Published: 19 January 2016

Committees

MINUTES OF THE 164th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING - 3 december 2015

MINUTES OF THE 164th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING
3 December 2015

The one hundred and sixty-fourth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 3 December 2015 at The Rydges, 75 Featherston Street, Pipitea, Wellington, New Zealand. The meeting commenced at 9am and closed at 3pm.

MARC MEMBERS PRESENT

Dr L Bryant
Dr N Cole
Dr K Eggleton
Dr S Jayathissa (Co-Chair)
Dr P Jones (Co-Chair)
Associate Professor D Menkes
J Tatler
C Ryan
Dr M Tatley
Dr K Wallis

MARC SECRETARIAT PRESENT

J Prankerd (Advisor, Pharmacovigilance)

MEDSAFE STAFF IN ATTENDANCE

S Kenyon (Principal Technical Specialist, Pharmacovigilance)
R Pollock (Acting Manager, Clinical Risk Management)
S Stubbs (Advisor, Pharmacovigilance)
A Kerridge (Advisor, Pharmacovigilance)
L Chan (Advisor, Pharmacovigilance)
F Colson (Advisor, Regulatory Practice and Analysis)

INVITED GUESTS AND EXPERTS IN ATTENDANCE

Dr R Savage (Senior Medical Assessor, Centre for Adverse Reactions Monitoring)
Dr S Donald (Public Health Registrar)

1. MATTERS OF ADMINISTRATION

1.1. Welcome and Apologies

The Chair welcomed the attendees to the meeting. Apologies were received from I Raiman, Professor C Frampton and Associate Professor D Reith. The attendees introduced themselves around the table.

1.2. Minutes of the 163rd MARC Meeting

The minutes of the 163rd meeting were accepted as a true and accurate record of the meeting.

1.3. Potential Conflicts of Interest

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.

2. MEDSAFE PHARMACOVIGILANCE ACTIVITIES

2.1. Report on Standing Agenda Items from Previous Meetings of the MARC

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

2.1.1. Cephalosporins and cross-reactivity

At the 163rd meeting held on 10 September 2015, 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.

Outcome

Medsafe contacted the Australian Society of Clinical Immunology and Allergy as well as Dr Andrew Baker and Dr Richard Steele to obtain further information.

Discussion

The Committee noted the additional information received from the immunologists contacted by Medsafe.

The Committee discussed the availability of skin testing in the community. The Committee considered that the availability of skin testing is limited in New Zealand. The Committee considered that although skin testing would help GPs make a decision, it will not always be possible and guidance is needed.

The Committee noted that the rate of cross-reactivity between penicillins and cephalosporins is often quoted as around 10% however in practice it is possibly less than this.

The potential for false negative results to result from skin testing and the implications of this was also discussed by the Committee.

Additionally, the Committee discussed possible data sheet wording.

Recommendation 1

The Committee recommended that Medsafe request the sponsors of cephalosporin-containing products to update the contraindications and warnings and precautions sections of the data sheets.

Recommendation 2

The Committee recommended that an article should be published in a future edition of Prescriber Update highlighting the potential issue of false negatives in skin testing. Additionally the Committee recommended the Prescriber Update article includes a table regarding beta-lactam side chains as well as practical information on alternatives and clarification on the 10% cross-reactivity rate which is frequently quoted.

[Professor D Menkes joined the meeting at this time]

There were no other standing agenda items for which the MARC made further recommendations. The Committee noted that many of the outstanding recommendations made by the MARC will be addressed in the December 2015 edition of the Prescriber Update.

2.2. Medsafe Pharmacovigilance Activities

The Committee noted the report detailing Medsafe’s recent pharmacovigilance activities and obtained clarification on some of these activities.

The Committee discussed the issue of abuse, misuse and drug dependence in association with quetiapine and challenged Medsafe’s assertion that there was not sufficient evidence that this was a problem in New Zealand requiring regulatory action. Medsafe’s conclusion was based on the number of adverse reaction reports provided to CARM and lack of communication of concerns from healthcare professionals directly. The Committee however considered that there was anecdotal evidence of the misuse of quetiapine in New Zealand and alerted Medsafe to this issue.

Recommendation 3

The Committee recommended that Medsafe contacts the National Addictions Centre in Christchurch and the New Zealand Alcohol and Drug Services to obtain further information.

2.3. Prescriber Update Volume 36, Number 4, December 2015

The Committee noted the latest edition of Prescriber Update.

2.4. Quarterly Summary of Medsafe Early Warning System

The Committee noted the quarterly summary of Medsafe early warning system communications.

The Committee discussed the alert communication on Use of Sodium Valproate (Epilim) in Pregnancy. It was noted Medsafe had also published a Prescriber Update article and that the alert includes links to consumer support groups. The data sheets and Consumer Medicine Information (CMI) have also been updated. The CMI was reviewed by the Committee and considered satisfactory. The Committee did not consider further communication was required at this time.

3. PHARMACOVIGILANCE ISSUES

3.1. Matters Referred to the MARC under Section 36 of the Medicines Act 1981

No items.

3.2. Matters Referred to the MARC by Medsafe

3.2.1. Gardasil and complex regional pain syndrome, postural orthostatic tachycardia syndrome and other concerns

Background

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 stains 6, 11, 16 and 18. 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 nine to 45 years of age for the prevention of cervical, vulvar, vaginal and anal cancer, precancerous or dysplastic lesions, genital warts and infection caused by human papillomavirus 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.

The purpose of this paper was to provide information on the possible association between HPV vaccine and Complex Regional Pain Syndrome (CRPS), Postural Orthostatic Tachycardia Syndrome (POTS), Premature Ovarian Failure (POF) and Autoimmune/Inflammatory Syndrome induced by Adjuvants (ASIA).

Discussion

The Committee firstly discussed CRPS. CRPS was considered to be distressing for patients and their families and challenging for health care systems as it is not well understood and comes in many forms. CRPS was noted to be more than limb pain and can include sensory changes, structural changes and vascular colour changes. It can be difficult to assign a diagnosis and consequently there may be potential for cases to be labelled as CRPS without any diagnostic classification. The company was considered to have carried out a complex search to identify cases. However, this can be difficult in case reports when symptoms and/or timings are not reported fully; this makes it difficult to determine if the case actually described CRPS or not.

The Committee discussed the potential influence of emotional reactions to the vaccination procedure. The Committee considered that the impact of an emotional reaction cannot be discounted and that these reactions can influence the autonomic nervous system to produce a systemic illness. The Committee considered that the decision to vaccinate with Gardasil was potentially more emotional than for other activity and the developmental stage at which it is administered. The availability of the internet to gather information could additionally be a potential cause of concern.

The Committee noted that the number of reported cases of CRPS was lower than expected, even if only a very small fraction of the total cases had been reported. The Committee also noted that there was no consistency in the symptoms reported or the onset times. Although it was noted that it may be hard to pinpoint exact onset times in this condition.

The Committee also noted a possible psychosomatic relationship may exist, at least in some cases.

The Committee then discussed the available information around Gardasil and POTS. Autonomic disturbance may be related to both chronic fatigue and POTS and overlap is often seen between the two. There are also similarities with CRPS.

The Committee speculated that the physiological changes seen in POTS are probably common but experiencing symptoms is probably quite uncommon. The Committee also noted that some people won't express the diagnostic symptoms but when they are tested, other indications of POTS may be present. The Committee noted that many cases of POTS occur in association with Chronic Fatigue Syndrome and that patients exhibit signs of deconditioning. For these patients a programme of graded exercise is helpful.

The Committee had a discussion around the prevalence of POTS. The Committee considered a prevalence study is needed to determine the true prevalence of POTS. However the Committee accepted that the prevalence estimates provided by the company reflected the known information. The Committee considered from the information available it is difficult to investigate a causal association. The Committee noted that the influence a person’s emotional state has on the autonomic outflow is very well established. The Committee noted that again there was no consistency in the symptoms reported or the onset time of the reported cases. In addition the number of cases reported was only high in Denmark; the observed cases were similar to the expected number.

The Committee concluded that based on the available information they were not convinced there is a safety concern from the use of Gardasil in respect of CRPS and POTS. The Committee noted that the evidence is based on case reports where attribution is speculative. In terms of site of vaccination and the affected limbs, there is a lack of temporal relationship, and both conditions are known to occur preferentially in the target population of the vaccination so some occurrence of these conditions in association with the vaccination is to be expected. The Committee did not see any clear evidence for an excess of expected cases.

The Committee noted that there had been a very small number of case reports of premature ovarian failure. No concern was raised considering the incidence of this condition and the millions of girls vaccinated.

The Committee also noted the speculative condition of ASIA.

Recommendation 4

The Committee considered that based on the available information there is no safety concern relating to the development of CRPS and POTS after the Gardasil vaccination.

3.2.2. Inhaled corticosteroids and pneumonia.

Background

Corticosteroids are anti-inflammatory drugs and are used in the management of reversible and irreversible airways disease. Treatment with inhaled corticosteroids for chronic obstructive pulmonary disease (COPD) may reduce repeated exacerbations and benefit people with worsening COPD symptoms. However treatment may also increase the incidence of pneumonia while the disease outcome is not altered.

Inhaled corticosteroids are commonly used in combination with long-acting beta2-agonists to reduce COPD exacerbations and all-cause mortality.

The UK's Pharmacovigilance Risk Assessment Committee (PRAC) has started an Article 31 referral of inhaled corticosteroid-containing medicines that are used for COPD to review the risk of pneumonia. This review has been requested by the European Commission.

The risk of pneumonia with these medicines is known. A study in 2007 showed that fluticasone was associated with a higher risk of developing pneumonia than those given placebo. However new studies and combined study results have provided further data on the class of inhaled corticosteroids and the risk of pneumonia.

The purpose of this report was to inform the Committee of new information relating to the use of inhaled corticosteroids for COPD and the risk of pneumonia.

Discussion

The Committee discussed the availability and use patterns of inhaled corticosteroids in New Zealand.

The Committee noted the information available and considered it is difficult to compare studies as there were differences in the studies and pneumonia wasn't a pre-specified end point. Despite the number of potential confounders the Committee considered that there does appear to be a link between the risk of pneumonia and fluticasone and probably also with budesonide. The Committee noted there is stronger evidence for the association between fluticasone and the risk of pneumonia compared to budesonide and the risk of pneumonia.

The presence of potential confounders may be why different rates of pneumonia are seen in the different populations. The Committee did not consider there to be a link between inhaled corticosteroids and increased mortality.

The Committee discussed the current data sheet wording together with the possible increased risk of pneumonia with certain inhaled corticosteroids. The Committee considered that although the agents may differ the evidence is not strong enough to influence prescribing. If there is an increased risk of pneumonia it is likely associated with all inhaled corticosteroids and the data sheets should be aligned.

The Committee considered pneumonia has a large impact from a public health perspective however it is not known how much is in relation to the use of inhaled corticosteroids.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) was discussed in relation to inhaled corticosteroids used in New Zealand. The Committee considered inhaled corticosteroids may be over used in New Zealand however the funding system in New Zealand may not allow New Zealand to follow the GOLD guidelines in entirety and alternatives such as tiotropium and ipratropium are more difficult to access compared to inhaled corticosteriods.

Recommendation 5

The Committee recommended that Medsafe requests the data sheets for budesonide-containing products are updated to include pneumonia as an adverse effect.

Recommendation 6

The Committee recommended that a link to the 2015 Best Practice Advocacy Centre (BPAC) article regarding COPD be added to the MARC’s Remark for this topic.

3.2.3. Hormone replacement therapy and risk of ovarian cancer

Background

Hormone replacement therapy (HRT) describes the use of medicines containing hormones used to supplement or replace hormones. Most commonly, HRT refers to replacement of female hormones no longer made by the body after menopause. The purpose is to treat hot flushes and other symptoms, most commonly in cases of early menopause (before age 45) or when menopausal symptoms are severe.

Although the duration of menopausal symptoms is generally around two years, this varies considerably between women. Whilst around 20% of women experience no symptoms, around 15% report severe symptoms. The use of HRT has changed dramatically over time with a peak use in the late 1990s. The use decreased dramatically after the results of the Women's Health Initiative (WHI) study were published (the aim of this study was to determine any association between heart disease, fractures, breast and colorectal cancer and use of HRT).

In February 2015, a meta-analysis was published in the Lancet describing an increased risk of ovarian cancer in women taking HRT.

The purpose of this paper was to review the Lancet publication and other relevant information to determine whether any regulatory action is required.

Discussion

The Committee was presented with the new information and noted that there is a known association between ovarian cancer and HRT. The Committee noted the current data sheet wording in comparison with the new information.

The Committee considered that in terms of the community and consumers it is important that the information is available for people to make an informed choice around the use of HRT. The Committee considered that the risks are currently well articulated in the data sheets and this new information does not mean that changes are required at this time. However the Committee considered that there was value in having class wording in all the data sheets.

The Committee noted in addition to the data sheets, consumer information is available on the Medsafe website and no further information relating to the use of hormone replacement therapy was considered to be necessary.

The Committee concluded that there is an association between HRT and ovarian cancer. However based on the available information there is a lack of clarity around whether there is a difference between the types of HRT and risks of ovarian cancer.

Recommendation 7

The Committee recommended that Medsafe considers requesting companies to update the data sheet with a class warning such as that used in Europe.

3.2.4. Epoetin beta and increased risk of retinopathy in preterm infants

Background

Epoetin beta is a glycoprotein that stimulates the proliferation and differentiation processes of the erythroid stem cell compartment and also has a stimulatory effect on the proliferation and maturation compartment of the erythron. Epoetin beta therefore leads to an increase in haemoglobin formation and an associated acceleration of cell maturation with reduction in the cell cycle time. A further effect of epoetin beta is the acceleration of reticulocyte maturation and an increase in the release of reticulocytes into the bloodstream.

Red blood cell transfusion in neonates provides an immediate increase in oxygen delivery to tissues and is an effective and rapid intervention to treat acute anaemia. However, transfusion is a temporary measure and has the disadvantages of further inhibiting erythropoiesis and being associated with risks of infection, graft-versus-host disease, transfusion related acute lung injury, transfusion-associated circulatory overload and toxic effects of anticoagulants or preservatives.

On 20 May 2015, the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK published a Drug Safety Update suggesting epoetin beta (NeoRecormon) may increase the underlying risk of retinopathy in premature infants. The summary of product characteristics (data sheet) for epoetin beta has been amended to include this possible risk of retinopathy. The New Zealand data sheet does not list retinopathy. The purpose of this review was to determine whether any regulatory action is required in New Zealand.

Discussion

The Committee noted that retinopathy occurs in premature infants with many different factors and confounders.

The Committee discussed the UK Drug Safety Update and whether retinopathy is also seen with epoetin alpha. It was noted that epoetin alpha does not have the same indication and therefore there is little research associating it with retinopathy. Epoetin alpha and epoetin beta are biosimilars and are interchangeable. Epoetin beta is no longer funded in New Zealand (since 1 March 2015).

The Committee noted the product use in New Zealand. This was not considered to be high.

The Committee concluded that while a potential risk cannot be excluded, the Committee is not convinced that epoetin beta causes retinopathy in premature infants. No regulatory action is required.

Recommendation 8

The Committee recommended that no changes to data sheets are required.

[Dr P Jones left the meeting at this time]

3.2.5. Oral contraceptives containing drospirenone or dienogest and risk of VTE

Background

Oral contraceptives were first introduced in the early 1950’s. Studies soon showed that the use of these preparations was associated with an increased risk of venous thromboembolism (VTE) and that this was dependent on the dose of the oestrogen component. Subsequent studies showed that the risk was much reduced by lowering the dose of oestrogen resulting in the introduction of newer preparations containing < 50 μg oestrogen.

However, with the lower doses of oestrogen came the realisation that the characteristics of the progestogen may also have an influence on the risk of thromboembolism. The earliest progestogens were derived from testosterone or testosterone derivatives, including levonorgestrel and norethisterone. Concerns about potential cardiovascular risks as well as undesirable effects such as acne and hirsutism associated with the androgenicity of these progestogens became apparent. Non-androgenic or anti-androgenic progestogens were developed as a result. These newer progestogens include gestodene, drospirenone and dienogest.

The European Medicines Agency (EMA) initiated a review of combined hormonal contraceptives, particularly of the risk of VTE associated with their use, in February 2013. The review included nine different progestogens, including drospirenone and dienogest. This review was concluded in November 2013 with the EMA's Committee for Medicinal Products for Human Use (CHMP) concluding that the benefits of combined hormonal contraceptives (CHCs) in preventing unwanted pregnancies continue to outweigh their risks, and the well-known risk of VTE with all CHCs is small.

Subsequently, an article by Dinger et al was published in the Contraception journal in 2014. This article was brought to Medsafe’s attention by Family Planning.

The purpose of this paper was to consider the benefits of CHCs containing either drospirenone or dienogest and risk of VTE.

Discussion

The Committee discussed the use of oral contraceptives containing drospirenone and dienogest in New Zealand. The Committee noted that the risk of VTE tends to be higher in the first one or two years of use and that neither of these oral contraceptives is funded in New Zealand.

The Committee noted some studies have shown an increased risk of VTE with third generation oral contraceptives compared to second generation oral contraceptives although more recent studies did not show this risk.

The Committee discussed information on VTE provided in data sheets and consumer medicine information of oral contraceptives containing drospirenone or dienogest. The Committee considered that the data sheets and consumer medicine information contain clear wording which reflects the available information on the risk of venous thromboembolism at this time. Additionally the Committee noted that Consumer Educational Material is available on the Medsafe website regarding hormonal contraceptives and blood clots. This document was also considered to reflect the known information on this risk and provides consumers with information on the benefits and risks of harm of hormonal contraceptives.

Recommendation 9

The Committee recommended that a link to the Consumer Educational Material should be included in the MARC’s Remark on this topic in the next edition of Prescriber Update.

4. MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE

4.1. Centre for Adverse Reactions Monitoring (CARM) Quarterly Reports

4.1.1. Fatal Cases (Causal Cases Only)

Members were given a brief description of the fatal reports for which CARM had assessed the causality to be at least possible.

Review of CARM's Quarterly Report indicated that some prescribing issues may have influenced the development of some serious and fatal adverse reactions. The Committee discussed these cases and wished to highlight the following issues to prescribers:

  • Failure to note MedicAlert or medical practice note warnings about serious adverse drug reactions leading to re-administration of the same medicine.
  • Use of a non-steroidal anti-inflammatory drug (NSAID) with two antithrombotic agents.
  • Administration of a medicine contraindicated in severe renal failure to a patient with creatinine clearance below cut-off point.
  • Administration of an NSAID to a very elderly patient without gastroprotection.
  • Addition of an NSAID to an ACE inhibitor and a diuretic.
Recommendation 10

The Committee recommended that Medsafe highlights the medication error themes discussed in this meeting in the next MARC's Remarks.

4.1.2. Special Populations: Serious Cases Associated with Medicines in Children under 18 years (Causal Cases Only)

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.

4.1.3. Special Populations: Serious Cases Reporting Adverse Events Following Immunisation Terms with Vaccines in Children under 18 years

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.

4.1.4. Special Populations: Serious Non-Fatal Cases Causally Associated with Critical Terms in Patients Over 80 Years

Reports of events occurring in patients over 80 years were briefly outlined for the Committee.

The Committee did not consider any of the reports required further action.

4.1.5. Special Reports: Serious Paediatric Adverse Drug Reactions (ADRs)

The Committee did not consider any of the reports required further action.

5. OTHER BUSINESS

5.1. Therapeutic Products Regulation Project - Update

The Committee was given an update on the therapeutic products regulation project.

5.2. Celebration of 50 years of spontaneous adverse reaction reporting

Dr Michael Tatley, Director of the New Zealand Pharmacovigilance Centre, gave a presentation to the Committee on the history of CARM and adverse reporting in New Zealand.

6. ANNEXES

3.2.1 Gardasil and Complex Regional Pain Syndrome, Postural Orthostatic Tachycardia Syndrome and other concerns

  1. Richards S, Chalkiadis G, Lakshman R et al 2012 'Complex regional pain syndrome following immunisation' Arch Dis Child 97: 913–915.'
  2. Kinoshita T, Abe RT, Hineno A et al 2014 'Peripheral sympathetic nerve dysfunction in adolescent Japanese girls following immunization with the human papillomavirus vaccine'. Intern Med 53: 2185–2200.
  3. Blitshteyn S. 2014 'Postural tachycardia syndrome following human papillomavirus vaccination'. Eur J Neurol. 21:135–139.
  4. Brinth L, Theibel AC, Pors K, Mehlsen J. Suspected side effects to the quadrivalent human papilloma vaccine. Dan Med J. 2015 Apr; 62(4): A5064.
  5. Brinth LS, Pors K, Theibel AC, Mehlsen J. Orthostatic intolerance and postural tachycardia syndrome as suspected adverse effects of vaccination against human papilloma virus. Vaccine. 2015 May 21; 33(22):2602–2605.
  6. CARM cases.

3.2.2 Inhaled Corticosteroids and pneumonia

  1. Global Initiative for Chronic Obstructive Lung Disease. Updated 2015. Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease. [Online]. Available from: www.goldcopd.org/guidelines-global-strategy-for-diagnosis-management.html.
  2. GlaxoSmithKline. 2015. Article 31 response to the European Medicines Authority (EMA) regarding the risk of pneumonia and inhaled corticosteroid containing products for COPD. Response Document. [confidential].
  3. AstraZeneca. 2015. Responses to the PRAC’s List of Questions for AstraZeneca's Inhaled Corticosteroid-Containing Medicinal Products Indicated in the Treatment of Chronic Obstructive Pulmonary Disease (Article 31 Procedure EMEA/H/A-31/1415). Response Document. [confidential].

3.2.3 Hormone replacement therapy and risk of ovarian cancer

  1. Collaborative group on epidemiological studies of ovarian cancer 2015 'Menopausal hormone use and ovarian cancer risk: individual participant meta-analysis of 52 epidemiological studies' Lancet 385: 1835-42.
  2. Greiser CM, Greiser EM and Doeren M 2007 'Menopausal hormone therapy and risk of ovarian cancer: systematic review and meta-analysis' Human Reproduction Update 13: 453-463
  3. Pearce CL, Chung K, Pike MC et al 2009 'Increased ovarian cancer risk associated with menopausal estrogen therapy is reduced by adding a progestin' Cancer 115: 531-539
  4. Zhou B, Sun Q, Cong R et al 2008 'Hormone replacement therapy and ovarian cancer risk: a meta-analysis' Gynecol Oncol 108: 641-51
  5. Beral V, Reeves G, Green J, Bull D, for the Million Women Study Collaborators.2007 Ovarian cancer and hormone replacement therapy in the Million Women Study. Lancet 369: 1703-10.
  6. Bayer response
  7. Novo Nordisk response
  8. Pfizer response

3.2.4 Epoetin beta and increased risk of retinopathy in preterm infants

  1. MHRA. 2015. Drug Safety Update – Epoetin beta (NeoRecormon: increased risk of retinopathy in preterm infants cannot be excluded. URL: https://www.gov.uk/drug-safety-update/epoetin-beta-neorecormon-increased-risk-of-retinopathy-in-preterm-infants-cannot-be-excluded (accessed 20 October 2015).
  2. Ohlsson A, Aher SM. 2014. Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants (review). The Cochrane Library Issue 4. URL: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004863.pub4/epdf (accessed 5 November 2015).
  3. Aher SM, Ohlsson A 2014. Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants (review). The Cochrane Library Issue 4. URL: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004868.pub4/epdf (accessed 5 November 2015).
  4. Roche Products (New Zealand) Limited. 2013. Data sheet – NeoRecormon. URL: www.medsafe.govt.nz/profs/datasheet/n/Neorecormoninj.pdf (accessed 5 November 2015).
  5. Hoffman-La Roche F. 2015. Evaluation of the risk of retinopathy in preterm infants treated with epoetin – results of meta-analysis performed. Auckland: Roche Products (New Zealand) Limited.

3.2.5 Oral contraceptives containing drospirenone or dienogest and risk of VTE

  1. Minutes from the 140th, 144th and 146th MARC meetings
  2. NZ data sheets (Yasmin, Yaz, Qlaira)
  3. Consumer medicine information (Yasmin, Yaz, Qlaira)
  4. European Medicines Agency. 2013. Review of combined hormonal contraceptives containing chlormadinone, desogestrel, dienogest, drospirenone, etonogestrel, gestodene, nomegestrol, norelgestromin or norgestimate. Start of review, assessment report (with annexes), CHMP endorses PRAC recommendation. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Combined_hormonal_contraceptives/human_referral_prac_000016.jsp&mid=WC0b01ac05805c516f (accessed 12 November 2015).
  5. UK Summary of Product Characteristics (Yasmin, Qlaira)
  6. FDA. 2011 & 2012. Safety review update on the possible increased risk of blood clots with birth control pills containing drospirenone. Updated information about the risk of blood clots in women taking birth control pills containing drospirenone. FDA Drug Safety Communication. Available from: http://www.fda.gov/Drugs/DrugSafety/ucm273021.htm and http://www.fda.gov/Drugs/DrugSafety/ucm299305.htm (accessed 5 November 2015).
  7. Dinger J, Bardenheuer K, Heinemann K. 2014. Cardiovascular and general safety of a 24-day regimen of drospirenone-containing combined oral contraceptives: final results from the International Active Surveillance Study of Women Taking Oral Contraceptives. Contraception 89: 253–263.
  8. Bayer. 2013. Yaz/Yasmin combined oral contraceptive pills and venous thromboembolism risk. Executive Summary. [confidential].
  9. Bayer. 2013. Combined hormonal contraceptives containing dienogest/estradiol valerate. Response Document. [confidential].
  10. Medsafe. 2011. Combined oral contraceptives and VTE – putting the risk into perspective. Prescriber Update 32(1): 2 [Online] Available from: www.medsafe.govt.nz/profs/PUArticles/CombinedOralContraceptives.htm (accessed 17 November 2015).
  11. Medsafe. 2014. Hormonal contraceptives and blood clots. Patient Information Leaflet [Online] Available from: http://www.medsafe.govt.nz/consumers/educational-material/Hormonal Contraceptives.pdf (accessed 17 November 2015).

The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 3pm.

Dr S Jayathissa Chair,
Medicines Adverse Reactions Committee

Dr P Jones Chair,
Medicines Adverse Reactions Committee

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