Published: 29 September 2015
The one hundred and sixty-third meeting of the Medicines Adverse Reactions Committee (MARC) was held on 10 September 2015 at The Rydges, 75 Featherston Street, Pipitea, Wellington, New Zealand. The meeting commenced at 9am and closed at 2pm.
MARC MEMBERS PRESENT
Associate Professor D Reith (Chair)
Dr L Bryant
Dr N Cole
Professor C Frampton
Dr K Eggleton
Dr S Jayathissa
Dr P Jones
Associate Professor D Menkes
Dr M Tatley
Dr K Wallis
MARC SECRETARIAT PRESENT
L Chan (MARC Secretary, Medsafe)
MEDSAFE STAFF IN ATTENDANCE
S Kenyon (Acting Manager, Clinical Risk Management)
J Prankerd (Advisor, Pharmacovigilance)
S Stubbs (Advisor, Pharmacovigilance)
INVITED GUESTS AND EXPERTS IN ATTENDANCE
Dr S Donald (Public Health Registrar)
Dr R Savage (Senior Medical Assessor, Centre for Adverse Reactions Monitoring)
The Chair welcomed the attendees to the meeting. Apologies were received from J Tatler.
The minutes of the 162nd meeting were accepted as a true and accurate record of the meeting.
Committee members submitted their Conflicts of Interest Declaration forms to the Secretary. The Chair reminded the MARC members that in addition to conflicts disclosed in the declaration forms, members should declare conflicts of interest at the commencement of discussion of any relevant agenda item.
There were no potential conflicts of interest which were considered likely to influence the discussions or decisions of the MARC at this meeting.
The Committee reviewed the list of outstanding recommendations made by the MARC at previous meetings. Background information on these issues can be found in the minutes of previous MARC meetings on the Medsafe website: www.medsafe.govt.nz/profs/MARC/Minutes.asp
The Committee noted the report detailing Medsafe's recent pharmacovigilance activities and obtained clarification on some of these activities.
The Committee noted the latest edition of Prescriber Update. The Committee discussed ways in which the uptake of this publication could be improved.
The Committee noted the quarterly summary of Medsafe early warning system communications.
Nitrofurantoin is indicated for the prophylaxis and treatment of infections of the genitourinary tract due to susceptible bacteria. Its efficacy in lower urinary tract infections is dependent upon it being concentrated in the bladder. Due to its metabolism and excretion properties, blood plasma levels of nitrofurantoin in healthy subjects are low. However, in subjects with reduced renal function there may be more systemic accumulation and less urinary accumulation, which increases the risk of adverse effects and reduces the efficacy.
Recently, the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom amended the nitrofurantoin contraindication in renal impairment. Previously, nitrofurantoin was contraindicated in patients with a creatinine clearance of less than 60 mL/min. It is now contraindicated in most patients with a creatinine clearance of less than 45 mL/min. A short course of three to seven days may be used with caution in certain patients with a creatinine clearance of 30 to 44 mL/min. Nitrofurantoin may be used in these patients with urinary tract infection with suspected or proven multidrug resistant pathogens when the benefits of nitrofurantoin are considered to outweigh the risk of adverse effects.
The purpose of this report was to inform the Committee of these changes and for the Committee to consider whether any further advice or action is required regarding the use of nitrofurantoin in renal impairment.
[Professor C Frampton joined the meeting at this time.]
The Committee was presented with the New Zealand data of antimicrobial resistance to various antibiotics including nitrofurantoin. It was noted that data for nitrofurantoin were only available for urinary E. coli and Enterococcus species with low antimicrobial resistance rates of 1.3% and 1.6% respectively. Whereas the resistance rates for trimethoprim are higher. However, midstream urine tests are not obtained for all patients presenting with acute urinary tract infections therefore the true rate of resistance is unknown. The need to amend the nitrofurantoin contraindication in renal impairment in the United Kingdom (UK) could be due to different rates of antimicrobial resistance compared to New Zealand.
Pulmonary adverse reactions have been reported to occur with both short and long term use of nitrofurantoin. Although drug-induced lung disease is often idiosyncratic, poor renal function could lead to more systemic accumulation of nitrofurantoin leading to more adverse reactions, including pulmonary reactions. The Committee noted that acute pulmonary reactions can appear within the first week of using nitrofurantoin and the symptoms of breathlessness and coughing could be confused with symptoms of a cold. These pulmonary symptoms can be more severe with subsequent exposures to nitrofurantoin.
The Committee discussed the differences between the Cockroft-Gault equation and eGFR (estimated glomerular filtration rate) in estimating renal function. The Cockroft-Gault equation estimates creatinine clearance from serum creatinine, age, gender and body weight. eGFR is calculated using the Modification of Diet in Renal Disease equation which is based on age, serum creatinine, gender and ethnicity. There could be significant differences in the two values calculated with each of these equations in people at extremes of body size.
The Committee clarified the nitrofurantoin contraindication in renal impairment in New Zealand. The data sheet states that significant impairment of renal function (creatinine clearance under 60 mL/min or clinically significant elevated serum creatinine) are contraindications due to an increased risk of toxicity because of impaired excretion of the medicine. The Committee considered that there was no public health need to increase access to nitrofurantoin and the contraindication for use should remain at a creatinine clearance of less than 60 mL/min. The data on efficacy in patients with renal impairment was limited and although no statistical difference in efficacy was noted there were limitations to the data including sample size. Similarly no statistically significant difference in the rate of adverse effects was seen in patients with renal impairment, however, there was a trend to an increased risk and the sample size was small.
The Committee discussed the use of nitrofurantoin for both acute uncomplicated urinary tract infections and long term prophylaxis. It was noted that the 2013 edition of the Antibiotic Guide produced by the Best Practice Advocacy Centre (BPAC) recommends trimethoprim or nitrofurantoin as first choice agents for the treatment of urinary tract infections in adults. The Committee considered that the use of nitrofurantoin as a first choice agent in acute uncomplicated urinary tract infections could be problematic due to safety concerns and this should be communicated to BPAC. Nitrofurantoin is also used as long term prophylaxis for patients with recurrent urinary tract infections and is often first choice for this purpose due to the low risk of antimicrobial resistance. The Committee considered that the differences between the use of nitrofurantoin for acute uncomplicated urinary tract infections and long term prophylaxis should be highlighted to prescribers.
The Committee recommended that the nitrofurantoin contraindication in patients with a creatinine clearance of less than 60 mL/min should remain.
The Committee recommended that an article should be published in the next edition of Prescriber Update on the use of nitrofurantoin highlighting acute and delayed onset reactions.
The Committee recommended that Medsafe communicates the outcome of this discussion to the Best Practice Advocacy Centre.
In the 1960s, studies of penicillin-allergic patients were published which reported incidences of cross-reactivity with cephalosporins up to 41.7%. Later studies reported cross-reactivity from 0% to 10.5% in penicillin-allergic patients who had been treated with a cephalosporin. This overestimate is thought to be due to contamination as penicillin related compounds were produced by Cephalosporium mould until mid-1980 and cephalosporin compounds also contained penicillin.
The beta-lactam ring was also considered to be responsible for the cross-reactivity that was seen as penicillins and cephalosporins both share this structure. Later on, cross-reactivity between penicillins and cephalosporins was thought more likely to be due to the similarities of the side chains as it was discovered that the degradation products of penicillins and cephalosporins differed.
Recently, studies have shown a much lower rate of cross-reactivity than that concluded in earlier studies. Recent studies suggest a cross-reactivity rate of <5% between cephalosporins and penicillins.
During a review of the quality of data sheets for cephalosporin-containing medicines Medsafe noted an important inconsistency in the contraindications in relation to cross-reactivity.
The purpose of this review was to discuss the contraindication to treatment with cephalosporins in patients allergic to penicillins. In other words, to review beta-lactam cross-reactivity.
The Committee discussed the availability of penicillin allergy skin testing in New Zealand. Currently, allergy skin testing to determine the presence of IgE antibody is available through immunology clinics, allergy testing clinics and anaesthetic departments. It was noted that skin testing is generally not practical at the time of prescribing a cephalosporin to a patient who has reported previous sensitivity to penicillins. Most skin testing for medicines allergy appears to take place after a reaction has occurred to confirm if it was an immediate immunological response.
The Committee noted that data from observational studies show a decline of cross reactivity rates from the first to fifth generation of cephalosporins. However, data on actual cross reactivity rates and comparisons with other potential cross reactivities are limited.
The Committee considered that it was important to differentiate between immediate and non-immediate immunological responses. Immediate responses are IgE-mediated whereas non-immediate responses are non-IgE-mediated.
The Committee considered that advice from the Australasian Society of Clinical Immunology and Allergy would be useful to aid in the decision-making process.
The Committee recommended that Medsafe consults with the New Zealand branch of the Australasian Society of Clinical Immunology and Allergy to obtain advice on penicillin cross reactivity with cephalosporins. This agenda item will be discussed again at a subsequent Committee meeting.
Gardasil is a recombinant vaccine against human papilloma virus (HPV) types 6, 11, 16 and 18. It is prepared from highly purified virus-like particles (VLPs) of the major capsid protein of the four strains. The vaccine is produced in recombinant yeast: Saccharomyces cerevisiae and the VLPs self-assemble and are adsorbed onto amorphous aluminium hydroxyphosphate sulphate.
Gardasil is indicated in females aged nine to 45 years for the prevention of cervical, vulvar, vaginal and anal cancer, precancerous or dysplastic lesions, genital warts and infection caused by HPV types 6, 11, 16 and 18. In males nine to 26 years of age it is indicated for the prevention of anal cancer, precancerous or dysplastic lesions, external genital lesions and infection caused by HPV types 6, 11, 16 and 18.
Cervarix is a similar vaccine against HPV types 16 and 18.
Both vaccines are approved in New Zealand but only Gardasil is funded. The immunisation schedule is 0, 2 and 6 months (ie, second dose is given 2 months after the first dose and the third dose is given 6 months after the first dose).
Some HPV infections are sexually transmitted (including 6, 11, 16 and 18), consequently HPV vaccines have attracted concern from people who are anti-vaccine and those who consider that this vaccine promotes promiscuity.
The purpose of this paper was to provide a summary of published observational studies investigating the possible association between HPV vaccine and autoimmune conditions.
Members were reminded of the Committee's terms of reference which is to provide expert advice to the Minister of Health on the safety of approved medicines. The Committee noted that this is a political and highly emotive issue. It is important that the discussion is balanced and the general public informed accordingly.
Gardasil was shown to have very high efficacy in clinical trials. Post-market data from Australia indicate that the incidence of cervical abnormalities being detected through smear testing is lower among vaccinated subjects compared with non-vaccinated subjects. The conditions that this vaccine prevents can be serious, in particular cervical and throat cancer. The Committee considered that the threshold for safety concerns with vaccines is lower than with medicines. This is because vaccines are administered to healthy people.
The Committee discussed the timing of HPV vaccination which in the New Zealand Immunisation Schedule starts in females aged 12 years. One of the reasons why HPV vaccination starts at this age is to ensure that vaccination covers the peak risk period. However, the Committee noted that autoimmune conditions have a higher incidence during puberty and adolescence than in early childhood.
The Committee noted that autoimmune conditions include a wide range of conditions that have varying mechanisms of occurring. This was a limitation of some of the observational studies which grouped different conditions together. The difficulty in determining the onset time of these conditions also makes it difficult to perform these studies. However the additional sensitivity analyses and case investigation in these studies supported a lack of association.
The Committee were unanimous that based on the evidence presented, there is no safety concern relating to the development of autoimmune conditions after HPV vaccination. Ongoing surveillance and reporting of adverse reactions to the Centre for Adverse Reactions Monitoring (CARM) is occurring and it is important that this continues.
Additional information presented and discussed:
The Coroner's draft report on the death of an 18 year old female was made available to Medsafe a few days before this meeting. A copy of this draft report was circulated to Committee members before the meeting and was presented to the Committee at the meeting. The Committee was reminded that this case of a sudden death six months following the third dose of Gardasil vaccination was reported to CARM in November 2009 and was presented to the Committee at the 141st meeting held on 11 March 2010 (agenda item 18.104.22.168, minutes available from www.medsafe.govt.nz/profs/adverse/Minutes141.htm#4.1).
The Committee noted that the Coroner's draft report includes a comment that death may have been due to an arrhythmic event secondary to undiagnosed cardiac pathology which remains a possibility. The family elected not to further engage in a clinical investigation of first degree relatives including parents and siblings. Based on the evidence, the Coroner commented that sudden arrhythmic death was a real possibility but there was insufficient evidence to elevate this possibility to a probability. The Committee expressed their sympathy for the family and noted that the Coroner's formal finding for the cause of death in this case was unascertained.
The Committee considered that there is no safety concern relating to the development of autoimmune conditions after HPV vaccination. Ongoing surveillance and reporting of adverse reactions to the Centre for Adverse Reactions Monitoring should continue.
The Committee noted the Coroner's findings that the cause of death in this case was unascertained but may possibly have been due to a cardiac arrhythmia.
Statins are medicines widely prescribed for treating high cholesterol. They are generally well tolerated. The most commonly reported adverse effects include gastrointestinal upset, headache and rash. The best characterised rare adverse effects include myopathy and polyneuropathy.
Pulmonary adverse effects, including interstitial lung disease, relating to statin use is not currently well described and a mechanism for this potential risk is unclear. The Centre for Adverse Reactions Monitoring (CARM) recently received a report describing a patient taking a statin who subsequently displayed symptoms consistent with interstitial lung disease.
Therefore, the purpose of this paper was to review the available information on this potential risk.
The Committee noted that interstitial lung disease is likely to be underdiagnosed generally and statins are a widely prescribed group of medicines. There appears to be a very low risk of interstitial lung disease with the use of statins based on the number of reports and the number of people taking a statin.
The published literature includes a few case reports and a cohort study. The Committee noted that the cohort study did not find an association between statin use and incidence of interstitial lung disease after adjusting for confounders. However, one of the case reports reported a positive dechallenge/rechallenge.
The Committee noted that interstitial lung disease presents with nonspecific symptoms such as breathlessness and cough. Statins are widely prescribed to older people or to people who have heart disease, including heart failure, many of whom will experience breathlessness as a symptom. Therefore, it is difficult to conclusively attribute the cause of this symptom to interstitial lung disease caused by a statin.
As information on interstitial lung disease is included in all statin data sheets, the Committee considered that no regulatory action is required. The Committee considered that prescribers should be made aware that interstitial lung disease may be associated with statins through MARC's Remarks in Prescriber Update.
The Committee recommended that Medsafe includes information on statins and interstitial lung disease in MARC's Remarks in the next edition of Prescriber Update.
Members were given a brief description of the fatal reports for which CARM had assessed the causality to be at least possible.
The Committee did not consider any of the reports required further action.
Reports of serious cases associated with medicines in children under 18 years were briefly outlined for the Committee.
The Committee did not consider any of the reports required further action.
Reports of events occurring in children under 18 years were briefly outlined for the Committee.
The Committee did not consider any of the reports required further action.
Reports of events occurring in patients over 80 years were briefly outlined for the Committee.
The Committee noted a number of cases of bleeding in elderly patients taking dabigatran and recommended that an article in Prescriber Update be written to remind prescribers of the need to monitor renal function.
The Committee recommended that Medsafe includes an article reminding prescribers of the need for renal monitoring of patients taking dabigatran in a future edition of Prescriber Update.
The Committee was given an update on the therapeutic products regulation project.
The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 2pm.
Associate Professor D Reith Date
Chair, Medicines Adverse Reactions Committee