gov/medwatch. 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 the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The safety of XELSTRYM for the treatment of ADHD in adults and pediatric patients 6 to 17 years is based on a study with XELSTRYM in pediatric patients (presented below) and adequate and well-controlled studies of lisdexamfetamine in adult and pediatric patients with ADHD.
XELSTRYM was studied in pediatric patients 6 to 17 years with ADHD. The safety data are from a 7-week study including a 5-week open-label dose optimization phase (n=110) followed by a 2-week randomized, parallel-group, crossover, placebo-controlled double-blind treatment phase (n=105) [see CLINICAL TRIALS (14) ] .
7% (3/110) of patients treated with XELSTRYM discontinued due to adverse reactions. 9%). There were no discontinuations due to adverse reactions during the double-blind phase. Adverse Reactions Occurring at an Incidence of 5% or More in XELSTRYM Treated Pediatric Patients Ages 6 to 17 Years During Dose-optimized Treatment Adverse reactions (incidence of ≥ 5%) that occurred during the dose-optimization phase of the clinical study include: decreased appetite (54%), insomnia 1 (32%), headache (21%), irritability (16%), abdominal pain 2 (16%) affect lability 3 (16%), application site pain 4 (13%), nausea (9%), application site pruritus (7%), and fatigue (5%).
1 insomnia includes insomnia, delayed sleep phase, initial insomnia, middle insomnia, and terminal insomnia 2 abdominal pain includes abdominal pain and abdominal pain upper 3 affect lability includes affect lability, emotional disorder, mood swings, and mood altered 4 application site pain includes application site pain and application site burn Adverse Reactions Occurring at an Incidence of 2% or More of XELSTRYM-Treated Pediatric Patients Ages 6 to 17 Years During Double-blind Treatment Adverse reactions (incidence of ≥ 2% and incidence greater than placebo) that occurred during the double-blind, placebo-controlled phase of the clinical study are shown in Table 1 .
Table 1:
Adverse Reactions Reported by ≥ 2% of Pediatric Patients 6 to 17 Years with ADHD Receiving XELSTRYM and Greater Incidence Than Placebo in the Double-Blind Phase * The following terms were combined: Insomnia includes insomnia, delayed sleep phase, initial insomnia, middle insomnia, and terminal insomnia Abdominal pain includes abdominal pain and abdominal pain upper Blood pressure increased includes blood pressure increased and blood pressure systolic increased Heart rate increased includes heart rate increased and tachycardia System Organ Class Preferred Term XELSTRYM All Doses (n = 105) % Placebo (n = 105) % Metabolism and nutrition disorders Decreased appetite 12 2 Nervous system disorders Headache 6 4 Psychiatric disorders Insomnia* 8 6 Affect lability 3 0 Tic 2 0 Gastrointestinal Disorders Vomiting 4 0 Abdominal pain * 4 2 Nausea 3 1 General disorders and administration site conditions Irritability 2 1 Investigations/Cardiac Disorders Blood pressure increased * 2 1 Heart rate increased * 2 0 Application Site Reactions Based on daily patient diaries and dermal reaction scales at clinic assessments, local skin reactions were reported with XELSTRYM.
During the wear time or immediately after removal of XELSTRYM, patients experienced pain, pruritus, burning sensation, erythema, discomfort, edema, and swelling. Patients who experienced discomfort and pain at the application site during the wear time reported resolution within 2 to 4 hours after XELSTRYM application.
Most dermal irritation was limited to the site of application. All patients who reported application site reactions in the 7-week pediatric classroom study continued to use XELSTRYM, and there were no discontinuations from the study due to application site reactions.
During the dose-optimization phase of the clinical study, 45% of patients reported application site discomfort associated with the use of XELSTRYM in daily patient diaries; 72% of patients reported discomfort at clinic visit assessments; and 13% of patients reported severe discomfort at clinic visit assessments.
5 mg was the starting dose for all patients undergoing titration during the dose optimization phase and the majority of application site discomfort was reported at this starting dose. During the dose-optimization phase, 73% of patients reported application site irritation.
Application site reactions that occurred during the double-blind phase of the clinical study are presented in Table 2 . 1 pounds after 5 weeks of XELSTRYM. Leukopenia and Neutropenia In the 2-week crossover phase of the 7-week trial of XELSTRYM in pediatric patients ages 6 to 17 years, shifts in WBCs from normal to low occurred in 10% of patients treated with XELSTRYM and 2% of patients treated with placebo.
Shifts in neutrophils from normal to low occurred in 14% of patients treated with XELSTRYM and 6% of patients treated with placebo. Weight Loss and Slowing Growth Rate in Pediatric Patients with ADHD with Lisdexamfetamine and Other Stimulants Lisdexamfetamine The long-term safety of XELSTRYM for the treatment of ADHD relies on information from adequate and well-controlled studies of lisdexamfetamine.
5 pounds, respectively, for patients receiving 30 mg, 50 mg, and 70 mg of lisdexamfetamine, compared to 1 pound weight gain for patients receiving placebo. Higher doses were associated with greater weight loss with 4 weeks of treatment.
2, respectively). 8 pounds, respectively, for patients receiving 30 mg, 50 mg, and 70 mg of lisdexamfetamine, compared to a 2 pound weight gain for patients receiving placebo. 7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development.
8 pounds, respectively, for patients receiving 10 mg and 20 mg of amphetamine. 5) ] . Clinical Trials Experience in Adult Patients with ADHD Treated with Lisdexamfetamine Adverse Reactions Associated with Discontinuation of Treatment in Adult ADHD Clinical Trials In a controlled trial of lisdexamfetamine in adults with ADHD, 6% (21/358) of lisdexamfetamine-treated patients discontinued due to adverse reactions compared to 2% (1/62) of placebo-treated patients.
The most frequently reported adverse reactions (1% or more and twice rate of placebo) were insomnia (8/358; 2%), tachycardia (3/358; 1%), irritability (2/358; 1%), hypertension (4/358; 1%), headache (2/358; 1%), anxiety (2/358; 1%), and dyspnea (3/358; 1%).
Less frequently reported adverse reactions (less than 1% or less than twice rate of placebo) included palpitations, diarrhea, nausea, decreased appetite, dizziness, agitation, depression, paranoia and restlessness. Adverse Reactions Occurring at an Incidence of ≥5% or More Among Lisdexamfetamine-Treated Patients with ADHD in Clinical Trials The most common adverse reactions (incidence ≥5% and at a rate at least twice placebo) were: Decreased appetite, insomnia, dry mouth, diarrhea, nausea, and anxiety.
4% of subjects on lisdexamfetamine and 0% on placebo. 5 pounds for patients receiving placebo. Adverse Reactions with Other Amphetamine Products in Pediatric Patients and Adults with ADHD Cardiac Disorders: Palpitations, tachycardia, and chest pain.
, teeth clenching, tooth infection).
General Disorders and Administration Site Conditions:
Asthenia, fatigue, pyrexia, and feeling jittery.
Infections and Infestations:
Infection, urinary tract infection.
Injury, Poisoning, and Procedural Complications:
Accidental injury.
Investigations:
Weight decreased, blood pressure increased, and ECG voltage criteria for ventricular hypertrophy.
Metabolism and Nutrition Disorders:
Loss of appetite.
Musculoskeletal and Connective Tissue Disorders:
Muscle twitching, growth retardation. , stuttering, excessive speech), psychomotor hyperactivity, and agitation.
Psychiatric Disorders:
Depression, anxiety, dermatillomania, mood swings, anger, affect lability, logorrhea, irritability, nervousness, paranoia, and restlessness.
Reproductive System and Breast Disorders:
Impotence, libido decreased, erectile dysfunction, and dysmenorrhea.
Respiratory, Thoracic, and Mediastinal Disorders:
Dyspnea, rhinitis allergic.
Skin and Subcutaneous Tissue Disorders:
Rash, photosensitivity reaction, and hyperhidrosis.
Vascular Disorders:
Hypertension, epistaxis. 2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of amphetamines. 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.
Cardiac Disorders:
Palpitations, chest pain, sudden death, and myocardial infarction. There have been isolated reports of cardiomyopathy associated with chronic amphetamine use.
Eye Disorders:
Vision blurred, diplopia, difficulties with visual accommodation, and mydriasis.
Gastrointestinal Disorders:
Dysgeusia, constipation, intestinal ischemia, and other gastrointestinal disturbances.
Hepatobiliary Disorders:
Eosinophilic hepatitis.
Immune System Disorders:
Urticaria, rash, hypersensitivity reactions including angioedema and anaphylactic reaction. Serious skin rashes, including Stevens-Johnson Syndrome and toxic epidermal necrolysis, have been reported.
Musculoskeletal and Connective Tissue Disorders:
Rhabdomyolysis.
Nervous System Disorders:
Seizures, overstimulation, restlessness, dyskinesia, tremor, motor and verbal tics, and paresthesia (including formication).
Psychiatric Disorders:
Psychotic episodes at recommended doses, depression, logorrhea, aggression, anger, dermatillomania, bruxism, dysphoria, euphoria, and irritability.
Reproductive System and Breast Disorders:
Impotence, changes in libido, and frequent or prolonged erections.
Skin and Subcutaneous Tissue Disorders:
Alopecia.
Vascular Disorders:
Raynaud's phenomenon.