Names of individuals have also been deleted where that person's contribution is not in the public domain, or will not shortly be so. For example, the names of those to be approached to write an article are deleted, but the names of those who have contributed to a draft article are not usually deleted. In addition, names are not usually deleted when a contribution has been made in an official capacity.

The material listed as being considered on an issue is not intended to be exhaustive.

The recommendations of the Committee are in bold typeface.

Minutes:

The one hundred and forty-ninth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 8 March 2012 in the Board Room, Medsafe, Wellington, New Zealand. The meeting commenced at 9.00 am and closed at 2.55 pm.

marc members present

Associate Professor D Reith (Chair)
Dr L Bryant
Dr N Cole
Associate Professor C Frampton
Associate Professor P Jones
Dr S Jayathissa
Associate Professor D Menkes
Dr S Sime
Dr M Tatley
Dr K Wallis

marc secretariat present

J Carey (MARC Secretary, Medsafe)

MEDSAFE STAFF IN ATTENDANCE

C James (Manager, Clinical Risk Management)
S Kenyon (Senior Advisor, Pharmacovigilance)
R Pollock (Advisor, Pharmacovigilance)
A Taylor (Senior Advisor, Pharmacovigilance)
E Yousuf (Principal Clinical Advisor)

Invited guests and experts IN ATTENDANCE

Dr R Savage

1. Matters of Administration

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting. There were no apologies.

1.2 Minutes of the 148^th MARC Meeting

The minutes of the 148^th meeting of the Committee were accepted as a true and accurate record of the meeting.

1.3 Dates of Future MARC Meetings

The dates for the 2012 MARC meetings were scheduled for 21 June, 13 September, and 6 December.

1.4 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.

1.5 Prescriber Update

1.5.1 Prescriber Update. Volume 33, Number 1. December 2012

Discussion

The Committee noted the latest edition of Prescriber Update.

2. STANDING AGENDA ITEMS

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 from the Medsafe website at www.medsafe.govt.nz/profs/MARC/Minutes.asp.

There were no standing agenda items for which the MARC made further recommendations.

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 Safety of Anti-epileptic Medicines in Pregnancy

Background

The use of anti-epileptic medicines (AEDs) in pregnancy is of concern due to a consistent association with major congenital malformations (MCM) in newborns exposed in utero. It is widely accepted that exposure to AEDs increases the risk of a major congenital malformation to 4-9%, from the background risk of 1-2%. There is a significant risk of hypoxia and subsequent death to the foetus if the mother experiences seizures whilst pregnant. Therefore it is generally considered that the benefits of AED treatment in pregnancy outweigh the risks. It should be noted that Epilim (sodium valproate) is contraindicated in pregnancy in New Zealand (but not in the US or Europe). None of the other anti-epileptics are contraindicated in pregnancy.

In 2009 the MARC reviewed the safety of sodium valproate in pregnancy. As a result of these reviews the sodium valproate data sheet was updated. Recently, data has started to become available to enable a better estimate of the risk associated with individual anti-epileptic medicines.

In February 2011 the FDA issued an alert regarding the risk of development of cleft lip and cleft palate in newborns exposed to topiramate. Medsafe reviewed the data provided by the sponsor and required updates to the data sheet. This alert prompted Medsafe to consider the need to review the safety of other antiepileptic medicines in pregnancy.

This paper presented the results of this review. The review was restricted to medicines funded by PHARMAC at the time the review was initiated in 2011. Information for valproate and topiramate was not specifically included since the reviews for these medicines were completed previously.

In order to provide some background information on the general risk an overview of recent and important literature publications was provided. In common with all studies of this type there were a number of limitations which restrict the applicability of the results, especially when comparing the risk between different medicines and between studies. These limitations included:

Different definitions of congenital malformation.
Different indications for the different medicines, including indications other than epilepsy.
Different time periods of follow up to detect a malformation.
Different methodologies to collect the data - some data sources are dependent on voluntary reporting.
The time period over which the study was conducted, since standards of care have changed over time.
Changes in screening techniques, and differences in how these are used in different countries.
Small samples sizes for individual medicines.
Lack of information on dose and how this may have changed over the course of the pregnancy.
Lack of information on confounding factors in some studies, and lack of information on family history.
Lack of a proper control group.

In order to help complete Medsafe's review relevant sponsors were requested to provide information on the use of their medicine(s) in pregnancy

A summary of the responses was provided to the MARC. The Committee was asked whether there was enough information to identify and/or quantify the risk of birth defects, premature birth and withdrawal symptoms in the neonate associated with the funded anti-epileptics in New Zealand.

Discussion

The Committee noted the 2012 Medsafe report.

The Committee considered each of the anti-epileptic medicines individually.

The Committee agreed that there was sufficient information to identify an increased risk of major congenital malformations (MCM) with phenytoin. The data sheet provides extensive information but no estimate of the actual incidence. The committee overall considered that where possible it would be helpful to prescribers if an estimate of incidence with an individual medicine was provided. The Committee recommended that the company be requested to update the phenytoin data sheet to include an indication of the absolute risk and the margins of error, with a qualifying statement that it is unclear how phenytoin compares with other AEDs.

The Committee noted that ethosuximide is generally used in combination therapy in patients with epilepsy that is difficult to control, and its use as monotherapy is less common. They considered that exposure to ethosuxamide is too low to confirm or refute a risk of MCM, and no changes to the data sheet are necessary at this time, although it was noted that the benefit risk statement could be improved.

The Committee agreed that there is sufficient information to identify an increased risk of MCM with carbamazepine and that the data would support an estimate of the level of risk. They noted the data collected by the EURAP registry over eleven years showed the risk of MCM increased in a dose-dependent manner (lowest with doses under 400mg per day) and considered that this information would be useful for prescribers. They recommended that the company be requested to update the carbamazepine data sheet to include an indication of the level of the increase in risk of MCM including information on the margins of error, along with information regarding the dose-dependent effect.

The Committee noted that phenobarbitone was rarely used for the treatment of epilepsy due to its cognitive effects. They noted that the data sheet contains comprehensive information regarding the use of phenobarbitone in pregnancy. Whilst the Committee agreed that no changes to the data sheet are necessary at this time, it was noted that the benefit risk statement could be improved.

The Committee noted that clonazepam is a benzodiazepine, and as such, the major risk of use during pregnancy is sedation, dependence, and withdrawal symptoms in the infant. The Committee considered that this information was adequately covered in the product data sheet.

The Committee noted that vigabatrin is indicated in adults for refactory epilepsy only and usually in combination with other AEDs. They agreed that there is currently insufficient data to confirm or refute a risk of MCM with vigabatrin. It was noted that the benefit risk statement in the data sheet could be improved. The Committee reviewed the information provided by the manufacturer of levetiracetam (Keppra) following the identification of a potential safety signal of congenital malformations, specifically ventricular septal defect (VSD) associated with exposure to levetiracetam. The Committee agreed that this constituted a safety signal but there was insufficient evidence at this time to conclude an association between levetiracetam and MCM. They concluded that there was sufficient evidence to request that the company provide Periodic Safety Reviews (PSURs) to Medsafe for ongoing monitoring.

Gabapentin (Neurontin) is indicated for the treatment of partial seizures with or without secondarily generalised tonic-clonic seizures who have not achieved adequate control with standard anti-epileptic drugs. The Committee noted that the number of exposures to gabapentin during pregnancy is low and therefore the risk cannot be accurately determined.

The Committee noted that estimates of the risk with regard to oral clefts in association with lamotrigine are lower in more recent publications. They noted that more recently a signal of clubfoot has been identified however there is insufficient evidence to conclude that there is an association. The Committee recommended that the company be requested to update the data sheet with the recalculated rate of oral clefts. The Committee reviewed data which indicated a possible dose effect with lamotrigine (lower risk with doses below 300mg per day), and recommended that the data sheet be updated with this information.

The Committee reviewed the data provided for clonazepam, another benzodiazepine. They noted that it is also used for other indications in some countries and this data was included in the analysis. The Committee considered that the data presented did not provide evidence of a risk requiring data sheet changes. The Committee agreed that although there is an increased risk of MCM in newborns exposed to AEDs in utero, given the seriousness of the potential effects of seizures in pregnancy this risk does not adversely affect the benefit risk balance for these medicines.

Recommendation 1

The MARC recommended that the company be requested to update the phenytoin data sheets to include an indication of the absolute risk, including the margins of error.

Recommendation 2

The Committee recommended that the company be requested to update the carbamazepine data sheet to include an indication of the level of the absolute risk including the margins of error, along with information regarding the possible dose-dependent effect.

Recommendation 3

The MARC recommended that the manufacturer of levetiracetam (Keppra) provide Periodic Safety Reviews (PSURs) to Medsafe for ongoing close monitoring.

Recommendation 4

The Committee recommended that the company be requested to update the lamotrigine data sheet with the recalculated rates for oral clefts and indicate that there may be a dose dependent effect.

3.2.2 Serotonergic agents and the risk of reversible cerebral vasoconstriction syndrome

Background

The purpose of the 2012 Medsafe report was to review the available data on the risk of reversible cerebral vasoconstriction syndrome (RCVS) in association with the use of serotonergic agents including Selective Serotonin Reuptake Inhibitor antidepressants (SSRIs) and triptans.

In February 2011, Medsafe received a case report of RCVS in a patient who had been receiving fluoxetine.

After reviewing this case, along with the available literature on RCVS, Medsafe requested that the sponsors of all SSRI antidepressants and triptans in New Zealand review the risk of RCVS in association with the use of their products. In addition, Medsafe sought information from international medicines regulators on this issue.

RCVS is a unifying term for a number of conditions characterised by acute onset of thunderclap headache (TCH) with evidence of reversible segmental cerebral vasoconstriction. The majority of information on RCVS has come from three large case series conducted in France, Taiwan and the United States. These case series found that RCVS can occur spontaneously (40-75%) or be caused by secondary factors (25-60%). The most commonly implicated secondary factors are the use of vasoactive substances (eg serotonergic agents, illicit drugs or OTC sympathomimetics).

Diagnosis of RCVS requires all of the following:

Presence of recurrent, sudden onset, severe thunderclap headaches; and
Demonstration of segmental vessel constriction (string and beads of the vessels) of the cerebral arteries; and its reversibility (complete or marked normalisation of arteries) within 12 weeks of onset by initial and repeated cerebral angiography such as MRA, CT angiography or conventional angiography.
Exclusion of other causes of thunderclap headache such as aneurysmal subarachnoid haemorrhage, Primary Central Nervous System Arteritis (PCNSA) (see table 2 below), intracerebral haemorrhage, cerebral venous sinus thrombosis, cervicocerebral arterial dissection and pituitary apoplexy.

RCVS is thought to be a rare condition, although most authors agree that it is probably under diagnosed. Although generally considered to be a benign condition, neurological deficits were found to be permanent in 3-6% of patients in two recent large case series (Sattar A et al.2010).

A review of the medicine data sheets revealed that only the sertraline data sheet includes any information on a risk of RCVS. Headache, but not thunderclap headache, is listed in all SSRI data sheets.

Cerebrovascular accidents are listed in the escitalopram and citalopram data sheets but not the other SSRI data sheets.

Although RCVS is not listed in any triptan data sheets, all triptan data sheets include information on the risk of cerebrovascular events occurring although the sumatriptan data sheet contains the most information on the risk. The triptan data sheets also advise against the treatment of atypical headaches.

The Committee was asked to advise whether:

a causal association between the use of serotonergic agents and the development of RCVS has been demonstrated
any regulatory action is recommended
any communication is necessary.

Discussion

The Committee noted the 2012 Medsafe report.

The Committee noted that the term RCVS is a relatively new one which encompasses a diverse range of conditions, and there may be a lack of awareness of the condition amongst health professionals.

The Committee noted that diagnosis requires two angiograms and this is likely to be one of the difficulties surrounding diagnosis and possible under-reporting. They noted that one of the recent case series has indicated that clinical presentation may be enough to confirm diagnosis.

The Committee reviewed the data provided by the product sponsors.

The Committee noted that the review of RCVS by the triptan sponsors highlighted the difficulties in investigating a headache signal in spontaneous reporting data for medicines that are used to treat headache. Cases of RCVS were identified primarily in association with the use of sumatriptan; however in the majority of cases headache onset was prior to administration of sumatriptan, although exacerbation of headache or precipitation of subsequent TCHs could not be ruled out. The Committee agreed that there appeared to be an association with RCVS and the triptans as a class, however, there was insufficient evidence at this time to confirm a causal association.

The Committee noted that the review of RCVS by the SSRI sponsors had identified cases of RCVS in association with the use of duloxetine, sertraline, citalopram, paroxetine and fluoxetine. The Committee discussed a possible class effect and whether information should be included in all SSRI data sheets or only those where confirmed cases of RCVS had occurred. They considered that there was insufficient evidence to confirm a casual association at this time.

The Committee agreed that this was not an easy signal to detect and the syndrome was most likely to be underreported. The Committee considered that raising awareness of RCVS as a syndrome would aid in determining if the association between serotonergic agents and RCVS was causal. The MARC recommended that this issue be added to the M² scheme.

The Committee recommended that a Prescriber Update article be published describing the conditions which comprise RCVS, including severity of headache.

Recommendation 5

The MARC recommended that the issue of RCVS in association with serotonergic agents be added to the M² scheme.

Recommendation 6

The Committee recommended that a Prescriber Update article be published describing the conditions which comprise RCVS, including the severity of headache.

3.2.3 Risk Management Plan : rivaroxaban (Xarelto)

Background

The purpose of this paper is to present the Risk Management Plan (RMP) for rivaroxaban. The Committee are requested to advise Medsafe whether the RMP would be adequate.

Currently, the 10mg rivaroxaban tablet is approved in NZ for the prevention of venous thromboembolism (VTE) in adult patients who have undergone major orthopaedic surgery of the lower limbs (elective total hip replacement, treatment for up to five weeks; elective total knee replacement, treatment for up to two weeks).

Summary of Risk Management Plan

Safety concern	Proposed pharmacovigilance activities (routine and additional)	Proposed risk minimisation activities (routine and additional)
Important identified risks
Haemorrhage	Routine pharmacovigilance activities Additional information from ongoing trials Modified Prescription event monitorng study Drug utilisation database studies Post-marketing non-interventional cohort studies in the VTE prevention population (XA0801; XAMOS study 13802), the SPAF population (XA1101; study 15914) and the VTE treatment population (XA1102; study 15915)	Contraindication in Product information Warning in product information section "Special warnings and precautions for use" Warning in product information section "Interactions" Haemorrhage is listed in the product information section "Adverse effects"
Important potential risks
Increase in LFTs, bilirubin	Routine pharmacovigilance activities Additional information from ongoing trials Post-marketing non-interventional cohort studies (XA0801; XAMOS study 13802, XA1101; study 15914 and XA1102; study 15915) VTE treatment and SPAF indication Drug utilisation database studies	Elevated liver enzymes/bilirubin are listed in the product information.
Important missing information
Patients undergoing major orthopaedic surgery other than elective hip or knee	Routine pharmacovigilance activities Drug utilisation database studies	Product information section "Therapeutic indications" and section "Special warnings and precautions for use"
Patients with severe renal impairment (CrCl < 30 mL/min)	Routine pharmacovigilance activities Post-marketing non-interventional cohort studies (XA0801; XAMOS study 13802, XA1101; study 15914 and XA1102; study 15915)	Product information section dosage(Renal impairment) and section "Special warnings and precautions for use" (Renal impairment)
Remedial pro-coagulant therapy for excessive haemorrhage	Routine pharmacovigilance activities Additional information from ongoing trials Post-marketing non interventional cohort studies (XA0801; XAMOS study 13802, XA1101; study 15914 and XA1102; study 15915)	Product information section "Overdose"
Patients receiving systemic treatment with CYP3A4 and P-gp inhibitors other than azole antimycotics (e.g. ketoconazole) and HIV-protease inhibitors (e.g. ritonavir)	Routine pharmacovigilance activities Modified Prescription event monitoring study Drug utilisation database studies Post-marketing non-interventional cohort studies (XA0801; XAMOS study 13802, XA1101; study 15914 and XA1102; study 15915)	Product information section "Interaction with other medicinal products and other forms of interaction"
Pregnant or breast-feeding women	Routine pharmacovigilance activities Drug utilisation database studies Modified Prescription event monitoring study Post-marketing non-interventional cohort studies (XA1101; study 15914 and XA1102; study 15915)	Product information section "Contraindication" section "Fertility, pregnancy and breast feeding"
Patients with AF and a prosthetic heart valve	Routine pharmacovigilance activities	Product information section "Special warnings and precautions for use" (Patients with prosthetic valves)

Discussion

The Committee noted the 2012 Medsafe report.

The Committee agreed that the Risk Management Plan was acceptable.

3.2.4 Review of the pharmacokinetic interaction between ciclosporin and individual statins

Background

The purpose of the 2012 Medsafe report was to provide the MARC with a review of the available data on the nature and clinical significance of the interaction between ciclosporin and individual statins.

In June 2011 the Food and Drug Administration (FDA) issued a Drug Safety Communication informing health professionals of changes being made to the simvastatin prescribing information to minimise the risk of myopathy. Specifically the FDA advised that the risk of myopathy with the 80mg dose of simvastatin is greater than with other statins with similar low-density lipoprotein cholesterol (LDL-C) lowering efficacy. Therefore, the FDA recommended that the 80mg dose is now only used in patients at high risk for cardiovascular complications who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the risks. In addition, it was announced that a number of medicines, including ciclosporin, would now be contraindicated for use in combination with simvastatin. In November 2011 the New Zealand simvastatin data sheets were similarly updated.

Subsequently, Medsafe was contacted by a New Zealand specialist who expressed concern that New Zealand patients may be changed to atorvastatin which may put them at an even greater risk of myopathy due to the potential for a greater interaction with ciclosporin. In view of this concern, Medsafe reviewed the available literature and international regulatory activity on this issue.

Clinical studies have demonstrated that patients who have undergone solid organ transplantation and in particular those taking ciclosporin or corticosteroids are at high risk of dyslipidaemia, atherosclerosis and cardiovascular disease. As a consequence of this, transplant patients are likely to require statin therapy in addition to their immunosuppressant therapy. This is supported by New Zealand data which showed that approximately 1/3 of patients receiving ciclosporin were also receiving statin therapy.

Myopathy is the most serious adverse reaction to statin therapy. Statin induced myopathy appears to be dose dependent and the risk increases with increasing systemic exposure. Therefore any interaction that increases systemic exposure of the statin is likely to increase the risk of myopathy. It has also been suggested that the risk of myopathy is greater with lipophilic statins. The risk of myopathy does not appear to be related to the magnitude of reduction in LDL cholesterol; therefore it has been suggested that a lower dose of a more potent statin may cause less myopathy than a higher dose of a less potent statin.

A comparison of the metabolism of the individual statins showed that they have different metabolic pathways which includes CYP3A4, OATP2 and P-glycoprotein .. See table 1

Table 1: Characteristics of statins available in New Zealand (from Kahwaji et al, 2006)

Statin	Equipotent Doses(mg/day)S*	Usual daily dosage (mg/day)	CYP metabolism	P glycoprotein substrate	OATP2 substrate	Lipophilic
Atorvastatin	5	10-80	3A4	Yes	Yes	Yes
Pravastatin	20	10-80	None	Yes	Yes	No
Rosuvastatin	?	10-40	2C9 (minor)	No	Yes	No
Simvastatin	10	20-80	3A4	Yes	Possibly	Yes

*Equivalent dose to reduce LDL-cholesterol from baseline by 25-30%.

Ciclosporin has no single major metabolic pathway. It inhibits both CYP3A4 and the membrane transporters OATP2 and P-glycoprotein, and therefore ciclosporin may increase plasma levels of all the statins.

The available pharmacokinetic (PK) data investigating ciclosporin/statin interactions comes largely from uncontrolled studies. A number of authors have summarised the PK data and have concluded that all statins interact with ciclosporin but the magnitude of the interaction is variable. The demonstrated increase in systemic exposure (AUC) varies between studies of the same statin which may indicate that there is significant inter-individual variability in metabolism. Although there have been reports of myopathy with all statin-ciclosporin combinations the clinical significance of the individual statin/ciclosporin interactions is not well defined.

CARM has received six reports of serious muscle reactions and two reports of mild myopathy associated with the concomitant use of simvastatin and ciclosporin. In the majority of cases the patients were receiving doses higher than the previously recommended dose of 10mg when taken with ciclosporin. CARM has not received any reports of serious muscle reactions with the concomitant use of ciclosporin with any other statins.

The Committee was asked to advise on the clinical significance of the documented PK interaction between ciclosporin and the individual statins, with consent for distribution in New Zealand. .

Discussion

The Committee noted the 2012 Medsafe report.

The Committee noted that there are four statins with consent for distribution in New Zealand - simvastatin (also in combination with ezetimibe), atorvastatin, pravastatin and rosuvastatin. The Committee also noted that the first 3 statins are now fully subsidsed by PHARMAC without special authority although at the time of the original enquiry to Medsafe only simvastatin and atorvastatin were available.

Currently, only the simvastatin data sheet contraindicates the concomitant use of ciclosporin, although the rosuvastin data sheet advises against using the combination.

The Committee reviewed the pharmacokinetic data provided. They agreed that although it was clear that all statins undergo a PK interaction with ciclosporin, the available data was inadequate to clearly define the magnitude of the interaction with the individual statin/ciclosporin combinations. The MARC also considered that the available clinical data was inadequate to determine whether or not the individual statin/ciclosporin combinations were associated with the same risk of myopathy.

The Committee discussed the recommendation by one author that pravastatin should be used first line to treat hyperlipidaemia in transplant patients. It was noted that this was due to both its lack of metabolism by CYP 450 enzymes (thus minimising the risk of interaction with other medicines including ciclosporin); and also because it is not lipophilic which has been shown to be associated with a lower risk of myopathy.

The Committee was reassured that patients who have undergone solid organ transplantation are under specialist care and are closely monitored. They agreed that adverse reactions were related to plasma levels, and that patients should be prescribed the lowest possible dose and monitored closely for both effectiveness and possible adverse reactions.

The Committee agreed that there was insufficient data to determine the relative risk of myopathy associated with individual statin/ciclosporin combinations. The MARC recommended that a Prescriber Update article be published summarising the available data on the ciclopsorin/statin interaction. .

Recommendation 7

The Committee recommended that a Prescriber Update article be published summarising the available data on the ciclopsorin/statin.

4 Matters arising from the New Zealand Pharmacovigilance Centre

4.1 Centre for Adverse Reactions Monitoring (CARM) Quarterly Reports

4.1.1 Potential Safety Signals from Single Case Reports

No potential safety signals were identified by CARM this quarter.

4.1.2 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. The Committee were given the option of requesting that any particular reports be discussed at the current or a subsequent meeting if they considered that there may be a safety issue that prescribers should be informed about or for which regulatory action was required.