ALPRAZOLAM Drug Interactions: What You Need to Know

INTERACTIONS Use with Opioids: Increase the risk of respiratory depression. ( 7.1 ) Use with Other CNS Depressants: Produces additive CNS depressant effects. ( 7.1 ) Use with Digoxin: Increase the risk of digoxin toxicity. ( 7.1 ) Use with CYP3A Inhibitors (except ritinovir): Increase the risk of adverse reactions of alprazolam. ( 4 , 5.5 , 7.1 ) Use with CYP3A Inducers: Increase the risk of reduced efficacy of alprazolam. ( 7.1 )

7.1 Drugs Having Clinically Important Interactions with Alprazolam Extended-Release Tablets Table 4 includes clinically significant drug interactions with alprazolam extended-release tablets <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

Table

4: Clinically Significant Drug Interactions with Alprazolam Extended-Release Tablets 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 ) 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 alprazolam extended-release tablets 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 extended-release tablets 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 extended-release tablets 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 extended-release tablets 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 extended-release tablets with CYP3A inhibitors may increase the concentrations of alprazolam extended-release tablets, resulting in increased risk of adverse reactions [see Clinical Pharmacology ( 12.3 )]. Prevention or management Avoid use and consider appropriate dose reduction when alprazolam extended-release tablets 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 extended-release tablets dose when a patient is initiated with ritonavir and alprazolam extended-release tablets concomitantly, or when ritonavir is added to a regimen where alprazolam extended-release tablets is stabilized. Increase alprazolam extended-release tablets dosage to the target dosage after 10 to 14 days of dosing ritonavir and alprazolam extended-release tablets concomitantly. No dosage adjustment of alprazolam extended-release tablets is necessary in patients receiving ritonavir for more than 10 to 14 days [see Dosage and Administration ( 2.5 )] . Concomitant use of alprazolam extended-release tablets with a strong CYP3A inhibitor, except ritonavir, is contraindicated [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 extended-release tablets. Continue monitoring digoxin serum concentration and toxicity frequently. Reduce the digoxin dose if necessary.

7.2 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.

7.1 Drugs Having Clinically Important Interactions with Alprazolam Extended-Release Tablets Table 4 includes clinically significant drug interactions with alprazolam extended-release tablets <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

Table

4: Clinically Significant Drug Interactions with Alprazolam Extended-Release Tablets 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 ) 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 alprazolam extended-release tablets 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 extended-release tablets 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 extended-release tablets 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 extended-release tablets 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 extended-release tablets with CYP3A inhibitors may increase the concentrations of alprazolam extended-release tablets, resulting in increased risk of adverse reactions [see Clinical Pharmacology ( 12.3 )]. Prevention or management Avoid use and consider appropriate dose reduction when alprazolam extended-release tablets 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 extended-release tablets dose when a patient is initiated with ritonavir and alprazolam extended-release tablets concomitantly, or when ritonavir is added to a regimen where alprazolam extended-release tablets is stabilized. Increase alprazolam extended-release tablets dosage to the target dosage after 10 to 14 days of dosing ritonavir and alprazolam extended-release tablets concomitantly. No dosage adjustment of alprazolam extended-release tablets is necessary in patients receiving ritonavir for more than 10 to 14 days [see Dosage and Administration ( 2.5 )] . Concomitant use of alprazolam extended-release tablets with a strong CYP3A inhibitor, except ritonavir, is contraindicated [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 extended-release tablets. Continue monitoring digoxin serum concentration and toxicity frequently. Reduce the digoxin dose if necessary.

7.2 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.

Alprazolam orally disintegrating tablets are contraindicated in patients with acute narrow angle glaucoma. Alprazolam orally disintegrating tablets can exacerbate narrow angle closure. Alprazolam orally disintegrating tablets may be used in patients with open angle glaucoma who are receiving appropriate therapy. Alprazolam orally disintegrating tablets are contraindicated in patients treated with potent CYP3A4 inhibitors (e.g., ketoconazole and itraconazole), because these medications significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP3A) and can increase alprazolam exposures [see Clinical Pharmacology ( 12.3 ), Warnings and Precautions ( 5.8 ), and Drug Interactions ( 7.4 )] . Acute narrow angle glaucoma. Alprazolam can exacerbate narrow angle closure ( 4 ).

Concomitant

Use with potent CYP3A inhibitors (e.g., ketoconazole and itraconazole). Can increase the serum concentration of alprazolam ( 4 ).

AND PRECAUTIONS Effects on Driving and Operating Machinery: Patients receiving alprazolam extended-release tablets should be cautioned against operating machinery or driving a motor vehicle, as well as avoiding concomitant use of alcohol and other central nervous system (CNS) depressant drugs. ( 5.4 ) Patients with Depression: Exercise caution in patients with signs or symptoms of depression. Prescribe the least number of tablets feasible to avoid intentional overdosage. ( 5.6 )

Neonatal

Sedation and Withdrawal Syndrome: Alprazolam extended-release tablets use during pregnancy can result in neonatal sedation and/or neonatal withdrawal. ( 5.8 , 8.1 )

5.1 Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including alprazolam extended-release tablets, 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 alprazolam extended-release tablets 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 alprazolam extended-release tablets than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking alprazolam extended-release tablets, 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 alprazolam extended-release tablets 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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span>.

5.2 Abuse, Misuse, and Addiction The use of benzodiazepines, including alprazolam extended-release tablets, 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 <span class="opacity-50 text-xs">[see Drug Abuse and Dependence ( 9.2 )]</span> . Before prescribing alprazolam extended-release tablets and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of alprazolam extended-release tablets, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of alprazolam extended-release tablets 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 alprazolam extended-release tablets or reduce the dosage (a patient-specific plan should be used to taper the dose) <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 )]</span> . 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 alprazolam extended-release tablets, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of alprazolam extended-release tablets 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 ( 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 ( 9.3 )] . Certain adverse clinical events, some life-threatening, are a direct consequence of physical dependence to alprazolam extended-release tablets. 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 alprazolam, 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 alprazolam 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 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 alprazolam 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 alprazolam extended-release tablets 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 alprazolam extended-release tablets <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span> .

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 Alprazolam extended-release tablets are contraindicated in patients receiving strong inhibitors of CYP3A such as azole antifungal agents <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . 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 alprazolam extended-release tablets and ritonavir are initiated concomitantly or when ritonavir is added to a stable dosage of alprazolam extended-release tablets <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 ), Drug Interactions ( 7.1 )]</span>. Drugs demonstrated to be CYP3A inhibitors on the basis of clinical studies involving alprazolam: nefazodone, fluvoxamine, and cimetidine <span class="opacity-50 text-xs">[see Drug Interaction ( 7.1 ), Clinical Pharmacology ( 12.3 )]</span>. Use caution and consider dose reduction of alprazolam extended-release tablets, 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 extended-release tablets in patients with depression <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>.

5.8 Neonatal Sedation and Withdrawal Syndrome Use of alprazolam extended-release tablets 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 )]</span> . Monitor neonates exposed to alprazolam extended-release tablets during pregnancy or labor for signs of sedation and monitor neonates exposed to alprazolam extended-release tablets 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 alprazolam extended-release tablets.

5.1 Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including alprazolam extended-release tablets, 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 alprazolam extended-release tablets 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 alprazolam extended-release tablets than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking alprazolam extended-release tablets, 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 alprazolam extended-release tablets 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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span>.

5.2 Abuse, Misuse, and Addiction The use of benzodiazepines, including alprazolam extended-release tablets, 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 <span class="opacity-50 text-xs">[see Drug Abuse and Dependence ( 9.2 )]</span> . Before prescribing alprazolam extended-release tablets and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of alprazolam extended-release tablets, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of alprazolam extended-release tablets 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 alprazolam extended-release tablets or reduce the dosage (a patient-specific plan should be used to taper the dose) <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 )]</span> . 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 alprazolam extended-release tablets, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of alprazolam extended-release tablets 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 ( 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 ( 9.3 )] . Certain adverse clinical events, some life-threatening, are a direct consequence of physical dependence to alprazolam extended-release tablets. 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 alprazolam, 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 alprazolam 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 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 alprazolam 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 alprazolam extended-release tablets 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 alprazolam extended-release tablets <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span> .

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 Alprazolam extended-release tablets are contraindicated in patients receiving strong inhibitors of CYP3A such as azole antifungal agents <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . 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 alprazolam extended-release tablets and ritonavir are initiated concomitantly or when ritonavir is added to a stable dosage of alprazolam extended-release tablets <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 ), Drug Interactions ( 7.1 )]</span>. Drugs demonstrated to be CYP3A inhibitors on the basis of clinical studies involving alprazolam: nefazodone, fluvoxamine, and cimetidine <span class="opacity-50 text-xs">[see Drug Interaction ( 7.1 ), Clinical Pharmacology ( 12.3 )]</span>. Use caution and consider dose reduction of alprazolam extended-release tablets, 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 extended-release tablets in patients with depression <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>.

5.8 Neonatal Sedation and Withdrawal Syndrome Use of alprazolam extended-release tablets 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 )]</span> . Monitor neonates exposed to alprazolam extended-release tablets during pregnancy or labor for signs of sedation and monitor neonates exposed to alprazolam extended-release tablets 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 alprazolam extended-release tablets.