhea Reproductive System and Breast Disorders : Priapism Skin and Subcutaneous Tissue Disorders : Alopecia, Bullous conditions, Erythema, Exfoliative conditions, Pruritus, Urticarias Vascular Disorders : Raynaud’s phenomenon
( 6.1 ) Adults up to 65 years of age: decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, tachycardia, and hyperhidrosis.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 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 clinical trials of another drug and may not reflect the rates observed in clinical practice.
The data below is based on a total of 3,906 patients in clinical studies who received methylphenidate hydrochloride extended-release tablets.
Patients aged 6 up to 65 years old with ADHD were evaluated in 6 controlled clinical studies and 11 open-label clinical studies [see Table 3] .
Table 3.
Methylphenidate Hydrochloride Extended-Release Tablets-treated Patients in Double-Blind and Open-Label Clinical Studies Patient Population N Dosage Range Pediatric patients 6 to 12 years of age 2,216 18 to 54 mg once daily Adolescents 502 18 to 72 mg once daily Adults up to 65 years of age 1,188 18 to 108 mg once daily The most common adverse reactions (≥5%) in double-blind clinical trials were: Pediatric patients: upper abdominal pain [see Table 4] .
Adults: decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, tachycardia, and hyperhidrosis [see Table 5] .
The most common adverse reactions associated with methylphenidate hydrochloride extended-release tablets discontinuation (≥1%) from the pediatric and adult clinical trials were anxiety, irritability, insomnia, and increased blood pressure.
Most Common Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials: Adverse reactions in either the pediatric or adult double-blind adverse reactions tables may be relevant for both patient populations.
Adverse Reactions in Pediatric Patients Aged 6 years and Older Table 4 displays adverse reactions reported in 2% or more of methylphenidate hydrochloride extended-release tablets -treated pediatric patients ages 6 and older with ADHD in 4 placebo-controlled, double-blind clinical trials.
Table 4: Most Common Adverse Reactions 1 in Pediatric Patients 6 Years of Age and Older with ADHD in 4 Placebo-Controlled, Double-Blind Clinical Trials Methylphenidate Hydrochloride Extended-Release Tablets (n=321) Placebo (n=318) Upper abdominal pain 6% 4% Insomnia 2 3% 1% Nasopharyngitis 3% 2% Vomiting 3% 2% Pyrexia 2% 1% 1 Reported in ≥ 2% of Methylphenidate Hydrochloride Extended-Release Tablets-treated patients 2 Initial insomnia (Methylphenidate Hydrochloride Extended-Release Tablets=0.6%) and insomnia (Methylphenidate Hydrochloride Extended-Release Tablets=2.2%) terms were combined into Insomnia.
Adverse Reactions in Adults Table 5 lists the adverse reactions reported in 2% or more of Methylphenidate Hydrochloride Extended-Release Tablets-treated adults with ADHD in 2 placebo-controlled, double-blind clinical trials.
Table 5: Most Common Adverse Reactions 1 in Adults with ADHD in 2 Placebo- Controlled, Double-Blind Clinical Trials Methylphenidate Hydrochloride Extended-Release Tablets 2 (n=415) Placebo (n=212) Decreased appetite 25% 7% Headache 22% 16% Dry mouth 14% 4% Nausea 13% 3% Insomnia 12% 6% Anxiety 8% 2% Decreased weight 7% 3% Dizziness 7% 5% Irritability 6% 1% Tachycardia 5% 0% Hyperhidrosis 5% 1% Depressed mood 4% 1% Initial insomnia 4% 3% Restlessness 3% 0% Palpitations 3% 1% Nervousness 3% 1% Tremor 3% 1% Upper respiratory tract infection 2% 1% Agitation 2% 1% Dyspepsia 2% 1% 1 Reported in ≥ 2% of Methylphenidate Hydrochloride Extended-Release Tablets-treated patients 2 Included dosages up to 108 mg/day (1.5 times the maximum recommended dosage).
Other Adverse Reactions Observed in Clinical Trials of Methylphenidate Hydrochloride Extended-Release Tablets The following adverse reactions occurred in less than 2% of methylphenidate hydrochloride extended-release tablets-treated patients ages 6 to 65 years of age in the double-blind and open-label clinical ADHD trials.
Blood and Lymphatic System Disorders : Leukopenia Cardiac Disorders : Cardiac murmur, Hypertension, Heart rate increased Ear and Labyrinth Disorders : Vertigo Eye Disorders : Accommodation disorder, Dry eye, Vision blurred Gastrointestinal Disorders : Abdominal discomfort/pain, Constipation, Diarrhea, Vomiting General Disorders and Administration Site Conditions : Asthenia, Fatigue, Feeling jittery, Thirst Hepatobiliary Disorders : Hepatic enzymes increased Infections and Infestations : Sinusitis Metabolism and Nutrition Disorders : Anorexia Musculoskeletal and Connective Tissue Disorders: Muscle spasms, Muscle tightness Nervous System Disorders : Lethargy, Paresthesia, Psychomotor hyperactivity, Sedation, Somnolence, Tension headache Psychiatric Disorders : Affect lability, Aggression, Anger, Bruxism, Confusional state, Depression, Hypervigilance, decreased libido, Mood swings, Panic attack, Sleep disorder, Tearfulness, Tension, Tic Reproductive System and Breast Disorders : Erectile dysfunction Respiratory, Thoracic and Mediastinal Disorders : Cough, Dyspnea, Oropharyngeal pain Skin and Subcutaneous Tissue Disorders : Rash Vascular Disorders : Hot flush Discontinuation Due to Adverse Reactions In the 2 placebo-controlled studies in adults with ADHD, 25 (6%) methylphenidate hydrochloride extended-release tablets-treated patients and 6 (3%) placebo-treated patients discontinued due to an adverse reaction.
In the methylphenidate hydrochloride extended-release tablets group, adverse reactions leading to discontinuation with an incidence of >0.5% were anxiety (1.7%), irritability (1.4%), increased blood pressure (1%), and nervousness (0.7%).
In the placebo group, adverse reactions leading to discontinuation with an incidence of >0.5% were increased blood pressure (0.9%) and depressed mood (0.9%).
In the 11 open-label studies in patients 6 to 65 years of age with ADHD, 266 (7%) methylphenidate hydrochloride extended-release tablets-treated patients discontinued due to an adverse reaction including insomnia (1.2%), irritability (0.8%), anxiety (0.7%), decreased appetite (0.7%), and tic (0.6%).
Blood Pressure and Heart Rate Increases In the 1-week treatment, controlled trials in pediatric patients 6 to 12 years of age with ADHD (Studies 1 and 2) [see Clinical Studies ( 14.2 )] , both the methylphenidate hydrochloride extended-release tablets once daily group and the methylphenidate three times daily group increased resting pulse by an average of 2 to 6 beats per minute (bpm) and increased the average systolic and diastolic blood pressure roughly 1 to 4 mm Hg during the day, relative to placebo.
In the randomized withdrawal portion of the double-blind, placebo-controlled trial with pediatric patients 13 to 17 years of age with ADHD (Study 4) [see Clinical Studies ( 14.3 )] , mean increases from baseline in resting pulse rate were observed with methylphenidate hydrochloride extended-release tablets and placebo at the end of the double-blind phase (5 and 3 beats/minute (bpm), respectively).
At the end of four weeks of treatment, mean increases from baseline in blood pressure for 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 the 7-week dose-titration, placebo-controlled study in adults 18 to 65 years of age with ADHD (Study 5) [see Clinical Studies (1 4.4 )] , mean changes from baseline in resting pulse rate were 3.6 in methylphenidate hydrochloride extended-release tablets-treated patients and -1.6 for placebo-treated patients after 7 weeks of treatment.
Mean changes from baseline in blood pressure after 7 weeks of treatment in methylphenidate hydrochloride extended-release tablets-treated 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 )] .
In the 5-week fixed-dose, placebo-controlled trial in adults 18 to 65 years of age with ADHD (Study 5) [see Clinical Studies (14.4)] , dose-dependent mean increases of 3.9 to 9.8 bpm from baseline in standing pulse rate were observed with methylphenidate hydrochloride extended-release tablets-treated patients and 2.7 bpm with placebo-treated patients at the end of 5 weeks.
Mean changes from baseline in standing blood pressure after 5 weeks of treatment ranged from 0.1 to 2.2 mm Hg (systolic) and -0.7 to 2.2 mm Hg (diastolic) for methylphenidate hydrochloride extended-release tablets-treated patients and 1.1 mm Hg (systolic) and -1.8 mm Hg (diastolic) for placebo-treated patients.
6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of methylphenidate 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: Blood and Lymphatic System Disorders : Pancytopenia, Thrombocytopenia, Thrombocytopenic purpura Cardiac Disorders : Angina pectoris, Bradycardia, Supraventricular tachycardia, Ventricular extrasystoles Eye Disorders : Diplopia, Increased intraocular pressure, Mydriasis General Disorders and Administration Site Conditions : Chest pain, Drug effect decreased, Hyperpyrexia Hepatobiliary Disorders : Hepatocellular injury, Acute hepatic failure, Blood bilirubin increased Immune System Disorders : Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Exanthemas NEC Investigations : Blood alkaline phosphatase increased, Platelet count decreased, Musculoskeletal and Connective Tissue Disorders : Arthralgia, Myalgia, Muscle twitching, Rhabdomyolysis Nervous System Disorders : Convulsion, Grand mal convulsion, Stroke in pediatric patients, Dyskinesia, Serotonin syndrome in combination with serotonergic drugs, Motor and Verbal Tics Psychiatric Disorders : Disorientation, Hallucination, Mania, Logorrhea Reproductive System and Breast Disorders : Priapism Skin and Subcutaneous Tissue Disorders : Alopecia, Bullous conditions, Erythema, Exfoliative conditions, Pruritus, Urticarias Vascular Disorders : Raynaud’s phenomenon