Adverse reactions : תופעות לוואי

6   ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling: • Risks from Concomitant Use with Opioids [see Warnings and Precautions (5.1)] • Abuse, Misuse, and Addiction [see Warnings and Precautions (5.2)] • Dependence and Withdrawal Reactions [see Warnings and Precautions (5.3)] • Effects on Driving and Operating Machinery [see Warnings and Precautions (5.4)] • Patients with Depression [see Warnings and Precautions (5.6)]
• Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.8)] • Risks in Patients with Impaired Respiratory Function [see Warnings and Precautions (5.9)]

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.

The information included in the section on Adverse Reactions Observed in Short-Term, Placebo-Controlled Trials with XANAX XR is based on pooled data of five 6- and 8-week placebo-controlled clinical studies in panic disorder.

Adverse Reactions Observed in Short-Term, Placebo-Controlled Trials of XANAX XR Adverse Reactions Reported as Reasons for Discontinuation of Treatment in Placebo- Controlled Trials
Approximately 17% of the 531 patients who received XANAX XR in placebo-controlled clinical trials for panic disorder had at least one adverse event that led to discontinuation compared to 8% of 349 placebo-treated patients. The most common events leading to discontinuation and considered to be drug-related (I e. , leading to discontinuation in at least 1% of the patients treated with XANAX XR at a rate at least twice that of placebo) are shown in Table 1.

Table 1: Adverse Reactions Leading to Discontinuation in ≥1% of XANAX XR-treated Patients and at least twice the Rate of Placebo-treated Patients in Placebo-Controlled Trials
Percentage of Patients Discontinuing
Due to Adverse Reactions
XANAX XR               Placebo
(n=531)              (n=349)
Nervous system disorders
Sedation                                               7.5                  0.6 Somnolence                                             3.2                  0.3 Dysarthria                                             2.1                   0 Coordination abnormal                                  1.9                  0.3 Memory impairment                                      1.5                  0.3 General disorders/administration site conditions
Fatigue                                                1.7                  0.6 Psychiatric disorders
Depression                                             2.5                  1.2 n=number of patients

Adverse Reactions Occurring at an Incidence of 1% or More Among Patients Treated with XANAX XR
Table 2 shows the incidence of adverse reactions that occurred during 6- and 8-week placebo-controlled trials in 1% or more of patients treated with XANAX XR where the incidence in patients treated with XANAX XR was greater than the incidence in placebo- treated patients. The most commonly observed adverse reactions in panic disorder patients treated with XANAX XR (incidence of 5% or greater and at least twice the incidence in placebo patients) were: sedation, somnolence, memory impairment, dysarthria, coordination abnormal, ataxia, libido decreased.
Table 2: Adverse Reactions Occuring in ≥ 1% in XANAX-treated Patients and Greater than Placebo-treated Patients in 6 and 8 week Placebo-Controlled Trials Panic Disorder 
XANAX XR               Placebo
(n=531)               (n=349)
Nervous system disorders
Sedation                                           45%                 23% Somnolence                                         23%                  6% Memory impairment                                  15%                  7% Dysarthria                                         11%                  3% Coordination abnormal                               9%                  1% Mental impairment                                   7%                  6% Ataxia                                              7%                  3% Disturbance in attention                            3%                  1% Balance impaired                                    3%                  1% Dyskinesia                                          2%                  1% Hypoesthesia                                        1%                 <1% Hypersomnia                                         1%                  0% General disorders/administration site conditions
Fatigue                                            14%                  9% Lethargy                                            2%                  1% Psychiatric disorders
Depression                                         12%                  9% Libido decreased                                    6%                  2% Disorientation                                      2%                  0% Confusion                                           2%                  1% Depressed mood                                      1%                 <1% Metabolism and nutrition disorders
Appetite increased                                 7%                   6% Anorexia                                           2%                   0% Gastrointestinal disorders
Constipation                                       8%                   4% Nausea                                             6%                   3% Investigations
Weight increased                                    5                    4 
Injury, poisoning, and procedural complications
Road traffic accident                              2%                   0% Reproductive system and breast disorders
Dysmenorrhea                                       4%                   3% Sexual dysfunction                                 2%                   1% Musculoskeletal and connective tissue disorder
Arthralgia                                         2%                   1% XANAX XR                  Placebo
(n=531)                  (n=349)
Myalgia                                                 2%                       1% Pain in limb                                            1%                       0% Respiratory, thoracic, and mediatinal disorders
Dyspnea                                                   2%                      0% 

Other Adverse Reactions Observed During the Premarketing Evaluation of XANAX XR Following is a list of other adverse reaction reported by 531 patients with panic disorder treated with XANAX XR. Adverse reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions: those occurring in at least 1/100 patients (frequent); those occurring in less than1/100 patients but at least 1/1000 patients (infrequent); those occurring in fewer than 1/1000 patients (rare).

Cardiac disorders: Frequent: palpitation; Infrequent: sinus tachycardia Ear and Labyrinth disorders: Frequent: Vertigo; Infrequent: tinnitus, ear pain Eye disorders: Frequent: blurred vision; Infrequent: mydriasis, photophobia Gastrointestinal disorders: Frequent: diarrhea, vomiting, dyspepsia, abdominal pain; Infrequent: dysphagia, salivary hypersecretion
General disorders and administration site conditions: Frequent: malaise, weakness, chest pains; Infrequent: fall, pyrexia, thirst, feeling hot and cold, edema, feeling jittery, sluggishness, asthenia, feeling drunk, chest tightness, increased energy, feeling of relaxation, hangover, loss of control of legs, rigors
Musculoskeletal and connective tissue disorders: Frequent: back pain, muscle cramps, muscle twitching
Nervous system disorders: Frequent: headache, dizziness, tremor; Infrequent: amnesia, clumsiness, syncope, hypotonia, seizures, depressed level of consciousness, sleep apnea syndrome, sleep talking, stupor
Psychiatric system disorders: Frequent: irritability, insomnia, nervousness, derealization, libido increased, restlessness, agitation, depersonalization, nightmare; Infrequent: abnormal dreams, apathy, aggression, anger, bradyphrenia, euphoric mood, logorrhea, mood swings, dysphonia, hallucination, homicidal ideation, mania, hypomania, impulse control, psychomotor retardation, suicidal ideation
Renal and urinary disorders: Frequent: difficulty in micturition; Infrequent: urinary frequency, urinary incontinence
Respiratory, thoracic, and mediastinal disorders: Frequent: nasal congestion, hyperventilation; Infrequent: choking sensation, epistaxis, rhinorrhea Skin and subcutaneous tissue disorders: Frequent: sweating increased; Infrequent: clamminess, rash, urticaria
Vascular disorders: Infrequent: hypotension

Discontinuation-Emergent Adverse Reactions Occurring at an Incidence of 5% or More Among Patients Treated with XANAX XR
Table 3 shows the incidence of discontinuation-emergent adverse reactions that occurred during short-term, placebo-controlled trials in 5% or more of patients treated with XANAX XR where the incidence in patients treated with XANAX XR was 2 times greater than the incidence in placebo-treated patients.
Table 3: Discontinuation-Emergent Symptom
Incidence Reported in ≥5% of XANAX XR-treated Patients and at least twice the Rate of Placebo-treated Patients in Short-Term, Placebo-Controlled Trials 

XANAX XR           Placebo n=422 (%)         n=261 (%)
Nervous system disorders
Tremor                                              28.2             10.7 Headache                                            26.5             12.6 Hypoesthesia                                         7.8              2.3 Paraesthesia                                         7.1              2.7 Psychiatric disorders
Insomnia                                            24.2              9.6 Nervousness                                         21.8              8.8 Depression                                          10.9              5.0 Derealization                                        8.0              3.8 Anxiety                                              7.8              2.7 Depersonalization                                    5.7              1.9 Gastrointestinal disorders
Diarrhea                                            12.1              3.1 Respiratory, thoracic and mediastinal disorders
Hyperventilation                                     8.5              2.7 Metabolism and nutrition disorders
Appetite decreased                                   9.5              3.8 Musculosketal and connective tissue disorders
Muscle twitching                                     7.4              2.7 Vascular disorders
Hot flushes                                          5.9              2.7 

There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of alprazolam [see Warning and Precautions (5.2), Drug Abuse and Dependence (9.3)].

Paradoxical reactions such as stimulation, increased muscle spasticity, sleep disturbances, hallucinations, and other adverse behavioral effects such as agitation, rage, irritability, and aggressive or hostile behavior have been reported rarely. In many of the spontaneous case reports of adverse behavioral effects, patients were receiving other CNS drugs concomitantly and/or were described as having underlying psychiatric conditions. Should any of the above events occur, alprazolam should be discontinued. Isolated published reports involving small numbers of patients have suggested that patients who have borderline personality disorder, a prior history of violent or aggressive behavior, or alcohol or substance abuse may be at risk for such events. Instances of irritability, hostility, and intrusive thoughts have been reported during discontinuation of alprazolam in patients with posttraumatic stress disorder.
6.2    Postmarketing Experience

The following adverse reactions have been identified during post approval use of alprazolam tablets. 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.
Endocrine disorders: Hyperprolactinemia
General disorders and administration site conditions: Edema peripheral Hepatobiliary disorders: Hepatitis, hepatic failure, jaundice
Investigations: Liver enzyme elevations
Psychiatric disorders: Hypomania, mania
Reproductive system and breast disorders: Gynecomastia, galactorrhea, menstruation irregular
Skin and subcutaneous tissue disorders: Photosensitivity reaction, angioedema, Stevens- Johnson syndrome

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/