Alprazolam Xr Drug Information

Alprazolam XR is indicated for the treatment of panic disorder with or without agoraphobia, in adults.

Recommended Dosage

Administer alprazolam XR orally once daily, preferably in the morning. Swallow tablets whole; do not divide, crush, or chew. The recommended starting oral dosage for alprazolam XR is 0.5 mg to 1 mg once daily.

Depending on the response, the dosage may be adjusted at intervals of every 3 to 4 days in increments of no more than 1 mg daily. The recommended dosage range is 3 mg to 6 mg once daily. Controlled trials of alprazolam XR for the treatment of panic disorder included dosages in the range of 1 mg to 10 mg per day.

Most patients showed a response in the dosage range of 3 mg to 6 mg per day. Occasional patients required as much as 10 mg per day. The longer-term efficacy of alprazolam XR has not been systematically evaluated.

If alprazolam XR is used for periods longer than 8 weeks, the healthcare provider should periodically reassess the usefulness of the drug for the individual patient. After a period of extended freedom from panic attacks, a carefully supervised tapered discontinuation may be attempted, but there is evidence that this may often be difficult to accomplish without recurrence of symptoms and/or the manifestation of withdrawal phenomena.

Discontinuation or Dosage Reduction of Alprazolam XR

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue alprazolam XR or reduce the dosage. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly.

Reduce the dosage by no more than 0.5 mg every three days. Some patients may benefit from an even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens.

In a controlled postmarketing discontinuation study of panic disorder patients which compared the recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome.

Dosage Recommendations in Geriatric Patients

In geriatric patients, the recommended starting dosage of alprazolam XR is 0.5 mg once daily. This may be gradually increased if needed and tolerated. Geriatric patients may be sensitive to the effects of benzodiazepines.

Dosage Modifications for Drug Interactions Alprazolam XR should be reduced to half of the recommended dosage when a patient is started on ritonavir and alprazolam XR together, or when ritonavir is added to a patient treated with alprazolam XR. Increase alprazolam XR dosage to the target dose after 10 to 14 days of dosing ritonavir and alprazolam XR together. It is not necessary to reduce alprazolam XR dosage in patients who have been taking ritonavir for more than 10 to 14 days.

Alprazolam XR is contraindicated with concomitant use of all strong CYP3A inhibitors, except ritonavir.

Switching Patients from Alprazolam Tablets to Alprazolam XR Tablets Patients who are currently being treated with divided doses of alprazolam may be switched to alprazolam XR at the same total daily dose taken once daily. If the clinical response after switching is inadequate, titrate the dosage as outlined above.

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 Alprazolam 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 Alprazolam XR Adverse Reactions Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials Approximately 17% of the 531 patients who received alprazolam XR in placebo-controlled clinical trials for panic disorder had at least 1 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 alprazolam 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 Alprazolam XR-Treated Patients and at Least Twice the Rate of Placebo-Treated Patients in Placebo-Controlled Trials Adverse Reactions Occurring at an Incidence of 1% or More Among Patients Treated with Alprazolam 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 alprazolam XR where the incidence in patients treated with alprazolam XR was greater than the incidence in placebo-treated patients. The most commonly observed adverse reactions in panic disorder patients treated with alprazolam 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 Occurring in ≥ 1% in Alprazolam-Treated Patients and Greater than Placebo-Treated Patients in 6- and 8-Week Placebo-Controlled Trials Panic Disorder Other Adverse Reactions Observed During the Premarketing Evaluation of Alprazolam XR Following is a list of other adverse reaction reported by 531 patients with panic disorder treated with alprazolam 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 than 1/100 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 Alprazolam 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 alprazolam XR where the incidence in patients treated with alprazolam XR was 2 times greater than the incidence in placebo-treated patients.

Table 3: Discontinuation-Emergent Symptom Incidence Reported in ≥5% of Alprazolam XR-Treated Patients and at Least Twice the Rate of Placebo-Treated Patients in Short-Term, Placebo-Controlled Trials There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of alprazolam. 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 post-approval use of alprazolam and/or alprazolam XR. 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

Drugs Having Clinically Important Interactions with Alprazolam XR Table 4 includes clinically significant drug interactions with alprazolam XR. Table 4: Clinically Significant Drug Interactions with Alprazolam XR 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. Prevention or management Limit dosage and duration of concomitant use of alprazolam XR and opioids, and monitor patients closely for respiratory depression and sedation.

Limit dosage and duration of alprazolam XR during concomitant use with CNS depressants. 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 alprazolam XR 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.

Prevention or management Concomitant use of alprazolam XR with a strong CYP3A4 inhibitor (except ritonavir) is contraindicated. Examples Ketoconazole, itraconazole, clarithromycin Moderate or Weak Inhibitors of CYP3A Clinical implication Concomitant use of alprazolam XR with CYP3A inhibitors may increase the concentrations of alprazolam XR, resulting in increased risk of adverse reactions. Prevention or management Avoid use and consider appropriate dose reduction when alprazolam XR is coadministered with a moderate or weak CYP3A inhibitor.

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. No dosage adjustment of alprazolam XR is necessary in patients receiving ritonavir for more than 10 to 14 days. 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 alprazolam XR. 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.

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including alprazolam XR, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/pregnancyregistry/. Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal.

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 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 alprazolam XR during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems.

Manage these neonates accordingly. 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.

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

• Alprazolam XR is contraindicated in patients:
• With known hypersensitivity to alprazolam or other benzodiazepines. Angioedema has been reported.
• Taking strong cytochrome P450 3A (CYP3A) inhibitors (e.g., ketoconazole, itraconazole), except ritonavir.
• Known hypersensitivity to alprazolam or other benzodiazepines.
• Concomitant use with strong cytochrome P450 3A (CYP3A) inhibitors, except ritonavir.

Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur.

In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal. Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage.

In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy.

Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information.

Consider contacting the Poison Help Line at (1-800-222-1222), or a medical toxicologist for additional overdosage management recommendations.