Drugs and devices

Greg Merlo
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Prominent GP and former member of parliament Kerryn Phelps has entered the turf war between doctors and pharmacists over who gets to prescribe.Pharmacy groups have long called for changes to allow pharmacists to prescribe specified medications, such as the oral contraceptive pill and antibiotics for urinary tract infections.But Phelps argues allowing pharmacists to prescribe will lead to perverse incentives – where pharmacists prescribe inappropriately – because they have a financial interest in the sale of medicines.Phelps has a point. Studies in countries where doctors have dispensing roles have found evidence of financial profits influencing prescribing behaviour.A Swiss study, for instance, found physician dispensing leads to a 34% increase in drug costs per patient, as doctors overprescribe and prescribe more expensive medications.

Expert/s: Greg Merlo
Dr Linda Calabresi
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Dr Linda Calabresi
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Dr Linda Calabresi
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Dr Linda Calabresi
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This resource is a little different to the usual guideline or website that is commonly discussed in this newsletter.This is a product that was recommended by a number of patients and has the potential to really improve the quality of someone’s life.Quite simply it’s a waterproof protector that goes over a patient’s plaster or dressing.Called Blocc’s protectors, these covers are made of a type of rubber that stretches over the cast or dressing to make a waterproof seal. And apparently they are excellent at keeping the dressing or plaster dry.

Dr Linda Calabresi
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Recognise this scenario? You prescribe an inhaler for the patient. You educate the patient on why they need the inhaler. You draw diagrams. You demonstrate the technique on the placebo inhaler. You write the script. And then… you cross your fingers.

Dr Linda Calabresi
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While the ‘opioid epidemic’ might be grabbing all the headlines at the moment, Australian toxicologists are reminding us that paracetamol is the most common drug used in overdoses in this country.What’s more the numbers of both paracetamol-related hospital admissions and liver injury have been increasing over the past decade at a rate that far exceeds the rate of population increase.According to a retrospective study recently published in The Medical Journal of Australia, there has been an average 3.8% annual increase in the number of paracetamol-related hospital admissions since 2007, and a mean 7.7% annual increase in paracetamol-related liver injury cases, whereas the population has been increasing at a rate of only 1.6% annually.

Dr Linda Calabresi
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Glucosamine’s effectiveness in treating arthritis remains controversial, however a study suggesting that the supplement, when taken regularly, will help prevent heart attacks certainly adds to its appeal.According to findings from a large prospective study just published in The BMJ, habitual glucosamine use is associated with a 15% lower risk of cardiovascular events. Breaking that down a bit further, it appears regular glucosamine lowered the risk of dying from a cardiovascular event by 22%, lowered the risk of coronary heart disease by 18% and lowered the risk of stroke by 9%. All statistically significant results.The research involved over 440,000 people from the UK biobank who didn’t have cardiovascular disease at the outset. Courtesy of an initial questionnaire, researchers knew who was taking glucosamine and how often.Interestingly about 20% of the cohort, reported they took the non-vitamin, non-mineral supplement daily – a figure the researchers said was representative in other adult populations around the world – including Australia.The cohort was then followed for a median of seven years. Over this time there were over 10,000 CVD events including heart attacks and strokes, with over 3,000 of these resulting in death.Even though the study was basically observational, the size of the sample strengthens its value. As does the fact that the researchers obtained a wealth of information about the patient’s diet, medical history and lifestyle at the initial questionnaire, which was all utilised in the final analysis.Consequently the 15% lower risk of a cardiovascular event associated with taking glucosamine can’t be easily written off as caused by another confounder.The researchers were able to conclude the association was “independent of traditional risk factors, including sex, age, income, body mass index, physical activity, healthy diet, alcohol intake, smoking status, diabetes, hypertension, high cholesterol, arthritis, drug use, and other supplement use.”So how does it work? How does glucosamine positively affect the cardiovascular system?According to the study authors, there are a number of plausible mechanisms that could explain the link. One relates to the anti-inflammatory properties of glucosamine. There already exists evidence that regular glucosamine reduces CRP levels, a marker of systemic inflammation.Another theory relates to how glucosamine affects metabolism.“[A] previous study found that glucosamine could mimic a low carbohydrate diet by decreasing glycolysis and increasing amino acid catabolism in mice; therefore, glucosamine has been treated as an energy restriction mimetic agent,” they said.But while the study findings appear very exciting, the study authors themselves suggest caution, claiming their study had some limitations. Among these limitations was the fact that details about the dose, duration of use, type of glucosamine supplement was not recorded. Obviously further research is needed to test this association.Nonetheless, the trial is destined to fuel on-going interest in the supplement, albeit for a totally different condition from the one we’re used to. 

References:

Ma H, Li X, Sun D, Zhou T, Ley SH, Gustat J, et al. Association of habitual glucosamine use with risk of cardiovascular disease: prospective study in UK Biobank. BMJ. 2019 May 14; 365: l1628. DOI: 10.1136/bmj.l1628
Dr Linda Calabresi
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Got a patient with multiple sun spots on their head that need treatment?Well it looks like the old, tried and true 5FU cream is still the way to go, according to a randomised trial just published in the New England Journal of Medicine.Among more than 600 randomly assigned patients, Dutch researchers compared the effectiveness of four topical treatments commonly used to treat multiple actinic keratoses as part of a ‘field treatment’.In addition to the 5% fluorouracil cream (Efudix), the study looked at the effectiveness of 5% imiquimod cream (Aldara), methyl aminolevulinate photodynamic therapy (MAL PDT or Metvix PDT) and 0.015% ingenol mebutate gel (Picato gel).After 12 months, the study showed that the Efudix was the most effective in terms of maintaining a reduction of at least 75% of actinic keratoses from the baseline. In other words, this cream was the best of the four therapies, at getting rid of these sun spots completely.“And the differences between fluorouracil cream and imiquimod, PDT and ingenol mebutate were significant,” the study authors said.They found the likelihood of success for those patients using fluorouracil was almost 75%, compared with only 54% for imiquimod, 38% for PDT and 29% for those using ingenol mebutate.And this independent study didn’t do anything tricky with the dosing regimen either.“In our trial, we used the most commonly prescribed dosing regimens of the therapies studied,” they said.In terms of sticking to the dosing regimen, patients were much better adhering to the schedule when they were taking ingenol mubutate (99% adherence) or PDT (97%) rather than the fluorouracil (89%) or the imiquimod (88%), but this appeared to directly correlate with how often they had to take the therapy and for how long.Overall, however this adherence rate did not reflect treatment satisfaction rate.“Satisfaction with treatment and improvement in health-related quality of life at 12 months after the end of treatment were highest in the fluorouracil,” the study authors reported. Nothing like a treatment actually working to make a patient feel happy about having had it.A bonus of this study, according to the researchers was the inclusion of patients with the more severe actinic keratosis lesions (Grade III lesions), patients who have been commonly excluded from previous similar trials of topical treatments.“[Including these patients] is more representative of patients seen in daily practice,” they said.In addition to effectiveness, cost is another appealing factor for fluorouracil over the other treatments.This study has the capacity to change practice.The study authors quote the prevalence actinic keratoses among whites aged 50 and over as being at 37.5%.While cryotherapy remains the treatment of choice for single lesions, where there are multiple lesions present field treatment should be considered.Currently the guidelines for this field treatment don’t advocate one treatment over any other, more or less suggesting all four of the treatments in this study as being efficacious.However, as these Dutch researchers say “our results could affect treatment choices in both dermatology and primary care.”

Reference

Jansen MHE, Kessels JPHM, Nelemans PJ, Kouloubis N, Arits AHMM, van Pelt HPA, et al. Randomized Trial of Four Treatment Approaches for Actinic Keratosis. N Engl J Med. 2019 Mar 7; 380(10): 935-46.  DOI: 10.1056/NEJMoa1811850
Dr Linda Calabresi
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It would be a brave doctor who would ignore the warning ‘allergic to penicillin’ when deciding which antibiotic to prescribe for a patient.But according to a new review published recently in JAMA, despite up to 10% of the population reporting allergies to penicillin, few have clinically significant reactions.“Although many patients report they are allergic to penicillin, clinically significant IgE-mediated or T lymphocyte-mediated penicillin hypersensitivity is uncommon (<5%),” the US review authors said.And the issue is an important one. As the authors point out, not only will patients, labelled as having a penicillin allergy be given alternative antibiotics that are more likely to fail and cause side-effects but the use of these alternatives increase the risk of antimicrobial resistance developing. So for all these reasons, the researchers propose that is worthwhile that all patients labelled as having an allergy to penicillins be re-evaluated.As a starting point, a comprehensive history should be taken. And while the reviewers acknowledge that, to date no allergy questionnaires have been validated in terms of defining risk levels, there are plenty of features in a history that can give a clue as to whether a person could safely be offered skin prick testing or a drug challenge.Broadly speaking, patients with a history of a minor rash, that was not significantly itchy that developed over the course of days into the course of the antibiotic are considered low-risk. This is opposed to people who have a history of developing a very pruritic rash within minutes to hours of taking the drug (which tends to indicate an IgE-mediated reaction) or people who experienced significant blistering and/or skin desquamation after taking penicillin (which generally represents a severe T-cell-mediated reaction).Among those patients whose rash-history suggests they are at low-risk, other factors should be considered before attempting a challenge.“Even in the context of low-risk allergy history, patients with unstable or compromised haemodynamic or respiratory status and pregnant patients should be considered as having at least a moderate-risk history,” they said.However, patients whose penicillin allergy history included non-allergic-type symptoms such gastrointestinal symptoms or patients who only have a family history of penicillin allergy should be considered at low-risk.Once the patient has been assessed as being at low-risk of having an acute allergic reaction, the study authors suggest they be given amoxicillin under medical observation.“For penicillin allergy, administration of 250mg of amoxicillin with one hour of observation demonstrates penicillin tolerance,” they said.Should the patient tolerate this dose of amoxicillin, it can be concluded that all beta-lactams can be administered safely, and the issue of cross-reactivity (between penicillin and cephalosporin which occurs in about 2% of truly penicillin-allergic people) is rendered irrelevant.Patients who are considered at moderate-risk of having an allergic reaction to penicillin, namely those patients with a history of urticaria or mild pruritic rashes but no anaphylaxis should be considered for skin-prick testing. Only those with a negative skin prick test should be considered for an oral drug challenge.People with a history of high-risk reactions – usually anaphylaxis should not be skin-prick tested or challenged. They might be considered for desensitisation programs but only in select circumstances and only under the close supervision of a specialist.All in all, the authors advocate health professionals not simply take the label of ‘allergic to penicillin’ as gospel.“Evaluation of penicillin allergy has substantial benefits for patients by allowing improved antimicrobial choice for treatment and prophylaxis,” they concluded.

Reference

Shenoy ES, Macy E, Rowe T, Blumenthal KT. Evaluation and Management of Penicillin Allergy: A Review. JAMA 2019 Jan 15; 321(2): 188-99. DOI: 10.1001/jama.2018.19283  
Dr Linda Calabresi
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Finally, we’ve got some robust evidence to answer the question - is ondansetron safe to take for morning sickness.Published in JAMA, a very large retrospective study involving over 1.8 million pregnancies, almost 90,000 of which included exposure to ondansetron in the first trimester has found that taking the drug did not increase the risk of cardiac malformations or congenital malformations overall. However, first trimester ondansetron was associated with a very small increased risk of oral clefts (three additional cases per 10,000 women treated).Interestingly the increased risk for oral clefts was confined to cleft palate, there was no evidence for an increased risk of cleft lip.The information will be eagerly received by the thousands of pregnant women who experience severe nausea and vomiting, and the clinicians who care for them many of whom have been prescribing ondansetron because of its effectiveness, despite the lack of detailed safety data.“Although not formally approved for the treatment of nausea and vomiting during pregnancy, ondansetron, a 5-HT receptor antagonist, has rapidly become the most frequently prescribed drug for nausea and vomiting during pregnancy in the United States because of its perceived superior antiemetic effects and improved adverse effect profile compared with treatment alternatives,” the study authors said.“In 2014, an estimated 22% of pregnant women used ondansetron in the United States,” they said.The major strengths of this study lie in the size of the cohort and the fact that the information on ondansetron exposure was based on filled prescriptions, thereby negating any possible recall bias. Both these factors are particularly important given how rare these abnormalities are and how many possible confounders there could be.As for limitations of the study, of course just because a prescription has been filled doesn’t always mean the medication has been taken, but even if the exposure wasn’t as great as calculated, the risk would be only lessened rather than raised. There is also the possibility that there might have been some other unrecognised factor involved especially since all the women in the study were uninsured and treated under Medicaid insurance and therefore included a higher percentage of women from disadvantaged communities. However, given the detailed information collected on these women and their pregnancies, and the multiple analyses conducted on this data, the likelihood of unmeasured confounders affecting the findings was thought to be low.Overall the results of this study should provide reassurance for clinicians and pregnant women, according to an accompanying editorial, written by a US obstetrician and gynaecologist.“As clinicians and pregnant women engage in informed, shared decision-making surrounding treatment for nausea and vomiting, the current information is important for contextualising risks in light of the potential benefits,” he concluded.

References

Huybrechts KF, Hernández-Díaz S, Straub L, Gray KJ, Zhu Y, Patorno E, et al. Association of Maternal First-Trimester Ondansetron Use With Cardiac Malformations and Oral Clefts in Offspring. JAMA. 2018 Dec 18; 320(23): 2429-37. DOI: [10/1001/jama.2018.18307]Haas DM. Helping Pregnant Women and Clinicians Understand the Risk of Ondansetron for Nausea and Vomiting During Pregnancy. JAMA. 2018 Dec 18; 320(23): 2425-6. DOI: [10.1001/jama.2018.19328]
Dr Julia Marcello
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“Be patient with yourself… nothing in Nature blooms all year.” One of my favourite quotes regarding perinatal depression and anxiety which affects 10-16% of all new parents.The importance of perinatal mental health cannot be overstated. Research has shown that an untreated perinatal mental health condition can lead to substance misuse, poor antenatal attendance as well as poor self-care.There is also a risk of poor attachment to the infant, and a long-term risk of poor child development outcomes through neglect. Suicide is the final risk. The government have recently supported our concerns regarding this important topic by changing the MBS item numbers (16590, 16591, 16407) to include a mental health assessment.We have a duty of care to our patients to know what is safe to prescribe or continue to use in pregnancy- remembering that pregnancy is not protective against mental illness.Did you know that more than half of all women abruptly discontinue antidepressant medication upon confirming a pregnancy? Almost 70% of these women suffer a relapse of depression.Currently the recommendations for a woman on an antidepressant who has been euthymic for at least 12 months include cease the medication in pregnancy, continue the current medication, change to an alternative, safer medication or cease the medication and then reintroduce it if a relapse occurs.Antidepressant medications can cross the placenta, meaning the fetus is exposed. There are also potential pregnancy complications, but the risks to the fetus and the pregnancy are very low.Congenital malformation may occur from exposure to some antidepressants in the first trimester. Growth restriction and neurobehavioural problems may result from exposure in the second trimester. And congenital cardiac defects have been associated with paroxetine use in pregnancy.Postpartum haemorrhage is the only significant potential obstetric complication associated with SSRI and SNRI use. There is also a small increased risk of persistent pulmonary hypertension of the newborn associated with SSRI, SNRI and TCA use in late pregnancy.Antidepressants taken in late pregnancy, may also cause poor neonatal adaptation syndrome (PNAS). This manifests as hypotonia, respiratory distress, hypoglycaemia, seizures and most commonly ‘jittery-ness’ in the infant. Paroxetine has the highest risk of PNAS.Despite this, it is NOT recommended that the dose of medication be reduced in late pregnancy. Because the fetus may not clear the medication in the same way the mother does, lowering the dose might simply risk a relapse of depression in the mother while gaining little or no benefit to the infant.RANZCOG states that SSRIs are generally considered low risk and safe to prescribe in pregnancy and breastfeeding. It is important to know that sertraline has the lowest placental exposure and the lowest excretion into breastmilk.Other medications are listed in the table below as a quick reference guide:

Table 1. ANTIDEPRESSANT CATEGORIES FOR PREGNANCY AND BREASTFEEDING:

MedicationPregnancy CategoryBreastfeeding
TCAs* avoid doxepin during breastfeedingCCompatible
CitalopramCCompatible
Escitalopram*preferred to citalopram in breastfeedingCCompatible
FluoxetineCCompatible
MirtazapineCCompatible
Paroxetine*can cause cardiac defects with high dose first trimester but safest for breastfeeding along with sertralineDCompatible
SertralineBCompatible
VenlafaxineCCompatible
Compatible- an acceptably low relative infant dose or no significant plasma concentrations or no adverse effects in breastfed infants. When managing perinatal depression is it important to consider potential risk against the known benefits of the medications and the potential detrimental effects of mental illness on the development of the infant and other children in the home.

Key References:

  1. The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.  Perinatal Depression and Anxiety: C-Obs 48. East Melbourne (AU): RANZCOG; Mar 2015. 16 p. RANZCOG Cat. No.: C-Obs 48. Available from: https://www.ranzcog.edu.au/RANZCOG_SITE/media/RANZCOG-MEDIA/Women%27s%20Health/Statement%20and%20guidelines/Clinical-Obstetrics/Mental-health-care-in-the-perinatal-period-(C-Obs-48).pdf?ext=.pdf
  2. White L. Antidepressants in Pregnancy. O&G Magazine. 2018; 20(3): 24-25. Available from: https://www.ogmagazine.org.au/20/3-20/antidepressants-in-pregnancy/
  3. Galbally M, Lewis AJ, Snellen M. Introduction Pharmacological management of major depression in pregnancy. In: Gabally M, Snellen M, Lewis AJ, editors. Psychopharmacology and Pregnancy. Berlin: Springer; 2014. p. 67-85.
 Dr Julia Marcello works at Bentley Maternity Unit which provides maternity services to low risk women in WA. The unit is staffed by GP obstetricians, specialist obstetricians and gynaecologists and midwives and offers the option of private care within a public setting. The midwife service is available to low risk women and includes antenatal care, birthing services and postnatal care through the visiting midwifery service and lactation consultant support.  GP shared care services are also available. The Unit also provides a gynaecology service led by Dr Aseel Alkiaat and specialists from King Edward Hospital. For further information go to www.bhs.health.wa.gov.auFor-health-professionals