Adverse reactions : תופעות לוואי

ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling: • Risks from Concomitant Use with Opioids [see Warnings and Precautions ] • Abuse, Misuse, and Addiction [see Warnings and Precautions ]
• Dependence and Withdrawal Reactions [see Warnings and Precautions ] • Effects on Driving and Operating Machinery [see Warnings and Precautions ] • Patients with Depression [see Warnings and Precautions ]
• Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions ] • Risks in Patients with Impaired Respiratory Function [see Warnings and Precautions ] 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 data in the two tables below are estimates of adverse reaction incidence among adult patients who participated in:

•   4-week placebo-controlled clinical studies with Xanagis dosages up to 4 mg per day for the acute treatment of generalized anxiety disorder (Table 1)
•   Short-term (up to 10 weeks) placebo-controlled clinical studies with Xanagis dosages up to 10 mg per day for panic disorder, with or without agoraphobia (Table 2).

Table 1: Adverse Reactions Occurring in ≥1% in Alprazolam-treated Patients and Greater than Placebo- treated Patients in Placebo-Controlled Trials for Generalized Anxiety 


Alprazolam n=565                         Placebo n=505
Nervous system disorders
Drowsiness                                               41%                                     22% Light -headedness                                        21%                                     19% Dizziness                                                 2%                                      1% Akathisia                                                 2%                                      1% Gastrointestinal disorders
Dry mouth                                                15%                                     13% Increased salivation                                      4%                                      2% 
Cardiovascular disorders
Hypotension                                              5%                                       2% Skin and subcutaneous tissue disorders
Dermatitis/Allergy                                       4%                                       3% 

In addition to the adverse reactions (i.e., greater than 1%) enumerated in the table above for patients with generalized anxiety disorder, the following adverse reactions have been reported in association with the use of benzodiazepines: dystonia, irritability, concentration difficulties, anorexia, transient amnesia or memory impairment, loss of coordination, fatigue, seizures, sedation, slurred speech, jaundice, musculoskeletal weakness, pruritus, diplopia, dysarthria, changes in libido, menstrual irregularities, incontinence and urinary retention.



Table 2: Adverse Reactions Occuring in ≥1% in Alprazolam-treated Patients and Greater than Placebo- treated Patients in Placebo-Controlled Trials (Up to 10 Weeks) for Panic Disorder 


Number of Patients                                                                              Placebo Alprazolam                                n=1231 n=1388
Drowsiness                                         77%                                     43% Fatique and Tiredness                              49%                                     42% Impaired Coordination                              40%                                     18% Irritability                                       33%                                     30% Memory Impairment                                  33%                                     22% Cognitive Disorder                                 29%                                     21% Decreased Libido                                   14%                                      8% Dysartharia                                        23%                                      6% Confusional state                                  10%                                      8% Increased libido                                    8%                                     4% Change in libido (not specified)                    7%                                     6% Disinhibition                                       3%                                     2% Talkativeness                                       2%                                     1% Derealization                                       2%                                     1% 
Gastrointestinal disorders
Constipation                                          26%                                     15% Increased                                             6%                                      4% salivation


Skin and subcutaneous tissue disorders
Rash                                                11%                                     8% Other
Increased appetite                                  33%                                     23% Decreased appetite                                  28%                                     24% Weight gain                                         27%                                     18% Weight loss                                         23%                                     17% Micturition difficulties                            12%                                      9% Menstrual disorders                                 11%                                      9% Sexual dysfunction                                   7%                                      4% Incontinence                                         2%                                      1% 

In addition to the reactions (i.e., greater than 1%) enumerated in the table above for patients with panic disorder, the following adverse reactions have been reported in association with the use of XANAGIS: seizures, hallucinations, depersonalization, taste alterations, diplopia, elevated bilirubin, elevated hepatic enzymes, and jaundice.

Adverse Reactions Reported as Reasons for Discontinuation in Treatment of Panic Disorder in Placebo-Controlled Trials
In a larger database comprised of both controlled and uncontrolled studies in which 641 patients received Alprazolam discontinuation-emergent symptoms which occurred at a rate of over 5% in patients treated with Alprazolam and at a greater rate than the placebo-treated group are shown in Table 3.
Table 3: Discontinuation-Emergent Symptom Incidence Reported in ≥5% of Alprazolam-treated Patients and > Placeb 

-treated Patients n=641

Nervous system disorders
Insomnia                                                                         29.5% Light-headedness                                                                 19.3% Abnormal involuntary movement                                                    17.3% Headache                                                                         17.0% Muscular twitching                                                               6.9% Impaired coordination                                                            6.6% Muscle tone disorders                                                            5.9% Weakness                                                                         5.8% Psychiatric disorders
Anxiety                                                                          19.2% Fatigue and Tiredness                                                            18.4% Irritability                                                                     10.5% Cognitive disorder                                                               10.3% Memory                                                                           5.5% impairment                                                                       5.1% Depression                                                                       5.0% Confusional state
Gastrointestinal disorders
Nausea/Vomiting                                                                  16.5% Diarrhea                                                                         13.6% Decreased salivation                                                             10.6% Metabolism and nutrition disorders
Weight loss                                                                      13.3% Decreased                                                                        12.8% appetite
Dermatological disorders
Sweating                                                                         14.4% Cardiovascular disorders
Tachycardia                                                                      12.2% Special Senses
Blurred vision                                                                   10.0% n=number of patients.

There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of Alprazolam Tablets (see WARNINGS).
[see Warning and Precautions ) and Drug Abuse and Dependence ].

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.

Postmarketing Experience
The following adverse reactions have been identified during postapproval use of XANAGIS. 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
Investigations: Liver enzyme elevations
Psychiatric disorders: Hypomania, mania
Reproductive system and breast disorders: Gynecomastia, galactorrhea
Skin and subcutaneous tissue disorders: Photosensitivity reaction, angioedema, Stevens-Johnson syndrome 
DRUG INTERACTIONS

Drugs Having Clinically Important Interactions with Xanagis
Table 4 includes clinically significant drug interactions with [see Clinical Pharmacology].

Table 4: Clinically Significant Drug Interactions with Xanagis

Opioids
Clinical implication               The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at gamma- aminobutyric acid(GABAA) sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists.
Prevention or management           Limit dosage and duration of concomitant use of Xanagis and opioids, and monitor patients closely for respiratory depression and sedation [see Warnings and Precautions].
Examples                           Morphine, buprenorphine, hydromorphone, oxymorphone, oxycodone, fentanyl, methadone, alfentanil, butorpenol, codeine, dihydrocodeine, meperidine, pentazocine, remifentanil, sufentanil, tapentadol, tramadol.
CNS Depressants
Clinical implication          The benzodiazepines, including alprazolam, produce additive CNS depressant effects when coadministered with other CNS depressants.
Prevention or management      Limit dosage and duration of Xanagis during concomitant use with CNS depressants [see Warnings and Precautions ].
Examples                      Psychotropic medications, anticonvulsants, antihistaminics, ethanol, and other drugs which themselves produce CNS depression.
Strong Inhibitors of CYP3A (except ritonavir)
Clinical implication            Concomitant use of Xanagis with strong CYP3A inhibitors has a profound effect on the clearance of alprazolam, resulting in increased concentrations of alprazolam and increased risk of adverse reactions [see Clinical
Pharmacology ].


Prevention or management      Concomitant use of Xanagis with a strong CYP3A4 inhibitor (except ritonavir) is contraindicated [see Contraindications (4), Warnings and Precautions ].
Examples                      Ketoconazole, itraconazole, clarithromycin Moderate or Weak Inhibitors of CYP3A
Clinical implication          Concomitant use of Xanagis with CYP3A inhibitors may increase the concentrations of Xanagis, resulting in increased risk of adverse reactions of alprazolam [see Clinical Pharmacology ].
Prevention or management      Avoid use and consider appropriate dose reduction when Xanagis is coadministered with a moderate or weak CYP3A inhibitor [see Warnings and Precautions].
Examples                      Nefazodone, fluvoxamine, cimetidine, erythromycin CYP3A Inducers
Clinical implication          Concomitant use of CYP3A inducers can increase alprazolam metabolism and therefore can decease plasma levels of alprazolam [see Clinical
Pharmacology ].
Prevention or management      Caution is recommended during coadministration with Xanagis.
Examples                      Carbamazepine, phenytoin
Ritonavir
Clinical implication          Interactions involving ritonavir and alprazolam are complex and time dependent. Short term administration of ritonavir increased alprazolam exposure due to CYP3A4 inhibition. Following long term treatment of ritonavir (>10 to 14 days), CYP3A4 induction offsets this inhibition.
Alprazolam exposure was not meaningfully affected in the presence of ritonavir.
Prevention or management      Reduce Xanagis dosage when ritonavir and Xanagis are initiated concomitantly, or when ritonavir is added to a regimen where Xanagis is stabilized.

Increase Xanagis dosage to the target dosage after 10 to 14 days of dosing ritonavir and Xanagis concomitantly. No dosage adjustment of Xanagis is necessary in patients receiving ritonavir for more than 10 to14 days [see Dosage and Administration ].

Concomitant use of Xanagis with a strong CYP3A inhibitor, except ritonavir, is contraindicated [see Contraindications, Warnings and
Precautions].
Digoxin
Clinical implication            Increased digoxin concentrations have been reported when alprazolam was given, especially in geriatric patients (>65 years of age).
Prevention or management        In patients on digoxin therapy, measure serum digoxin concentrations before initiating Xanagis. Continue monitoring digoxin serum concentration and toxicity frequently. Reduce the digoxin dose if necessary.
Drug/Laboratory Test Interactions

Although interactions between benzodiazepines and commonly employed clinical laboratory tests have occasionally been reported, there is no consistent pattern for a specific drug or specific test.

USE IN SPECIFIC POPULATIONS

Pregnancy
Risk Summary
Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions and Clinical Considerations)].
Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations
Fetal/Neonatal adverse reactions
Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to Xanagis during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to Xanagis during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions ].

Data
Human Data
Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco, and other medications, have not confirmed these findings.

Lactation
Risk Summary
Limited data from published literature reports the presence of alprazolam in human breast milk. There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. The effects of alprazolam on lactation are unknown.

Because of the potential for serious adverse reactions, including sedation and withdrawal symptoms in breastfed infants, advise patients that breastfeeding is not recommended during treatment with Xanagis.

Pediatric Use
Safety and effectiveness of Xanagis have not been established in pediatric patients.

Geriatric Use
Xanagis-treated geriatric patients had higher plasma concentrations of alprazolam (due to reduced clearance) compared to younger adult patients receiving the same doses. Therefore, dosage reduction of Xanagis is recommended in geriatric patients [see Dosage and Administration (2.4) and Clinical Pharmacology ].

Hepatic Impairment
Patients with alcoholic liver disease exhibit a longer elimination half-life (19.7 hours), compared to healthy subjects (11.4 hours). This may be caused by decreased clearance of alprazolam in patients with alcoholic liver disease. Dosage reduction of Xanagis is recommended in patients with hepatic impairment [see Dosage and Administration , Clinical Pharmacology ].

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
Additionally, you can also report to www.Padagis.co.il

DRUG ABUSE AND DEPENDENCE

Controlled Substance
XANAGIS contains alprazolam, which is a Schedule IV controlled substance.
Abuse

XANAGIS is a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.
Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction.

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. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders [see Warnings and Precautions].

The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo.

The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol).

Dependence
Xanagis may produce physical dependence from continued therapy. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening.
Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions ].

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue XANAGIS or reduce the dosage [see Dosage and Administration , Warnings and Precautions ].

Acute Withdrawal Signs and Symptoms
Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality.

Protracted Withdrawal Syndrome
Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used.

Tolerance
Tolerance to XANAGIS may develop from continued therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of XANAGIS may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.