Chapter 20 USE OF DRUGS FOR NEUROLOGICAL DISORDER Sapiah S. 1, Mohd. Sufian A. 1, Norsima Nazifah S. 2, Nurul Faezah M.Y. 2, Khutrun Nada Z. 1, Md. Hanip M.R. 1 1. Kuala Lumpur Hospital, Kuala Lumpur, 2. Sultanah Nur Zahirah Hospital, Kuala Terengganu Introduction: In 2008, there were four major categories of neurological drugs being analysed. These include the antiepileptics (AEDs), drugs for Parkinson s disease (PD), antimigraine preparations and Central Nervous System (CNS) drugs for other nervous system disorders (drugs mainly used to treat vertigo and motor neuron disease). The later drugs were grouped together as other nervous system drugs. This year we also analysed another group of drug (Interferons-β) which is used to treat multiple sclerosis. AEDs remained the largest group of neurological drugs being dispensed with the total utilisation of 1.5757 DDD/1000 population/day. This can be explained by the used of AEDs for other indications, including neuropathic pain, bipolar affective disorder and generalised anxiety disorder. 1 The second largest drugs being dispensed was antiparkinson drugs (0.8784), other nervous system drugs (0.8247), interferon-β (0.0734) and antimigraine preparations (0.068). Generally there is a significant reduction in the utilisation of AEDs and antimigraine mainly in the private sector while usage in the public sector (MOH, Universities Hospitals and Armed-Forces Hospitals) showed an increment in all group of drugs. The changes in the trend of prescribing were probably contributed by the slow economic growth worldwide in 2008, which also affected Malaysia. Antiepileptics Drugs: Phenytoin was the most commonly prescribed AED with 0.507 DDD/1000 population/day, followed by valproic acid, carbamazepine, and phenobarbital (0.4076 DDD/1000 population/day, 0.323 DDD/1000 population/day, and 0.0839 DDD/1000 population/day respectively). The utilisations of these older AEDs were lower compared to 2007 due to new trend of management towards usage of new generation of AEDs. The overall dispensing trend for the new generation of AEDs showed reduction in 2008, especially for levetiracetam which showed tremendous reduction (0.0383 DDD/1000 population/day) as compared to 2007 (0.0752 DDD/1000 population/day) mainly in the private sector (0.0099 DDD/1000 population/day and 0.0538 DDD/1000 population/day respective years). However, gabapentin showed a slight increment in utilisation in public sector which is used mainly for neuropathic pain. The reversed trend was observed in the private sector, probably due to the introduction of pregabalin for the same indication. The utilisation of other AEDs such as vigabatrin, oxcarbazepine, ethosuximide and primidone were very low since they were used mainly by the university hospitals and private sectors. Anti-Parkinson Drugs: The five main classes of drugs used for PD are the levodopa (+ peripheral dopamine decarboxylase inhibitors), dopamine agonists (ergot and non-ergot), anticholinergics, adamantane derivatives and the catechol-o-methyltransferase inhibitors. 2 Trihexyphenidyl (Artane) was the most commonly prescribed drug for tremor in PD with 0.6022. It is also widely used for the prevention and treatment of drug-induced extrapyramidal syndrome (EPS). 2 Levodopa and decarboxylase inhibitor persistently remains the gold standard treatment in PD 2 with the usage of 0.1822 DDD/1000 population/day. In 2008, the usage of pramipexole and ropinirole were similar but a huge jump in utilisation of pramipexole was observed compared to 2007; (0.0013 DDD/1000 population/day to 0.0042 DDD/1000 population/day). There was remarkable reduction in piribedil; this may be due to the lack of neuroprotective effect compared with non-ergot dopamine agonist. 2 Comparing other enzyme inhibitor groups, selegiline was dispensed more frequently entacapone, 0.0515 DDD/1000 population/day and 0.0114 DDD/1000 population/day, respectively. 123
Anti-migraine preparations: The total utilisation of antimigraine preparation in Malaysia was 0.068 DDD/1000 population/day which showed a reduction compared to utilisation in 2007. Flunarizine is the preferred drugs used for prophylaxis of migraine in Malaysia and the utilization in 2008 is 0.0635 DDD/1000 population/day while the usage of pizotifen is 0.0238 DDD/1000population/day. For drugs used in abortive migraine attack, the utilisation of sumatriptan is 00006 DDD/1000 population/day. Ergotamine and combination ergotamine utilisation in public sector is generally low but their usage is more preferred in private sector. Ergotamine combination excluding psycholeptics showed a utilisation records of 0.038 DDD/1000 population/day in private sector compared to only 0.0004 DDD/1000 population/ day in public sector. In general, similar pattern of utilisation for antimigraine preparations can be seen in Australia whereby selective serotonin (5HT 1 ) receptor agonist ranked the highest followed by ergot alkaloids. 3 Other nervous system drugs: Other nervous system drugs: Other nervous system drugs are categorised as parasympathomimetics, antivertigo and riluzole. Parasympathomimetics drugs such as neostigmine and pyridostigmine contributed to 0.1 DDD/1000 population/day. This finding was comparable to Finland statistic at 0.19, suggestive of its low prevalence of Myasthenia Gravis worldwide. 4 In Finland and Australia, the only antivertigo drug listed is betahistine at 2.37 and 24.00, respectively. 3,4 In Malaysia, total utilisation of antivertigo is 0.7245 DDD/1000 population/day with betahistine ranked the highest at 0.4006 DDD/1000 population/day. This indicates that the other two antivertigo preparation, cinnarizine and flunarizine were mainly used for other indication such as antimigraine. Finally, riluzole which is used for motor neuron disease, it usage stands at 0.0001 DDD/1000 population/day in Malaysia compared to Finland and Australia stand at 0.03 and 0.10, respectively. 3,4 Interferon: The immunomodulating drugs, namely Interferon-β 1-a (Rebif) and Interferon-β 1-b (Betaferon) were used in treating Remitting-Relapsing Multiple Sclerosis (RRMS). The total utilisation were 0.0734 and <0.0001DDD/1000 population/day, respectively. There was an increasein utilisation of Rebif by 0.0694 DDD/1000 population/day from 2007 which is due to the inclusion of the drug into the MOH drug formulary. The utilisation of Betaferon was very low because it has not been listed in MOH drug formulary. Table 20.1: Use of Drugs for Neurological Disorder, in DDD/1000 population/day 2007-2008 N02C Antimigraine preparations 0.0803 0.0680 N03 Antiepileptics 1.6553 1.5757 N04 Anti-parkinson drugs 0.8105 0.8784 N07 Other nervous system drugs 0.9097 0.8247 Table 20.2: Use of Anti-Epileptics by Drug Class, in DDD/1000 population/day 2007-2008 N03A Antiepileptics 1.6553 1.5757 N03A A Barbiturates and derivatives 0.1072 0.0846 N03A B Hydantoin derivatives 0.4797 0.5070 N03A D Succinimide derivatives <0.0001 <0.0001 N03A E Benzodiazepine derivatives 0.0537 0.0565 N03A F Carboxamide derivatives 0.3409 0.3241 N03A G Fatty acid derivatives 0.4391 0.4078 N03A X Other antiepileptics 0.2346 0.1957 124
Table 20.3: Use of Anti-Epileptics by Drug Class and Agents, in DDD/1000 population/day 2007-2008 N03A A N03A A02 N03A A03 N03A B N03A B02 N03A D N03A D01 N03A E N03A E01 N03A F N03A F01 N03A F02 N03A G N03A G01 N03A G04 N03A X N03A X09 N03A X11 N03A X12 N03A X14 N03A X16 Barbiturates and derivatives Phenobarbital Primidone Hydantoin derivatives Phenytoin Succinimide derivatives Ethosuximide Benzodiazepine derivatives Clonazepam Carboxamide derivatives Carbamazepine Oxcarbazepine Fatty acid derivatives Valproic acid Vigabatrin Other antiepileptics Lamotrigine Topiramate Gabapentin Levetiracetam Pregabalin Public 0.0809 0.0710 Private 0.0225 0.0129 Total 0.1033 0.0839 Public 0.0010 0.0007 Private 0.0029 <0.0001 Total 0.0039 0.0007 Public 0.4354 0.4757 Private 0.0444 0.0313 Total 0.4797 0.5070 Public <0.0001 <0.0001 Total <0.0001 <0.0001 Public 0.0429 0.0430 Private 0.0108 0.0135 Total 0.0537 0.0565 Public 0.3139 0.2881 Private 0.0261 0.0349 Total 0.3400 0.3230 Public 0.0001 0.0001 Private 0.0008 0.0010 Total 0.0009 0.0011 Public 0.3718 0.3659 Private 0.0671 0.0417 Total 0.4389 0.4076 Public <0.0001 <0.0001 Private 0.0001 <0.0001 Total 0.0002 0.0002 Public 0.0525 0.0467 Private 0.0034 0.0033 Total 0.0559 0.0500 Public 0.0127 0.0133 Private 0.0061 0.0019 Total 0.0187 0.0153 Public 0.0476 0.0585 Private 0.0370 0.0327 Total 0.0846 0.0912 Public 0.0213 0.0284 Private 0.0538 0.0099 Total 0.0752 0.0383 Public <0.0001 0.0001 Private 0.0002 0.0008 Total 0.0002 0.0010 125
Table 20.4: Use of Anti-Parkinson by Drug Class, in DDD/1000 population/day 2007-2008 N04A Anticholinergic agents 0.5444 0.6048 N04A A Tertiary amines 0.5436 0.6026 N04A C Ethers of tropine or tropine derivatives 0.0008 0.0022 N04B Dopaminergic agents 0.2662 0.2735 N04B A Dopa and dopa derivatives 0.1794 0.1866 N04B B Adamantane derivatives 0.0069 0.0076 N04B C Dopamine agonists 0.0209 0.0165 N04B D Monoamine oxidase B inhibitors 0.0472 0.0515 N04B X Other dopaminergic agents 0.0117 0.0114 Table 20.5: Use of Anti-Parkinson by Drug Class and Agents, in DDD/1000 population/day 2007-2008 N04A A N04A A01 N04A A04 N04A C N04A C01 N04B A N04B A02 N04B A03 N04B B N04B B01 N04B C N04B C01 N04B C02 N04B C04 N04B C05 N04B C08 Tertiary amines Trihexyphenidyl Procyclidine Ethers of tropine or tropine derivatives Benzatropine Dopa and dopa derivatives Levodopa and decarboxylase inhibitor Levodopa, decarboxylase inhibitor and COMT inhibitor Adamantane derivatives Amantadine Dopamine agonists Bromocriptine Pergolide Ropinirole Pramipexole Piribedil Public 0.5051 0.5639 Private 0.0378 0.0384 Total 0.5429 0.6022 Public 0.0007 0.0004 Private <0.0001 <0.0001 Total 0.0007 0.0004 Public 0.0008 0.0022 Total 0.0008 0.0022 Public 0.1574 0.1615 Private 0.0174 0.0207 Total 0.1748 0.1822 Public 0.0034 0.0031 Private 0.0013 0.0013 Total 0.0046 0.0044 Public 0.0042 0.0054 Private 0.0027 0.0022 Total 0.0069 0.0076 Public 0.0005 - Private <0.0001 0.0002 Total 0.0005 0.0002 Public - - Total - - Public 0.0053 0.0037 Private 0.0013 0.0004 Total 0.0067 0.0040 Public 0.0002 0.0033 Private 0.0012 0.0009 Total 0.0013 0.0042 Public 0.0107 0.0067 Private 0.0016 0.0014 Total 0.0123 0.0081 126
N04B D Monoamine oxidase B inhibitors Public 0.0421 0.0434 N04B D01 Selegiline Private 0.0051 0.0081 Total 0.0472 0.0515 N04B X Other dopaminergic agents Public 0.0109 0.0108 N04B X02 Entacapone Private 0.0008 0.0006 Total 0.0117 0.0114 Table 20.6: Use of Antimigraine Preparations by Drugs Class, in DDD/1000 population/day 2007-2008 N02C Antimigraine preparations 0.0803 0.0680 N02C A Ergot alkaloids 0.0493 0.0382 N02C C Selective serotonin (5HT 1 ) agonists 0.0074 0.0060 N02C X Other antimigraine preparations 0.0236 0.0238 Table 20.7: Use of Antimigraine Preparations by Drugs Class and Agents, in DDD/1000 population/day 2007-2008 N02C A Ergot alkaloids Public - <0.0001 N02C A02 Ergotamine Private 0.0006 0.0001 Total 0.0006 0.0002 Public 0.0014 0.0004 N02C A52 Ergotamine, combinations excl. psycholeptics Private 0.0473 0.0376 Total 0.0487 0.0380 N02C C Selective serotonin (5HT1) agonists Public 0.0036 0.0024 N02C C01 Sumatriptan Private 0.0039 0.0036 Total 0.0074 0.0060 N02C X Other antimigraine preparations Public 0.0198 0.0166 N02C X01 Pizotifen Private 0.0039 0.0073 Total 0.0236 0.0238 Public - - N02C X02 Clonidine Private <0.0001 - Total <0.0001 - Table 20.8: Use of Other Nervous System Drugs by Drug Class, in DDD/1000 population/day 2007-2008 N07A Parasympathomimetics 0.1046 0.1000 N07A A Anticholinesterases 0.1046 0.1000 N07C Antivertigo preparations 0.8049 0.7245 N07C A Antivertigo preparations 0.8049 0.7245 N07X Other nervous system drugs 0.0002 0.0001 N07X X Other nervous system drugs 0.0002 0.0001 127
Table 20.9: Use of Other Nervous System Drugs by Drug Class and Agents, in DDD/1000 population/day 2007-2008 N07A A Anticholinesterases Public 0.0162 0.0169 N07A A01 Neostigmine Private 0.0132 0.0158 Total 0.0294 0.0327 Public 0.0705 0.0635 N07A A02 Pyridostigmine Private 0.0046 0.0038 Total 0.0751 0.0674 Public - - N07A A03 Distigmine Total - - N07C A Antivertigo preparations Public 0.1880 0.2078 N07C A01 Betahistine Private 0.2024 0.1928 Total 0.3885 0.4006 Public 0.1132 0.0925 N07C A02 Cinnarizine Private 0.2304 0.1679 Total 0.3436 0.2604 Public 0.0178 0.0180 N07C A03 Flunarizine Private 0.0531 0.0455 Total 0.0709 0.0635 N07X X Other nervous system drugs Public - <0.0001 N07X X02 Riluzole Private 0.0002 0.0001 Total 0.0002 0.0002 Table 20.10: Use of Interferons by Drug Class and Agents, in DDD/1000 population/day 2007-2008 L03A B Interferons Public 0.0038 0.0730 L03A B07 Interferon beta-1a Private 0.0002 0.0004 Total 0.004 0.0734 Public - <0.0001 L03A B08 Interferon beta-1b Private <0.0001 <0.0001 Total <0.0001 <0.0001 References: 1. Epilepsy Council, Malaysian Society of Neurosciences. Malaysian Consensus Guidelines on the Management of Epilepsy 2010 2. Malaysian Parkinson s Disease Association (MPDA). Malaysian Consensus on Parkinson s Disease 2006 3. Australian Government Department of Health and Ageing. Australian Statistics on Medicines. 2008 4. Finnish Statistic on Medicine 2009 5. WHO Collaborating Centre for Drug Statistics Methodology, Guidelines for ATC Classification and DDD Assignment 2011. Oslo 2010 128