Clinical medicine profile
Alprazolam
Benzodiazepine [EPC]
- Route
- See product SmPC
- Schedule
- POM
- ATC
- Not assigned
- PPB status
- registered
Safety essentials
The information most likely to change a prescribing or dispensing decision.
WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation [see Warnings and Precautions (5.1) , Drug Interactions (7.1) ] . The use of benzodiazepines, including alprazolam, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing alprazolam and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction [see Warnings and Precautions (5.2) ] . The continued use of benzodiazepines, including alprazolam, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of alprazolam after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue alprazolam or reduce the dosage [see Dosage and Administration (2.2) , Warnings and Precautions (5.3) ] . WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS See full prescribing information for complete boxed warning. Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation. ( 5.1 , 7.1 ) The use of benzodiazepines, including alprazolam, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Before prescribing alprazolam and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction. ( 5.2 ) Abrupt discontinuation or rapid dosage reduction of alprazolam after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue alprazolam or reduce the dosage. ( 2.2 , 5.3 )
Contraindications
- 4 CONTRAINDICATIONS 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) ] Known hypersensitivity to alprazolam or other benzodiazepines.
- ( 4 ) Concomitant use with strong cytochrome P450 3A (CYP3A) inhibitors, except ritonavir.
- ( 4 , 5.5 , 7.1 )
Precautions
- Machinery: Patients receiving alprazolam 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 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, 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 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 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, 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, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death.
Dosing matrix
Population and organ-function guidance, shown together for faster comparison.
: ( 2.1 ) Recommended starting oral dosage is 0.25 mg to 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 : Recommended starting oral dosage is 0.5 mg three times daily. The dosage may be increased at intervals of every 3 to 4 days in increments of no more than 1 mg per day. ( 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. ( 2.3 , 5.2 ) See the Full Prescribing Information for the recommended dosage in geriatric patients, patients with hepatic impairment, and with use with ritonavir. ( 2.4 , 2.5 , 2.6 ) 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 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) ]. 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 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) ] . 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 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 (5.5) ] .
8.4 Pediatric Use Safety and effectiveness of alprazolam have not been established in pediatric patients.
Start low.
- CrCl 0–120: See renal_dose_adjustment; confirm product SmPC.
Caution.
Use, effects & interactions
Indications
- 1 INDICATIONS AND USAGE 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.
Adverse effects
- 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 > 5% and at least twice that of placebo) include: impaired coordination, hypotension, dysarthria, and increased libido.
- ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 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 Drowsiness Light-headedness Dizziness Akathisia Gastrointestinal disorders Dry mouth Increased salivation 41% 21% 2% 2% 15% 4% 22% 19% 1% 1% 13% 2% Cardiovascular disorders Hypotension Skin and subcutaneous tissue disorders Dermatitis/allergy 5% 4% 2% 3% In addition to the adverse reactions (i.e., greater than 1%) enumerated in the table above for patients with generalized anxiety disorder, the following adverse reactions have been reported in association with the use of benzodiazepines: dystonia, irritability, concentration difficulties, anorexia, transient amnesia or memory impairment, loss of coordination, fatigue, seizures, sedation, slurred speech, jaundice, musculoskeletal weakness, pruritus, diplopia, dysarthria, changes in libido, menstrual irregularities, incontinence and urinary retention.
- Table 2: Adverse Reactions Occuring in ≥1% in Alprazolam-treated Patients and Greater than Placebo-treated Patients in Placebo-Controlled Trials (Up to 10 Weeks) for Panic Disorder Alprazolam n=1388 Placebo n=1231 Drowsiness Fatique and Tiredness Impaired Coordination Irritability Memory Impairment Cognitive Disorder Decreased Libido Dysartharia Confusional state Increased libido Change in libido (not specified) Disinhibition Talkativeness Derealization 77% 49% 40% 33% 33% 29% 14% 23% 10% 8% 7% 3% 2% 2% 43% 42% 18% 30% 22% 21% 8% 6% 8% 4% 6% 2% 1% 1% Gastrointestinal disorders Constipation Increased salivation 26% 6% 15% 4% Skin and subcutaneous tissue disorders Rash 11% 8% Other Increased appetite Decreased appetite Weight gain Weight loss Micturition difficulties Menstrual disorders Sexual dysfunction Incontinence 33% 28% 27% 23% 12% 11% 7% 2% 23% 24% 18% 17% 9% 9% 4% 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: 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 Insomnia Light-headedness Abnormal involuntary movement Headache Muscular twitching Impaired coordination Muscle tone disorders Weakness 29.5% 19.3% 17.3% 17.0% 6.9% 6.6% 5.9% 5.8% Psychiatric disorders Anxiety Fatigue and Tiredness Irritability Cognitive disorder Memory impairment Depression Confusional state 19.2% 18.4% 10.5% 10.3% 5.5% 5.1% 5.0% Gastrointestinal disorders Nausea/Vomiting Diarrhea Decreased salivation 16.5% 13.6% 10.6% Metabolism and nutrition disorders Weight loss Decreased appetite 13.3% 12.8% Dermatological disorders Sweating 14.4% Cardiovascular disorders Tachycardia 12.2% Special Senses Blurred vision 10.0% There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of alprazolam [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.
- 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.
Drug interactions
Open multi-drug checker ↗- Professional use: confirm indication, dose, duration, monitoring and patient counselling points against current Kenya STG / EML and the product SmPC.
- Document allergy status and key interactions.
Mechanism & disposition
12.
Read complete mechanism
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 (GABA A ) receptors in the brain and enhances GABA-mediated synaptic inhibition.
Product-specific
Product-specific
See product SmPC
Following oral administration, peak plasma concentration of alprazolam (C max ) occurs in 1 to 2 hours post dose.
Alprazolam is 80% bound to human serum protein, and albumin accounts for the majority of the binding.
Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to 2 major active metabolites in the plasma: 4-hydroxyalprazolam and α-hydroxyalprazolam. The plasma circulation levels of the two active metabolites are less than 4% of the parent. The re...
The mean plasma elimination
(T 1/2 ) of alprazolam is approximately 11.2 hours (range: 6.3 to 26.9 hours) in healthy adults.
Pregnancy, lactation & diet
8.1 Pregnancy 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)]. 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 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.
: Breastfeeding not recommended. ( 8.2 ) 8.1 Pregnancy 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)]. 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 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. 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. 8.4 Pediatric Use Safety and effectiveness of alprazolam 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) ] .
Brands & loaded prices
| Brand | Manufacturer | Pack | Observed price |
|---|---|---|---|
| ALZOLAM | DAIMA BIASHARA / Wholesale Import | 0.25MG TAB * 100 DDA | KES 2,580.00Daima Chemist price-list reference ↗ Source date not recorded · verify current price |
| Atrest | Centaur | tabs 0.25mg 10x10's | Unavailable |
Sources & review state
Decision support only. Confirm patient-specific decisions against the current product SmPC, Kenya STG/EML, and professional judgement.