Alprazolam: Fachinformation – Dosierung, Gegenanzeigen, Wechselwirkungen, Nebenwirkungen

Für Fachkreise

Anwendungsgebiete

Alprazolam-Tabletten sind angezeigt zur:

Akutbehandlung der generalisierten Angststörung (GAD) bei Erwachsenen.
Behandlung der Panikstörung (PD) mit oder ohne Agoraphobie bei Erwachsenen.

Englisches Original anzeigen

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.

Dosierung und Art der Anwendung

2.1 Dosierung bei generalisierter Angststörung

Die empfohlene orale Anfangsdosis von Alprazolam-Tabletten zur Akutbehandlung von Patienten mit GAD beträgt 0,25 mg bis 0,5 mg, dreimal täglich angewendet. Je nach Ansprechen kann die Dosierung in Abständen von jeweils 3 bis 4 Tagen angepasst werden. Die maximale empfohlene Dosierung beträgt 4 mg täglich (aufgeteilt auf mehrere Dosen).

Es ist die niedrigstmögliche wirksame Dosis anzuwenden und die Notwendigkeit einer Fortsetzung der Behandlung häufig zu überprüfen [siehe Warnhinweise und Vorsichtsmaßnahmen (5.2)].

2.2 Dosierung bei Panikstörung

Die empfohlene orale Anfangsdosis von Alprazolam-Tabletten zur Behandlung der PD beträgt 0,5 mg dreimal täglich. Je nach Ansprechen kann die Dosierung in Abständen von jeweils 3 bis 4 Tagen in Schritten von höchstens 1 mg pro Tag erhöht werden.

Kontrollierte Studien mit Alprazolam-Tabletten zur Behandlung der Panikstörung umfassten Dosierungen im Bereich von 1 mg bis 10 mg täglich. Die mittlere Dosierung betrug etwa 5 mg bis 6 mg täglich. Vereinzelt benötigten Patienten bis zu 10 mg pro Tag.

Bei Patienten, die Dosen von mehr als 4 mg pro Tag erhalten, wird eine regelmäßige Neubewertung und die Erwägung einer Dosisreduktion empfohlen. In einer kontrollierten Dosis-Wirkungs-Studie nach Markteinführung konnten Patienten, die 3 Monate lang mit Dosen von mehr als 4 mg pro Tag Alprazolam-Tabletten behandelt wurden, ohne erkennbaren Verlust des klinischen Nutzens auf 50% ihrer gesamten Erhaltungsdosis ausgeschlichen werden.

Die erforderliche Behandlungsdauer der PD bei Patienten, die auf Alprazolam-Tabletten ansprechen, ist nicht bekannt. Nach einer längeren Phase ohne Panikattacken kann ein sorgfältig überwachtes, ausschleichendes Absetzen versucht werden; es gibt jedoch Hinweise darauf, dass dies oft nur schwer ohne Wiederauftreten der Symptome und/oder das Auftreten von Entzugserscheinungen zu erreichen ist [siehe Dosierung und Art der Anwendung (2.3)].

2.3 Absetzen oder Dosisreduktion von Alprazolam-Tabletten

Um das Risiko von Entzugsreaktionen zu verringern, ist zum Absetzen von Alprazolam-Tabletten oder zur Dosisreduktion eine schrittweise Ausschleichung anzuwenden. Entwickelt ein Patient Entzugsreaktionen, ist zu erwägen, die Ausschleichung zu unterbrechen oder die Dosierung auf die vorherige Stufe der Ausschleichung zu erhöhen. Anschließend ist die Dosierung langsamer zu reduzieren [siehe Warnhinweise und Vorsichtsmaßnahmen (5.3), Arzneimittelmissbrauch und Abhängigkeit (9.3)].
Die Dosierung um höchstens 0,5 mg alle 3 Tage reduziert. Manche Patienten können von einem noch langsameren Absetzen profitieren. Manche Patienten können sich gegenüber allen Absetzschemata als resistent erweisen.

In einer kontrollierten Absetzstudie nach Markteinführung bei Patienten mit Panikstörung, in der das empfohlene Ausschleichschema mit einem langsameren Ausschleichschema verglichen wurde, wurde zwischen den Gruppen kein Unterschied im Anteil der Patienten beobachtet, die bis auf eine Dosis von null ausschlichen; das langsamere Schema war jedoch mit einer Verringerung der mit einem Entzugssyndrom verbundenen Symptome assoziiert.

2.4 Dosierungsempfehlungen bei geriatrischen Patienten

Bei geriatrischen Patienten beträgt die empfohlene orale Anfangsdosis von Alprazolam-Tabletten 0,25 mg, 2- oder 3-mal täglich angewendet. Diese kann bei Bedarf und Verträglichkeit schrittweise erhöht werden. Geriatrische Patienten können besonders empfindlich auf die Wirkungen von Benzodiazepinen reagieren. Treten bei der empfohlenen Anfangsdosis Nebenwirkungen auf, kann die Dosierung reduziert werden [siehe Anwendung bei besonderen Patientengruppen (8.5), Klinische Pharmakologie (12.3)].

2.5 Dosierungsempfehlungen bei Patienten mit Leberfunktionsstörung

Bei Patienten mit Leberfunktionsstörung beträgt die empfohlene orale Anfangsdosis von Alprazolam-Tabletten 0,25 mg, 2- oder 3-mal täglich angewendet. Diese kann bei Bedarf und Verträglichkeit schrittweise erhöht werden. Treten bei der empfohlenen Anfangsdosis Nebenwirkungen auf, kann die Dosierung reduziert werden [siehe Anwendung bei besonderen Patientengruppen (8.6), Klinische Pharmakologie (12.3)].

2.6 Dosisanpassungen aufgrund von Wechselwirkungen

Alprazolam-Tabletten sollten auf die Hälfte der empfohlenen Dosierung reduziert werden, wenn ein Patient gleichzeitig mit Ritonavir und Alprazolam-Tabletten beginnt oder wenn Ritonavir einem mit Alprazolam behandelten Patienten gegeben wird. Nach 10 bis 14 Tagen gemeinsamer Gabe von Ritonavir und Alprazolam ist die Alprazolam-Dosierung auf die Zieldosis zu erhöhen. Bei Patienten, die Ritonavir seit mehr als 10 bis 14 Tagen einnehmen, ist eine Reduktion der Dosis von Alprazolam-Tabletten nicht erforderlich.
Alprazolam-Tabletten sind bei gleichzeitiger Anwendung aller starken CYP3A-Inhibitoren, mit Ausnahme von Ritonavir, kontraindiziert [siehe Gegenanzeigen (4), Warnhinweise und Vorsichtsmaßnahmen (5.5)].

Englisches Original anzeigen

2.1 Dosage in Generalized Anxiety Disorder

The recommended starting oral dosage of alprazolam tablets for the acute treatment of patients with GAD is 0.25 mg to 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)].

2.2 Dosage in Panic Disorder

The recommended starting oral dosage of alprazolam tablets for the treatment of PD is 0.5 mg three times daily. 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 is 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)].

2.3 Discontinuation or Dosage Reduction of Alprazolam Tablets

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 0.5 mg every 3 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.

2.4 Dosage Recommendations in Geriatric Patients

In geriatric patients, the recommended starting oral dosage of alprazolam tablets are 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)].

2.5 Dosage Recommendations in Patients with Hepatic Impairment

In patients with hepatic impairment, 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. 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)].

2.6 Dosage Modifications for Drug Interactions

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. Increase the alprazolam dosage to the target dose after 10 to 14 days of dosing ritonavir and alprazolam 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 is contraindicated with concomitant use of all strong CYP3A inhibitors, except ritonavir [see Contraindications (4), Warnings and Precautions (5.5)].

Darreichungsformen und Stärken

Alprazolam tablets are available as:
0.25 mg: White colored, oval shaped biconvex tablets one side debossed by ‘N’ on the left side and ‘A’ on the right side of score line and other side debossed with ‘0.25
0.5 mg: Orange colored, oval shaped biconvex tablets one side debossed by ‘N’ on the left side and ‘A’ on the right side of score line and other side debossed with ‘0.5
1 mg: Blue colored, oval shaped biconvex tablets one side debossed by ‘N’ on the left side and ‘A’ on the right side of score line and other side debossed with ‘1.0
2 mg: White to off white, oblong shaped, multi scored debossed ‘2’ on one side and plain on other side.

Gegenanzeigen

Alprazolam-Tabletten sind kontraindiziert bei Patienten:

mit bekannter Überempfindlichkeit gegen Alprazolam oder andere Benzodiazepine. Über Angioödeme wurde berichtet [siehe Nebenwirkungen (6.2)].
die starke Inhibitoren von Cytochrom P450 3A (CYP3A) einnehmen (z. B. Ketoconazol, Itraconazol), mit Ausnahme von Ritonavir [siehe Dosierung und Art der Anwendung (2.6), Warnhinweise und Vorsichtsmaßnahmen (5.5), Wechselwirkungen (7.1)]

Englisches Original anzeigen

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.g., ketoconazole, itraconazole), except ritonavir [see Dosage and Administration (2.6), Warnings and Precautions (5.5), Drug Interactions (7.1)]

Nebenwirkungen

The following clinically significant adverse reactions are described elsewhere in the labeling:

Risks from Concomitant Use with Opioids [see Warnings and Precautions (5.1)]
Abuse, Misuse, and Addiction [see Warnings and Precautions (5.2)]
Dependence and Withdrawal Reactions [see Warnings and Precautions (5.3)]
Effects on Driving and Operating Machinery [see Warnings and Precautions (5.4)]
Patients with Depression [see Warnings and Precautions (5.6)]
Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.8)]
Risks in Patients with Impaired Respiratory Function [see Warnings and Precautions (5.9)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The 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 tablets 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 tablets 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 Tablets-treated Patients and Greater than Placebo-treated Patients in Placebo-Controlled Trials for Generalized Anxiety

| Alprazolam Tablets 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 Tablets-treated Patients and Greater than Placebo-treated Patients in Placebo-Controlled Trials (Up to 10 Weeks) for Panic Disorder

| Alprazolam Tablets n=1388 | Placebo n=1231
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 salivation | 6% | 4%
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 alprazolam tablets: 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 tablets, discontinuation-emergent symptoms which occurred at a rate of over 5% in patients treated with alprazolam tablets 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 Tablets -treated Patients and > Placebo-treated Patients.

There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of alprazolam tablets [see Warning and Precautions (5.2) and Drug Abuse and Dependence (9.3)].
Paradoxical reactions such as stimulation, increased muscle spasticity, sleep disturbances, hallucinations, and other adverse behavioral effects such as agitation, rage, irritability, and aggressive or hostile behavior have been reported rarely. In many of the spontaneous case reports of adverse behavioral effects, patients were receiving other CNS drugs concomitantly and/or were described as having underlying psychiatric conditions. Should any of the above events occur, alprazolam should be discontinued. Isolated published reports involving small numbers of patients have suggested that patients who have borderline personality disorder, a prior history of violent or aggressive behavior, or alcohol or substance abuse may be at risk for such events. Instances of irritability, hostility, and intrusive thoughts have been reported during discontinuation of alprazolam in patients with posttraumatic stress disorder.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of alprazolam tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Endocrine disorders: Hyperprolactinemia
General disorders and administration site conditions: Edema peripheral
Hepatobiliary disorders: Hepatitis, hepatic failure 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

Warnhinweise und Vorsichtsmaßnahmen

5.1 Risks from Concomitant Use with Opioids

Concomitant use of benzodiazepines, including alprazolam 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 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 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 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 is used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined [see Drug Interactions (7.1)].

5.2 Abuse, Misuse, and Addiction

The use of benzodiazepines, including alprazolam 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 [see Drug Abuse and Dependence (9.2)].

Before prescribing alprazolam tablets and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of alprazolam tablets, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of alprazolam 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 tablets or reduce the dosage (a patient-specific plan should be used to taper the dose) [see Dosage and Administration (2.3)].

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 tablets, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of alprazolam 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 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 tablets, 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 tablets greater than 4 mg/day had more difficulty tapering to zero dose than those treated with less than 4 mg/day.

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

Interdose Symptoms

Early morning anxiety and emergence of anxiety symptoms between doses of alprazolam tablets 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 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 tablets [see Drug Interactions (7.1)].

5.5 Interaction with Drugs that Inhibit Metabolism via Cytochrome P450 3A

The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs that inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam.
Strong CYP3A Inhibitors
Alprazolam tablets are contraindicated in patients receiving strong inhibitors of CYP3A (such as azole antifungal agents), except ritonavir [see Contraindications (4)]. Ketoconazole and itraconazole have been shown in vivo to increase plasma alprazolam concentrations 3.98 fold and 2.70 fold, respectively.
Dosage adjustment is necessary when alprazolam tablets and ritonavir are initiated concomitantly or when ritonavir is added to a stable dosage of alprazolam tablets [see Dosage and Administration (2.6), Drug Interactions (7.1)].
Drugs demonstrated to be CYP3A inhibitors on the basis of clinical studies involving alprazolam: nefazodone, fluvoxamine, and cimetidine [see Drug Interaction (7.1), Clinical Pharmacology (12.3)]. Use caution and consider dose reduction of alprazolam 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 tablets in patients with depression [see Adverse Reactions (6.2)].

5.8 Neonatal Sedation and Withdrawal Syndrome

Use of alprazolam 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 [see Use in Specific Populations (8.1)]. Monitor neonates exposed to alprazolam tablets during pregnancy or labor for signs of sedation and monitor neonates exposed to alprazolam tablets during pregnancy for signs of withdrawal; manage these neonates accordingly.

5.9 Risk 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 tablets. Closely monitor patients with impaired respiratory function. If signs and symptoms of respiratory depression, hypoventilation, or apnea occur, discontinue alprazolam tablets.

Wechselwirkungen

7.1 Drugs Having Clinically Important Interactions with Alprazolam Tablets

Table 4 includes clinically significant drug interactions with alprazolam tablets [see Clinical Pharmacology (12.3)].

Table 4: Clinically Significant Drug Interactions with Alprazolam 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 (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 alprazolam 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 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 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 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 tablets with CYP3A inhibitors may increase the concentrations of alprazolam tablets, 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 tablets.
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 tablets dosage when ritonavir and alprazolam tablets are initiated concomitantly, or when ritonavir is added to a regimen where alprazolam tablets is stabilized. Increase alprazolam tablets dosage to the target dosage after 10 to 14 days of dosing ritonavir and alprazolam tablets concomitantly. No dosage adjustment of alprazolam tablets is necessary in patients receiving ritonavir for more than 10 to14 days [see Dosage and Administration (2.6)] . Concomitant use of alprazolam 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 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.

Schwangerschaft, Stillzeit, Kinder, ältere Menschen

8.1 Pregnancy

Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including alprazolam tablets, 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)]. 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 alprazolam tablets during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to alprazolam tablets 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.

8.2 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 alprazolam tablets.

8.4 Pediatric Use

Safety and effectiveness of alprazolam tablets have not been established in pediatric patients.

8.5 Geriatric Use

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) and Clinical Pharmacology (12.3)].

8.6 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 alprazolam is recommended in patients with hepatic impairment [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

Überdosierung

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)]. 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 (1-800-222-1222), or a medical toxicologist for additional overdosage management recommendations.

Klinische Pharmakologie

12.1 Mechanism of Action

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 (GABAA) receptors in the brain and enhances GABA-mediated synaptic inhibition.

12.3 Pharmacokinetics

Plasma levels of alprazolam increase proportionally to the dose over the range of 0.5 to 3.0 mg.
Absorption
Following oral administration, peak plasma concentration of alprazolam (Cmax) occurs in 1 to 2 hours post dose.
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 (T½) of alprazolam is approximately 11.2 hours (range: 6.3 to 26.9 hours) in healthy adults.
Metabolism
Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to 2 major active metabolites in the plasma: 4-hydroxyalprazolam and α-hydroxy alprazolam. 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 0.20 and 0.66, respectively, for 4-hydroxyalprazolam and α-hydroxyalprazolam. The low concentrations and low potencies of 4-hydroxyalprazolam and α-hydroxy alprazolam 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.
Excretion
Alprazolam and its metabolites are excreted primarily in the urine.
Specific Populations
Geriatric Patients
The mean T½ of alprazolam was 16.3 hours (range: 9.0 to 26.9 hours) in healthy elderly subjects compared to 11.0 hours (range: 6.3 to -15.8 hours, n=16) in healthy younger adult subjects.
Obese Patients
The mean T½ of alprazolam was 21.8 hours (range: 9.9 to 40.4 hours) in a group of obese subjects.
Patients with Hepatic Impairment
The mean T½ of alprazolam was 19.7 hours (range: 5.8 to 65.3 hours) in patients with alcoholic liver disease.
Racial or Ethnic Groups
Maximal concentrations and T½ of alprazolam are approximately 15% and 25% higher in Asians compared to Caucasians.
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, along with their effect on increasing alprazolam AUC, are as follows: ketoconazole, 3.98 fold; itraconazole, 2.66 fold; nefazodone, 1.98 fold; fluvoxamine, 1.96 fold; and erythromycin, 1.61 fold [see Contraindications (4), Warnings and Precautions (5.5),

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Quelle: U.S. Food and Drug Administration (FDA), Prescribing Information, über DailyMed (NLM); gemeinfrei. Keine Werbung, keine Therapieempfehlung. Bei Fragen zur eigenen Behandlung: Ärztin, Arzt oder Apotheke.