Adverse reactions : תופעות לוואי

8 ADVERSE REACTIONS

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.

8.1 Clinical Trials Experience

The premarketing development program for MAS ER included exposures in a total of 1315 participants in clinical trials (635 pediatric patients, 350 adolescent patients, 248 adult patients, and 82 healthy adult subjects).
Of these, 635 patients (ages 6 to 12) were evaluated in two controlled clinical studies, one open-label clinical study, and two single-dose clinical pharmacology studies (N= 40). Safety data on all patients are included in the discussion that follows. Adverse reactions were assessed by collecting adverse reactions, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs.

Adverse reactions during exposure were obtained primarily by general inquiry and recorded by 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 reactions into a smaller number of standardized event categories. In the tables and listings that follow, COSTART terminology has been used to classify reported adverse reactions.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed.

Adverse Reactions Leading to Discontinuation of Treatment
Attent XR 5, 10, 15, 20, 25, 30 mg RC New SmpC 11.2022
In two placebo-controlled studies of up to 5 weeks duration among children with ADHD, 2.4% (10/425) of MAS ER-treated patients discontinued due to adverse reactions (including 3 patients with loss of appetite, one of whom also reported insomnia) compared to 2.7% (7/259) receiving placebo.

The most frequent adverse reactions leading to discontinuation of MAS ER in controlled and uncontrolled, multiple-dose clinical trials of children (N=595) were anorexia (loss of appetite) (2.9%), insomnia (1.5%), weight loss (1.2%), emotional lability (1%), and depression (0.7%). Over half of these patients were exposed to MAS ER for 12 months or more.

In a separate placebo-controlled 4-week study in adolescents with ADHD, five patients (2.1%) discontinued treatment due to adverse events among MAS ER-treated patients (N=233) compared to none who received placebo (N=54). The most frequent adverse event leading to discontinuation and considered to be drug-related (i.e. leading to discontinuation in at least 1% of MAS ER-treated patients and at a rate at least twice that of placebo) was insomnia (1.3%, n=3).

In one placebo-controlled 4-week study among adults with ADHD with doses 20 mg to 60 mg, 23 patients (12.0%) discontinued treatment due to adverse events among MAS ER-treated patients (N=191) compared to one patient (1.6%) who received placebo (N=64). The most frequent adverse events leading to discontinuation and considered to be drug-related (i.e. leading to discontinuation in at least 1% of MAS ER-treated patients and at a rate at least twice that of placebo) were insomnia (5.2%, n=10), anxiety (2.1%, n=4), nervousness (1.6%, n=3), dry mouth (1.6%, n=3), anorexia (1.6%, n=3), tachycardia (1.6%, n=3), headache (1.6%, n=3), and asthenia (1.0%, n=2).

Adverse Reactions Occurring in Controlled Trials
Adverse reactions reported in a 3-week clinical trial of children and a 4-week clinical trial in adolescents and adults, respectively, treated with MAS ER or placebo are presented in the tables below.

Table 1 Adverse Reactions Reported by 2% or More of Children (6 to 12 Years Old) Receiving MAS ER with Higher Incidence Than on Placebo in a 584-Patient Clinical Study
MAS ER                     Placebo
Body System                           Preferred Term                        (n=374)                    (n=210) General                               Abdominal Pain (stomachache)          14%                        10% Fever                                 5%                         2%
Infection                             4%                         2%
Accidental Injury                     3%                         2%
Asthenia (fatigue)                    2%                         0%
Digestive System                      Loss of Appetite                      22%                        2% Vomiting                              7%                         4%
Nausea                                5%                         3%
Dyspepsia                             2%                         1%
Nervous System                        Insomnia                              17%                        2% Emotional Lability                    9%                         2%
Nervousness                           6%                         2%
Dizziness                             2%                         0%
Metabolic/Nutritional                 Weight Loss                           4%                         0% 
Table 2 Adverse Reactions Reported by 5% or More of Adolescents (13 to 17 Years Old) Weighing ≤ 75 kg/165 lbs Receiving MAS ER with Higher Incidence Than Placebo in a 287 Patient Clinical Forced Weekly-Dose Titration Study*
MAS ER                            Placebo
Body System                         Preferred Term
(n=233)                           (n=54)
General                             Abdominal Pain (stomachache) 11%                                 2% Digestive System                    Loss of Appetite b             36%                               2% Nervous System                      Insomnia b                     12%                               4% Attent XR 5, 10, 15, 20, 25, 30 mg RC New SmpC 11.2022
Nervousness                          6%                                  6%a Metabolic/Nutritional                   Weight Loss b                        9%                                  0% *Included doses up to 40 mg a
Appears the same due to rounding b
Dose-related adverse reactions
Note: The following reactions did not meet the criterion for inclusion in Table 2 but were reported by 2% to 4% of adolescent patients receiving MAS ER with a higher incidence than patients receiving placebo in this study: accidental injury, asthenia (fatigue), dry mouth, dyspepsia, emotional lability, nausea, somnolence, and vomiting.

Table 3 Adverse Reactions Reported by 5% or More of Adults Receiving MAS ER with Higher Incidence Than on Placebo in a 255 Patient Clinical Forced Weekly-Dose Titration Study*
MAS ER                           Placebo
Body System                            Preferred Term
(n=191)                          (n=64)
General                                Headache                     26%                              13% Asthenia                     6%                               5%
Digestive System                       Dry Mouth                    35%                              5% Loss of Appetite             33%                              3%
Nausea                       8%                               3%
Diarrhea                     6%                               0%
Nervous System                         Insomnia                     27%                              13% Agitation                    8%                               5%
Anxiety                      8%                               5%
Dizziness                    7%                               0%
Nervousness                  13%                              13%a
Cardiovascular System                  Tachycardia                  6%                               3% Metabolic/Nutritional                  Weight Loss                  10%                              0% Urogenital System                      Urinary Tract Infection      5%                               0% *Included doses up to 60 mg.
a
Appears the same due to rounding
Note: The following reactions did not meet the criterion for inclusion in Table 3 but were reported by 2% to 4% of adult patients receiving MAS ER with a higher incidence than patients receiving placebo in this study: infection, photosensitivity reaction, constipation, tooth disorder (e.g., teeth clenching, tooth infection), emotional lability, libido decreased, somnolence, speech disorder (e.g., stuttering, excessive speech), palpitation, twitching, dyspnea, sweating, dysmenorrhea, and impotence.

Hypertension [see Warnings and Precautions (7)]
In a controlled 4-week outpatient clinical study of adolescents with ADHD, isolated systolic blood pressure elevations ≥15 mmHg were observed in 7/64 (11%) placebo-treated patients and 7/100 (7%) patients receiving MAS ER 10 or 20 mg. Isolated elevations in diastolic blood pressure ≥8 mmHg were observed in 16/64 (25%) placebo-treated patients and 22/100 (22%) MAS ER-treated patients. Similar results were observed at higher doses.

In a single-dose pharmacokinetic study in 23 adolescents with ADHD, isolated increases in systolic blood pressure (above the upper 95% CI for age, gender, and stature) were observed in 2/17 (12%) and 8/23 (35%), subjects administered 10 mg and 20 mg MAS ER, respectively. Higher single doses were associated with a greater increase in systolic blood pressure. All increases were transient, appeared maximal at 2 to 4 hours post dose and not associated with symptoms.

8.2 Adverse Reactions Associated with the Use of MAS ER or MAS IR

The following adverse reactions have been identified during post-approval use of MAS ER, or MAS IR.
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.

Cardiovascular

Attent XR 5, 10, 15, 20, 25, 30 mg RC New SmpC 11.2022
Palpitations. There have been isolated reports of cardiomyopathy associated with chronic amphetamine use.
Central Nervous System
Psychotic episodes at recommended doses, overstimulation, restlessness, irritability, euphoria, dyskinesia, dysphoria, depression, tremor, tics, aggression, anger, logorrhea, dermatillomania, paresthesia (including formication), and bruxism.

Eye Disorders
Vision blurred, mydriasis.

Gastrointestinal
Unpleasant taste, constipation, other gastrointestinal disturbances.
Allergic
Urticaria, rash, hypersensitivity reactions including angioedema and anaphylaxis. Serious skin rashes, including Stevens-Johnson Syndrome and toxic epidermal necrolysis have been reported.

Endocrine
Impotence, changes in libido, frequent or prolonged erections.

Skin
Alopecia.
Vascular Disorders
Raynaud’s phenomenon.

Musculoskeletal and Connective Tissue Disorders
Rhabdomyolysis.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il