526

priately high doses of gabapentin for 3 weeks and had a 2. Elwes RDC, Binnie CD. Clinical pharmacokinetics of newer antiepileptic (ra6araMMa); Gabalept (ra6a.rrem); Gabantin (ra6rumrn); Gato­ drugs: lamotrigine, vigabatrin, gabapentin and oxcarbazepine. Clin serum gabapentin concentration of 85 micrograms/mL nin (raroHHH)t; Meditan (Me�nTaH); Tebantin (Te6rumrn); USA: Pharmacokinet 1996; 30: 403-1 5. Gabarone; Gralise; Horizant; Neurontin; Venez.: Neurontin. without serious adverse effects. However, a patient with 3. Berry DJ, et al. The absorption of gabapentin following high dose end-stage renal disease who twice took extra doses of escalation. Seizure 2003; 12: 28-36. Multi-ingredient Preparations. India: Alcobal; Alnacob-G; Armel gabapentin between haemodialysis sessions developed 4. Cundy KC, et a!. Clinical pharmacokinetics of XP13512, a novel G; Bigvin Forte; Capin-G; Chiny-GP; Cobalvit-GT; Cobanerve­ transported prodrug of gabapentin. J Clin Pharmacal 2001:1; 48: 1378-88. marked somnolence and hypoxia severe enough to require 5. Chen C, et a!. Pharmacokinetics of gabapentin in a novel gastric­ G; Cobaver-M; Cobsa-G; Doloneuron; Electa-GP; Encentin intubation on both occasions; haemodialysis produced retentive extended-release formulation: comparison with an immedi· Plus; Encentin-AM; Encentin-M; G-Care; G-Neuro; Gaba-MC; rapid improvement. 3 A prospective observational study4 of ate-release formulation and effect of dose escalation and food. J Clin Gabafact; Gabaneuron; Gabanez-M; Gabapentin Forte; Gabastar gabapentin exposures reported to 3 poison centers has Phannacol 201 1; 51: 346-58. M; Gabator M; Gabaz; Gabil; Gabin-M; Gabion-M; Gabsoft-M; 6. La! Ret al. Clinical pharmacokinetics of gabapentin after administration Game; Gamet; GBN-M; Gelina-M; Gentin-MC; Gibi Forte; Gic­ described a case series of 20 patients who took from 50 mg of gabapentin enacarbil extended-release tablets in patients with varying M; Hyteron-M; Indcobal; Magic-M; Malzix-GB; Marinol-GB; to 35 g of gabapentin alone. Of these, 12 had clinical degrees of renal function using data from an open-label, single-dose symptoms including drowsiness, dizziness, gastrointestinal pharmacokinetic study. Clin Ther 2012; 34: 201-13. Me-Gab; Mecobal-GB; Mecoday-G; Mecoriv-G; Melife-G; Meri­ disturbance, hypotension, and mild tachycardia. These cobal-G; Methipas-GP; Mewin-GB; Miko G; Mokia-G; Motrin GB; Mycovit-GB; Nervic-G; Nervicin-G; Nervimax-G; Nervon· effects developed in under 5 hours and lasted for less than Children. A study1 of the pharmacokinetics of single doses GM; Nervoptin; Nervuptin; Nervz-G; Nerwin-GT; Neuro-GM; 24 hours; toxicity was generally mild and there were no of gabapentin in healthy children aged month to 12 Neuroage GF; Neurocap-G; Neurogab; Neuromas-G; Neu­ fatalities. years found that peak plasma concentrationsI occurred 2 to romed-GF; Neuropill; Neurotop·G; Nexcob-G; Novomine-GB; I. Fischer JH, et a!. Lack of serious toxicity following gabapentin overdose. 3 hours after the dose in all age groups but that the mean NTOmec-G; Nuroclad-GB; Nurokind-G; Nuthyl-GB; Orogab-M; Neurology 1994; 44: 982-3. value was higher in those older than 5 years than in Gavindo; Tremecox; Tremepen. 2. Verma A, et al. A case of sustained massive gabapentin overdose without Mex.: younger children, and the exposure was calculated to be serious side effects. Ther Drug Monit 1999; 21: 615-17. 3. Jones H, et at. Gabapentin toxicity requiring intubation in a patient about 30% less in the younger age group. As a result it PharmacopoeialPreparations receiving long-term hemodialysis. Ann Intern Med 2002; 137: 74. was suggested that the initial dose of gabapentin in studies USP 36: Gabapentin Capsules; Gabapentin Tablets. 4. Klein-Schwartz W, et al. Characterization of gabapentin overdose using a of safety and efficacy should be 40 mg/kg daily in children 41: poison center case series. J Toxicol Clin Toxico/ 2003; 11-15. aged from month up to 5 years, and 30 mg/kg daily in children aged 5 to 12 years. (For licensed doses, see raAN, usAN. rtNN! Porphyria. The Drug Database for Acute Porphyria, com­ I Lacosamide Administration in Children, p. 524.1.) A pharmacokinetics piled by the Norwegian Porphyria Centre (NAPOS) and study2 in children with uncontrolled seizures (aged from 3 the Porphyria Centre Sweden, classifies gabapentin as to about 15 years) also found a markedly higher mean probably not porphyrinogenic; it may be used as a drug of oral clearance of gabapentin when compared with adults. first choice and no precautions are needed. 1 I. Haig GM, et a!. Single-dose gabapentin pharmacokinetics and safety in l. The Drug Database for Acute Porphyria. Available at: http:/lwww. healthy infants and children. J Clin Phannaco/ 2001; 41: 507-14. drugs-porphyria.org (accessed 17/10/ll) 2. Tallian et al. Pharmacokinetics of gabapentin in paediatric patients KB, with uncontrolled seizures. J Clin Pharm Ther 2004; 29: 511-15. Pregnancy. For mention of the pharmacokinetics of gaba­ pentin during pregnancy and breast feeding, see under Pregnancy and breast feeding. The pharmacokinetics of Pharmacokinetics, below. gabapentin were studied1 in 6 women, and in their off­ For comments on the management of epilepsy during spring, during pregnancy, delivery, and breast feeding. Uses and Administration pregnancy, see p. 509 .2. Findings suggested that gabapentin is actively transported across the placenta and accumulates in the fetus although Lacosamide is an antiepileptic used as adjunctive therapy in Withdrawal. Withdrawal symptoms, including akathisia, its effect was unclear. All the deliveries, including one pre­ partial seizures with or without secondary generalisation anxiety, confusion, diaphoresis, headache, and palpita­ term, were uneventful and all of the infants were healthy, (below) in patients aged 16 years and older. tions, have been reported1-3 after abrupt withdrawal of apart from one who became cyanosed and mildly hypo­ The initial oral dose of lacosamide is 00 mg daily, gabapentin. A withdrawal syndrome with flu-like symp­ tonic 8 hours after birth. increased to 200 mg daily after week. FurtherI weekly toms has also been reported4 after gradual withdrawal n The distribution of gabapentin into breast milk was increments of 100 mg may be given,I accordi g to response over week. A literature search3 found 0 case reports extensive and neonates were found to have a lower capacity and tolerability, to a maximum daily dose of 400 mg. The with symptoms that occurred from 12 hours to 3 days I I to eliminate gabapentin than adults, with an elimination total daily dose of lacosamide should be given in 2 equally after stopping gabapentin and generally resolved on half-life of about 4 hours. However, the plasma divided doses. restarting; patients had been taking doses that ranged concentrations in theI breast-fed infants appeared to be When oral use is not feasible, lacosamide may be given from 0.4 to 8 g daily for durations of 3 weeks to 5 years. low and the relative infant dose was estimated to be 1. 3 to by intravenous infusion over 15 to 60 minutes in the same 1. Hellwig TR, et al. Withdrawal symptoms after gabapentin discontinua­ 3.8% of the mothers' weight-adjusted dose at 0.2 to doses as those used orally. Licensed product information tion. Am J Health-Syst Pharm 2010; 67: 910-12. states that there is experience with the use of intravenous 2. Finch CK, et a!. Gabapentin withdrawal syndrome in a post-liver 1.3 mg/kg daily. No adverse effects were reported in the lacosamide for up to 5 days. transplant patient. J Pain Palliat Care Pharmacother 2010; 24: 236-8. infants, and the authors considered that gabapentin was 3. See S, et a!. Akathisia induced by gabapentin withdrawal. Ann generally safe during breast feeding. Reduced doses are recommended by some authorities in Phannacother2011; 45: e3l. patients with hepatic and severe renal impairment (see l. Ohman I, et al. Pharmacokinetics of gabapentin during delivery, in the 4. Iran KT, et a!. Gabapentin withdrawal syndrome in the presence of a neonatal period, and lactation: does a fetal accumulation occur during below). taper. Bipolar Disord 2005; 7: 302-4. pregnancy? Epilepsia 2005; 46: 1621-4. As with other antiepileptics, withdrawal of lacosamide therapy or transition to or from another type of antiepileptic Interactions therapy should be made gradually to avoid precipitating an increase in the frequency of seizures. Licensed product The absorption of gabapentin from the gastrointestinal tract (details are given in Volume B) is reduced by antacids containing aluminium with ProprietaryPreparations information recommends reducing the dose of lacosamide magnesium; it is recommended that gabapentin is taken at Single-ingredient Preparations. Arg.: Abaglin; Alidial; Elifer; by 200 mg each week. For a discussion on whether or not to least 2 hours after any such antacid. Morphine has been Logistic; Neurontin; Ultraneural; Austral.: Gabahexalt; Gabar­ withdraw antiepileptic therapy in seizure-free patients, see reported to reduce the clearance of gabapentin; patients an; Gabatine; Gantin; Neurontin; Nupentin; Pendinet; Austria: p. 506.1. receiving both drugs should be monitored for signs of CNS Gabatal; Neurontin; Belg.: Neurontin; Braz.: Gabaneurin; Neu­ Lacosamide is also being studied for use in fibromyalgia, depression and doses should be reduced accordingly. rontin; Progresse; Canad.: Neurontin; Chile: Dineurin; Gaba­ osteoarthritis, and migraine prophylaxis. Cimetidine has also been reported to reduce the renal cross; Gabex; Gabictal; Neugabint; Normatol; Ritmenal; China: Die Li (i!JJ); Neurontin Pai Ting (i!i\IT); Wei Nuo clearance of gabapentin but licensed product information Administration in hepatic impairment. Although UK Ding Apo-Gab; Gabagamma; Gabaleptt; Gaba­ does not consider this to be of clinical importance. For Cz.: (�1llliiT); licensed product information states that no dosage adjust­ nox; Gabatem; Gabator; Gabentat; Gordius; Grirnodin;Neuron­ references to possible interactions with other antiepileptics, (tii'llilE); ment of lacosamide is needed for patients with mild to tin; Nurabaxt; Denm.: Gabadoz; Gabalept; Gabalix; Gabamed; moderate hepatic impairment, US licensed information see under Phenytoin, p. 543.2 and under Felbamate, Gabanicht; Gabaratio; Gabatifin; Neuril; Neurontin; Pentagab; suggests a maximum dose of 300 mg daily orally or by p. 522.3. Fin.: Gabrion; Neurontin; Fr.: Neurontin; Ger.: Gabagamma; intravenous infusion; use in severe impairment is not GabaLich; Gabax; Neurontin; Gr.: Belgabin; Brilian; Gabantin; Pharmacokinetics Gabapen; Gabaront; Gabental; Gabiton; Gapenten; Medivapom; recommended due to lack of data. Neurontin; Neuros; Pentin; Peronten; Seni-Ven; Hong Kong: Gabapentin is absorbed from the gastrointestinal tract by Gabenil; Neurontin; Hung.: Gabagamma; Gordius; Grimodin; Administration in renal impairment. In patients with means of a saturable mechanism. After multiple dosing peak Neuroba; Neurontin; India: Encentin; Gaba; Gabacap; Gaba­ severe renal impairment (creatinine clearance of 30 mLI plasma concentrations usually occur within 2 to 3 hours of a cent; Gabalept; Gabantin; Gabapin; Gabata; Gabatin; Gabator; min or less) and in those with end-stage renal disease, UK dose and a steady state within to 2 days. When given as its Gaby; Gentin; Goben; Mygaba; Neogaba; Neupent AF; Neuron­ licensed product information recommends a maximum prodrug, gabapentin enacarbil,I peak plasma concentrations tin; Indon.: Alpentin; Epiven; Gabexal; Galepsi; Ganin; Nepatic; daily dose of lacosamide 2 50 mg orally or by intravenous are reached in 5 hours in fasted subjects and 7.3 hours in fed Neurontin; Repligen; Sipentin; Tineuron; Irl. : Gabin; Gabture; infusion whereas US licensed information recommends a subjects; the bioavailability of gabapentin from its prodrug is Neurontin; Neurostil; Rangabax; Israel: Neurontin; Ital.: Apen­ maximum dose of 300mg daily. increased when given with food, particularly meals high in tin; Gabexine; Neurontin; Semerialt; Yalipentt; Jpn: Gabapen; In patients undergoing haemodialysis a supplemental fat. Regnite; Malaysia: Neurontin; Mex. : Aconeuba; Bapex; Blugat; dose of up to 50% of the morning dose should be given at Gabapentin enacarbil undergoes extensive first-pass Clozepaxel; Compulxinet; Gabantin; Gapridol; Microleptin; the end of the procedure. Neurontin; Nopatic; Nyepzyl; Wermy; Neurontin; metabolism, mainly in enterocytes and to a lesser extent in Neth.: Norw.: Neurontin; NZ: Neurontin; Nupentin; Philipp.: Calm­ the liver, to form gabapentin, carbon dioxide, acetaldehyde, Epilepsy. Lacosamide is used in the treatment of epilepsy pent; Gabalept; Gabatin; Gabatrex; Gabix; Gonnaz; Neurontin; and isobutyric acid; blood levels of the enacarbil are low and Reinin; Pol.: Gabagamma; Gabatem; Gabaxt; Neuran; Neuron­ (p. 506.1) as adjunctive therapy for partial seizures with transient. Gabapentin itself is not appreciably metabolised tin; Symleptic; Port.: Anabixt; Aneptir; Gabacalma; Gabamox; or without secondary generalisation. It has also been and most of a dose is excreted unchanged in the urine with Mengaptrixt; Molnarux; Neurontin; Rus.: Convalis (KoHBMHC); investigated as a second-line drug in status epilepticus. the remainder appearing in the faeces. Gabapentin is widely Gabagamma (fa6araMMa); Gapentek (faneHTeK); Katena References. distributed throughout the body but binding to plasma (KaT3Ha); Lepsitin (JierrcHTIIH); Neurontin (HeiipoHTHH); Tebantin I. Doty P, et al. Lacosamide. Neurotherapeutics 2007; 4: 145-8. proteins is minimal. The elimination half-life has been (Te6aHTHH); S.Afr. : Epleptin; Neurexal; Neurontin; Singapore: 2. Ben-Menachem E, et al. Efficacy and safety of oral lacosamide as reported to be about 5 to 7 hours. Gabapentin is distributed Neurontin; Nupentin; Spain: Equipaxt; Gabamerckt; Gabatur; adjunctive therapy in adults with partial-onset seizures. Epilepsia 2007; 48: into breast milk. Gabmylant; Neurontin; Neurontin; Gabantine; 1308-17. Swed.: Switz.: 3. Biton V, et a!. Intravenous lacosamide as replacement for oral lacosamide Neurontin; Gabantin; Gabutin; Neurontin; Neverpentin; References. Thai.: in patients with partial-onset seizures. Epilepsia 2008; 49: 418-24. Rontin; Vultin; Turk.: Gabaset; Gabateva; Gabtin; Nepitin; Ner­ 4. Cross SA. Curran Lacosamide: in partial-onset seizures. Drugs 2009; 1. Blum RA, et al. Pharmacokinetics of gabapentin in subjects with various MP. degrees of renal function. Clin Phannacol Ther 1994; 56: 154-9. uda; Neurontin; UK: Neurontin; Ukr.: Gabagamma 69: 449-59.

All cross-references refer to entries in Volume A 527

5. Wehner T, et a!. Six months of postrnarketing experience with P epa ons although a more abrupt withdrawal may be considered if adjunctive lacosarnide in patients with phannacoresistant focal epilepsy r rati ...... there are safety concerns . at a tertiary epilepsy center in Germany. Epilepsy Behav 2009; 16: 423-5. (details are given in Volume B) 6. Kellinghaus C. Lacosamide as treatment for partial epilepsy: ProprietaryPreparations mechanisms of action, pharmacology, effect�. and safety. Ther Clin Risk Single-ingredient Preparations. Arg.: Vimpat; Austral.: Vimpat; Administration in children. Lamotrigine is used as an Manag 2009; 5: 757-66. Austria: Vimpat; Belg.: Vimpat; Canad.: Vimpat; Cz.: Vimpat; adjunct in the treatment of partial seizures and primary 7. Kellinghaus C, et al. Intravenous lacosamidc a� successful treatment for Vimpat; Fr.: Vimpat; Vimpat; Vimpat; nonconvulsive statm epilepticus after failure of first-line therapy. Denm.: Ger.: Gr.: Irl. : and secondarily generalised tonic-clonic seizures in chil� Epilepsy Behav 2009; 14: 429-3 1. Vimpat; Israel: Vimpat; Neth.: Vimpat; Norw.: Vimpat; NZ: dren aged 2 to 12 years; it is also used as monotherapy for Vimpat; Pol.: Vimpat; Port.: Vimpat; Rus.: Vimpat (BHMIIaT); typical absence seizures in children aged 2 to 12 years. Spain: Vimpat; Swed.: Vimpat; Switz.: Vimpat; UK: Vimpat; Lamotrigine may also be used for seizures associated with Neuropathic pain. Lacosamide is being studied in the Ukr.: Vimpat (BHMrraT); USA: Vimpat. the Lennox-Gastaut syndrome. management of neuropathic pain1·3 but its role, if any, The doses given below are those licensed in the UK; remains to be established.4 similar doses are given in the USA although the use of I. Wymer JP, et al. Efficacy and safety of lacosarnidcin diabetic neuropathic (BAN, USAN, r/NN) lamotrigine is more limited than in the UK. pain: an 18-week double-blind placebo-controlled trial of fixed-dose Lamotrigine regimens. Clin Pain 2009; 25: 376-85. The initial oral dose of lamotrigine for use as monotherapy 1 La o.t iiS�iini; Lafuotrigin; · L mo.trigina; Lamotrigi­ • 2. Shaibani A, et al. Laco<;amide in painful diabetic neuropathy: an IS­ BW-43oe; � in typical absence seizures, given as a single dose or in 2 week double-blind placebo-controlled trial. Pain 2009; 10: 8I8-28. num; lamolrljfn; a 1 divided doses, is 300 micrograms/kg daily for 2 weeks, 3. Ziegler D, et al. Efficacy and safety of ioKosamide in painful diabetic 6-(2,HJ1chlordpheny1)·1naMOTP ,2,4·triaMfVIH.·zine-:1.5·diyldiamihe. followed by 600 micrograms/kg daily for 2 weeks; 33: neuropathy. Diabetes Care 2010; 839--41. C9H?Gi,N3"'256.1 4. McCleane G. Lacosamide for pain. Expert Opin Invest Drugs 2010; 19: thereafter the dose is increased by a maximum of Il29-34. c...... s�OSl-84·1. 600 micrograms/kg every I to 2 weeks to usual CAS maintenance doses of 1 to 10 mg/kg daily. Some patients . .N03AX09. have required up to 15 mg/kg daily. In those taking lamotrigine as an adjunct to therapy but Adverse Effects and Precautions Arc c_,· Q;Vo:JAX09. • UN/I U3H2 749BKS .. not taking valproate or enzyme-inducing or -inhibiting The most frequently reported adverse effects with (see p. vii) and US. lacosamide are usually mild to moderate in severity, and anti epilepticsthe initial oral dose of lamotrigine, given as a (Lamotrigine). A white or almost white powder. include dizziness, headache, nausea, and diplopia. Other Ph. Eur. 8: single dose or in 2 divided doses, is 300 micrograms/kg Very slightly soluble in water; slightly soluble in dehydrated commonly reported adverse effects include depression, CNS daily for 2 weeks, followed by 600 micrograms/kg daily alcohol. disorders such as abnormal coordination, memory impair­ for 2 weeks; thereafter the dose is increased by a ment, somnolence, tremor, and nystagmus, blurred vision, USP 36: (Lamotrigine). A white to pale cream-coloured maximum of 600 micrograms/kg every 1 to 2 weeks to vertigo, gastrointestinal disorders such as vomiting, powder. Slightly soluble in water, in methyl alcohol, in O.IN usual maintenance doses of 1 to 10 mg/kg daily. The constipation, and flatulence, pruritus, gait disturbance, hydrochloric acid, and in acetone. Store in airtight maximum dose is 200mg daily. asthenia, and fatigue. The incidence and severity of CNS and containers. • In those taking enzyme-inducing antiepileptics (but not with gastrointestinal disorders usually decrease over time. valproate) the initial oral dose of lamotrigine is Lacosamide has been associated with a dose-related Uses and Administration 600 micrograms/kg daily in 2 divided doses for 2 weeks increase in the PR interval, and should be used with caution followed by 1.2 mg/kg daily for 2 weeks; thereafter the in patients with cardiac conduction disorders or severe Lamotrigine, a phenyltriazine compound, is an antiepileptic dose is increased by a maximum of 1.2rng/kgevery I to 2 cardiac disease such as a history of myocardial infarction or used mainly for monotherapy or adjunctive treatment of weeks to usual maintenance doses of 5 to 15 mg/kg daily, heart failure. It is contra-indicated in those with second- or partial seizures and primary and secondarily generalised given as a single dose or in 2 divided doses. The third-degree AV block. tonic-clonic seizures. It may be used for seizures associated maximum dose is 400 mg daily. Doses of lacosamide should be titrated cautiously in with the Lennox-Gastaut syndrome and for the main­ • In those taking valproate the initial oral dose of patients with renal impairment. tenance treatment of bipolar disorder. lamotrigine is 150 micrograms/kg once daily for 2 Care is required when withdrawing lacosamide The doses given below for the use of lamotrigine in weeks followed by 300 micrograms/kg once daily lor 2 therapy-see also Uses and Administration, p. 526.3. epilepsy (p. 528.1) are those licensed in the UK; similar weeks; thereafter the dose is increased by a maximum of doses are given in the USA although the use of lamotrigine 300 micrograms/kg every 1 to 2 weeks to usual is more limited than in the UK. maintenance doses of 1 to 5 mg/kg daily, given as a Breast feeding. For comment on antiepileptic therapy and • The initial oral dose for use as monotherapy is 25 mg once single dose or in 2 divided doses. The maximum dose is breast feeding, see p. 508.3. daily for 2 weeks followed by 50 mg once daily for 2 200 mg daily. weeks; thereafter the dose is increased by a maximum of • In those taking lamotrigine as adjunctive therapy with Driving. For a comment on antiepileptic drugs and driv­ 50 to 100 mg every to 2 weeks to usual maintenance drugs where it is not known if an interaction may occur, ing, see p. 509.2. doses of I 00 to 200 mgI daily, given as a single dose or in 2 the doses as recommended for lamotrigine with divided doses. Some patients have required up to 500 mg concurrent valproate should be used. daily. If the calculated daily dose of lamotrigine lies between I and Effects on mental function. For the effects of antiepileptic • In those taking Iamotrigine as an adjunct to therapy but 2 mg, then 2 mg may be given on alternate days lor the first therapy on cognition and mood, including the risk of suici­ not taking valproate or enzyme-inducing or -inhibiting 2 weeks of therapy. Lamotrigine should not be given if the dal ideation, see p. 508.3. antiepileptics the dosage regimen is as for monotherapy. calculated daily dose is less than I mg. • The initial oral dose of lamotrigine for use as an adjunct The use and doses of lamotrigine in children over 12 Porphyria. The Drug Database for Acute Porphyria, com­ to therapy with enzyme-inducing antiepileptics (but not with years of age is as for adults (see above). piled by the Norwegian Porphyria Centre (NAPOS) and valproate) is 50 mg once daily for 2 weeks followed by the Porphyria Centre Sweden, classifies lacosamide as 50 mg twice daily for 2 weeks; thereafter the dose is Administration in hepatic impairment. UK licensed pro­ probably not porphyrinogenic; it may be used as a drug of increased by a maximum of I 00 mg every I to 2 weeks to duct information for lamotrigine recommends that doses first choice and no precautions are needed.1 usual maintenance doses of 200 to 400 mg daily given in should be reduced by about 50% in patients with moder­ 1. The Drug Database for Acute Porphyria. Available at: http://www. 2 divided doses. Some patients have required up to ate hepatic impairment (Child-Pugh category B), and by dmgs-porphyria.org (accessed 17/10/11) 700 mg daily. about 75% in severe impairment (Child-Pugh category C). • In those taking valproate (and regardless of any other US licensed product information recommends that doses concomitant drugs) the initial oral dose of lamotrigine is should be reduced by about 25% in patients with moder­ Pregnancy. For comments on the management of epilepsy 25 mg every other day for 2 weeks followed by 25 mg ate to severe hepatic impairment without ascites, and by during pregnancy, see p. 509.2. once daily for 2 weeks; thereafter the dose is increased by 1 about 50% in those with severe hepatic impairment with a maximum of 25 to 50mg every 1 to 2 weeks to usual ascites. Interactions maintenance doses of 100 to 200mg daily given as a single dose or in 2 divided doses. Anxiety disorders. Small studies have suggested that lam­ There are complex interactions between antiepileptics and If the potential for interaction with adjunctive antiepileptics otrigine may relieve some of the symptoms of post-trau­ toxicity may be enhanced without a corresponding increase is unknown, treatment with lamotrigine should be started matic stress disorder (p. 1029.2). in antiepileptic activity. Such interactions are very variable with lower doses such as those used with valproate. For and unpredictable and plasma monitoring is often advisable comment on the need to modify maintenance doses when References. with combination therapy. Lacosamide plasma concentra­ I. Hertzberg MA, et at. A preliminary study of lamotrigine for the treatment starting or stopping oral contraceptives, see Sex Hormones, of posttraumatic stress disorder. Biol Psychiatry I999; 45: I226-9. tions may be reduced by carbamazepine, phenytoin, and under Interactions, p. 530.2. 2. Hageman I, et a!. Post-traumatic stress disorder: a review of phenobarbital. For doses in children, see below. psychobiology and pharmacotherapy. Acta Psychiatr Scand 2001; 104: Systemic exposure to lacosamide may be reduced by In the management of bipolar disorder (below), the 411-22. strong inducers of cytochrome P450 isoenzymes such as target dose of lamotrigine is 200 mg daily as monotherapy; for rifampicin or St John's wort. Lacosamide should be used patients taking valproate the target dose is 100 mg daily and Bipolar disorder. In a multicentre placebo-controlled with caution in patients also receiving other drugs that in those taking enzyme-inducing drugs (but not with study involving I95 patients, oral lamotrigine 50 or prolong the PR interval, and with class I antiarrhythmics. valproate) the target dose is 400 mg daily. Lamotrigine 200 mg daily produced dose-related improvement in should be started at a reduced dose and increased gradually patients with bipolar disorder (p. 397.2) experiencing a to the target dose in a regimen similar to that used in the major depressive episode .1 Further data from randomised Pharmacokinetics treatment of epilepsy (see above). controlled studies2•8 and meta-analysis9 have confirmed Lacosarnide is quickly and completely absorbed after oral Doses should be reduced in patients with hepatic benefit for depressive symptoms (although not for mania), doses. The oral bioavailability is about 100% and peak impairment regardless of indication (see below). and reviews10-14 have generally favoured its use, although plasma concentrations occur within 4 hours. Steady state is As with other antiepileptics, withdrawal of lamotrigine some have queried the strength of the evidence.15 Guide­ achieved after 3 days. About 95% of a dose is excreted in the therapy or transition to or from another type of antiepileptic lines for the treatment of bipolar disorder now recom­ urine, about 40% as unchanged drug and less than 30% as therapy should be made gradually to avoid precipitating an mend lamotrigine as a first-line option for bipolar depres­ the inactive 0-desmethyl metabolite. Less than 0.5% of a increase in the frequency of seizures. For a discussion on sion, and it is licensed for such use in some countries (see dose is excreted in the faeces. The elimination half-life of whether or not to withdraw antiepileptic therapy in seizure­ also Uses and Administration, above). lacosamide is about 13 hours. Lacosamide is removed by free patients, see p. 506.1. In patients with epilepsy the I. Calabrese JR, et al. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. J Clin withdrawal of lamotrigine should be tapered over at least 2 haemodialysis. Psychiatry 1999; 60: 79-88. The pharmacokinetics of lacosamide are affected by use weeks. A step-wise reduction is also suggested when 2. Bowden CL, et al. Lamotrigine in the treatment of bipolar depression. with other antiepileptics (see Interactions, above). lamotrigine is stopped in patients with bipolar disorder Bur Neuropsychopharmacol 1999; 9 (suppl 4): Sll3-S I17.

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