Mitigating Cutaneous Side Effects of Lamotrigine

By Antai-Otong, Deborah

Question: I plan to start one of my patients on lamotrigine because she has been a poor responder to previous pharmacologie treatment. I know this medication has proven its efficacy in treating bipolar Il depression. My chief concern about this medication is the serious rash, specifically Stevens-Johnson syndrome (SJS). Please discuss foremost treatment considerations for lamotrigine and the risk of cutaneous side effects.

Deborah Antai-Otong responds: Your concerns about serious rash (cutaneous) side effects associated with lamotrigine are well founded, although this condition is rare. Despite the risk of rash, current studies indicate the efficacy of lamotrigine in the treatment of bipolar depression. The following is a synopsis of this novel mood stabilizer and prescribing considerations associated with serious rash.

Actions and Efficacy of Lamotrigine (LTG) in Bipolar Depression

Lamotrigine is a novel anticonvulsant agent that appears to act chiefly by blocking voltage-sensitive sodium channels and indirectly by inhibiting glutamate release (Macdonald & Greenfield, 1997). This action inhibits the activation of vast presynaptic receptors and the stabilization of neuronal membranes. Its precise antidepressant properties are poorly understood, but indicate that it binds with 5HT3 receptors, producing a weak inhibitory effect (Li, Ketter, & Frye, 2002). Collectively, these actions may explain its efficacy in the treatment and prevention of depressive episodes in bipolar disorders. Unlike other mood stabilizers such as lithium and valproic acid, lamotrigine does not require serum monitoring. A serious rash is its most troublesome side effect.

The American Psychiatric Association (2002) practice guidelines recommend lamotrigine as a first-line treatment for bipolar depression (APA, 2002). In 2003, lamotrigine was approved by the FDA for maintenance treatment of bipolar disorders. Apparently, its antidepressant and mood-stabilizing properties make it superior to lithium in rapid-cycling bipolar disorders and preventive in depressive relapse (Calabrese et al, 2003; Ichim, Berk, & Brook, 2000). Double-blind placebo-controlled studies found lamotrigine effective in the maintenance treatment in bipolar I disorder (Bowden et al., 2003; Calabrese et al., 2000). McElroy et al. (2004) demonstrated the efficacy of lamotrigine in a 12-month open-label continuation study as adjunctive therapy or monotherapy in bipolar depression. These data indicate antidepressant efficacy for the 200 mg/day dose of lamotrigine (slow titration) compared with placebo as early as 3 weeks on structured instruments (e.g., Hamilton rating scale for depression [HAM-D], Montgomery-Asberg depression rating scale [MADRS], Clinical Global Impression scale for severity (CGI- S]).

Rash (Cutaneous) Side Effects

The FDA rendered product information for lamotrigine to include a “black box” warning because of the risk of serious rash, including SJS, requiring hospitalization and discontinuation of treatment. Most rashes occur during early treatment between 2 and 8 weeks after drug initiation. The risk of SJS is higher in pediatric patients than in adults, approximately 1-2% in children and 0.1% in adults (CuIy & Goa, 2000; Messenheimer, 1998). Rashes occurring within 5 days or in 8-12 weeks of treatment are seldom drug induced. In controlled multicenter clinical trials in patients with mood disorders, 100/1198 or 8.3% had rash and none had serious rash. In comparison, open clinical trials in this population showed that 257/ 1955 or 13.1% had rash and 2/1955 or 0.1% had serious rash (Calabrese et al., 2002). Conclusions from these data indicate serious drug-induced eruptions associated with lamotrigine are rare and although SJS is a potentially life-threatening syndrome, clinicians must weigh the risk benefit of this medication with more common risks associated with untreated bipolar depression (e.g., suicide).

Pathophysiology

It is important to note the risk of serious rash is not limited to lamotrigine but also occurs with carbamazepine (CBZ), phenytoin, phenobarbital, valproic acid (VPA), and oxcarbazepine. Lamotrigine is associated with a lower risk compared to phenytoin, phenobarbital, and CBZ (Rzany, 1999). Phenytoin and CBZ reduce the half-life of lamotrigine, whereas VPA markedly reduces metabolism. Research indicates the underpinnings of SJS are immunologie and treatment that includes short-term, high-dose intravenous steroids or immunoglobulin show promise in survival and long-term morbidity (Letko et al., 2005).

Risk factors associated with higher incidence of rash include:

* Higher and rapid initiation or initial titration

* Concomitant VPA (doubles lamotrigine levels)

* Use in children under the age of 12.

In general, lamotrigine is well tolerated in maintenance studies. The decision to use any medication is based on differential diagnosis of bipolar disorder, co-existing psychiatric and medical conditions, patient preferences, and past adverse reactions. Apart from the risk of rash, less common and transient adverse effects occur during initial initiation and include headaches, GI disturbances, infection, sedation, cognitive effects (e.g., blunting, abnormal dreams, dizziness), back pain, fatigue, rhinitis, and pruritis. FDA classifies it as pregnancy category C.

Table 1. Lamotrigine: Recommended Titration

The initial recommended titration of lamotrigine is 25 mg/day and a gradual increase to 200 mg/day over 6 weeks to reduce the risk of serious rash. Higher doses are not recommended as no additional efficacy has been proven (Table 1).

Clinical Manifestations of SJS

Differential Diagnosis

Prior to initiating lamotrigine, a complete psychosocial and differential medical evaluation must be performed, including relevant diagnostic studies (chemistries, complete blood count with differential). Because of the high risk of suicide in persons with bipolar disorder, the nurse must, initially and throughout treatment, assess the patient’s level of danger to self and others. Equally important is assessing if the patient has had a rash, viral syndrome or vaccination within the past 2 weeks and during the first 3 months on lamotrigine.

Because of the serious and potentially fatal consequences of SJS, early recognition and treatment are paramount. The psychiatric nurse prescriber is in a key position to identify patients taking lamotrigine and recognize signs and symptoms of this potentially fatal cutaneous side effect. These skin conditions carry mortality rates as high as 30% (Wolf, Orion, Marcos, & Matz, 2005). The mere nature of this life-threatening situation requires prompt diagnosis, withdrawal of the offensive medication, and hospitalization to reduce serious sequel.

Diagnosis or strong suspicion of SJS requires emergent medical interventions. Prodromal signs of SJS include:

* Fever (sometimes as high as 104.50 F (40.50 C))

* Headache

* Malaise

* Sore throat

* Cough occurs in 1 /3 cases

* Eosinophilia.

Typically, cutaneous manifestations occur during early initiation of lamotrigine or other anticonvulsants (e.g., 2 to 8 weeks). The rash often begins as a maculopapular eruption distribution on the neck and chest and rapidly progresses to target lesions. The rash is confluent and widespread and eventually becomes purpuric and tender. Painful eruptions of the mucosa of the conjunctiva, lips, mouth, urethra, esophagus, and vagina are usually involved and further indicate the seriousness of the rash. Normally, lesions rupture and cause erosion and crusting. Severe cases cause corneal ulcerations, dysphagia, dyspnea, and dysuria. Other major organs affected include kidneys and upper respiratory system. In severe cases the syndrome can be fatal. Duration of mild symptoms, often self-limiting, range from 10-14 days, whereas severe symptoms involve kidney, ophthalmic, and pulmonary function and require aggressive medical interventions, and resolution often occurs within 8 to 10 days. Mucosal lesions normally heal within 6 weeks.

Patient Education: Minimizing SJS

Prior to prescribing any medication, it is imperative to assess the patient’s and family’ educational needs. This is particularly significant with lamotrigine and other mood stabilizers. Black box information recommends that lamotrigine be discontinued at the first indication of a rash. Patients and families must be instructed to report any signs of rash (before taking the next dose of lamotrigine) and seek emergency treatment if rash occurs with conjunctivitis, sore mouth, dysuria, fever, or swollen lymph nodes, avoid adding new medications, including over-the-counter drugs or herbs, new foods, fabric detergents or softener, perfumes or deodorants, sunburns or exposure to plant allergens to minimize benign rash.

Normally, health education includes reasons for taking the medication, dosing schedule, importance of taking medication as prescribed, side effects/adverse drug reactions, drug interactions, and reasons to seek emergent care or follow-up with the prescriber. In addition, emphasis is placed on maintaining a healthy lifestyle- balanced diet, regular exercise and taking nonpsychotropic medications as ordered by primary care provider.

Finally, the patient and family must be educated about the importance of taking the m\edication as ordered, and if the former fails to take medication for more than 5 days, an appointment to restart (slow titration) the medication is necessary to minimize the rash. Patient education is an essential part of all treatment and must be provided both orally and in written form to ensure safety and reduce the incidence of potentially life-threatening side effects.

Summary

The pharmacologie treatment of bipolar disorder is the maintenance of euthymia and prevention of cycling. Psychiatric nurses have a litany of treatment options to treat bipolar disorders, including monotherapy and/or adjunctive mood stabilizers with other medications, such as atypical antipsychotics and novel antidepressants. Some agents are more effective than others in preventing rapid cycling and most have a host of serious side effects. Lamotrigine has demonstrated efficacy for bipolar depression, particularly rapid cycling as monotherapy and adjunctive therapy with sustained mood stabilization.

Ultimately, the decision to prescribe lamotrigine or other mood stabilizers must be based on evidence-based practice, individual patient preference, history of efficacy and side effects, and efficacy in all phases of the illness mania, depression, and mixed episodes. It is imperative that regardless of benefits, risks, side- effect profile, and potential serious drug reactions, patient education and informed consent must be the cornerstone of all treatment. Finally, before prescribing any medication, psychiatric nurses must discern risk benefits of drugs used to treat bipolar disorder and consequences of ineffective pharmacotherapy.

References

American Psychiatric Association. (2002). Practice guidelines for the treatment of patients with bipolar disorder (revision). American Journal of Psychiatry, 159, 1-50.

Bowden, C.L., Calabrese, J.R., Sachs, G., Yatham, L.N., Asghar, S.A., Hompland, M. et al.; Lamictal 606 Study Group (2003). A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic and hypomanic patients with bipolar I disorder. Archives of General Psychiatry, 60, 392-400.

Calabrese, J.R., Bowden, C.L., Sachs, G., Yatham, L.N., Behnke, K., Mehtonen, O.P. et al.; Lamictal 605 Study Group. (2003). A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. Journal of Clinical Psychiatry, 64, 1013-1024.

Calabrese, J.R., Sullivan, J.R., Bowden, CL., Suppes, T., Goldberg, J.F. et al. (2002). Rash in multicenter trials of lamotrigine in mood disorders: Clinical relevance and management. Journal of Clinical Psychiatry, 63,1012-1019.

Calabrese, J.R., Suppes, T., Bowden, C.L., Sachs, G.S., Swann, A.C., McElroy, S.L. et al. (2000). A double-blind, placebo- controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. Lamictal 614 Study Group. Journal of Clinical Psychiatry, 61, 841-850.

Culy, C.R., & Goa, K.L. (2000). Lamotrigine. A review of its use in childhood epilepsy. Paediatric Drugs, 2, 299-330.

Ichim, L., Berk, M., & Brock, S. (2000). Lamotrigine compared with lithium in mania: A double-blind randomized controlled trial. Annals of Clinical Psychiatry, 12, 5-10.

Letko, E., Papaliodis, D.N., Papaliodis, G.N., Daoud, Y.J., Ahmed, A.R., & Foster, C.S. (2005). Stevens-Johnson syndrome and toxic epidermal necrolysis: A review of literature. Annals of Allergy and Asthma Immunology, 94, 419-436.

Li, X., Ketter, T.A., & Frye, M.A. (2002). Synaptic, intracellular, and neuroprotective mechanisms of anticonvulsants: Are they relevant for the treatment and course of bipolar disorders? Journal of Affective Disorders, 69,1-14.

Macdonald, R.L., & Greenfield, LJ. Jr. (1997). Mechanisms of action of new antiepileptic drugs. Current Opinion of Neurology, 10, 121-128.

McElroy, S.L., Zarate, C.A., Cookson, J., Suppes, T., Huffman, R.F., Greene, P. et al. (2004). A 52-week, open-label continuation study of lamotrigine in the treatment of bipolar depression. Journal of Clinical Psychiatry, 65, 204-210.

Messenheimer, J.A. (1998). Rash in adult and pediatric patients treated with lamotrigine. Canadian Journal of Neurology Science, 25, S14-S18.

Rzany, B. (1999). Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis during first weeks of antiepileptic therapy. Lancet, 353, 2190-2194.

Wolf, R., Orion, E., Marcos, B., & Matz, H. (2005). Life- threatening acute adverse cutaneous drug reactions. Clinical Dermatology, 23, 171-181.

Deborah Antai-Otong, MS, RN, CNS, NP, CS, FAAN

Author contact: deborah.antai-otong@med.va.gov, with a copy to the Editor: mary@artwindows.com

Copyright Nursecom, Inc. Oct-Dec 2005