Special Warning : אזהרת שימוש

5     WARNINGS AND PRECAUTIONS

5.1 Risks from Concomitant Use with Opioids
Concomitant use of benzodiazepines, including XANAX XR, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe XANAX XR concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In patients already receiving an opioid analgesic, prescribe a lower initial dose of XANAX XR than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking XANAX XR, prescribe a lower initial dose of the opioid and titrate based upon clinical response.

Advise both patients and caregivers about the risks of respiratory depression and sedation when XANAX XR is used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined [see Drug Interactions (7.1)].

5.2    Abuse, Misuse, and Addiction

The use of benzodiazepines, including XANAX XR, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death [see DRUG ABUSE AND DEPENDENCE – Abuse (9.2)].
Before prescribing XANAX XR and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of XANAX XR, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of XANAX XR along with monitoring for signs and symptoms of abuse, misuse, and addiction. Prescribe the lowest effective dosage; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate.

5.3 Dependence and Withdrawal Reactions
To reduce the risk of withdrawal reactions, use a gradual taper to discontinue XANAX XR or reduce the dosage (a patient-specific plan should be used to taper the dose) [see DOSAGE AND ADMINISTRATION (3.2].
Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use.

Acute Withdrawal Reactions
The continued use of benzodiazepines, including XANAX XR, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of XANAX XR after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) [see DRUG ABUSE AND DEPENDENCE – Dependence (9.3)].

Protracted Withdrawal Syndrome
In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months [see DRUG ABUSE AND DEPENDENCE – Dependence (9.3)].
Certain adverse clinical events, some life-threatening, are a direct consequence of physical dependence to XANAX XR. These include a spectrum of withdrawal symptoms; the most important is seizure [see Drug Abuse and Dependence (9.3)]. Even after relatively short-term use at doses of < 4 mg/day, there is some risk of dependence. Spontaneous reporting system data suggest that the risk of dependence and its severity appear to be greater in patients treated with doses greater than 4 mg/day and for long periods (more than 12 weeks).
However, in a controlled postmarketing discontinuation study of panic disorder patients who received XANAX, the duration of treatment (3 months compared to 6 months) had no effect on the ability of patients to taper to zero dose. In contrast, patients treated with doses of XANAX greater than 4 mg/day had more difficulty tapering to zero dose than those treated with less than 4 mg/day.

In a controlled clinical trial in which 63 patients were randomized to alprazolam tablets and where withdrawal symptoms were specifically sought, the following were identified as symptoms of withdrawal: heightened sensory perception, impaired concentration, dysosmia, clouded sensorium, paresthesias, muscle cramps, muscle twitch, diarrhea, blurred vision, appetite decrease, and weight loss. Other symptoms, such as anxiety and insomnia, were frequently seen during discontinuation, but it could not be determined if they were due to return of illness, rebound, or withdrawal.

Interdose Symptoms
Early morning anxiety and emergence of anxiety symptoms between doses of XANAX have been reported in patients with panic disorder taking prescribed maintenance doses. These symptoms may reflect the development of tolerance or a time interval between doses which is longer than the duration of clinical action of the administered dose. In either case, it is presumed that the prescribed dose is not sufficient to maintain plasma levels above those needed to prevent relapse, rebound, or withdrawal symptoms over the entire course of the interdosing interval.

5.4 Effects on Driving and Operating Machinery
Because of its CNS depressant effects, patients receiving XANAX XR should be cautioned against engaging in hazardous occupations or activities requiring complete mental alertness such as operating machinery or driving a motor vehicle. For the same reason, patients should be cautioned about the concomitant use of alcohol and other CNS depressant drugs during treatment with XANAX XR [see Drug Interactions (7.1)].

5.5     Interaction with Drugs that Inhibit Metabolism via Cytochrome P450 3A The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs that inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam.

Strong CYP3A Inhibitors
XANAX XR is contraindicated in patients receiving strong inhibitors of CYP3A such as azole antifungal agents [see Contraindications (4)]. Ketoconazole and itraconazole have been shown in vivo to increase plasma alprazolam concentrations 3.98 fold and 2.70 fold, respectively.

Dosage adjustment is necessary when XANAX XR and ritonavir are initiated concomitantly or when ritonavir is added to a stable dosage of XANAX XR [see Drug Interactions (7.1)].

Drugs demonstrated to be CYP3A inhibitors on the basis of clinical studies involving alprazolam: nefazodone, fluvoxamine, and cimetidine [see Drug Interaction (7.1), Clinical Pharmacology (12.2)]. Use caution and consider dose reduction of XANAX XR, as appropriate, during co-administration with these drugs.

5.6 Patients with Depression
Benzodiazepines may worsen depression. Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients. Consequently, appropriate precautions (e.g., limiting the total prescription size and increased monitoring for suicidal ideation) should be considered in patients with depression.
5.7 Mania
Episodes of hypomania and mania have been reported in association with the use of alprazolam tablets in patients with depression [see Adverse Reactions (6.1)].

5.8 Neonatal Sedation and Withdrawal Syndrome
Use of XANAX XR late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate [see Use in Specific Populations (8.1)]. Monitor neonates exposed to XANAX XR during pregnancy or labor for signs of sedation and monitor neonates exposed to XANAX XR during pregnancy for signs of withdrawal; manage these neonates accordingly.


5.9      Risks in Patients with Impaired Respiratory Function
There have been reports of death in patients with severe pulmonary disease shortly after the initiation of treatment with alprazolam. Closely monitor patients with impaired respiratory function. If signs and symptoms of respiratory depression, hypoventilation, or apnea occur, discontinue XANAX XR.
5.10 Excipients

Each XANAX® XR 0.5 mg, 1 mg & 2 mg sustained release tablet contains 221.7 mg lactose 
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucosegalactose malabsorption should not take Xanax XR.

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/

Effects on Driving