The manufacturer of Phenergan, Sanofi, undertook a safety review (currently unpublished), that highlighted concern about an association with central nervous system (CNS) and psychiatric adverse effects in children, prompting the change in age limit. The manufacturers safety review showed an increased risk of both CNS and psychiatric adverse effects in children aged under six years. Adverse effects included aggression, hallucinations and psychomotor hyperactivity. The use of high doses of promethazine has also been associated with reversible cognitive deficit and intellectual disability. N.B. Medsafe has previously advised that antihistamines should not be used for sedation in children (also reported in Bulletin 9).

The data sheet and consumer medicine information leaflet for Phenergan oral liquid and tablets have been updated to reflect this new contraindication. Medicine with updated packaging will take some time to reach pharmacies. Sponsors of the other brands of promethazine have been asked by Medsafe to amend their data sheets and product information.

There appears to be a number of reasons why the Ministry of Health, Manatū Hauora, has not adopted the WHO advice. These include:

• Cow’s milk is not nutritionally equivalent to breast milk or infant formula
• The recommendation was conditional and based on low certainty evidence
  • The conclusion of the systematic review and meta-analysis used to inform the WHO guideline was that feeding cow’s milk from age six months in non-breastfed/mixed breastfed infants was unlikely to affect growth but may result in anaemia. The review was unable to fully assess other aspects such as the effect on neurodevelopment, the effect of the higher protein level of cow’s milk on the kidneys and adverse gastrointestinal effects, e.g. diarrhoea, constipation. The combined systematic review and meta-analysis was also limited in its conclusions due to the small number of included studies, and that many were relatively old and they were not uniformly spread over countries of different income levels. N.B. The WHO recommendation only applies to cow’s milk, not other animal milks, plant milks, sweetened or flavoured milks. For further information on using alternative milks in children, see: https://bpac.org.nz/2021/plant-based-diets.aspx.
• The WHO recommendations are intended for a global population which includes countries of all income levels. In some lower-income countries, access to clean drinking water used to prepare infant formula in non-breast fed infants may mean that feeding cow’s milk presents fewer risks.

The ongoing supply issue affecting the oral liquid formulation of morphine (as reported in Bulletins 88 and 95) has likely resulted in additional demand for oxycodone oral liquid meaning that stocks are now also constrained. An alternative oxycodone oral liquid product has been sourced and should be available and listed on the Pharmaceutical Schedule in mid-June, 2024. Pharmac reminds prescribers that there is stock of the Oramorph brand (Section 29) of morphine oral liquid available and if oxycodone liquid has been used as an alternative due to a stock shortage, patients should be changed back to morphine if available.

Prescribers should be aware that all patients taking cilazapril should be moved to another antihypertensive option as stocks will soon be exhausted. Data show that there are still a number of patients remaining on this medicine. As reported in Bulletin 94, stock of the 5 mg presentation is expected to run out by July, 2024. The 0.5 mg and 2.5 mg strengths will expire in October, 2024, and cilazapril will be delisted on 1^st January, 2025.

For further information on selecting an ACE inhibitor or ARB, see: https://bpac.org.nz/2021/ace.aspx

Dispensing of oestradiol valerate (Progynova) 1 mg tablets has been temporarily switched to monthly since 1^st March, 2024, due to an ongoing supply issue (as reported in Bulletin 93). Stock has now arrived and is expected to reach pharmacies in the coming weeks. Stat dispensing will be reinstated from 1^st June, 2024.

For further information on menopausal hormone therapy formulations, see: https://bpac.org.nz/2019/mht.aspx

Supply issues affecting oestradiol patches remain ongoing and are unlikely to resolve before 2025. Stock levels are continually fluctuating; click here for the latest supply information.

For further information on menopausal hormone therapy, see: https://bpac.org.nz/2019/mht.aspx

The guideline is grouped into four main sections: (1) Whakapapa of knowledge and evidence – details the evidence base that has guided recommendations; (2) Diagnostic guideline – overview of diagnosis and assessment, referral considerations, guidance for holistic assessment, Māori and Pacific health models, considerations for other communities that may experience barriers to care, e.g. refugees; (3) Recommendations and next steps for future service development and research; (4) Evaluation - a summary of evaluation methods.

The following criteria must be met for a patient to be diagnosed with FASD:

• Evidence of prenatal alcohol exposure
• Presence of pervasive neurodevelopmental impairments
• The neurodevelopmental impairments necessitate significant supports across multiple areas of functioning as appropriate for an individual’s developmental stage and cultural context to support equity across the lifespan
• The onset of neurodevelopmental impairments is evident during development
• The symptoms are not better attributed to another condition or exposure

Click here to view the full diagnostic criteria

• Self-directed activities/coping skills (“hobbies”) can benefit people with anxiety, e.g. exercise, yoga, Tai chi, mindfulness, meditation, journalling.
• Cognitive behavioural therapy (CBT) is the most widely used and effective form of psychotherapy for anxiety, however, access can be limited in New Zealand due to cost or wait times for both public and private services
  • Online therapy courses can be useful for some people, e.g. Just a Thought which offers a free online CBT course for anxiety
  • Some primary care clinicians may be skilled in simple CBT techniques that they can guide patients through, however, consultation time is often a limiting factor
• Patient preference is important when considering whether to start pharmacological treatment. If anxiety is interfering with the patient’s life, e.g. affecting their work, relationships with family or friends, disrupting sleep, pharmacological treatment is usually appropriate.
  • Consider offering an “as needed” medicine first in people who are hesitant to start a regular regimen. Buspirone prescribed as needed is usually trialled in this instance as it has a lower adverse effect profile than other anxiolytic medicines.
  • Behavioural interventions should continue alongside pharmacological treatment
• First-line medicines for people with anxiety are SSRIs and SNRIs. In practice, SSRIs are often trialled first, as SNRIs are difficult to withdraw and cause greater adverse effects from missed doses. Bupropion (unapproved indication) may be considered first-line for patients concerned about weight gain and sexual dysfunction.
  • Half of the starting dose for 1 – 1.5 weeks is usually recommended when initiating a SSRI/SNRI to reduce the risk of adverse effects, particularly worsened anxiety
  • Up-titrate to an effective dose. Consider switching to an alternative anxiolytic if there is inadequate response after four to six weeks at the maximum dose. Patients often get switched to an alternative medicine before a trial at the maximum dose.
  • Augmentation with buspirone may be considered for patients who require more symptom relief but are taking the maximum dose of an SSRI or who do not wish to increase the dose further
• Second-line medicines include mirtazapine (unapproved indication), buspirone and short-term benzodiazepines (clonazepam; unapproved indication)
• Propranolol can be prescribed as needed for the physical symptoms of anxiety (unapproved formulation). Benzodiazepines or gabapentin may also be used as needed for anxiety, but these are sedating and associated with dependence, therefore should be considered as a “last resort”.

This qualitative study involved telephone interviews with 23 general practitioners (nine female) in England, who volunteered to participate. More than half of participants were aged 45 years or over and their time as a general practitioner ranged from 1 – 28 years (mean: 14 ± 8 years). Approximately two-thirds of participants only practiced in urban medical clinics and ten were recorded as having specialist expertise in cancer. The interviews were semi-structured and participants were asked to discuss personal experiences when managing younger patients with cancer symptoms (or given a vignette to discuss if they had no experience of this – which was the case for four participants). They were also asked about relevant considerations when deciding whether to refer and general views on age thresholds for cancer referrals. Six main themes were identified that impacted the referral decisions of general practitioners for younger patients presenting with possible symptoms of cancer:

1. Patient age
   • There was generally a lower suspicion of cancer in younger patients; alternative diagnoses or explanations for symptoms are often considered first. For patients with symptoms possibly suggestive of cancer, an urgent referral was more likely if the suspected cancer was perceived as being more common in younger people, e.g. colorectal cancer, or if the clinician had previously diagnosed cancer in a young patient. "So, definitely for breast cancer is something that I don’t take the age into account very much and sometimes patients who have got GI (gastrointestinal) symptoms..."
   • Referral was also influenced by how close to the age criteria the patient was
2. Clinical, patient and general practitioner related factors
   • An urgent referral, irrespective of age, would usually occur in patients who presented with red flag symptoms or signs, or who had abnormal or inconclusive findings on physical examination or investigations
   • Patient characteristics also influenced the decision to refer for further investigation, e.g. family history of cancer, smoking, ethnicity
   • A clinician’s personal and professional experience with cancer was a key influence on decision-making about referral. "I have a very low threshold to refer people just because of my own personal experience... I didn’t tick any of the boxes and yet still got cancer".
   • General practitioners with a special interest in cancer felt more confident when referring patients and advocating on their behalf
   • Gut-feeling or a “sixth sense” was identified as a crucial determinant of referral by several clinicians
   • Concerns raised by patients or relatives may strengthen a referral decision in some cases but would never underpin a referral in isolation
3. Interpretation, application and views of age criteria in guidelines
   • Patient referral was heavily influenced by whether the general practitioners believed guidelines are rigid rules, in which referral of patients who do not meet criteria rarely happens, or can be interpreted flexibly, based on their clinical judgement "I don’t think there is any flexibility in the cut-off age..." and "It does say in all guidelines that you can refer outside guidelines... perhaps it should be more explicit..."
   • The reasons for age criteria were acknowledged by some respondents, however, given the negative impact of worsening social deprivation on health outcomes, a question was raised whether the same age criteria can be equally applied to an entire population. "Morbidity comes much earlier (in areas of high deprivation)".
4. Options and constraints for referring younger patients
   • Many general practitioners felt that in situations where there was high clinical suspicion, referral through the available urgent pathways was still possible. “If I really thought they had cancer, there’s no barrier to me referring them urgently with suspected cancer. I would just have to explain what my concern was.”
   • Some interviewees noted that the referral system was designed to prevent this happening, e.g. online forms do not provide options for patients under a certain age, and some admitted to describing the patient’s symptoms in a way that more accurately fit the required criteria. “Make the symptoms kind of fit.”
   • Non-urgent referral systems or further investigations in primary care were an option for patients with a lower clinical suspicion for cancer. However, respondents were concerned about long waiting times and delays for these services. These factors may lead the clinicians to opt for an urgent referral.
5. Experience of, and attitude towards, rejection and criticism of referral outside of age criteria
   • Some general practitioners reported having referrals declined because of age criteria, while others had never. Some clinicians felt it important to justify their clinical reason for the referral in case it was rejected based only on age. "I always write a referral letter regardless but I probably, in anticipation of it getting rejected, just based on the age, I’d make sure I write more into the letter to explain my concerns".
   • Several had previously experienced personal criticism for referrals, however, it was noted that this did not influence their decisions to refer. Having a good relationship with secondary care colleagues was reported as having a positive impact on patient management.
6. Consequences of referral outside of age guidelines
   • The potential consequences of referral (on both the patient and healthcare system) influenced the decision to refer outside of age guidelines. While respondents were particularly conscious of the consequences that come with missing a cancer, they were also mindful of the potential harms associated with unnecessary referral in younger patients who may be at lower risk.
   • General practitioners were split when it came to resource management. Some expressed concern about increasing the burden of secondary care. "If you refer too many younger people, then your higher risk patients who are older and at a higher risk of cancer are going to wait even longer for their tests". Others felt their role was to do what was best for the patient in front of them, as opposed to the whole population. "It’s not my job to ration stuff (medical resources)".

In summary, general practitioners had a variable approach to interpreting and acting on age criteria in referral guidelines – some prioritised their own clinical judgement and intuition, whereas others considered age criteria as rigid guidelines that prevented referral. In the presence of high clinical suspicion, most general practitioners would refer younger patients anyway. Other factors that made referral more likely are abnormal results, no other explanation for symptoms or non-resolution of symptoms, strong family history, and previous experience or gut feeling. Patients with non-specific symptoms or alternative explanations for symptoms were more likely to be investigated further in primary care or via non-urgent referral, if available. System issues and resource constraints, e.g. timely access to investigations, limited local secondary care clinics, also had an effect on clinical decisions.

Limitations: The study results may be influenced by sampling bias. The authors note that recruiting only England-based general practitioners, and mostly from Yorkshire, was a limitation of the study as it may mean that data are not representative of the whole United Kingdom or other equivalent countries. Other bias considerations include participants actively volunteering to take part in the study, the high inclusion rate of general practitioners with specialist expertise in cancer and because three-quarters of general practitioners were from the same County, it is possible they were referring patients to the same secondary care specialists and within the same system constraints.

Guidelines are efficient tools for applying population wide health interventions, however, general practitioners have a wealth of clinical knowledge and experience and should be supported to apply their clinical judgement on an individual patient level.