Reduced pack sizes and delisting of 2 mg doses of alprazolam (Alprax, GenRx Alprazolam, Kalma) for panic disorder

Alprazolam has an Authority required PBS listing for the treatment of panic disorder when other treatments have failed or are inappropriate.¹

In response to concerns raised by clinicians and input received from clinical and professional organisations, changes to alprazolam on the PBS from February 2017 include:²

• all brands of 2 mg alprazolam being delisted from the PBS, Alprax 2, GenRx Alprazolam and Kalma 2.
• the maximum quantity of 250 microgram, 500 microgram and 1 mg formulations being reduced from 50 tablets to 10 tablets, with nil repeats, including all brands currently listed:
  • 1 mg: Alprax 1, GenRx Alprazolam and Kalma 1
  • 500 microgram: Alprax 0.5 and Kalma 0.5
  • 250 microgram: Alprax 0.25 and Kalma 0.25.

In addition to the existing PBS indication for prescribing alprazolam, the new listing also states that:²

• the panic disorder must not be attributable to some known organic factor.
• no increase in the maximum number of repeats may be authorised.

In March 2014 the PBAC considered a request to delist alprazolam from the PBS, as the potential harm outweighed the benefit.³

However, the Drug Utilisation Sub Committee (DUSC) review requested by the PBAC and considered by the DUSC in October 2015 showed use of alprazolam declined by about one-third after rescheduling alprazolam to Schedule 8, and has continued to decline.³

In Victoria, overdose deaths from alprazolam have also reduced from 57 in 2012 to 23 in 2015; however, rescheduling did not appear to impact the upward trend in overdose deaths from benzodiazepines as a class.⁴

The initial recommended dose for panic disorder is 0.5–1.0 mg at night, increasing by 0.25–1 mg every 3 days until symptoms are controlled. Some evidence suggests no need to use doses > 4 mg daily; however, the recommended maximum daily dose is 10 mg daily.^1,5

Alprazolam can also be used for anxiety, although it is not PBS listed for this indication, with the starting and maximum dose lower than for panic disorder.⁵

Benzodiazepines such as alprazolam should be reserved for short-term use.⁵

Nurse practitioners can prescribe alprazolam if it is permitted in their scope of practice and/or approved formulary.^6,7

Alprazolam is not recommended as first-line or long-term pharmacological treatment of panic disorder due to concerns about tolerance, dependence and abuse.^5,8,9

Evidence suggests alprazolam has greater risks associated with dependency and withdrawal compared with other benzodiazepines. This is because alprazolam has a rapid onset and offset of action, short half-life and high binding affinity to the gamma-aminobutyric acid (GABA) receptor, which has an anxiolytic effect.^8,10,11

Alprazolam for the treatment of panic disorder is only recommended for short-term use (limited to
2–4 weeks) as part of a broader treatment plan including non-pharmacological treatment.^3,5,9

From 1 February 2014 alprazolam was rescheduled from Schedule 4 to Schedule 8 in Australia in response to increasing illicit use and evidence of alprazolam dependence.^3,12

Withdrawal symptoms for benzodiazepines include anxiety, dysphoria, irritability, insomnia, nightmares, sweating, memory impairment, hallucinations, hypertension, tachycardia, psychosis, tremors and seizures.⁵

Withdrawal symptoms for short-acting benzodiazepines such as alprazolam may occur within a few hours, whereas for longer-acting benzodiazepines they may take days or weeks.⁵

Alprazolam is more toxic than other benzodiazepines in overdose,^3,13 and a meta-analysis failed to demonstrate alprazolam as superior in efficacy to other benzodiazepines for patients with panic disorder.¹¹

Misuse of alprazolam is common in association with opioids.^3,12

As part of Choosing Wisely Australia, the Royal Australian College of General Practitioners (RACGP) recommends avoiding prescribing benzodiazepines to patients with a history of substance abuse (including alcohol) or multiple psychoactive drug use.¹⁴

Prescribers must seek a permit or authority from their relevant State or Territory health department before prescribing alprazolam to persons who are drug dependent.^3,15

Australian guidelines recommend cognitive behavioural therapy (CBT) as first-line treatment for panic disorder.^9,16

In a meta-analyses of CBT for panic disorder, CBT showed significantly greater improvement in measures of anxiety, depression and quality of life, compared with no-treatment and placebo psychotherapy groups.¹⁷

If the patient does not improve with CBT or it is not available, pharmacotherapy may be required in combination with CBT if available.^9,16

When medicines are indicated, the role of benzodiazepines in the treatment of panic disorder has been replaced by antidepressants.¹⁶

Selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) are the recommended first-line coice due to their favourable safety and side-effect profile compared with those of tricyclic antidepressants(TCAs).^16,18 TCAs can be considered after unsuccessful trials of SSRIs or SNRIs.¹⁶

For prescribers

The decreased pack size may raise concerns from your patients. The RACGP’s Prescribing drugs of dependence in general practice, Part B provides examples of responses to patient requests for benzodiazepines.¹⁵

Patients taking alprazolam long term are at increased risk of significant withdrawal symptoms, rebound anxiety and susceptibility for dependence.^10,11,19 Switching to a long-acting benzodiazepine such as diazepam or clonazepam, and tapering the dose may assist with problematic withdrawal symptoms.^10,15

Although the maximum quantity will be 10 tablets, prescribers can apply for an authority for increased quantities when clinically indicated, but increased number of repeats will not be allowed.

An example of a clinical indication for increased quantity is a patient on a tapering regimen. If your patient is unable to self-manage the taper, consider working closely with the patient’s pharmacist regarding staged supply or supervised dosing.¹⁵

Consider alternative treatments, including psychological therapy appropriate for your patient with panic disorder, and whether they need a referral to a psychiatrist or addiction medicines specialist.²⁰

CBT as an adjunct to tapering benzodiazepines has demonstrated significantly increased rates of successful benzodiazepine discontinuation, including with alprazolam.^9,15,21,22

A mental health treatment plan, which provides Medicare rebates for allied mental health services, can assist patients with the costs of psychological therapy such as CBT.²³

For pharmacists

Until manufacturers market a 10-pack of alprazolam, you will need to split larger quantities. You will receive a broken pack fee to compensate for this. This fee, which is in addition to the dispensing and dangerous drugs fee, includes a wastage factor that is applied to the percentage of the amount supplied from the standard pack, and an appropriate container fee. A full explanation of broken pack pricing is available on the PBS website.

If your patient is on a tapering regimen and cannot self-manage this, their prescriber may request staged supply or supervised dosing.¹⁵

A proportion of patients with panic disorder may not respond, or respond partially, to antidepressants, and specialist review is required.^9,16,24

Some approaches the specialist may implement include optimising the current treatment, switching to another agent or treatment modality, or augmentation.²⁴

The specialist may also consider short-term use of benzodiazepines as a class in treatment-refractory patients with panic disorder.