Microsoft word - prescribing_policy_no_10 lamotrigine_topiramate_levetiracetam 061112

Prescribing of the Antiepileptic Drugs (AEDs) Lamotrigine, Topiramate and Levetiracetam in Patients with Epilepsy NHS Eastern Cheshire, South Cheshire and Vale Royal Clinical Commissioning Groups have agreed principles for the prescribing of the antiepileptic drugs (AEDs) lamotrigine, topiramate and levetiracetam in patients with Epilepsy. The guidance fulfils the recommendations within NICE guidance1 to offer informed choice between branded and generic formulations and optimises the cost effectiveness of prescribing.2 This policy applies to patients with epilepsy only. AEDs should routinely be prescribed generically when used for other indications not associated with seizures, such as neuropathic pain. Phenytoin, carbamazepine and sodium valproate are not included in this policy. These three AEDs are Narrow Therapeutic Index Drugs (NTIDs) that should always be prescribed by brand name for patients with epilepsy. Primary care prescribers, specialists, specialist nurses and other prescribers are asked to prescribe lamotrigine, topiramate and levetiracetam for patients with epilepsy according to the following principles. 1. Consider a generic prescription when initiating or changing therapy, and aim for consistency of supply as specified by NICE guidance. 2. If there is inadequate seizure control whilst taking a Branded form of these AEDs (e.g. Lamictal, Topamax and Keppra) consider changing to the generic form if changing the dose of the medicine. Aim for consistency of supply as specified by NICE guidance. 3. Do not substitute from a brand to a generic if the patient is seizure-free or stabilised with optimal seizure control. 4. Discuss all substitutions with client’s families and carers, highlight any implications, and promote concordance and compliance. 5. Discuss the implications of any change to medication on quality of life and maintenance of a driving licence, so that an informed decision may be made.
1 NICE CG137. The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. January 2012 2 The principles were agreed at the Local Health Economy Medicines Management Meeting on 25 September by representatives of local Trusts (Mid Cheshire and East Cheshire) and the CCGs and based on a paper adapted from work done by Tracey Byerley (pharmacist) for the David Lewis Centre Drugs & Therapeutics Committee. Prescribing Commissioning Policy No.10 Background According to the World Health Organisation (1) a generic drug may be defined as ‘a pharmaceutical product, usually intended to be interchangeable with an innovator product that is manufactured without a licence from the innovator company and marketed after the expiry date of the patent or other exclusive rights’. This would infer bioequivalence. However for a drug to be bioequivalent the pharmacokinetics need to be close to those of the innovator product. Both the Medicines and Healthcare products Regulatory Agency (MHRA) and the Federal Drug Agency (FDA) have the criteria that for a drug to be considered bioequivalent to the innovator, at a 90% confidence interval the area under the plasma curve (AUC) and peak plasma concentrations (Cmax) need to lie within an interval of 80-125%(2,5). So potentially if two different generic drugs were used then the variation in the pharmacokinetics between them could be as great as 45% (4). Although in practice this is unlikely as each generic manufacturer aims to be as close as possible to the innovator (6). For drugs with a narrow therapeutic index (NTID) such as phenytoin and carbamazepine such a range of pharmacokinetics could result in loss of seizure control or lead to toxic side effects. For this reason the intervals at 90% are in a closer range of 90-111% (11) NICE guidance 2012 (3) on the pharmacological interventions in epilepsy states that ‘there should be a consistent supply to a person with epilepsy, of a particular manufacturer’s anti-epileptic drug (AED), unless the prescriber, in consultation with the person and their family and/or carers considers this to not be of a concern’. This highlights the importance of continuity of supply as a person could be treated equally well with a continuous brand of generic, as with the innovator AED. The Evidence There have been documented studies of changing patients from innovator to generic AEDs (2). For phenytoin and carbamazepine outcomes such as increased toxicity, intolerance and or breakthrough seizures were reported. This is not surprising since these are NTID, and there was no evidence that continuity of generic drug was maintained. For lamotrigine there was a state-directed study in Ontario in 2003 (2) where it was decided to switch all patients presenting prescriptions for Lamictal to generic lamotrigine, and to monitor the switchback rates through a database where all prescription details were entered. They found that 12.9% of patients switched back; this was higher than for other drugs studied such as antidepressants and cholesterol lowering drugs. They also found that for those patients with polypharmacy, as a group, they had a higher rate of switchback. The authors concluded these higher rates of switchback could be attributed to a higher incidence of adverse events with the generic rather than brand. However the study was flawed as follows; • There were no investigations into the reasons for the switchbacks which • The use of lamotrigine was not confined to epilepsy only • The study was limited by data derived from claims for payment by the patients for their prescriptions, not actual prescribing data • There were no checks and balances in place to ensure all data entered was correct with regards to billing, dispensing dates, drug doses and codes. There have not been any good head to head trials to give us clearer direction on whether to substitute brand with generic AEDS(7). The Italian working group in 2006 (6) looked at all relevant literature. They concluded that • since the FDA had not been able to document a single example of therapeutic failure when an FDA approved generic AED had been substituted for the branded AED • that there was no reliable evidence against generic AEDs with regards the • and that epilepsy by its nature is not static and can spontaneously fluctuate in its control (which may or may not be due to pharmacological factors) In certain circumstances generic AEDs should be considered. They stated that international opinions are, • avoid substituting NTID such as phenytoin or carbamazepine • if a patient is seizure free do not substitute with generic AEDs • maintain consistency of supply • there is no good evidence of significant differences in bioavailability between branded and generic AEDs – with the exception of phenytoin and carbamazepine (NTIDs) • consideration must be given on the negative impact on quality of life and implications for driving if seizure control is lost • patients, their families and /or carers should be involved in the decision The Department of Health (DOH) (8), when lamotrigine was granted a generic licence, stated that ‘there is no compelling evidence to suggest that switching from the originating brand to the generic alternative will have an adverse clinical outcome. However it is open to prescribers to modify their usual generic prescribing practice, if, in their clinical judgement, the circumstances of individual patients warrant such action.’ Looking at the licence application details for generic lamotrigine by Dr Reddy’s (9), there is close correlation in the bioavailability between the generic and the brand. The presence of food seems to give the closest correlation. The licensing application for topiramate by TechnoPharm LTD(10), demonstrated close correlation at 90%, with the Cmax and AUC having a range of 98-107% of Topamax. There were applications also by Actavis, Arrow Generics and Accord Healthcare Ltd that demonstrated similar results (11,12,13). These applications were granted on the basis of being classed as bioequivalent. There have been generic licences granted for sodium valproate on the basis of bioequivalence (14). However despite the fact that the parameters were met with the 90% values lying within the range of 80 -125% of the innovator drug, the values were not as close to the 100% figures as for generic lamotrigine and topiramate. For levetiracetam the product licence application by Dr Reddy’s (granted) (15) showed that levetiracetam had linear pharmacokinetics and the 90% values for Cmax and AUC were close to 100 % (typically 97-107%). It should be noted that, in primary care, community pharmacies do not generally have sufficient control of the supply chain to guarantee that an individual patient will receive a particular manufacturer’s generic medication, and this risk should be considered and discussed with the patient and carers. Some manufacturers will develop so-called “Branded generics” but this has not yet occurred with lamotrigine, topiramate or levetiracetam. 1. www.who.int/trade/glossary/story034/en/index.html 2. Compulsory generic switching of antiepileptic drugs: high switchback rates to branded compounds compared with other drug classes. Andermann F et al Epilepsia.48(3):464-469,2007 3. NICE 2012 CG137 The epilepsies: the diagnosis and management 4. Antiepileptic drugs: the drawbacks of generic substitution. The Lancet Neurology, vol9, issue3, 227, March 2010. 5. Debate: Substitution of generic drugs in epilepsy: is there cause for concern? Gidal B et al. Epilepsia, 49(suppl. 9):56-62,2008 6. Recommendations of the Italian league against epilepsy working group on generic products of antiepileptic drugs. Perucca E. et al. Epilepsia, 47(suppl.5):16-20,2006 7. Antiepileptic drugs: generic versus branded treatments. Heaney D et al. The Lancet Neurology vol.6, issue5, May 2007 p465-468 8. www.dh.gov.uk/en/Healthcare/Medicinespharmacyindustry/Prescriptions/D treatment for epilepsy: generic lamotrigine. 2 March 2005 9. UKPAR lamotrigine 25,50,100,200mg tablets. PL 08931/0011-14 10. MHRA PAR; TOPIRAMATE 25,50,100,AND 200MG TABLETS PL 11. UKPARTopiramate 25,50,100,200mg film coated tablets. PL 24668/0007-14 12. PAR Topiramate 15mg and 25mg Hard capsules UK/H/1579/001-2/DC, 13. PAR Topiramate 25mg,50mg,100mg, and 200mg film coated tablets PL 14. PAR Orlept 150 & 300mg prolonged release capsule and Orlept LA 500 and 1000mg prolonged release granules PL 14040/0012-5 15. PAR Levetiracetam 250mg, 500mg, 750mg and 1000mg f/c tablets. PL

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