Special Warning : אזהרת שימוש

5 WARNINGS AND PRECAUTIONS

5.1 Abuse,Misuse and Addiction
VYVANSE has a high potential for abuse and misuse. The use of VYVANSE exposes individuals to the risks of abuse and misuse ,which can lead to the development of a substance use disorder, including addiction. VYVANSE can be diverted for non-medical use into illicit channels or distribution [see Drug Abuse and Dependence (9.2,)].
Misuse and abuse of CNS stimulants, including VYVANSE, can result in overdose and death, [see Overdosage (10)],and this risk is increase with higher doses or unapproved methods of administration, such as snorting or injection.

Before prescribing VYVANSE, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store VYVANSE in a safe place, preferably locked, and instruct patients to not give VYVANSE to anyone else. Throughout VYVANSE treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

5.2       Risks to Patients with Serious Cardiac Disease

Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosage. Avoid VYVANSE use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease.

5.3 Increased Blood Pressure and Heart Rate
CNS stimulants cause an increase in blood pressure (mean increase about 2 to 4 mm Hg) and heart rate (mean increase about 3 to 6 bpm). Some patients may have larger increases.
Monitor all VYVANSE-treated patients for potential tachycardia and hypertension.

5.4 Psychiatric Adverse Reactions
Exacerbation of Pre-existing Psychosis
CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder.

Induction of a Manic Episode in Patients with Bipolar Disorder
CNS stimulants may induce a /manic or mixed episode. Prior to initiating VYVANSE treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, and depression).

New Psychotic or Manic Symptoms
CNS stimulants, at the recommendeddosage, may cause psychotic or manic symptoms, (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients compared to 0% of placebo-treated patients. If such symptoms occur, consider discontinuing VYVANSE.


5.5 Long-Term Suppression of Growth in Pediatric Patients
CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients.

In a 4-week, placebo-controlled trial of VYVANSE in pediatric patients ages 6 to 12 years old with ADHD, there was a dose-related decrease in weight in the VYVANSE groups compared to weight gain in the placebo group. Additionally, in studies of another stimulant, there was slowing of the increase in height [see Adverse Reactions (6.1)].

Closely monitor growth (weight and height) in VYVANSE-treated pediatric patients.
Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. VYVANSE is not approved for use in pediatric patients below 6 years of age [see Use in Specific Populations (8.4)].

5.6 Peripheral Vasculopathy, including Raynaud's Phenomenon
CNS stimulants, including VYVANSE, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud's phenomenon. Signs and symptoms are usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud's phenomenon, were observed in post-marketing reports and at the therapeutic dosages of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms generally improved after dosage reduction or discontinuation of the CNS stimulant.

Careful observation for digital changes is necessary during VYVANSE treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for VYVANSE-treated patients who develop signs or symptoms of peripheral vasculopathy.


5.7 Serotonin Syndrome


Serotonin syndrome, a potentially life-threatening reaction, may occur when amphetamines are used in combination with other drugs that affect the serotonergic neurotransmitter systems such as monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort [see Drug Interactions (7.1)]. The co- administration with cytochrome P450 2D6 (CYP2D6) inhibitors may also increase the risk with increased exposure to the active metabolite of VYVANSE (dextroamphetamine). In these situations, consider an alternative non-serotonergic drug or an alternative drug that does not inhibit CYP2D6 [see Drug Interactions (7.1)].

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Concomitant use of VYVANSE with MAOI drugs is contraindicated [see Contraindications (4)].

Discontinue treatment with VYVANSE and any concomitant serotonergic agents immediately if symptoms of serotonin syndrome occur and initiate supportive symptomatic treatment. If concomitant use of VYVANSE with other serotonergic drugs or CYP2D6 inhibitors is clinically warranted, initiate VYVANSE with lower doses, monitor patients for the emergence of serotonin syndrome during drug initiation or titration, and informpatients of the increased risk for serotonin syndrome.

5.8 Motor and Verbal Tics, and Worsening of Tourette’s Syndrome

CNS stimulants, including amphetamine, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been reported [see Adverse Reactions (6.2)].

Before initiating VYVANSE, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor VYVANSE-treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue treatment if clinically appropriate.



6 ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling: • Known hypersensitivity to amphetamine products or other ingredients of VYVANSE [see Contraindications (4)]
• Hypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors [see Contraindications (4) and Drug Interactions (7.1)]
• Abuse,Misuse and Addiction[see Boxed Warning, Warnings and Precautions (5.1), and Drug Abuse and Dependence (9.2, 9.3)]
• Risks to Patients with Serious Cardiac Disease[see Warnings and Precautions (5.2)] • Increase Blood Pressure and Heart Rate [see Warnings and Precautions (5.3)] • Psychiatric Adverse Reactions [see Warnings and Precautions (5.4)] • Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions (5.5)] • Peripheral Vasculopathy, including Raynaud's phenomenon [see Warnings and Precautions (5.6)]
• Serotonin Syndrome [see Warnings and Precautions (5.7)]
• Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings and Precautions (5.8)]


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.

Attention Deficit Hyperactivity Disorder

The safety data in this section is based on data from the 4-week controlled parallel-group clinical studies of VYVANSE in pediatric and adult patients with ADHD [see Clinical Studies (14.1)].

Adverse Reactions Associated with Discontinuation of Treatment in ADHD Clinical Trials In the controlled trial in pediatric patients ages 6 to 12 years (Study 1), 8% (18/218) of VYVANSE- treated patients discontinued due to adverse reactions compared to 0% (0/72) of placebo-treated patients. The most frequently reported adverse reactions (1% or more and twice rate of placebo) were ECG voltage criteria for ventricular hypertrophy, tic, vomiting, psychomotor hyperactivity, insomnia, and rash [2 instances for each adverse reaction, i.e., 2/218 (1%)]. Less frequently reported adverse reactions (less than 1% or less than twice rate of placebo) included abdominal pain upper, dry mouth, weight decreased, dizziness, somnolence, logorrhea, chest pain, anger and hypertension.
In the controlled trial in pediatric patients ages 13 to 17 years (Study 4), 3% (7/233) of VYVANSE- treated patients discontinued due to adverse reactions compared to 1% (1/77) of placebo-treated patients. The most frequently reported adverse reactions (1% or more and twice rate of placebo) were decreased appetite (2/233; 1%) and insomnia (2/233; 1%). Less frequently reported adverse reactions (less than 1% or less than twice rate of placebo) included irritability, dermatillomania, mood swings, and dyspnea.
In the controlled adult trial (Study 7), 6% (21/358) of VYVANSE-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 VYVANSE Treated Patients with ADHD in Clinical Trials The most common adverse reactions (incidence ≥5% and at a rate at least twice placebo) reported in pediatric patients ages 6 to 17 years, and/or adults were anorexia, anxiety, decreased appetite, decreased weight, diarrhea, dizziness, dry mouth, irritability, insomnia, nausea, upper abdominal pain, and vomiting.

Adverse Reactions Occurring at an Incidence of 2% or More Among VYVANSE Treated Patients with ADHD in Clinical Trials
Adverse reactions reported in the controlled trials in pediatric patients ages, 6 to 12 years (Study 1), pediatric patients ages 13 to 17 years (Study 4), and adult patients (Study 7) treated with VYVANSE or placebo are presented in Tables 1, 2, and 3 below.

Table 1    Adverse Reactions Reported by 2% or More of Pediatric Patients Ages 6 to 12 Years with ADHD Taking VYVANSE and Greater than or Equal to Twice the Incidence in Patients Taking Placebo in a 4-Week Clinical Trial (Study 1) 

VYVANSE             Placebo
(n=218)             (n=72)
Decreased Appetite                39%                 4%
Insomnia                          23%                 3%
Abdominal Pain Upper              12%                 6%
Irritability                      10%                 0%
Vomiting                          9%                  4%
Weight Decreased                  9%                  1%
Nausea                            6%                  3%
Dry Mouth                         5%                  0%
Dizziness                         5%                  0%
Affect lability                   3%                  0%
Rash                              3%                  0%
Pyrexia                           2%                  1%
Somnolence                        2%                  1%
Tic                               2%                  0%
Anorexia                          2%                  0%
Table 2     Adverse Reactions Reported by 2% or More of Pediatric Patients Ages 13 to 17 Years with ADHD Taking VYVANSE and Greater than or Equal to Twice the Incidence in Patients Taking Placebo in a 4-Week Clinical Trial (Study 4) VYVANSE            Placebo
(n=233)            (n=77)

Decreased Appetite             34%                3%
Insomnia                       13%                4%
Weight Decreased               9%                 0%
Dry Mouth                      4%                 1%
Palpitations                   2%                 1%
Anorexia                       2%                 0%
Tremor                         2%                 0%



Table 3   Adverse Reactions Reported by 2% or More of Adult Patients with ADHD Taking VYVANSE and Greater than or Equal to Twice the Incidence in Patients Taking Placebo in a 4-Week Clinical Trial (Study 7)
VYVANSE            Placebo
(n=358)            (n=62)

Decreased Appetite             27%                2%
Insomnia                       27%                8%
Dry Mouth                      26%                3%
Diarrhea                       7%                 0%
Nausea                         7%                 0%
Anxiety                        6%                 0%
Anorexia                       5%                 0%
Feeling Jittery                4%                 0%
Agitation                      3%                 0%
Increased Blood Pressure       3%                 0%
Hyperhidrosis                  3%                 0%
Restlessness                   3%                 0%
Decreased Weight               3%                 0%
Dyspnea                        2%                 0%
Increased Heart Rate           2%                 0%
Tremor                         2%                 0%
Palpitations                   2%                 0%

In addition, in the adult population erectile dysfunction was observed in 2.6% of males on VYVANSE and 0% on placebo; decreased libido was observed in 1.4% of subjects on VYVANSE and 0% on placebo.
Weight Loss and Slowing Growth Rate in Pediatric Patients with ADHD
In a controlled trial of VYVANSE in pediatric patients ages 6 to 12 years (Study 1), mean weight loss from baseline after 4 weeks of therapy was -0.9, -1.9, and -2.5 pounds, respectively, for patients receiving 30 mg, 50 mg, and 70 mg of VYVANSE, compared to a 1 pound weight gain for patients receiving placebo. Higher doses were associated with greater weight loss with 4 weeks of treatment. Careful follow-up for weight in pediatric patients ages 6 to 12 years who received VYVANSE over 12 months suggests that consistently medicated pediatric patients (i.e. treatment for 7 days per week throughout the year) have a slowing in growth rate, measured by body weight as demonstrated by an age- and sex-normalized mean change from baseline in percentile, of -13.4 over 1 year (average percentiles at baseline and 12 months were 60.9 and 47.2, respectively).
In a 4-week controlled trial of VYVANSE in pediatric patients ages 13 to 17 years, mean weight loss from baseline to endpoint was -2.7, -4.3, and -4.8 lbs., respectively, for patients receiving 30 mg, 50 mg, and 70 mg of VYVANSE, compared to a 2.0 pound weight gain for patients receiving placebo.

Careful follow-up of weight and height in pediatric patients 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 pediatric patients over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated pediatric patients ages 7 to 13 years (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. In a controlled trial of amphetamine (d- to l-enantiomer ratio of 3:1) in pediatric patients ages 13 to 17 years, mean weight change from baseline within the initial 4 weeks of therapy was -1.1 pounds and -2.8 pounds, respectively, for patients receiving 10 mg and 20 mg of amphetamine. Higher doses were associated with greater weight loss within the initial 4 weeks of treatment [see Warnings and Precautions (5.5)].

Weight Loss in Adults with ADHD
In the controlled adult trial (Study 7), mean weight loss after 4 weeks of therapy was 2.8 pounds, 3.1 pounds, and 4.3 pounds, for patients receiving final doses of 30 mg, 50 mg, and 70 mg of VYVANSE, respectively, compared to a mean weight gain of 0.5 pounds for patients receiving placebo.

Binge Eating Disorder

The safety data in this section is based on data from two 12 week parallel group, flexible-dose, placebo- controlled studies in adults with BED [see Clinical Studies 14.2]. Patients with cardiovascular risk factors other than obesity and smoking were excluded.

Adverse Reactions Associated with Discontinuation of Treatment in BED Clinical Trials In controlled trials of patients ages 18 to 55 years, 5.1% (19/373) of VYVANSE-treated patients discontinued due to adverse reactions compared to 2.4% (9/372) of placebo-treated patients. No single adverse reaction led to discontinuation in 1% or more of VYVANSE-treated patients.
Less commonly reported adverse reactions (less than 1% or less than twice rate of placebo) included increased heart rate, headache, abdominal pain upper, dyspnea, rash, insomnia, irritability, feeling jittery and anxiety.

Adverse Reactions Occurring at an Incidence of 5% or More and At Least Twice Placebo Among VYVANSE Treated Patients with BED in Clinical Trials
The most common adverse reactions (incidence ≥5% and at a rate at least twice placebo) reported in adults were dry mouth, insomnia, decreased appetite, increased heart rate, constipation, feeling jittery, and anxiety.


Adverse Reactions Occurring at an Incidence of 2% or More and At Least Twice Placebo Among VYVANSE Treated Patients with BED in Clinical Trials
Adverse reactions reported in the pooled controlled trials in adult patients (Study 11 and 12) treated with VYVANSE or placebo are presented in Table 4 below.
Table 4        Adverse Reactions Reported by 2% or More of Adult Patients with BED Taking VYVANSE and Greater than or Equal to Twice the Incidence in Patients Taking Placebo in 12-Week Clinical Trials (Study 11 and 12)

VYVANSE            Placebo
(N=373)           (N=372)
Dry Mouth                               36%              7%
1
Insomnia                                20%              8%
Decreased Appetite                       8%              2%
2
Increased Heart Rate                     7%              1%
Feeling Jittery                          6%              1%
Constipation                             6%              1%
Anxiety                                  5%              1%
Diarrhea                                 4%              2%
Decreased Weight                         4%              0%
Hyperhidrosis                            4%              0%
Vomiting                                 2%              1%
Gastroenteritis                          2%              1%
Paresthesia                              2%              1%
Pruritus                                 2%              1%
Upper Abdominal Pain                     2%              0%
Energy Increased                         2%              0%
Urinary Tract Infection                  2%              0%
Nightmare                                2%              0%
Restlessness                             2%              0%
Oropharyngeal Pain                       2%              0%
1
Includes all preferred terms containing the word “insomnia.”
2
Includes the preferred terms heart rate increased and tachycardia.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post -approval use of VYVANSE. 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. These events are as follows: cardiomyopathy, mydriasis, diplopia, difficulties with visual accommodation, blurred vision, eosinophilic hepatitis, anaphylactic reaction, hypersensitivity, dyskinesia, dysgeusia,motor and verbal tics, bruxism, depression, dermatillomania, alopecia, aggression, Stevens-Johnson Syndrome, chest pain, angioedema, urticaria, seizures, libido changes, frequent or prolonged erections, constipation, rhabdomyolysis and intestinal ischemia.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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/

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