ALPRAZOLAM- alprazolam_tablet

Alprazolam is a 1,4 benzodiazepine. Alprazolam exerts its effect for the acute treatment of generalized anxiety disorder and panic disorder through binding to the benzodiazepine site of gamma-aminobutyric acid-A (GABA A Plasma levels of alprazolam increase proportionally to the dose over the range of 0. Following oral administration, peak plasma concentration of alprazolam (C max Distribution Alprazolam is 80% bound to human serum protein, and albumin accounts for the majority of the binding. Elimination The mean plasma elimination half-life (T 1/2 Metabolism Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to 2 major active metabolites in the plasma: 4-hydroxyalprazolam and alpha-hydroxyalprazolam. The plasma circulation levels of the two active metabolites are less than 4% of the parent. The reported relative potencies in benzodiazepine receptor binding experiments and in animal models of induced seizure inhibition are 0. 66, respectively, for 4-hydroxyalprazolam and alpha-hydroxyalprazolam. The low concentrations and low potencies of 4-hydroxyalprazolam and alpha-hydroxyalprazolam indicate that they unlikely contribute much to the effects of alprazolam. A benzophenone derived from alprazolam is also found in humans. Their half-lives appear to be similar to that of alprazolam. Alprazolam and its metabolites are excreted primarily in the urine. Geriatric Patients The mean T 1/2 The mean T 1/2 Patients with Hepatic Impairment The mean T 1/2 Racial or Ethnic Groups Maximal concentrations and T 1/2 Smoking Alprazolam concentrations may be reduced by up to 50% in smokers compared to non-smokers. Drug Interaction Studies In Vivo Studies Most of the interactions that have been documented with alprazolam are with drugs that modulate CYP3A4 activity. Compounds that are inhibitors or inducers of CYP3A would be expected to increase or decrease plasma alprazolam concentrations, respectively. Drug products that have been studied in vivo [see Contraindications (4) Warnings and Precautions (5. 5) Drug Interactions (7. 2) Cimetidine : 1/2 Fluoxetine : 1/2 Oral Contraceptives : 1/2 : 1/2 [see Drug Interactions (7. 2) Ritonavir : max 1/2 max 1/2 [see Warnings and Precautions (5. 5) Sertraline Imipramine and Desipramine Warfarin Data from in vitro.

Alprazolam tablets are indicated for the: acute treatment of generalized anxiety disorder (GAD) in adults. treatment of panic disorder (PD), with or without agoraphobia in adults. Alprazolam is a benzodiazepine indicated for the: Acute treatment of generalized anxiety disorder in adults. ( 1 Treatment of panic disorder with or without agoraphobia in adults.

Generalized Anxiety Disorder 2. 1 Recommended starting oral dosage is 0. 5 mg three times daily. Dosage may be increased, at intervals of every 3 to 4 days, to a maximum recommended daily dose of 4 mg, given in divided doses. Use the lowest possible effective dose and frequently assess the need for continued treatment. Panic Disorder 2. 2 When tapering, decrease dosage by no more than 0. 5 mg every 3 days. Some patients may require an even slower dosage reduction. 2 See the Full Prescribing Information for the recommended dosage in geriatric patients, patients with hepatic impairment, and with use with ritonavir. 6 The recommended starting oral dosage of alprazolam tablets for the acute treatment of patients with GAD is 0. 5 mg administered three times daily. Depending upon the response, the dosage may be adjusted at intervals of every 3 to 4 days. The maximum recommended dosage is 4 mg daily (in divided doses). Use the lowest possible effective dose and frequently assess the need for continued treatment [see Warnings and Precautions (5. 2) The recommended starting oral dosage of alprazolam tablets for the treatment of PD is 0. Depending on the response, the dosage may be increased at intervals of every 3 to 4 days in increments of no more than 1 mg per day. Controlled trials of alprazolam tablets in the treatment of panic disorder included dosages in the range of 1 mg to 10 mg daily. The mean dosage was approximately 5 mg to 6 mg daily. Occasional patients required as much as 10 mg per day. For patients receiving doses greater than 4 mg per day, periodic reassessment and consideration of dosage reduction is advised. In a controlled postmarketing dose-response study, patients treated with doses of alprazolam tablets greater than 4 mg per day for 3 months were able to taper to 50% of their total maintenance dose without apparent loss of clinical benefit. The necessary duration of treatment for PD in patients responding to alprazolam tablets are unknown. 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 [see Dosage and Administration (2. 3) To reduce the risk of withdrawal reactions, use a gradual taper to discontinue alprazolam tablets 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 [see Warnings and Precautions (5. 3) Drug Abuse and Dependence (9. 3) Reduced the dosage by no more than 0. Some patients may benefit from an even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens. In geriatric patients, the recommended starting oral dosage of alprazolam tablets is 0. 25 mg, given 2 or 3 times daily. This may be gradually increased if needed and tolerated. Geriatric patients may be especially sensitive to the effects of benzodiazepines. If adverse reactions occur at the recommended starting dosage, the dosage may be reduced [see Use in Specific Populations (8. 5) Clinical Pharmacology (12. 3) In patients with hepatic impairment, the recommended starting oral dosage of alprazolam tablets is 0. If adverse reactions occur at the recommended starting dose, the dosage may be reduced [see Use in Specific Populations (8. 6) Clinical Pharmacology (12. 3) Alprazolam tablets should be reduced to half of the recommended dosage when a patient is started on ritonavir and alprazolam tablets together, or when ritonavir administered to a patient treated with alprazolam tablets. Increase the alprazolam tablets dosage to the target dose after 10 to 14 days of dosing ritonavir and alprazolam tablets together. It is not necessary to reduce alprazolam tablets dose in patients who have been taking ritonavir for more than 10 to 14 days. Alprazolam tablets are contraindicated with concomitant use of all strong CYP3A inhibitors, except ritonavir [see Contraindications (4) Warnings and Precautions (5.

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) The most common adverse reactions reported in clinical trials for generalized anxiety disorder and panic disorder (incidence > 6. gov/medwatch 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 alprazolam 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 alprazolam 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 Gastrointestinal disorders Cardiovascular disorders Skin and subcutaneous tissue disorders 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 Alprazolam n=1388 Placebo n=1231 Drowsiness 77% 43% Gastrointestinal disorders Skin and subcutaneous tissue disorders Other In addition to the reactions (i. , 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 alprazolam: 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 > Placebo-treated Patients n=number of patients. Alprazolam-treated Patients n=641 Nervous system disorders Psychiatric disorders Gastrointestinal disorders Metabolism and nutrition disorders Dermatological disorders Cardiovascular disorders Special Senses 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. The following adverse reactions have been identified during postapproval use of alprazolam. 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: General disorders and administration site conditions: Hepatobiliary disorders: Investigations: Psychiatric disorders: Reproductive system and breast disorders: Skin and subcutaneous tissue disorders:.

Alprazolam tablets are contraindicated in patients: with known hypersensitivity to alprazolam or other benzodiazepines. Angioedema has been reported [see Adverse Reactions (6. 2) taking strong cytochrome P450 3A (CYP3A) inhibitors (e. , ketoconazole, itraconazole), except ritonavir [see Dosage and Administration (2. 6) Warnings and Precautions (5. 5) Drug Interactions (7. 1) Known hypersensitivity to alprazolam or other benzodiazepines. ( 4 Concomitant use with strong cytochrome P450 3A (CYP3A) inhibitors, except ritonavir.

Lactation 8. 2 Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including alprazolam, 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/research/pregnancyregistry/ 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 (5. 8) and Clinical Considerations)]. 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. 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 alprazolam during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to alprazolam during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5. 8) 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. 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 alprazolam. Safety and effectiveness of alprazolam have not been established in pediatric patients. Alprazolam-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 alprazolam is recommended in geriatric patients [see Dosage and Administration (2. 4) Clinical Pharmacology (12. 3) Patients with alcoholic liver disease exhibit a longer elimination half-life (19. 7 hours), compared to healthy subjects (11. This may be caused by decreased clearance of alprazolam in patients with alcoholic liver disease. Dosage reduction of alprazolam is recommended in patients with hepatic impairment [see Dosage and Administration (2.

Use with Opioids: Increase the risk of respiratory depression. 1 Use with Other CNS Depressants: Produces additive CNS depressant effects. 1 Use with Digoxin: Increase the risk of digoxin toxicity. 1 Use with CYP3A Inhibitors (except ritonavir): Increase the risk of adverse reactions of alprazolam. 1 Use with CYP3A Inducers: Increase the risk of reduced efficacy of alprazolam. 1 Table 4 includes clinically significant drug interactions with alprazolam [see Clinical Pharmacology (12. 3) Table 4: Clinically Significant Drug Interactions with Alprazolam 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(GABA A Prevention or management Limit dosage and duration of concomitant use of alprazolam and opioids, and monitor patients closely for respiratory depression and sedation [see Warnings and Precautions (5. 1) 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 alprazolam during concomitant use with CNS depressants [see Warnings and Precautions (5. 3) 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 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 (12. 3) Prevention or management Concomitant use of alprazolam with a strong CYP3A4 inhibitor (except ritonavir) is contraindicated [see Contraindications (4) Warnings and Precautions (5. 5) Examples Ketoconazole, itraconazole, clarithromycin Moderate or Weak Inhibitors of CYP3A Clinical implication Concomitant use of alprazolam with CYP3A inhibitors may increase the concentrations of alprazolam, resulting in increased risk of adverse reactions of alprazolam [see Clinical Pharmacology (12. 3) Prevention or management Avoid use and consider appropriate dose reduction when alprazolam is coadministered with a moderate or weak CYP3A inhibitor [see Warnings and Precautions (5. 5) 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 (12. 3) Prevention or management Caution is recommended during coadministration with alprazolam. 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 alprazolam dosage when ritonavir and alprazolam are initiated concomitantly, or when ritonavir is added to a regimen where alprazolam is stabilized. [see Dosage and Administration (2. 6) [see Contraindications (4) Warnings and Precautions (5. 5) 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. Continue monitoring digoxin serum concentration and toxicity frequently. 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.

OVERDOSAGE
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 [see Warnings and Precautions (5.2) 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 (1-800-222-1222), or a medical toxicologist for additional overdosage management recommendations.
NONCLINICAL TOXICOLOGY
Carcinogenesis No evidence of carcinogenic potential was observed in rats or mice administered alprazolam for 2-years at doses up to 30 and 10 mg/kg day respectively. These doses are 29 times and 4. 8 times the maximum recommended human dose of 10 mg/day based on mg/m 2 Mutagenesis Alprazolam was negative in the in vitro in vivo Impairment of Fertility Alprazolam produced no impairment of fertility in rats at doses up to 5 mg/kg per day, which is approximately 5 times the maximum recommended human dose of 10 mg per day based on mg/m 2 When rats were treated with alprazolam at oral doses of 3 mg, 10 mg, and 30 mg/kg day (3 to 29 times the maximum recommended human dose based on mg/m 2.
CLINICAL STUDIES
Alprazolam was compared to placebo in double-blind clinical studies (doses up to 4 mg per day) in patients with a diagnosis of anxiety or anxiety with associated depressive symptomatology. Alprazolam was significantly better than placebo at each of the evaluation periods of these 4-week studies as judged by the following psychometric instruments: Physician’s Global Impressions, Hamilton Anxiety Rating Scale, Target Symptoms, Patient’s Global Impressions, and Self-Rating Symptom Scale. The effectiveness of alprazolam in the treatment of panic disorder was studied in 3 short-term, placebo-controlled studies (up to 10 weeks) in patients with diagnoses closely corresponding to DSM-III-R criteria for panic disorder. The average dose of alprazolam was 5 mg to 6 mg per day in 2 of the studies, and the doses of alprazolam were fixed at 2 mg and 6 mg per day in the third study. In all 3 studies, alprazolam was superior to placebo on a variable defined as “the number of patients with zero panic attacks” (range, 37% to 83% met this criterion), as well as on a global improvement score. In 2 of the 3 studies, alprazolam was superior to placebo on a variable defined as “change from baseline on the number of panic attacks per week” (range, 3. 2), and also on a phobia rating scale. A subgroup of patients who improved on alprazolam during short-term treatment in 1 of these trials was continued on an open basis up to 8 months, without apparent loss of benefit.

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