Alprazolam

Registered South African indications:

• Short-term relief of symptoms of anxiety
• Treatment of anxiety disorders
• Anxiety associated with depression
• Mixed anxiety-depression
• Depression
• Panic disorders
  - With or without agoraphobia

Contraindications 

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to benzodiazepines
• Severe hepatic impairment
• Children <18 years old
• Patients whose primary diagnosis is schizophrenia
• Myasthenia gravis
• Severe respiratory insufficiency
• Sleep apnoea syndrome
• Coadministration with antiretroviral protease inhibitors
• Coadministration with ketoconazole
• Coadministration with itraconazole

Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to benzodiazepines
• Severe hepatic impairment
• Myasthenia gravis
• Severe respiratory insufficiency
• Sleep apnoea syndrome

Cautions 

South African recommendations

• Pregnancy
• Breastfeeding
• Renal impairment
• Mild to moderate hepatic impairment
• Elderly
• Certain types of depression
  - Depression with psychiatric features
  - Bipolar disorders
  - Endogenous depression (severely depressed inpatients)
• Risk factors for over sedation, respiratory depression and ataxia
• Pulmonary disease or limited pulmonary reserve
• Anxiety accompanied by an underlying depressive disorder
• Alcoholic liver disease
• Obesity
• Debilitated patients
• History of alcoholism/drug abuse
• Rapid decrease or abrupt withdrawal
• Epilepsy
• Psychosis (except with a marked component of anxiety)
• Mental depression (except with a marked component of anxiety)
• Severely depressed patients
• Suicidal ideation or plans
• Sleep disturbances
• High doses
• Prolonged use (>6 months)
• Coadministration with barbiturates
• Galactose intolerance
• Total lactase deficiency
• Glucose-galactose malabsorption
• May impair the ability to drive and operate machinery

Recommendations in other jurisdictions

• Pregnancy
• Breastfeeding
• Renal impairment
• Mild to moderate hepatic impairment
• Elderly
• Monotherapy in major depression or anxiety associated with depression
• Depressive disorder
• Suicidal tendencies
• History of alcohol and drug abuse
• Abrupt withdrawal
• Treatment duration longer than 8-12 weeks
• Sleep disturbances
• Psychotic illnesses
• Coadministration with other benzodiazepines
• Galactose intolerance
• Total lactase deficiency
• Glucose-galactose malabsorption
• May impair the ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: tab, srt

South African registered indications and dosages

Anxiety

• Oral (tab): Initial: 0.25-0.5mg, 8hrly; Maintenance: 0.5-4mg, dly, in divided doses
• Oral (srt): Initial: 1mg, dly in 1-2 divided doses; Maintenance: 0.5-4mg, dly in 1-2 divided doses

Mixed anxiety-depression
Anxiety associated with depression

• Oral (tab): Initial: 0.5mg, 8hrly; Maintenance: 1.5-4.5mg, dly in divided doses
• Oral (srt): Initial: 1mg, dly in 1-2 divided doses; Maintenance: 0.5-4.5mg, dly in 1-2 divided doses

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Alprazolam is indicated for ≤6 months duration for anxiety and depression

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Panic disorder
- With or without agoraphobia

• Oral (tab): Initial: 0.5-1mg, at bedtime OR 0.5mg, 8hrly; Titrate by 1mg at intervals of 3-4 days; Max: 10mg/24hrs
• Oral (srt): Initial: 0.5-1.0mg at bedtime OR 0.5mg, 12hrly; Titrate by 1mg at intervals of 3-4 days; Maintenance: 5-6mg, dly in 1-2 divided doses; Max: 10mg/24hrs

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Alprazolam is indicated for ≤8 months in the treatment of panic disorder with or without some phobic avoidance

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Discontinue by down-titrating gradually (suggested to decrease daily dosage by 0.5mg every 3 days)

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Sustained release tablets may be administered once daily, preferably in the morning. They should be taken intact, and not be chewed, crushed or broken

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See additional prescribing points

Not established for use in children below 18 years

Pregnancy

South African recommendations

• Caution; not recommended
• The safety of alprazolam during pregnancy has not been established
• The potential for congenital malformations in children of patients who have received alprazolam during pregnancy exists
• Alprazolam should not be administered during labour. Given during labour, it crosses the placenta and may cause the floppy-infant syndrome characterised by central respiratory depression, hypothermia and poor sucking

Recommendations in other jurisdictions

• Caution; positive evidence of risk
• The data concerning teratogenicity and effects on postnatal development and behaviour following benzodiazepine treatment are inconsistent. A large amount of data based on cohort studies indicate that first trimester exposure to benzodiazepine is not associated with an increase in the risk of major malformation. However, some early case-control epidemiological studies have found a twofold increased risk of oral clefts. Benzodiazepine treatment at high dose, during the second and/or the third trimester of pregnancy, has revealed a decrease of foetal active movements and variability of foetal cardiac rhythm
• When treatment has to be administered for medical reasons during the last part of pregnancy, even at low doses, floppy infant syndrome such as axial hypotonia, sucking troubles leading to a poor weight gain may be observed. These signs are reversible but they may last from 1-3 weeks, according to the half-life of alprazolam. At high doses, respiratory depression or apnoea and hypothermia in newborn may appear. Moreover, neonatal withdrawal symptoms with hyperexcitability, agitation and tremor may be observed a few days after birth, even if no floppy infant syndrome is observed. The apparition of withdrawal symptoms after birth depends on the half-life of the agent
• Alprazolam should not be used during pregnancy unless the clinical condition of the woman requires treatment with alprazolam. If alprazolam is used during pregnancy, or if the patient becomes pregnant while taking alprazolam, the patient should be apprised of the potential hazard to the foetus
• If alprazolam treatment is necessary during the last part of pregnancy, high doses should be avoided and withdrawal symptoms and/or floppy infant syndrome should be monitored in newborn

Breastfeeding

South African recommendations

• Caution; not recommended
• The safety of alprazolam during breastfeeding has not been established
• Alprazolam should not be administered to mothers breastfeeding their infants, since it is excreted in human breast milk

Recommendations in other jurisdictions

• Caution; not recommended
• Alprazolam is excreted in breast milk at low levels. However, alprazolam is not recommended during breastfeeding

Fertility

South African recommendations

• No information available

Recommendations in other jurisdictions

• In reproductive toxicity studies administration of alprazolam in rats and rabbits is associated at very high doses with developmental delay and an increased incidence of fetal death and skeletal malformations
• In fertility studies, treatment of male rats at high doses prior to mating resulted in a decrease in the percentage of dams conceiving

Renal Impairment

South African recommendations

• Caution; no dose adjustment recommended
• Alprazolam clearance has been reported to be delayed in patients with impaired renal function

Recommendations in other jurisdictions

• Caution; no dose adjustment recommended
  Repeated dosage may lead to accumulation in those with impaired renal function

Hepatic Impairment

South African recommendations

• Mild to moderate: Caution; dose adjustment recommended
  Oral (tab): Initial: 0.25mg, 8-12hrly; Titrate gradually, as needed
  Oral (SR tab): Initial: 0.5mg, daily; Titrate gradually, as needed
• Alprazolam clearance has been reported to be delayed in patients with impaired hepatic function
• Severe: Contraindicated

Recommendations in other jurisdictions

• Mild to moderate: Caution; no dose adjustment recommended
  Repeated dosage may lead to accumulation in those with impaired hepatic function
• Severe: Contraindicated

Elderly

South African recommendations

• Caution; dose adjustment recommended
  Oral (tab): Initial: 0.25mg, 8-12hrly; Titrate gradually, if needed and tolerated; Maintenance: 0.25-0.75mg, dly in divided doses 
  Oral (SR tab): Initial: 0.5-1mg, dly in 1-2 divided doses; Titrate gradually, if needed and tolerated; Maintenance: 0.5-1mg, dly
• It is recommended that the general principle of using the lowest effective dose be followed in elderly patients to preclude the development of ataxia or over sedation
• The elderly may be especially sensitive to the effects of benzodiazepines. If side effects occur at the recommended starting dose, the dose may be lowered 
• Alprazolam clearance has been reported to be delayed in elderly patients

Recommendations in other jurisdictions

• Caution; dose adjustment recommended
  Oral (tab): Initial: 0.25mg, 8-12hrly; Titrate gradually, if needed and tolerated
• Repeated dosage may lead to accumulation in elderly patients
• There is reduced clearance of the agent and, as with other benzodiazepines, increased sensitivity to the drug in elderly patients
• It is recommended that the general principle of using the lowest effective dose be followed in elderly patients to preclude the development of ataxia or over sedation
• The elderly are more prone to adverse behavioural effects and reactions

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Depression
• Confusional state
• Disorientation
• Decreased libido
• Increased libido
• Anxiety
• Insomnia
• Nervousness
• Mania
• Hallucinations
• Anger
• Agitation
• Drug dependence
• Hypomania
• Aggression
• Hostility
• Abnormal thinking
• Psychomotor hyperactivity
• Sedation
• Somnolence
• Ataxia
• Memory impairment
• Dysarthria
• Dizziness
• Headache
• Balance disorder
• Abnormal coordination
• Disturbances in attention
• Tremor
• Lethargy
• Amnesia
• Autonomic nervous system imbalance
• Dystonia
• Irritability
• Hypersomnia
• Fatigue
• Withdrawal symptoms
  - Mild dysphoria
  - Insomnia
  - Abdominal and muscle cramps
  - Vomiting
  - Sweating
  - Tremor
  - Seizures
• Restlessness
• Delusion
• Rages
• Nightmares
• Psychoses
• Inappropriate behaviour 
• Physical dependence
• Intrusive thoughts

Gastrointestinal Disorders

• Constipation
• Dry mouth
• Nausea

Hepatobiliary Disorders

• Hepatitis
• Abnormal hepatic function
• Jaundice

Genitourinary Disorders

• Incontinence
• Urinary retention
• Sexual dysfunction
• Irregular menstruation

Endocrine and Metabolic Disorders

• Hyperprolactinaemia
• Decreased appetite
• Increased weight
• Decreased weight

Musculoskeletal Disorders

• Muscular weakness

Skin and Subcutaneous Tissue Disorders

• Dermatitis
• Angioedema
• Photosensitivity reaction

Immune, Blood and Lymphatic System Disorders

• Peripheral oedema

Sensory Disorders

• Blurred vision
• Increased intraocular pressure

• Opioids
• Central nervous system depressants
• Antipsychotics (neuroleptics)
• Hypnotics
• Anxiolytics/sedatives
• Antidepressant agents
• Narcotic analgesics
• Anti-epileptic agents
• Anaesthetics
• Sedative antihistamines
• CYP3A4 inhibitors
• Ketoconazole
• Itraconazole
• Other azole-type antifungals
• Nefazodone
• Fluvoxamine
• Cimetidine
• Fluoxetine
• Propoxyphene
• Oral contraceptives
• Sertraline
• Diltiazem
• Macrolide antibiotics
• Erythromycin
• Clarithromycin
• Troleandomycin
• CYP3A4 inducers
• HIV protease inhibitors
• Ritonavir
• Digoxin

Other interactions

• Alcohol

• Respiratory status
• Cardiovascular status

Additional observations

• Assess risk for abuse, misuse and addiction

Dosing considerations

• Treatment should be as short as possible. It is recommended that the patient be reassessed at the end of no longer than 4 weeks of treatment and the need for continued treatment established, especially in case the patient is symptom free. The overall duration of treatment should not be more than 8-12 weeks, including a tapering off process
• In certain cases extension beyond the maximum treatment period may be necessary; if so, it should not take place without re-evaluation of the patient's status with special expertise. As with all benzodiazepines, physicians should be aware that long-term use might lead to dependence in certain patients
• The optimum dosage of alprazolam should be based upon the severity of the symptoms and individual patient response. The lowest dose which can control symptoms should be used. Dosage should be reassessed at intervals of no more than 4 weeks 
• In the few patients who require higher doses, the dosage should be increased cautiously to avoid adverse effects. When higher dosage is required, the evening dose should be increased before the daytime doses
• In general, patients who have not previously received psychotropic medications will require lower doses than those previously treated with minor tranquilisers, antidepressants or hypnotics, or those with a history of chronic alcoholism

Dependence, withdrawal symptoms and dose tapering

• Use of benzodiazepines may lead to the development of physical and psychic dependence upon these products. The risk of dependence increases with dose and duration of treatment; it is also greater in patients with a history of alcohol and drug abuse
• Pharmacodependency may occur at therapeutic doses and/or in patients with no individualised risk factor. There is an increased risk of pharmacodependency with the combined use of several benzodiazepines regardless of the anxiolytic or hypnotic indication. Cases of abuse have also been reported. Alprazolam may be subject to diversion. There have been reports of overdose-related deaths when alprazolam is abused with other central nervous system (CNS) depressants including opioids, other benzodiazepines, and alcohol
• These risks should be considered when prescribing or dispensing alprazolam. To reduce these risks the smallest appropriate quantity should be used and patients should be advised on the proper storage and disposal of the unused medicine
• Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms
• A transient syndrome whereby the symptoms that led to treatment with a benzodiazepine recur in an enhanced form may occur on withdrawal of treatment
• Treatment should always be tapered off gradually. During discontinuation of alprazolam treatment, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of alprazolam be decreased by no more than 0.5mg every three days. Some patients may require an even slower dosage reduction

Alprazolam has a high affinity for benzodiazepine binding site in the brain. It facilitates the inhibitory neurotransmitter action of gamma-aminobutyric acid, which mediates both pre- and post-synaptic inhibition in the central nervous system.

Tablet 0.25mg

• Adco-Alzam (Adcock Ingram)
• Azor (Pharmacare)
• Coprax 0.25 (Pharma-Q)
• Mylan-Alprazolam (Mylan)
• Xanor (UpJohn) originator
• Zopax (Cipla Medpro)

Tablet 0.5mg

• Adco-Alzam (Adcock Ingram)
• Azor (Pharmacare)
• Coprax 0.5 (Pharma-Q)
• Mylan-Alprazolam (Mylan)
• Xanor (UpJohn) originator
• Zopax (Cipla)

Tablet 1mg

• Adco-Alzam (Adcock Ingram)
• Azor (Pharmacare)
• Coprax 1.0mg (Pharma-Q)
• Mylan-Alprazolam (Mylan)
• Xanor (UpJohn) originator
• Zopax (Cipla)

Tablet 2mg

• Xanor (UpJohn) originator

Tablet sr 0.5mg

• Xanor SR (UpJohn) originator

Tablet sr 1mg

• Xanor SR (Pfizer) originator

Tablet sr 2mg

• Xanor SR (UpJohn) originator

Tablet xr 0.5mg

• Novapraz XR 0.5

Tablet xr 1mg

• Novapraz XR 1

Tablet xr 2mg

• Novapraz XR 2