Lamotrigine toxicosis in dogs and cats

Lamotrigine (Lamictal-GlaxoSmithKline) is a phenyltriazine anticonvulsant. It is available as a 2-, 5-, 25-, 50-, 100-, or 200-mg tablet. Available formulations include regular, chewable, orally disintegrating, and extended-release tablets. In people, lamotrigine is given to treat bipolar disorder and partial or generalized seizures.1 Lamotrigine is not given to companion animals because of toxicity concerns.

Pharmacokinetics and metabolism

Information regarding lamotrigine's pharmacokinetics in companion animals is largely unknown because this medication is not used in veterinary medicine.

In people, lamotrigine is rapidly and completely absorbed after oral administration with negligible first-pass effect and bioavailability of 98%. The peak plasma concentration occurs at one or one-and-a-half hours with the immediate-release formulations and four to 11 hours with the extended-release formulations.2 Lamotrigine is about 55% protein-bound.3 It is extensively metabolized in the liver by glucuronic acid conjugation. Elimination is primarily renal, with 94% of the drug excreted through the urine and 2% excreted in the feces.4

Mechanism of action

Lamotrigine's exact mechanism of action is unknown, but it is theorized that it may prevent seizures by inhibiting voltage-gated sodium channels, thus stabilizing neuronal membranes. The mechanism of action for the treatment of bipolar disorder is not fully understood.4

Toxicity

Lamotrigine appears to have a narrow margin of safety in companion and laboratory animals. The oral LD50 is 245 mg/kg in mice and 205 mg/kg in rats.5 Life-threatening signs can be seen at much lower doses in dogs and cats, however.

Lamotrigine is primarily metabolized by glucuronide conjugation, so medications that affect glucuronidation will affect the clearance of lamotrigine. Carbamazepine, phenytoin, phenobarbital, and primidone all induce glucuronidation and increase the clearance of the medication. Animals receiving these medications will be more tolerant of lamotrigine overdoses. Conversely, valproate decreases glucuronidation, which almost doubles lamotrigine's half-life. That decreases the clearance of lamotrigine and increases lamotrigine's toxicity.5 Cats may be more sensitive to lamotrigine than dogs are because of their limited capacity to glucuronidate.

Lamotrigine in dogs is extensively metabolized to a 2-N-methyl metabolite. This metabolite causes dose-dependent prolongation of the P-R interval, widening of the QRS complexes, and, at higher doses, complete atrioventricular (AV) conduction block. Similar cardiovascular effects are not anticipated in people because only trace amounts of the 2-N-methyl metabolite have been found in human urine.

Cases

A review of the ASPCA Animal Poison Control Center's (APCC) toxicology database from 2003 to 2011 identified 138 lamotrigine cases involving 128 dogs and 10 cats.6 These cases were single agent (lamotrigine only) and were assessed as medium- or high-suspect cases based on the animal's history of exposure and clinical signs. Follow-up was not available in 95 of the 128 dogs (74%), full recovery was noted in 23 (18%) of the dogs, and nine (7%) dogs died. One dog continued to show arrhythmias at follow-up. Of the 10 cat cases, one cat (10%) fully recovered, one cat (10%) continued to show clinical signs, and follow-up information was not available on the remaining eight cats (80%).

Of the nine dogs that died, two were found dead at home, one was seizing at home and died before medical attention could be sought, and the other six dogs died at veterinary facilities. One dog was presented to the veterinary facility in status epilepticus and was euthanized because the seizures were thought to be caused by underlying preexisting health conditions. The euthanasia occurred before the dog's exposure to lamotrigine was recognized.

The other five dogs arrested suddenly. The cause of the cardiac arrest was likely due to cardiac arrhythmias, as one dog was experiencing significant arrhythmias before arresting. The dog in that case was a 1.5-year-old Labrador retriever in previously good health that ingested 67.8 mg/kg of lamotrigine and was experiencing ventricular tachycardia, ventricular premature contractions (VPCs), and a bundle branch block before arresting. Resuscitation efforts were not successful. In three of the other cases, the dogs became rigid and vocalized before arresting.

Clinical signs of toxicosis most commonly occur within four hours after exposure, though they are sometimes delayed up to 12 hours with the extended-release products.6 Clinical signs typically last 24 to 48 hours. Signs in dogs, such as lethargy and somnolence, have been observed at exposure doses as low as 3.4 mg/kg. Cardiac signs such as tachycardia are generally not seen until the exposure dose is more than 20 mg/kg. Life-threatening cardiovascular signs such as arrhythmias and seizures are generally seen in dogs exposed to more than 40 mg/kg of lamotrigine.6

There are not enough feline exposures to lamotrigine to establish doses of concern for cats. However, a cat with underlying renal insufficiency did develop bradycardia and VPCs after ingesting a 5-mg/kg dose.6

The most commonly reported clinical signs in dogs and cats included vomiting (64/138 [46%]), ataxia (35/138 [25%]), lethargy (34/138 [25%]), tachycardia (20/138 [14%]), seizures (20/138 [14%]), tremors (15/138 [11%]), arrhythmias (not including sinus tachycardia or bradycardia; 15/138 [11%]), hypersalivation (11/138 [8%]), bradycardia (8/138 [6%]), and hypokalemia (5/138 [4%]). Eight of 138 animals (6%) died due to the exposure. Somnolence, recumbency, collapse, disorientation, and extensor rigidity are also sometimes seen.6

Monitoring

Diagnostic tests should be performed in all patients exposed to lamotrigine to check for underlying kidney or liver problems, as these conditions can significantly affect blood concentrations and can lower the doses at which clinical signs may be seen.1 Monitor for hypokalemia and acidosis. The patient's cardiovascular status (heart rate and rhythm, blood pressure, perfusion parameters) should also be closely monitored. A continuous electrocardiogram (ECG) should be considered, especially in animals exposed to high doses.

Treatment

Decontamination can be performed if the patient is asymptomatic. Emesis can be induced within one hour of exposure to the immediate-release product and within two or three hours of exposure to the extended-release product. Administering activated charcoal (0.7 to 1 g/kg) with a cathartic, such as sorbitol, will help in the adsorption of the lamotrigine and help reduce the systemic absorption. If activated charcoal is given, monitor the patient for hypernatremia.

Intravenous (IV) fluids are required for symptomatic pets. The rate of IV fluids should be based on the patient's cardiovascular status, with patients showing marked signs receiving fluid diuresis for cardiovascular support. Ventricular tachycardia and VPCs can be controlled with lidocaine. Lidocaine can be given as an IV bolus of 2 to 8 mg/kg to effect while monitoring the patient's ECG and then as a constant rate infusion of 25 to 75 µg/kg/min, tapering to the lowest effective dose.7 Treat bradyarrhythmias, such as AV blocks, with either atropine (0.02 mg/kg intravenously) or an isoproterenol infusion (0.04 to 0.08 µg/kg/min intravenously).7

Vomiting should be controlled with antiemetics. Methocarbamol should be given to tremoring pets at a dosage of 55 to 220 mg/kg intravenously. Give half the calculated dose rapidly (not exceeding 2 ml/min), allow the animal to relax, and then give to effect.7 Diazepam (0.5 to 1 mg/kg intravenously to effect) may be given to control seizures, but refractory seizures may require a phenobarbital bolus (2 to 5 mg/kg intravenously) or gas anesthesia.7 Patients with potassium concentrations < 2.5 mEq/L should be supplemented with potassium chloride.

There have been reports of giving intralipids to treat cardiac conduction impairment in people, but intralipid administration has not been adequately evaluated in veterinary medicine to determine its efficacy.8

Summary

Lamotrigine appears to have a narrow margin of safety in companion and laboratory animals. Pets currently receiving valproic acid or with preexisting liver or renal disease are more susceptible to toxicosis. Lamotrigine intoxication in dogs and cats can cause central nervous system depression and, at higher doses, life-threatening cardiac arrhythmias, seizures, and death. Treatment may include gastrointestinal decontamination, intravenous fluid support, and drug administration based on clinical findings. The prognosis is good for animals showing mild signs but guarded for animals with severe cardiac arrhythmias.

REFERENCES

1. POISINDEX editorial staff: Lamotrigine. POISINDEX System [intranet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare), 2011.

2. Product information: Lamictal XR oral extended-release tablets. GlaxoSmithKline. 2009.

3. Product information: Lamictal oral tablets. GlaxoSmithKline. 2009.

4. Lamictal. In: Physicians' desk reference. 63rd ed. Montvale, NJ: Thomson Reuters, 2009;1489.

5. Registry of toxic effects of chemical substances. (Internet version). Cincinnati, Ohio: National Institute for Occupational Safety and Health, 2001.

6. AnTox Database. Urbana, Ill: ASPCA Animal Poison Control Center, 2003-2011.

7. Plumb DC. Plumb's veterinary drug handbook. 6th ed. Ames, Iowa: Blackwell Publishing, 2008.

8. Castanares-Zapatero D, Wittebole X, Huberlant V, et al. Lipid emulsion as rescue therapy in lamotrigine overdose. J Emerg Med 2012;42:48-51.

The ASPCA Animal Poison Control Center (APCC) is a 24-hour animal emergency consultation service that provides treatment and diagnostic recommendations to animal owners and veterinarians regarding animal poisoning cases 24 hours a day, 7 days a week, 365 days a year. Since 1978, the veterinary staff at the APCC has experience of handling more than 2 million animal poisoning cases involving pesticides, herbicides, plants, human and animal drugs, heavy metals, and many other potentially hazardous chemicals. A $65 consultation fee may apply. This includes follow-up consultations for the duration of the case. If you think your animal may have ingested a potentially poisonous substance, call (888) 426-4435. Additional information can be found online at www.aspca.org/apcc.