595

Carbamazepine UpdateAFTER a slow start due to, as it turned out,

unwarranted concern regarding its propensity to

produce blood dyscrasias, carbamazepine has slowlyincreased its market share to become the best-sellinganticonvulsant in the world. The drug was

synthesised by Schindler (at Geigy) in 1953 as partof a programme investigating analogues of

chlorpromazine. Its anticonvulsant propertiesremained undetected for some years, and the firstclinical study in epilepsy was not done until 1963.Carbamazepine has proven efficacy in the prophylaxisof generalised tonic-clonic and partial seizuresl-3 but isnot appropriate treatment for absences or myoclonicepilepsy. It remains the drug of choice for trigeminalneuralgia and there is much interest in its

psychotropic properties--especially in the

prophylaxis of mania. 4The pharmacokinetics of carbamazepine are of

great relevance to its clinical use. Oral absorption isslow, with concentrations peaking around 4 hoursafter a dose; overall bioavailability, however,

1. Gram L, Bentsen KD, Parnas J, Flachs H. Controlled trials in epilepsy. a review.Epilepsia 1982; 23: 491-519.

2. Callaghan N, Kenny RA, O’Neill B, Crowley M, Groggini T. A prospective studybetween carbamazepine, phenytoin and sodium valproate as monotherapy inpreviously untreated and recently diagnosed patients with epilepsy. J NeurolNeurosurg Psychiatry 1985; 48: 639-44.

3. Mattson RH, Cramer JA, Collins JF, et al. Comparison of carbamazepine,phenobarbital and primidone in partial and scondary generalised tonic-clonicseizures. N Engl J Med 1985; 313: 145-51.

4. Crawford R, Silverstone T, eds. Carbamazepine in affective disorder. Int ClinPsychopharmacol 1987; 2 (suppl) 1

approaches 90%.5 The drug is eliminated by liverpartly in the form of carbamazepine-10,11-epoxide, ametabolite that not only contributes to itsanticonvulsant and antineuralgic propertiesS but alsois implicated in its neurotoxic side-effects.6 Childrenmetabolise carbamazepine faster than do adults andmay require larger doses to achieve comparable serumlevels.’ 7

Carbamazepine is a powerful enzyme inducer, andaccelerates its own metabolism8 as well as that of manyother lipid-soluble drugs.9 The elimination half-life,initially 24-36 hours, falls to around 12 hours onchronic dosing and is even lower in patients receivingcarbamazepine in combination with other enzyme-inducing anticonvulsants such as phenytoin or

phenobarbitone. 8 Autoinduction of metabolism

produces a variable but dose-dependent fall in steady-state concentrations1O which can result in

breakthrough seizures.ll The extent of this processcontributes to the three-fold variation in trough andpeak concentrations found in patients taking the samedose12-which is one reason for measuring the

circulating concentration. 13Pharmacokinetic interactions with carbamazepine

are common. 14 The drug accelerates the breakdown ofthe components of the oral contraceptive pill,necessitating for most women a daily oestrogen dose of35-100 g.1S Carbamazepine also induces themetabolism of corticosteroids, theophylline,haloperidol, and warfarin.9 Conversely, withdrawal ofcarbamazepine will be followed by a slow rise inconcentration of the target drug which can produceunexpected toxicity. 16 The property of stimulating itsown metabolism makes carbamazepine especiallysusceptible to inhibitory interactions since there isavailable a pure population of hepatic mono-

oxygenase enzymes to which an inhibitor can bind.Central nervous side-effects associated with

increasing carbamazepine concentrations can be

precipitated by cimetidine, danazol, dextro-

propoxyphene (in co-proxamol), diltiazem,

5. Bertilsson L, Tomson T. Clinical pharmacokinetics and effects of carbamazepine andcarbamazepine 10,11 epoxide-an update. Clin Pharmacokinet 1986; 11: 179-98.

6. Gillham RA, Williams N, Weidmann K, Butler E, Larkin JG, Brodie MJ.Concentration-effect relationships with carbamazepine and its epoxide onpsychomotor and cognitive function in epileptic patients. J Neurol NeurosurgPsychiatry 1988; 51: 929-33.

7. Rylance GW, Moreland TA, Butcher GM. Carbamazepine dose frequencyrequirements in children. Arch Dis Child 1979; 54: 454-58.

8. Eichelbaum M, Tomson T, Tybring G, Bertillson L. Carbamazepine metabolism inman: induction and pharmacogenetic aspects. Clin Pharmacokinet 1985; 10: 80-90.

9. McInnes GT, Brodie MJ. Drug interactions that matter-a critical reappraisal. Drugs1988; 36: 83-110.

10. Rapeport WG, McInnes GT, Thompson GG, Forrest G, Park BK, Brodie MJ.Hepatic enzyme induction and leucocyte delta aminolaevulinic add synthaseactivity. studies with carbamazepine. Br J Clin Pharmacol 1983; 16: 133-37.

11. Macphee GJA, Brodie MJ. Carbamazepine substitution in severe partial epilepsy:implication of autoinduction of metabolism. Postgrad Med J 1985; 61: 779-83.

12. Macphee GJA, Butler E, Brodie MJ. Intradose and circadian variation in circulatingcarbamazepine and its epoxide in epileptic patients: a consequence of autoinductionof metabolism. Epilepsia 1987, 28: 286-94.

13. Brodie MJ, Feely J. Practical clinical pharmacology. Therapeutic drug monitoring andclinical trials. Br Med J 1988; 296: 1110-14.

14 Baciewicz AM. Carbamazepine drug interactions. Ther Drug Monit 1986; 8: 305-17.15 Mattson RH, Cramer JA, Damey PD, Naftolin F Use of oral contraceptives by

women with epilepsy. JAMA 1986; 256: 238-40.16. Jann MW, Ereshefsky L, Saklad DR, et al. Effect of carbamazepine on plasma

halopendol levels. J Clin Psychopharmacol 1985; 5: 106-09.

596

erythromycin, isoniazid, verapamil, and viloxazine.9’aThe less predictable neurotoxic interaction withlithium (confusion, disorientation, drowsiness, ataxia,tremor, and hyperreflexia) is not associated withraised concentrations of either drug.17

Interactions between carbamazepine and otheranti-epileptic drugs are complex and are a good reasonin themselves for preferring monotherapy.Carbamazepine increases the clearances of clobazam,clonazepam, ethosuximide, and sodium valproate.Mutual enzyme induction or inhibition in patientstreated with concomitant phenobarbitone, phenytoin,or primidone can result in a small rise or fall in

steady-state concentrations of either or bothanticonvulsants.18 This is another situation in which

monitoring carbamazepine concentrations can be

helpful.13 Sodium valproate, in addition, inhibits thebreakdown of carbamazepine and, probably moreimportantly, that of its active epoxide metabolite.19

In the long-term, carbamazepine is safe andeffective. Rash can be troublesome at the start in up to5% of patients.2o Reversible mild leucopenia mayoccur but does not demand discontinuation of therapyunless accompanied by clinical or bacteriologicalevidence of infection. Routine monitoring of white cellnumbers is unnecessary. Blood dyscrasias and toxichepatitis have been reported but are rare.

Carbamazepine has been implicated in the productionof hypocalcaemia in sedentary patients in temperateclimates-presumably the result of increasedmetabolism of 25-hydroxycholecalciferol down a

wastage pathway-but frank osteomalacia arises lessoften than with phenytoin or phenobarbitone. At highconcentrations, carbamazepine has an antidiuretic-hormone-stimulating effect which is particularlytroublesome in patients with cardiac failure and in theelderly.21 Mild symptomless hyponatraemia is not

uncommon; confusion, fluid retention, and increasedseizure frequency associated with serum sodiumconcentrations below 120 mmol/1 are unusual.Orofacial dyskinesias and cardiac arrhythmias presentoccasional difficulties. There is anecdotal evidence to

implicate carbamazepine as a minor teratogen, with anincreased incidence of craniofacial defects, fingernailhypoplasia, and developmental delay22-a pattern notunlike that found in the fetal hydantoin syndrome.23

Although carbamazepine does not produceimportant cognitive impairment like high-dose

17. Shukla S, Godwin CD, Long LEB, Miller MG. Lithium-carbamazepineneurotoxicity and risk factors. Am J Psychiatry 1984; 141: 1604-06.

18. Zielinski JJ, Haidukewych D. Dual effect of carbamazepine-phenytoin interaction.Ther Drug Monit 1987; 9: 21-23.

19. Macphee GJA, Mitchell J, Wiseman L, et al. Effect of sodium valproate oncarbamazepine disposition and psychomotor profile in man. Br J Clin Pharmacol1988; 25: 59-60.

20. Beghi E, Di Mascio R, Tognoni G. Adverse effects of anticonvulsant drugs—a criticalreview. Adv Drug React Ac Pois Rev 1986; 2: 63-86.

21. Troupin AS. Carbamazepine re-examined. In: Pedley TA, Meldrum BS, eds. Recentadvances in epilepsy 1. Edinburgh: Churchill Livingstone, 1983: 47-56.

22. Jones KJ, Lacro RV, Johnson KA, Adams J. Pattern of malformations in children ofwomen treated with carbamazepine during pregnancy. N Engl J Med 1989; 320:1661-66.

23. Hopkins A. Epilepsy and anticonvulsant drugs. Br Med J 1987; 294: 497-501.

phenytoin,24 patients commonly complain of mildneurotoxic side-effects (nausea, headache, drowsi-ness, diplopia, and ataxia), especially at the start oftherapy. Symptoms are worst around 2 hours after adose and may be a function of rapid passage of thedrug across the blood-brain barrier.25-26 Tolerancedoes develop but these complaints often determinethe ceiling to dosage, especially in patients withrefractory epilepsy. 27 They can be overcome byprescribing three or even four daily doses,28 but at theexpense of compliance.29 These intermittent andirritating side-effects reflect the large diurnalfluctuations in carbamazepine concentration.30--32Variation in circulating concentrations within a

dosage interval of up to 100%"" makes the targetrange of 4--10 mg/1 imprecise13 and provides therationale for the recent introduction of a controlled-release formulation.New formulations of established drugs are often

marketed with considerable razzmatazz. The reasonsfor their introduction may be little more thancommercial. Before recommending such a new

preparation, there must be evidence of "improved"pharmacokinetics and, at least as important,pharmacodynamic advantage. Ciba-Geigy haveformulated carbamazepine in a crystalline matrix inEurope and are considering an osmotic deliverysystem for the United States-perhaps hedging theirbets? There are other companies, too, competing forthis market.33 Preliminary uncontrolled studies withCiba-Geigy’s European formulation suggestsubstantial reduction in intra-dose fluctuations of

carbamazepine concentrations,31-35 and this has beenquantified at 50% in a small controlled comparison.36Overall bioavailability of the two preparations lookssimilar although it may vary for individual patients.3’Evidence of pharmacodynamic advantage for the new

24. Trimble MR. Anticonvulsant drugs and cognitive function: a review of the literature.Epilepsia 1987; 28: S37-45.

25. Lesser RP, Pippenger CE, Luders H, Dinner DS. High-dose monotherapy intreatment of intractable seizures. Neurology 1984; 34: 707-11.

26. Macphee GJA, McPhail EM, Butler E, Brodie MJ. Controlled evaluation of asupplementary dose of carbamazepine on psychomotor function in epilepticpatients. Eur J Clin Pharmacol 1986; 31: 195-99.

27. Rapeport WG. Factors influencing the relationship between carbamazepine plasmaconcentration and its clinical effects in patients with epilepsy. Clin Neuropharmacol1985; 8: 141-49.

28. Brodie MJ. The optimum use of anticonvulsants. Practitioner 1985; 289: 921-27.29. Cramer JA, Mattson RH, Prevey ML, Scheyer RD, Ouellette VL. How often is

medication taken as prescribed? A novel assessment technique. JAMA 1989; 261:3273-77.

30. Hoppener RJ, Kuyer A, Meijer JWA, Hulsman J. Correlation between dailyfluctuations of carbamazepine serum levels and intermittent side effects. Epilepsia1980; 21: 341-50.

31. Riva R, Albani E, Ambrosetto G, et al. Diurnal fluctuations in free and total

steady-state plasma levels of carbamazepine and correlation with intermittent sideeffects. Epilepsia 1984; 25: 476-81.

32. Tomson T. Interdose fluctuations in plasma carbamazepine concentration determineintermittent side-effects. Arch Neurol 1984; 41: 840-34.

33. Sivenius J, Heinonen E, Lehto H, et al. Reduction of dosing frequency ofcarbamazepine with a slow-release preparation. Epilepsy Res 1988; 2: 32-36.

34. Kramer G, Besser R, Katzmann K, Theisohn M. Slow-release carbamazepine in thetreatment of epilepsy. Acta Neurol 1985; 12: 70-74.

35. May T, Rambeck B. Fluctuations of carbamazepine concentrations during the day fortwo slow-release preparations. Ther Drug Momt 1989; 11: 21-24.

36. Larkin JG, McLellan A, Munday A, Sutherland M, Butler E, Brodie MJA double-blind comparison of conventional and controlled-release carbamazepinein healthy subjects. Br J Clin Pharmacol 1989; 87: 313-22.

37. Canger R, Belvedere D, Canevini MP, et al. Studio multicentrico, in doppio deco,cross-over, di confronto tra CBZ informulazione convenzionale ed a rilasciocontrollato (CR). Boll Lega It Epil 1988; 62/63: 419-21.

597

formulation is only just emerging. Early work pointsto better tolerability38 and perhaps an opportunity forbetter seizure control. 37 More data are needed.Who should receive controlled-release carbam-

azepine ? It is worth trying in patients receivinghigh-dose carbamazepine, whether well or poorlycontrolled, who complain of intermittent diplopia,headache, nausea, dizziness, and tiredness. Many willbe taking the drug in three or four divided doses. Withthe new formulation a twice-daily regimen is possiblefor all patients and once-daily administration mayturn out to be suitable for some.39 In changing over, anidentical daily dose can be substituted. Theoretically,controlled-release carbamazepine should also provide"gentler" introduction of the drug without the highpeaks associated with the original formulation.Sustained or controlled-release formulations are

invariably more expensive and the "new"

carbamazepine is no exception. Nevertheless, thereare real difficulties in formulating carbamazepine andcare must be taken not to be seduced too readily byparsimony in prescribing when consistent absorptioncharacteristics are essential for therapeutic efficacy.Epilepsy is too dangerous a condition to compromisepatient care for a small financial saving. If the promiseinherent in its improved kinetic profile is borne out byproper trials, the controlled-release formulation willbe the one to use.

Long-term Survival in BiliaryAtresia

LONG-TERM survival of patients who have

undergone surgical treatment for extrahepatic biliaryatresia in early infancy represents a major advance inpaediatric surgery during the past 30 years. 1 in 14 000infants are born with this sclerosing inflammatorylesion of the biliary tree,l which if untreated causesearly death from cirrhosis and liver failure. Theconventional surgical technique of biliary entericanastomosis can achieve bile flow in the rare infantwho proves at laparotomy to have residual segments ofhepatic ducts, but in most infants the destruction ofthe extrahepatic bileducts extends up to the capsule ofthe liver. Intrahepatic damage with fibrosis or

cirrhosis is always present at the time of diagnosis.Most cases of biliary atresia were believed to beuncorrectable until Kasai, beginning in the mid-1950s, detected microscopic bile channels in theresidual fibrous tissue of the porta hepatis and showedthat some communicated with patent intrahepaticbileducts.2 He described the operation of

38. Aldencamp AP, Alpherts WCJ, Moerland MC, Ottevanger N, Van Parys JAP.Controlled release carbamazepine: cognitive side effects in patients with epilepsy.Epilepsia 1987; 28: 507-14.

39. Stefan H, Schafer H, Kuhnen C, Schneider S. Clinical monitonng duringcarbamazepine slow-release, once-daily monotherapy. Epilepsia 1988; 29: 571-77.

1. Howard ER, Tan KC. Biliary atresia. Br J Hosp Med 1989; 41: 123-30.2. Kasai M, Kimura S, Asakura Y, et al. Surgical treatment of biliary atresia. J Pediatr

Surg 1968; 3: 665-75.

portoenterostomy, in which a Roux-en-Y loop ofjejunum is anastomosed to the transected tissue of theporta hepatis, and reported the disappearance ofjaundice in some of the children. Surgeons outsideJapan were at first sceptical; in the United Kingdomthe operation was not accepted as a standard

procedure until after 1970.The development of liver transplantation

techniques and immunosuppression in children,especially after the introduction of cyclosporin in1980, increased still further the chances of cure forbiliary atresia; this condition is now the commonestindication for liver replacement in children. Between1980 and 1986, for example, biliary atresia was thereason for operation in 125 of the 244 patients under18 years of age who underwent orthotopic liver

transplantation in Pittsburgh,3 and 67% were alive2-5 years later. What, then, is the place of

portoenterostomy in the management of biliaryatresia, in the era of liver transplantation?

Bile flow after portoenterostomy is often substantialat 300-800 ml a day,4 and in Japan more than 80% ofpatients have become jaundice-free after surgery.sMany groups find that successful long-term bile flowdepends on the age at surgery. Mieli-Vergani et al,9for example, reported bile flow in 86% of infantstreated before eight weeks of age, compared with 36%in older infants. Unfortunately, establishment of bileflow does not guarantee long-term survival. Cirrhosis,portal hypertension, and recurrent ascendingcholangitis (which can further damage the liver) mayall complicate the postoperative course. Variceal

bleeding from portal hypertension can now becontrolled satisfactorily with injection sclerotherapy, 10but cholangitis has a pronounced adverse effect onlong-term survival. In a series reported by Houwen etal8 five-year survival was only 54% in a group ofpatients with postoperative bile flow who had hadepisodes of infection, compared with 91% in a

comparable group without infection. Efforts to

prevent such intrahepatic infections have includedsurgical modifications to the Roux-en-Y loops, long-term antibiotics, and choleretics to increase bile flowbut prospective randomised trials show no greatbenefit from these manoeuvres.11-15

3. Iwatsuki S. Liver transplantation for children with biliary atresia. In: Ohi R, ed. Biliaryatresia. Tokyo: Professional Postgraduate Services, 1987: 315-19.

4. Altman RP, Levy J. Biliary atresia. Pediatr Ann 1985; 14: 481-85.5. Ohi R. Presentation at the British Association of Paediatric Surgeons 36th Congress,

July, 1989.6. Hays DM, Kimura K. Biliary atresia: new concepts of management. Curr Probl Surg

1981; 18: 541-608.7. Kasai M, Ohi R, Chiba T. Long term survivors after surgery for biliary atresia. In: Ohi

R, ed. Biliary atresia. Tokyo: Professional Postgraduate Services, 1987: 277-80.8. Houwen RHJ, Zwierstra RP, Severijnen RS, et al. Prognosis of extrahepatic biliary

atresia. Arch Dis Child 1989; 64: 214-18.9. Mieli-Vergani G, Howard ER, Portmann B, Mowat AP. Late referral for biliary

atresia—missed opportunities for effective surgery. Lancet 1989; i: 421-2310. Stringer MD, Howard ER, Mowat AP. Endoscopic sclerotherapy in the management

of esophageal varices in 61 children with biliary atresia. J Pediatr Surg 1989; 24:438-42.

11. Ohi R, Hanamatsu M, Mochizuki I, Chiba T, Kasai M. Progress in the treatment ofbiliary atresia. World J Surg 1985; 9: 285-93.

12. Howard ER, Driver M, McClement JW, Mowat AP. Biliary atresia: the results ofsurgery in 88 consecutive cases. In: Daum F, ed. Extrahepatic biliary atresia. NewYork: Marcel Dekker, 1983: 99-103.