FDA label e42efee6-a11f-461e-acc0-03322e8274f4

WARNING: DRUG DEPENDENCE Daytrana should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during withdrawal from abusive use, since severe depression may occur. Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up. WARNING: DRUG DEPENDENCE See full prescribing information for complete boxed warning Daytrana should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior.

5 WARNINGS and PRECAUTIONS Serious Cardiovascular Events: Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Sudden death, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Stimulant products generally should not be used in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious heart problems. ( 5.1 ) Increase in Blood Pressure: Monitor patients for changes in heart rate and blood pressure and use with caution in patients for whom an increase in blood pressure or heart rate would be problematic. ( 5.1 ) Psychiatric Adverse Events: Use of stimulants may cause treatment-emergent psychotic or manic symptoms in patients with no prior history, or exacerbation of symptoms in patients with pre-existing psychiatric illness. Clinical evaluation for Bipolar Disorder is recommended prior to stimulant use. Monitor for aggressive behavior. ( 5.2 ) Seizures: Stimulants may lower the convulsive threshold. Discontinue in the presence of seizures. ( 5.3 ) Long-Term Suppression of Growth: Monitor height and weight at appropriate intervals in pediatric patients. ( 5.4 ) Visual Disturbance: Difficulties with accommodation and blurring of vision have been reported with stimulant treatment. ( 5.5 ) Contact Sensitization: Use of Daytrana may lead to contact sensitization. Treatment should be discontinued if contact sensitization is suspected. Erythema is commonly seen with use of Daytrana and is not by itself an indication of sensitization. However, contact sensitization should be suspected if erythema is accompanied by evidence of a more intense local reaction (edema, papules, vesicles) that does not significantly improve within 48 hours or spreads beyond the patch site. ( 5.6 ) External Heat: Patients should be advised to avoid exposing the Daytrana application site to direct external heat sources. When heat is applied to Daytrana after patch application, both the rate and extent of absorption are significantly increased. ( 5.7 ) Hematologic monitoring: Periodic CBC, differential, and platelet counts are advised during prolonged therapy. ( 5.8 ) 5.1 Serious Cardiovascular Events Sudden Death and Pre-existing Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug. Adults Sudden deaths, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs. Hypertension and Other Cardiovascular Conditions Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and average heart rate (about 3-6 bpm), and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia [ see Adverse Reactions (6.1) ]. Assessing Cardiovascular Status in Patients Being Treated With Stimulant Medications Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation. 5.2 Psychiatric Adverse Events Pre-Existing Psychosis Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Bipolar Illness Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in such patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Emergence of New Psychotic or Manic Symptoms Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3,482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to none in placebo-treated patients. Aggression Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behavior or hostility. 5.3 Seizures There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued. 5.4 Long-Term Suppression of Growth Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. 5.5 Visual Disturbance Difficulties with accommodation and blurring of vision have been reported with stimulant treatment. 5.6 Contact Sensitization In an open-label study of 305 subjects conducted to characterize dermal reactions in children with ADHD treated with Daytrana using a 9-hour wear time, one subject (0.3%) was confirmed by patch testing to be sensitized to methylphenidate (allergic contact dermatitis). This subject experienced erythema and edema at Daytrana application sites with concurrent urticarial lesions on the abdomen and legs resulting in treatment discontinuation. This subject was not transitioned to oral methylphenidate. Use of Daytrana may lead to contact sensitization. Daytrana should be discontinued if contact sensitization is suspected. Erythema is commonly seen with use of Daytrana and is not by itself an indication of sensitization. However, contact sensitization should be suspected if erythema is accompanied by evidence of a more intense local reaction (edema, papules, vesicles) that does not significantly improve within 48 hours or spreads beyond the patch site. Confirmation of a diagnosis of contact sensitization (allergic contact dermatitis) may require further diagnostic testing. Patients sensitized from use of Daytrana, as evidenced by development of an allergic contact dermatitis, may develop systemic sensitization or other systemic reactions if methylphenidate-containing products are taken via other routes, e.g., orally. Manifestations of systemic sensitization may include a flare-up of previous dermatitis or of prior positive patch-test sites, or generalized skin eruptions in previously unaffected skin. Other systemic reactions may include headache, fever, malaise, arthralgia, diarrhea, or vomiting. No cases of systemic sensitization have been observed in clinical trials of Daytrana. Patients who develop contact sensitization to Daytrana and require oral treatment with methylphenidate should be initiated on oral medication under close medical supervision. It is possible that some patients sensitized to methylphenidate by exposure to Daytrana may not be able to take methylphenidate in any form. 5.7 Patients Using External Heat Patients should be advised to avoid exposing the Daytrana application site to direct external heat sources, such as hair dryers, heating pads, electric blankets, heated water beds, etc., while wearing the patch. When heat is applied to Daytrana after patch application, both the rate and extent of absorption are significantly increased. The temperature-dependent increase in methylphenidate absorption can be greater than 2-fold [ see Clinical Pharmacology (12.3) ]. This increased absorption can be clinically significant and can result in overdose of methylphenidate [ see Overdosage (10) ]. 5.8 Hematologic Monitoring Periodic CBC, differential, and platelet counts are advised during prolonged therapy.

6 ADVERSE REACTIONS Detailed information on serious and adverse reactions of particular importance is provided in the Boxed Warning and Warnings and Precautions ( 5 ) sections: Drug dependence [ see box Warning ] Hypersensitivity to Methylphenidate [ see Contraindications (4.1) ] Marked anxiety, tension, or agitation [ see Contraindications (4.2) ] Glaucoma [ see Contraindications (4.3) ] Tics or a family history of Tourette's syndrome [ see Contraindications (4.4) ] Monoamine Oxidase Inhibitors [ see Contraindications (4.5) and Drug Interactions (7.1) ] Serious Cardiovascular Events [ see Warnings and Precautions (5.1) ] Increase in Blood Pressure [ see Warnings and Precautions (5.2) ] Psychiatric Adverse Events [ see Warnings and Precautions (5.2) ] Seizures [ see Warnings and Precautions (5.3) ] Long-Term Suppression of Growth [ see Warnings and Precautions (5.4) ] Visual Disturbance [ see Warnings and Precautions (5.5) ] Contact Sensitization [ see Warnings and Precautions (5.6) ] External Heat [ see Warnings and Precautions (5.7) ] Hematologic Monitoring [ see Warnings and Precautions (5.8) ] The most commonly reported (frequency ≥ 5% and twice the rate of placebo) adverse reactions in a controlled trial in children aged 6-12 included appetite decreased, insomnia, nausea, vomiting, weight decreased, tic, affect lability, and anorexia. The most commonly reported (frequency ≥ 5% and twice the rate of placebo) adverse reactions in a controlled trial in adolescents aged 13-17 were appetite decreased, nausea, insomnia, weight decreased, dizziness, abdominal pain and anorexia [ see Adverse Reactions (6.1) ]. The most common (≥ 2% of subjects) adverse reaction associated with discontinuations in double-blind clinical trials in children or adolescents was application site reactions [ see Adverse Reactions (6.3) ]. The overall Daytrana development program included exposure to Daytrana in a total of 2,152 participants in clinical trials, including 1,529 children aged 6-12, 223 adolescents aged 13-17, and 400 adults. The 1,752 child and adolescent subjects aged 6-17 years were evaluated in 10 controlled clinical studies, 7 open-label clinical studies, and 5 clinical pharmacology studies. In a combined studies pool of children using Daytrana with a wear time of 9 hours, 212 subjects were exposed for ≥ 6 months and 115 were exposed for ≥ 1 year; 85 adolescents have been exposed for ≥ 6 months. Most patients studied were exposed to Daytrana patch sizes of 12.5 cm 2 , 18.75 cm 2 , 25 cm 2 or 37.5 cm 2 , with a wear time of 9 hours. In the data presented below, the adverse reactions reported during exposure were obtained primarily by general inquiry at each visit, and were recorded by the clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of events into a smaller number of standardized event categories. Throughout this section adverse reactions reported are events that were considered to be reasonably associated with the use of Daytrana based on comprehensive assessment of the available adverse event information. A causal association for Daytrana often cannot be reliably established in individual cases. Further, 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. Children (ages 6-12): The most commonly (≥5% and twice the rate of placebo) reported adverse reactions in a placebo-controlled trial in children aged 6-12 included appetite decreased, insomnia, nausea, vomiting, weight decreased, tic, affective lability, and anorexia ( 6.1 ). Adolescents (ages 13-17): The most commonly (≥5% and twice the rate of placebo) reported adverse reactions in a placebo-controlled trial in adolescents aged 13-17 included appetite decreased, nausea, insomnia, weight decreased, dizziness, abdominal pain, and anorexia. The majority of subjects in these trials had erythema at the application site ( 6.1 ). The most common (≥2% of subjects) adverse reaction associated with discontinuations in double-blind clinical trials in children or adolescents was application site reactions ( 6.3 ) To report SUSPECTED ADVERSE REACTIONS, contact Shire US Inc. at 1-800-828-2088 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Adverse Reactions Associated With Discontinuation of Treatment In a 7-week double-blind, parallel-group, placebo-controlled study in children with ADHD conducted in the outpatient setting, 7.1% (7/98) of patients treated with Daytrana discontinued due to adverse events compared with 1.2% (1/85) receiving placebo. The most commonly reported (≥ 1% and twice the rate of placebo) adverse reactions leading to discontinuation in the Daytrana group were application site reaction (2%), tics (1%), headache (1%), and irritability (1%). In a 7-week double-blind, parallel-group, placebo-controlled study in adolescents with ADHD conducted in the outpatient setting, 5.5% (8/145) of patients treated with Daytrana discontinued due to adverse reactions compared with 2.8% (2/72) receiving placebo. The most commonly reported adverse reactions leading to discontinuation in the Daytrana group were application site reaction (2%) and decreased appetite/anorexia (1.4%). Commonly Observed Adverse Reactions in Double-Blind, Placebo-Controlled Trials Skin Irritation and Application Site Reactions Daytrana is a dermal irritant. In addition to the most commonly reported adverse reactions presented in Table 2, the majority of subjects in those studies had minimal to definite skin erythema at the patch application site. This erythema generally caused no or minimal discomfort and did not usually interfere with therapy or result in discontinuation from treatment. Erythema is not by itself a manifestation of contact sensitization. However, contact sensitization should be suspected if erythema is accompanied by evidence of a more intense local reaction (edema, papules, vesicles) that does not significantly improve within 48 hours or spreads beyond the patch site [ see Warnings and Precautions (5.6) ]. Most Commonly Reported Adverse Reactions Table 2 lists treatment-emergent adverse reactions reported in ≥ 1% Daytrana-treated children or adolescents with ADHD in two 7 week double-blind, parallel-group, placebo-controlled studies conducted in the outpatient setting. Overall, in these studies, 75.5% of children and 78.6% of adolescents experienced at least 1 adverse event. Table 2 Number (%) of Subjects with Commonly Reported Adverse Reactions (≥ 1% in the Daytrana Group) in 7-Week Placebo-controlled Studies in Either Children or Adolescents - Safety Population Adolescents Children * Six subjects had affect lability, all judged as mild and described as increased emotionally sensitive, emotionality, emotional instability, emotional lability, and intermittent emotional System Organ Class Preferred term Placebo N = 72 Daytrana N = 145 Placebo N = 85 Daytrana N = 98 Cardiac Disorders Tachycardia 0 (0) 1 (0.7) 0 (0) 1 (1.0) Gastrointestinal disorders Abdominal pain 0 (0) 7 (4.8) 5 (5.9) 7 (7.1) Nausea 2 (2.8) 14 (9.7) 2 (2.4) 12 (12.2) Vomiting 1 (1.4) 5 (3.4) 4 (4.7) 10 (10.2) Investigations Weight decreased 1 (1.4) 8 (5.5) 0 (0) 9 (9.2) Metabolism and nutrition disorders Anorexia 1 (1.4) 7 (4.8) 1 (1.2) 5 (5.1) Decreased appetite 1 (1.4) 37 (25.5) 4 (4.7) 25 (25.5) Nervous system disorders Dizziness 1 (1.4) 8 (5.5) 1 (1.2) 0 (0) Headache 9 (12.5) 18 (12.4) 10 (11.8) 15 (15.3) Psychiatric disorders Affect lability 1 (1.4) 0 (0) 0 (0) 6 (6.1)* Insomnia 2 (2.8) 9 (6.2) 4 (4.7) 13 (13.3) Irritability 5 (6.9) 16 (11) 4 (4.7) 7 (7.1) Tic 0 (0) 0 (0) 0 (0) 7 (7.1) Adverse Reactions With the Long-Term Use of Daytrana In a long-term open-label study of up to 12 months duration in 326 children wearing Daytrana 9 hours daily, the most common (≥ 10%) adverse reactions were decreased appetite, headache, and weight decreased. A total of 30 subjects (9.2%) were withdrawn from the study due to adverse events and 22 additional subjects (6.7%) discontinued treatment as the result of an application site reaction. Other than application site reactions, affect lability (5 subjects, 1.5%) was the only additional adverse reaction leading to discontinuation reported with a frequency of greater than 1%. In a long-term open-label study of up to 6 months duration in 162 adolescents wearing Daytrana 9 hours daily, the most common (≥ 10%) adverse reactions were decreased appetite and headache. A total of 9 subjects (5.5%) were withdrawn from the study due to adverse events and 3 additional subjects (1.9%) discontinued treatment as the result of an application site reaction. Other adverse reactions leading to discontinuation that occurred with a frequency of greater than 1% included affect lability and irritability (2 subjects each, 1.2%). 6.2 Postmarketing Experience In addition, the following adverse reactions have been identified during the postapproval use of Daytrana. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to Daytrana exposure. Cardiac Disorders: palpitation Eye Disorders: visual disturbances, blurred vision, mydriasis, accommodation disorder General Disorders and Administration Site Disorders : application site reactions such as bleeding, bruising, burn, burning, dermatitis, discharge, discoloration, discomfort, dryness, eczema, edema, erosion, erythema, excoriation, exfoliation, fissure, hyperpigmentation, hypopigmentation, induration, infection, inflammation, irritation, pain, papules, paresthesia, pruritus, rash, scab, swelling, ulcer, urticaria, vesicles, and warmth. Immune System Disorders: hypersensitivity reactions including generalized erythematous and urticarial rashes, allergic contact dermatitis, angioedema, and anaphylaxis Investigations: blood pressure increased Nervous System Disorders : convulsion, dyskinesia Psychiatric Disorders : transient depressed mood, hallucination, nervousness Skin and Subcutaneous Tissue Disorders : alopecia 6.3 Adverse Reactions With Oral Methylphenidate Products Nervousness and insomnia are the most common adverse reactions reported with other methylphenidate products. In children, loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and tachycardia may occur more frequently; however, any of the other adverse reactions listed below may also occur. Other reactions include: Cardiac: angina, arrhythmia, pulse increased or decreased Immune: hypersensitivity reactions including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura Metabolism/Nutrition: anorexia, weight loss during prolonged therapy Nervous System: drowsiness, rare reports of Tourette's syndrome, toxic psychosis Vascular: blood pressure increased or decreased, cerebral arteritis and/or occlusion Although a definite causal relationship has not been established, the following have been reported in patients taking methylphenidate: Blood/lymphatic: leukopenia and/or anemia Hepatobiliary: abnormal liver function, ranging from transaminase elevation to hepatic coma Psychiatric: transient depressed mood Skin/Subcutaneous: scalp hair loss Neuroleptic Malignant Syndrome: Very rare reports of neuroleptic malignant syndrome (NMS) have been received, and, in most of these, patients were concurrently receiving therapies associated with NMS. In a single report, a ten-year-old boy who had been taking methylphenidate for approximately 18 months experienced an NMS-like event within 45 minutes of ingesting his first dose of venlafaxine. It is uncertain whether this case represented a drug-drug interaction, a response to either drug alone, or some other cause.

<table width="80%"> <caption> Table 2 Number (%) of Subjects with Commonly Reported Adverse Reactions (&#x2265; 1% in the Daytrana Group) in 7-Week Placebo-controlled Studies in Either Children or Adolescents - Safety Population </caption> <col width="20%" align="left"/> <col width="20%" align="center"/> <col width="20%" align="center"/> <col width="20%" align="center"/> <col width="20%" align="center"/> <thead> <tr> <th styleCode="Botrule Lrule Rrule" align="center"/> <th colspan="2" styleCode="Botrule Lrule Rrule" align="center"> Adolescents </th> <th colspan="2" styleCode="Botrule Lrule Rrule" align="center"> Children </th> </tr> </thead> <tfoot> <tr> <td colspan="5" align="left"> * Six subjects had affect lability, all judged as mild and described as increased emotionally sensitive, emotionality, emotional instability, emotional lability, and intermittent emotional </td> </tr> </tfoot> <tbody> <tr> <td styleCode="Botrule Lrule Rrule"> System Organ Class Preferred term </td> <td styleCode="Botrule Lrule Rrule"> Placebo N = 72 </td> <td styleCode="Botrule Lrule Rrule"> Daytrana N = 145 </td> <td styleCode="Botrule Lrule Rrule"> Placebo N = 85 </td> <td styleCode="Botrule Lrule Rrule"> Daytrana N = 98 </td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Cardiac Disorders </td> <td styleCode="Botrule Lrule Rrule"/> <td styleCode="Botrule Lrule Rrule"/> <td styleCode="Botrule Lrule Rrule"/> <td styleCode="Botrule Lrule Rrule"/> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Tachycardia </td> <td styleCode="Botrule Lrule Rrule"> 0 (0) </td> <td styleCode="Botrule Lrule Rrule"> 1 (0.7) </td> <td styleCode="Botrule Lrule Rrule"> 0 (0) </td> <td styleCode="Botrule Lrule Rrule"> 1 (1.0) </td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Gastrointestinal disorders </td> <td styleCode="Botrule Lrule Rrule"/> <td styleCode="Botrule Lrule Rrule"/> <td styleCode="Botrule Lrule Rrule"/> <td styleCode="Botrule Lrule Rrule"/> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Abdominal pain </td> <td styleCode="Botrule Lrule Rrule"> 0 (0) </td> <td styleCode="Botrule Lrule Rrule"> 7 (4.8) </td> <td styleCode="Botrule Lrule Rrule"> 5 (5.9) </td> <td styleCode="Botrule Lrule Rrule"> 7 (7.1) </td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Nausea </td> <td styleCode="Botrule Lrule Rrule"> 2 (2.8) </td> <td styleCode="Botrule Lrule Rrule"> 14 (9.7) </td> <td styleCode="Botrule Lrule Rrule"> 2 (2.4) </td> <td styleCode="Botrule Lrule Rrule"> 12 (12.2) </td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Vomiting </td> <td styleCode="Botrule Lrule Rrule"> 1 (1.4) </td> <td styleCode="Botrule Lrule Rrule"> 5 (3.4) </td> <td styleCode="Botrule Lrule Rrule"> 4 (4.7) </td> <td styleCode="Botrule Lrule Rrule"> 10 (10.2) </td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Investigations </td> <td styleCode="Botrule Lrule Rrule"/> <td styleCode="Botrule Lrule Rrule"/> <td styleCode="Botrule Lrule Rrule"/> <td styleCode="Botrule Lrule Rrule"/> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Weight decreased </td> <td styleCode="Botrule Lrule Rrule"> 1 (1.4) </td> <td styleCode="Botrule Lrule Rrule"> 8 (5.5) </td> <td styleCode="Botrule Lrule Rrule"> 0 (0) </td> <td styleCode="Botrule Lrule Rrule"> 9 (9.2) </td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Metabolism and nutrition disorders </td> <td styleCode="Botrule Lrule Rrule"/> <td styleCode="Botrule Lrule Rrule"/> <td styleCode="Botrule Lrule Rrule"/> <td styleCode="Botrule Lrule Rrule"/> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Anorexia </td> <td styleCode="Botrule Lrule Rrule"> 1 (1.4) </td> <td styleCode="Botrule Lrule Rrule"> 7 (4.8) </td> <td styleCode="Botrule Lrule Rrule"> 1 (1.2) </td> <td styleCode="Botrule Lrule Rrule"> 5 (5.1) </td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Decreased appetite </td> <td styleCode="Botrule Lrule Rrule"> 1 (1.4) </td> <td styleCode="Botrule Lrule Rrule"> 37 (25.5) </td> <td styleCode="Botrule Lrule Rrule"> 4 (4.7) </td> <td styleCode="Botrule Lrule Rrule"> 25 (25.5) </td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Nervous system disorders </td> <td styleCode="Botrule Lrule Rrule"/> <td styleCode="Botrule Lrule Rrule"/> <td styleCode="Botrule Lrule Rrule"/> <td styleCode="Botrule Lrule Rrule"/> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Dizziness </td> <td styleCode="Botrule Lrule Rrule"> 1 (1.4) </td> <td styleCode="Botrule Lrule Rrule"> 8 (5.5) </td> <td styleCode="Botrule Lrule Rrule"> 1 (1.2) </td> <td styleCode="Botrule Lrule Rrule"> 0 (0) </td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Headache </td> <td styleCode="Botrule Lrule Rrule"> 9 (12.5) </td> <td styleCode="Botrule Lrule Rrule"> 18 (12.4) </td> <td styleCode="Botrule Lrule Rrule"> 10 (11.8) </td> <td styleCode="Botrule Lrule Rrule"> 15 (15.3) </td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Psychiatric disorders </td> <td styleCode="Botrule Lrule Rrule"/> <td styleCode="Botrule Lrule Rrule"/> <td styleCode="Botrule Lrule Rrule"/> <td styleCode="Botrule Lrule Rrule"/> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Affect lability </td> <td styleCode="Botrule Lrule Rrule"> 1 (1.4) </td> <td styleCode="Botrule Lrule Rrule"> 0 (0) </td> <td styleCode="Botrule Lrule Rrule"> 0 (0) </td> <td styleCode="Botrule Lrule Rrule"> 6 (6.1)* </td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Insomnia </td> <td styleCode="Botrule Lrule Rrule"> 2 (2.8) </td> <td styleCode="Botrule Lrule Rrule"> 9 (6.2) </td> <td styleCode="Botrule Lrule Rrule"> 4 (4.7) </td> <td styleCode="Botrule Lrule Rrule"> 13 (13.3) </td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Irritability </td> <td styleCode="Botrule Lrule Rrule"> 5 (6.9) </td> <td styleCode="Botrule Lrule Rrule"> 16 (11) </td> <td styleCode="Botrule Lrule Rrule"> 4 (4.7) </td> <td styleCode="Botrule Lrule Rrule"> 7 (7.1) </td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Tic </td> <td styleCode="Botrule Lrule Rrule"> 0 (0) </td> <td styleCode="Botrule Lrule Rrule"> 0 (0) </td> <td styleCode="Botrule Lrule Rrule"> 0 (0) </td> <td styleCode="Botrule Lrule Rrule"> 7 (7.1) </td> </tr> </tbody> </table>