Upfront: Unapproved medicines and unapproved uses of medicines: keeping prescribers and patients safe

An approved medicine is a medicine which has been through a regulatory process in New Zealand and can be considered safe to prescribe, under the conditions set out in the Medicine Data Sheet. The prescriber must still consider both the benefits and risks of using the medicine, before it is prescribed.

In New Zealand, medicines are approved by the Minister of Health, under advisement from the Medicines and Medical Devices Safety Authority (Medsafe). Medsafe’s regulatory approval process ensures that both prescribers and patients have access to safe, quality medicines and medical devices. For a medicine to be approved for sale, distribution and marketing in New Zealand, the company that markets the medicine must apply for consent in accordance with the Medicines Act 1981. When a medicine is approved, it is only approved for the specific indications, doses and routes of administration that were applied for. If the medicine is a prescription medicine or a restricted medicine the company must submit a Medicine Data Sheet that outlines the use of the medicine for prescribers. Any changes to the datasheet, such as a new indication or dose, must be applied for and approved.

The Medicines Adverse Reaction Committee (MARC) works with Medsafe to advise the Minister of Health on the safety of approved medicines, specifically the risk-benefit profile of new medicines. The Centre for Adverse Reactions Monitoring (CARM) collects reports of suspected adverse reactions to medicines and informs Medsafe of potential safety issues with approved medicines.

If a significant safety or quality issue is identified, a warning or recall is requested by Medsafe, and in extreme cases, the Minister of Health can withdraw consent for the approval of the medicine.

There are many reasons why a prescriber may consider an unapproved use of a medicine, ranging from following established treatment guidance to implementing new evidence that has emerged from the literature. In some cases, the prescriber may not even be aware that a medicine is being prescribed in an unapproved way, as it is used so commonly, e.g, the use of tricyclic antidepressants for neuropathic pain, omeprazole for reflux in infants (unapproved in children aged < 1 year) or nifedipine for the treatment of Raynaud’s phenomenon.

Prescribing medicines in children

Many of the medicines administered to children are used off-label. This is because trials have not usually been conducted in this patient group and, therefore, the company marketing the medicine has not applied for use to be approved for this age-group. This is also why it is common for a medicine to be contraindicated for use in pregnant women.

An example of off-label prescribing in children is azithromycin, which is recommended for prophylaxis and treatment of pertussis in children. Although azithromycin is an approved medicine, pertussis is currently an unapproved indication for use

It can be difficult for a practitioner to weigh up the risks and benefits of using a particular medicine in a child, when there is limited or conflicting evidence of effectiveness or safety. For example, selective serotonin reuptake inhibitors (SSRIs) are considered the first-line pharmacological treatment for depression, and the only pharmacological option considered for younger people. However, SSRIs are unapproved for use in people aged under 18 years, and are associated with potentially serious adverse effects.

Indication creep

Once a medicine has been approved in New Zealand, its use is often expanded across a broader range of conditions. However, the efficacy and safety of such use may not always be established. For example, quetiapine is indicated for the treatment of schizophrenia and related psychoses, but it is increasingly being prescribed for unapproved indications such as sedation in people with dementia, and for anxiety and insomnia. This is a worrying trend given that a larger population is being exposed to the potential serious adverse effects associated with quetiapine and other atypical antipsychotics, e.g. type 2 diabetes, sudden cardiac death and increased mortality in older people.*

Another concerning example of indication creep is oxycodone, which is approved for moderate to severe pain, including cancer pain, but appears to be frequently prescribed inappropriately in place of a weaker opioid.

Data sheets not updated

Sometimes medicines are prescribed off-label because evidence suggests that a non-indicated dose or route of administration is recommended, but the medicine supplier has, for whatever reason, not sought regulatory approval to update the data sheet. For example, low dose bendrofluazide has only recently been officially incorporated into the product datasheet despite guidelines for hypertension recommending low doses for many years.

* McKean A, Monasterio E. Off-label use of atypical antipsychotics: cause for concern? CNS Drugs 2012;26(5):383-90.

The decision to prescribe an unapproved medicine, or to prescribe off-label, is at the discretion of the practitioner, based on their clinical experience and judgement, and in consultation with the patient.

The Health and Disability Commissioner’s Code of Consumer Rights covers the obligation for a practitioner to obtain informed consent from the patient, before prescribing an unapproved medicine.

Increased professional responsibility and liability

If a patient experiences an adverse event while taking an unapproved medicine, or a medicine prescribed for an unapproved use, the responsibility, and liability, rests with the prescriber. Therefore, it is recommended that a decision to prescribe an unapproved medicine is documented in the patient’s notes, including the rationale for the prescription, and that the decision was discussed with the patient. In general, it is recommended that prescribers obtain written consent from the patient when prescribing an unapproved medicine. It is acknowledged, however, that when off-label use of a medicine is so common that it is regarded as usual practice, obtaining consent may not be considered necessary, and this is at the clinician’s discretion.

What should you tell the patient?

The patient should be fully informed that the medicine they are being prescribed is unapproved, or that the medicine is approved, but is being prescribed for a condition, at a dose, or via a route, that is unapproved.

The expected benefits, risks, adverse effects and cost should be discussed, along with other treatment options. Any warnings or contraindications associated with the medicine should be explained.

If the medicine is considered to be experimental, e.g. there is minimal or conflicting evidence to support its use, it is rarely used or it is part of a clinical trial, the prescriber must obtain written consent from the patient. A plan for monitoring treatment and adverse effects should be put in place.

If a patient is prescribed an unapproved medicine, the prescriber must advise them that the details about the supply of medicine (Section 29), including their name, will be recorded by the supplier and may also be sent to Medsafe.

What if the patient asks for a medicine they used overseas?

Patients who have immigrated to New Zealand or have spent time overseas may request that their doctor prescribes them a medicine that they have been using, which is not approved in New Zealand. Such medicines can be imported for use, but it is the obligation of the practitioner to consider approved, and subsidised, alternatives and be adequately informed about the medicine, e.g. researching the literature, consulting with colleagues, before assisting the patient to obtain it. Practitioners should have a plan in place to monitor the effect of the medicine.

N.B. Section 29 notification is not required if a medical practitioner imports a medicine to treat a patient. If the medicine is supplied from one medical practitioner to another, the supplying practitioner is encouraged to notify Medsafe. If a Pharmacist imports the medicine for the medical practitioner, they must notify Medsafe of the supply using the Section 29 reporting mechanism.

In New Zealand, the Pharmaceutical Management Agency (PHARMAC) is responsible for deciding which medicines are subsidised for use in New Zealand. The New Zealand Pharmaceutical Schedule indicates to prescribers which medicines are subsidised (either fully or partly), including any criteria for subsidy, e.g. Special Authority.

Although most medicines on the Pharmaceutical Schedule are approved medicines, and it is PHARMAC’s preference to subsidise approved medicines where possible, this is not a criterion for subsidy. The decision to subsidise a medicine is based on the pharmaceutical needs of patients in New Zealand, and is dependent on the available funding. All patients who meet the criteria for subsidy (as per the Schedule), have equal access to the funding for a medicine, should a practitioner decide to prescribe it. PHARMAC is not responsible for the safety or quality of the medicines listed on the Pharmaceutical Schedule, nor for the supply or use of the medicine in accordance with the Medicines Act.

Unapproved medicines are identified in the Pharmaceutical Schedule with this symbol: S29 Where an approved medicine is subsidised for an unapproved use, this is also clearly indicated in the Schedule.

The New Zealand Formulary also contains information about the approval and subsidy status of medicines.