Lamotrigine

Brand Canonpharma

In stock 1830 Items

Available since: 2019-09-19

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Clinical Pharmacology

Pharmacodynamics
Lamotrigine is a blocker of potential-dependent sodium channels. In the culture of neurons, it causes a potential-dependent blockade of continuously repetitive impulses and suppresses the pathological release of glutamic acid (an amino acid that plays a key role in the development of epileptic seizures), as well as inhibits the depolarization caused by glutamate.
Pharmacokinetics
Suction
Lamotrigine is rapidly and completely absorbed from the intestine, practically not undergoing first-pass first-pass metabolism. Maximum concentration (C_max) in blood plasma is reached approximately 2.5 hours after oral administration of the drug. Time to reach_max slightly increased after a meal, but the degree of absorption remains unchanged. Pharmacokinetics is linear when taking a single dose of up to 450 mg (the largest studied dose).
Distribution
Lamotrigine binds to plasma proteins by approximately 55%. Distribution Volume (V_R) is 0.92-1.22 l / kg.
Metabolism
The enzyme uridine diphosphate glucuronyltransferase (UDP-glucuronyltransferase) is involved in the metabolism of lamotrigine. Lamotrigine slightly increases its own metabolism, depending on the dose.
Removal
In healthy adults, lamotrigine clearance in a state of equilibrium concentrations averages 39 ± 14 ml / min. Lamotrigine is metabolized to glucuronides, which are excreted by the kidneys. Less than 10% of the drug is excreted by the kidneys unchanged, about 2% by the intestines. Clearance and half-life (T_½) Do not depend on the dose. T_½ in healthy adults, it averages from 24 hours to 35 hours. Patients with Gilbert's syndrome showed a 32% reduction in drug clearance compared to the control group, which, however, did not go beyond the normal values for the general population. The average half-life is reduced to about 14 hours while being administered with drugs that stimulate glucuronization, such as carbamazepine and phenytoin, and increases to an average of 70 hours when co-administered with valproate.
In children, lamotrigine clearance in terms of body weight is higher than in adults; it is highest in children under 5 years old. T_½ usually shorter than adults. Its mean value is approximately 7 hours when administered concurrently with drugs that stimulate glucuronization, such as carbamazepine and phenytoin, and rises on average to 45-50 hours when co-administered with valproate.
Elderly patients showed no clinically significant differences in lamotrigine clearance compared with young patients.
With a significant reduction in kidney function, a reduction in the dose of lamotrigine may be required.
In patients with moderate and severe hepatic insufficiency, the dose of lamotrigine should be reduced.

Indications

Epilepsy (partial and generalized seizures, including tonic-clonic convulsions, as well as seizures in Lennox-Gastaut syndrome) in combination therapy or monotherapy in adults and children over 12 years of age;
Epilepsy (partial and generalized seizures, including tonic-clonic convulsions, as well as seizures in Lennox-Gastaut syndrome) as part of combination therapy in children from 3 to 12 years old;
Monotherapy typical absans;
To prevent mood disorders (depression, mania, hypomania, mixed episodes) in adults with bipolar affective disorder.

Composition

One tablet contains:
Active ingredient: lamotrigine 100 mg
Excipients: Hyprolosis (hydroxypropylcellulose) 11 mg, sodium carboxymethyl starch 9.5 mg, lactose monohydrate 120 mg, magnesium hydroxycarbonate 77 mg, magnesium stearate 2.5 mg

Lamotrigine is marketed under different brands and generic names, and comes in different dosage forms:

Brand name	Manufacturer	Country	Dosage form
Lamotrigine	Canonpharma	Russia	pills
Lamitor	Torrent	India	pills
Seyzar	Alkaloid	Macedonia	pills
Lamictal	GlaxoSmithKline	UK	pills
Lamictal	GlaxoSmithKline	UK	solution
Lamolep	Gedeon Richter	Hungary	pills

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Dosage and Administration

For oral use. If the calculated dose of lamotrigine (for example, when prescribed to children or patients with impaired liver function) cannot be divided into a whole number of lower dosage pills, the patient should be assigned such a dose that corresponds to the nearest value of the whole tablet in a lower dosage.
In patients taking drugs whose pharmacokinetic interaction with lamotrigine is currently unknown, the regimen recommended for prescribing lamotrigine in combination with valproic acid should be used. In children weighing less than 25 kg or if the calculated maintenance dose in children is less than 25 mg / day, the drug Lamotrigine Canon should not be prescribed.
In case of resumption of lamotrigine, doctors should evaluate the need to increase the dose in patients who have stopped taking the drug for any reason, since high initial doses and exceeding the recommended doses are associated with the risk of developing a severe rash. The more time passed after the last dose of the drug, the more caution should be increased to a maintenance dose. If the time after stopping the administration exceeds 5 half-life, then the dose of lamotrigine should be increased to maintain according to the appropriate scheme.
It is not recommended to resume the prescription of lamotrigine for patients who have stopped taking the drug due to a rash, unless the potential benefits of using the drug obviously outweigh the possible risks.
Epilepsy
The recommended dosing regimen for treating epilepsy in adults and children over 12 years old is presented in Table 1, and in children aged 3 to 12 years (see Table 1).
Due to the risk of rash, the initial dose of the drug and the recommended mode of increasing doses should not be exceeded.
If necessary, more accurate dosing, for example, as part of complex therapy in children, dosage forms are used that contain lamotrigine in lower dosages.
When canceling concomitant antiepileptic drugs, switching to lamotrigine therapy or prescribing other drugs or antiepileptic drugs while taking lamotrigine, it is necessary to take into account that this may affect lamotrigine pharmacokinetics.

Table 1. Recommended dosing regimen in the treatment of epilepsy in adults and children over 12 years old

1-2 week	3-4 week		Maintenance doses
Monotherapy
25 mg 1 time / day	50 mg 1 time / day	100-200 mg / day (in 1 or 2 doses). To achieve a therapeutic effect, the dose can be increased by 50-100 mg every 1-2 weeks. Some patients require a dose of 500 mg.
Combination therapy with valproic acid drugs
25 mg every other day	25 mg 1 time / day		100-200 mg / day (in 1 or 2 doses). To achieve a therapeutic effect, the dose may be increased by 25-50 mg every 1-2 weeks.
Combination therapy without valproic acid drugs, but with lamotrigine glucuronidation inducers
50 mg 1 time / day	100 mg / day (in 2 doses)		200-400 mg / day (in 2 doses). To achieve a therapeutic effect, the dose may be increased by 100 mg every 1-2 weeks. Some patients require a dose of 700 mg.
Combination therapy without valproic acid and without lamotrigine glucuronidation inducers
25 mg 1 time / day	50 mg 1 time / day		100-200 mg / day (in 2 doses). If necessary, the dose may be increased by 50-100 mg every 1-2 weeks.

Adverse reactions

Epilepsy
Skin and Subcutaneous Tissues
Very often: skin rash.
Rarely: Stevens-Johnson syndrome.
Very rare: toxic epidermal necrolysis.
Blood and lymphatic system
Very rarely: neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplastic anemia, agranulocytosis, lymphadenopathy.
The immune system
Very rarely: hypersensitivity syndrome (including symptoms such as fever, lymphadenopathy, swelling of the face, blood and liver function disorders, disseminated intravascular coagulation syndrome (DIC), multiple organ failure).
From the psyche
Often: aggressiveness, irritability.
Very rarely: tics, hallucinations, confusion.
The nervous system
With monotherapy
Very often: headache; often: drowsiness, insomnia, dizziness, tremor; infrequently: ataxia; rarely: nystagmus.
As part of combination therapy
Very often: drowsiness, ataxia, headache, dizziness; often: nystagmus, tremor, insomnia.
Rarely: aseptic meningitis.
Very rarely: agitation, instability of gait, movement disorders, worsening of symptoms of Parkinson's disease, extrapyramidal disorders, choreoathetosis, increased frequency of seizures.
On the part of the organ of vision
With monotherapy
Infrequently: diplopia, blurred vision.
As part of combination therapy
Very often: diplopia, blurred vision; rarely: conjunctivitis.
From the gastrointestinal tract
With monotherapy
Often: nausea, vomiting, diarrhea.
As part of combination therapy
Very often: nausea, vomiting.
Often: diarrhea.
Liver and biliary tract
Very rarely: increased activity of “liver” enzymes, impaired liver function, liver failure. Liver dysfunction usually develops in combination with symptoms of hypersensitivity, but in isolated cases they were also observed in the absence of obvious signs of hypersensitivity.
From the musculoskeletal and connective tissues
Very rarely: lupus-like syndrome; frequency unknown: osteomalacia, osteoporosis, bone fractures (especially in patients with long-term lamotrigine, when combined with other AEDs).
Common disorders
Often: fatigue.
Bipolar affective disorder.
From the skin and subcutaneous tissue
Very often: skin rash.
Rarely: Stevens-Johnson syndrome.
In evaluating all studies (controlled and uncontrolled) to study lamotrigine in patients with bipolar affective disorder, skin rash occurred in 12% of all patients who received lamotrigine, while the frequency of skin rash in controlled studies was only 8% in patients who received lamotrigine, and 6% in patients receiving placebo.
The nervous system
Very often: headache.
Often: agitation, drowsiness, dizziness.
Gastrointestinal system
Often: dryness of the oral mucosa.
From the musculoskeletal and connective tissues
Often: arthralgia.
Common disorders
Often: pain, pain in the back.

Carefully
Impaired liver and kidney function.

Drug interactions

UDP-glucuronyltransferase is the main enzyme metabolizing lamotrigine. There is no evidence of lamotrigine's ability to cause clinically significant induction or inhibition of liver microsomal enzymes. In this regard, the interaction between lamotrigine and drugs metabolized by cytochrome P450 isoenzymes is unlikely. Lamotrigine can induce its own metabolism, but this effect is mild and has no clinically significant effects.
Table 6. The effect of other drugs on lamotrigine glucuronidation

Powerful inhibitors of lamotrigine glucuronidation	Powerful inductors of lamotrigine glucuric induction	Means that have little effect on lamotrigine glucuronidation
valproic acid	Carbamazepine, Phenytoin, Primidone, Phenobarbital, Rifampicin, Lopinavir / Ritonavir, Atazanavir / Ritonavir, Ethinyl Estradiol / Levonorgestrel Combination^**	Lithium preparations, bupropion, olanzapine, oxcarbazepine, felbamate, gabapentin, levetiracetam, pregabalin, topiramate, zonisamide, aripiprazole

** The effects of other oral contraceptives and hormone replacement therapy have not been studied, although they may have a similar effect on the pharmacokinetic indices of lamotrigine.

Interactions with probe
Valproic acid inhibits lamotrigine glucuronidation, reducing its metabolic rate and lengthens its T_½ almost 2 times. Some PEPs (for example, phenytoin, carbamazepine, phenobarbital, and primidone), which induce liver microsomal enzymes, accelerate lamotrigine glucuronidation and its metabolism. Dizziness, ataxia, diplopia, blurred vision and nausea have been reported in patients taking carbamazepine in combination with lamotrigine (these symptoms usually disappear when the dose of carbamazepine is reduced). A similar effect was observed when prescribing lamotrigine and oxcarbazepine, the result of dose reduction was not studied. With simultaneous intake of lamotrigine in a dose of 200 mg and oxcarbazepine in a dose of 1200 mg, neither oxcarbazepine nor lamotrigine disrupt each other's metabolism.
The combined use of felbamate at a dose of 1200 mg 2 times a day and lamotrigine 100 mg 2 times a day did not lead to clinically significant changes in the pharmacokinetics of lamotrigine.
No pharmacologic interaction of lamotrigine and gabapentin has been identified.
The possible drug interactions of levitiracetam and lamotrigine were investigated in assessing the serum concentrations of both drugs in placebo-controlled clinical studies. These data indicate that lamotrigine and levetiracytes do not affect each other's pharmacokinetics.
The effect of pregabalin at a dose of 200 mg 3 times per day was not observed on equilibrium concentrations of lamotrigine, i.e. pregabalin and lamotrigine do not interact pharmacokinetically with each other.
With simultaneous use of lamotrigine and topiramate, the plasma concentration of the latter increases by 15%. Taking zonisamide (at a dose of 200–400 mg per day) during the clinical program together with lamotrigine (at a dose of 150–500 mg per day) did not lead to a change in the pharmacokinetic parameters of lamotrigine. Studies have shown that lamotrigine does not affect plasma concentrations of other antiepileptic drugs. Lamotrigine does not displace other antiepileptic drugs from binding to plasma proteins.

Interactions with combined use with other psychotropic drugs
Lamotrigine at a dose of 100 mg / day does not cause a violation of the pharmacokinetics of anhydrous lithium gluconate (2 g 2 times a day for 6 days) when administered together. Repeated intake of bupropion does not have a statistically significant effect on the pharmacokinetics of a single dose of lamotrigine and causes a slight increase in the area under the concentration-time curve (AUC) of lamotrigine glucuronide. Olanzapine in a dose of 15 mg reduces AUC and C_max lamotrigine on average by 24% and 20%, respectively, which is clinically insignificant. Lamotrigine 200 mg does not change the kinetics of olanzapine. Repeated intake of lamotrigine at a dose of 400 mg per day did not have a clinically significant effect on the pharmacokinetics of risperidone after taking a single dose of 2 mg by healthy volunteers. At the same time, drowsiness was noted in 12 of 14 patients with the combined intake of lamotrigine and risperidone; in 1 out of 20 patients with risperidone alone; none of the patients - while taking one lamotrigine. In a study of 18 adult patients with bipolar disorder receiving lamotrigine (100-400 mg / day), increasing the dose of aripiprazole from 10 mg / day to 30 mg / day for 7 days revealed a decrease of 10% AUC and C_max lamotrigine without clinically significant consequences. Inhibition of lamotrigine by amitriptyline, bupropion, clonazepam, fluoxetine, haloperidol or lorazepam has a minimal effect on the formation of the primary metabolite of lamotrigine 2-N-glucuronide. The study of the metabolism of bufuralol with microsomal liver enzymes isolated from humans suggests that lamotrigine does not decrease the clearance of drugs metabolized mainly by CYP2D6 isoenzymes. In vitro studies also suggest that clozapine, phenelzine, risperidone, sertraline, or trazodone are unlikely to affect lamotrigine clearance.

Interactions with hormonal contraceptives

Effect of hormonal contraceptives on lamotrigine pharmacokinetics
Reception of combined oral contraceptives containing 30 µg of ethinyl estradiol and 150 µg of levonorgestrel causes an approximately twofold increase in lamotrigine clearance (after ingestion), which leads to a decrease in AUC and C_max lamotrigine on average by 52% and 39%, respectively. During the week free from taking the active drug, an increase in the plasma concentration of lamotrigine is observed, while the concentration of lamotrigine, measured at the end of this week before the next dose, is on average 2 times higher than during the period of active therapy.

Effect of lamotrigine on the pharmacokinetics of hormonal contraceptives
During the period of equilibrium concentrations, lamotrigine at a dose of 300 mg does not affect the pharmacokinetics of ethinyl estradiol. There is a slight increase in clearance of levonorgestrel, which led to a decrease in AUC and C_max levonorgestrel by 19% and 12%, respectively. Measurement of serum FSH, LH and estradiol during this study revealed a slight decrease in the suppression of the hormonal activity of the ovaries in some women, although measuring the plasma concentration of progesterone in none of the 16 women showed hormonal evidence of ovulation. The effect of a moderate increase in clearance of levonorgestrel and changes in plasma concentrations of FSH and LH on the ovulation activity of the ovaries has not been established. The effect of other doses of lamotrigine (except 300 mg / day) has not been studied, and studies with the inclusion of other hormonal drugs have not been conducted.

Interactions with other drugs.
Rifampicin increases the clearance of lamotrigine and reduces its half-life, due to the induction of microsomal liver enzymes responsible for glucuronidation. For patients taking rifampicin as concomitant therapy, the regimen of lamotrigine should follow the regimen recommended for co-administration of lamotrigine and drugs that induce glucuronidation.
When using lopinavir / ritonavir, there was a decrease of approximately 50% in the concentration of lamotrigine in the plasma, possibly due to the induction of glucuronidation. In patients taking concomitant treatment with lopinavir / ritonavir, lamotrigine dosing regimen with concomitant glucuronidation injectors should be recommended. In a study on healthy volunteers, taking atazanavir / ritonavir (300 mg / 100 mg) resulted in lower AUC and C values_max lamotrigine (in a single dose of 100 mg) by about 32% and 6%, respectively. The results of in vitro studies have shown that lamotrigine (not its metabolite 2-N-glucuronide) is a more potent inhibitor of the carrier of organic cations 2 than cimetidine. The combined use of lamotrigine with drugs, excreted kidneys and substrates of the carrier of organic cations 2 (for example, metformin, gabapentin, varenicline) can lead to an increase in plasma concentrations of these drugs. The clinical significance of this is not clearly defined, however, caution should be exercised while using these drugs.

Pregnancy and Lactation

Fertility
Studies on the reproductive function of animals in the application of lamotrigine did not reveal any impairment of fertility. Studies on the effect of lamotrigine on human fertility have not been conducted.
Pregnancy
The risk associated with antiepileptic drugs (PEP) in general.
Women capable of childbearing, you need to get the recommendation of experts.
If a woman is planning a pregnancy, the need for treatment of ELVs should be reviewed. In women, epilepsy is being treated, the sudden cessation of antiepileptic therapy should be avoided, as this can lead to a resumption of seizures, which can have serious consequences for the woman and the unborn child.In the offspring of mothers who received AED, the risk of congenital malformations increases by 2-3 times compared with the expected incidence of the population as a whole, which is about 3%. The most frequently reported defects are cleft lip, cardiovascular heart defects and neural tube defects. Multiple PEP therapy is associated with a higher risk of congenital malformations than monotherapy, in this regard, whenever possible, monoterpy should be used.
The risk associated with taking lamotrigine
Lamotrigine has a mild inhibitory effect on dihydrofolic acid reductase and therefore, theoretically, it may lead to an increased risk of impaired embryo and fetal development due to a decrease in folic acid levels. You should consider taking folic acid during pregnancy planning and in the early stages of pregnancy. Post-registration observation data from several prospective pregnancy registries made it possible to document pregnancy outcomes in about 2,000 women who received lamotrigine monotherapy during the first trimester of pregnancy. In general, the data obtained do not confirm a general increase in the risk of developing congenital malformations, however, from a limited number of pregnancy registers there are reports of an increased risk of developing oral malformations. A case-control study did not reveal an increase in the risk of developing malformations of the oral cavity compared with other defects resulting from the use of lamotrigine. There is not enough data when using the drug in combination therapy to assess whether the risk of malformations depends on other drugs used in combination with lamotrigine. Like other AEDs, lamotrigine should be administered during pregnancy only if the expected benefit outweighs the potential risk.
Physiological changes during pregnancy can influence concentration and / or its therapeutic effect. There are reports of decreased lamotrigine concentrations during pregnancy. Administration of the drug to pregnant women should be ensured by the appropriate state of management of patients.
Breastfeeding period
Lamotrigine in varying degrees, penetrates into breast milk, the total concentration of lamotrigine in infants can reach about 50% of the concentration of lamotrigine recorded from the mother. Thus, in some breastfed babies, serum concentrations of lamotrigine can reach levels at which pharmacological effects appear. It is necessary to correlate the potential benefits of breastfeeding with the possible risk of adverse reactions in the infant.

Special instructions

Skin rash
There are reports of adverse skin reactions that may occur during the first 8 weeks after starting lamotrigine. Most rashes are lightweight and go away on their own, but there are reports of rashes that required the patient to be hospitalized and to stop taking lamotrigine. They included such potentially life-threatening skin reactions as Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome). Severe skin reactions in adult patients using lamotrigine in accordance with generally accepted recommendations develop with a frequency of approximately 1 in 500 patients with epilepsy. In about half of these cases, Stevens-Johnson syndrome (1 in 1000) was recorded. In patients with bipolar disorders, the incidence of severe skin rashes according to clinical studies is approximately 1 per 1000 patients. In children, the risk of developing severe skin rash is higher than in adults.In children, the initial manifestations of a rash can be mistaken for an infection, so doctors should take into account the children's ability to react to the drug, manifested by the development of rash and fever in the first 8 weeks of therapy. Caution is necessary when prescribing patients with a history of allergic reactions or a rash in response to taking other antiepileptic drugs, since the incidence of rash (not classified as serious) in patients with this history was observed three times more often with lamotrigine than in patients with uncomplicated history. When a rash is detected, all patients should be examined immediately by a doctor. Reception of a lamotrigine has to be immediately stopped except for those cases when it is obvious that development of rash is not connected with administration of drug. It is not recommended to resume taking lamotrigine in cases where its previous appointment was canceled due to the development of a skin reaction, unless the expected therapeutic effect from the use of the drug does not exceed the risk of side effects. It has been reported that the rash may be part of hypersensitivity syndrome associated with various systemic manifestations, including fever, lymphadenopathy, swelling of the face, and disorders of the blood and liver. The severity of the syndrome varies widely and in rare cases can lead to the development of disseminated intravascular coagulation syndrome (DIC) and multiple organ failure. It should be noted that the early manifestations of hypersensitivity syndrome (fever, lymphadenopathy) can be observed, even if there are no obvious manifestations of a rash. If these symptoms develop, the patient should be immediately examined by a doctor and, unless another cause of the symptoms is identified, lamotrigine should be canceled.

Risk of Aseptic Meningitis
It has been reported that children and adults taking lamotrigine have an increased risk of developing aseptic meningitis. Patients should be advised to consult a doctor immediately if they develop symptoms and signs of meningitis. With the development of meningitis, the doctor should cancel lamotrigine therapy. With the abolition of the drug in most cases, the symptoms of meningitis disappeared, but in some patients they were resumed with the repeated appointment of lamotrigine. Patients who have stopped taking the drug due to aseptic meningitis associated with previous lamotrigine should not be resumed.

Clinical deterioration and suicidal risk
Suicidal thoughts and suicidal behavior were observed in patients taking AED for several reasons, including epilepsy and bipolar disorder. The mechanism of this action is unknown, and the available data do not exclude the possibility of increasing the risk of suicide with the use of lamotrigine. Therefore, patients taking lamotrigine should be carefully monitored for suicidal thoughts and behaviors. Patients (and caregivers) should be informed of the need for medical advice if symptoms occur.

Dehydrofolate reductase
Lamotrigine is a weak inhibitor of dehydrofolate reductase, so there is a likelihood that the drug will interfere with folate metabolism during long-term therapy. However, it was shown that lamotrigine did not cause significant changes in the hemoglobin concentration, the average red blood cell volume, the serum erythrocyte folate concentration during the administration of the drug for up to 1 year and did not reduce the folate concentration in the erythrocytes for the administration of lamotrigine for up to 5 years.

Renal failure
A single appointment of lamotrigine to patients in the final stage of renal failure did not reveal significant changes in the concentration of the drug.However, accumulation of the glucuronide metabolite is very likely, so care must be taken when treating patients with renal insufficiency.

Patients taking other drugs containing lamotrigine
Do not prescribe the drug Lamotrigine Canon to patients already receiving other drugs containing lamotrigine without consulting a doctor.

Epilepsy.
Abrupt cancellation of lamotrigine, as well as other AEDs, can trigger the development of seizures. If abrupt discontinuation of therapy is not a safety requirement (for example, when a rash appears), the dose of lamotrigine should be reduced gradually over a period of 2 weeks. There are reports that severe convulsive seizures, including status epilepticus, can lead to the development of rhabdomyolysis, multiorgan disorders and disseminated intravascular coagulation, sometimes with fatal outcome. Similar cases were observed in patients with lamotrigine.

Bipolar affective disorder
In patients with bipolar affective disorder, clinical deterioration and / or aggravation of suicidal thoughts and suicidal behavior can be observed along with techniques for the treatment of bipolar disorder, including lamotrigine. Patients taking lamotrigine should be strictly monitored during treatment. Patients (and caregivers) should be informed about the need to monitor any deterioration in the patient's condition, including the emergence of new symptoms and / or suicidal thoughts / behavior and seek medical help immediately if these symptoms are present. At the same time, the situation should be assessed and appropriate changes should be made in the therapy regimen, including the possibility of drug withdrawal.

Impact on the ability to drive vehicles and mechanisms
During the period of use of the drug Lamotrigine Canon, it is recommended to refrain from driving and occupations that require increased concentration of attention and speed of psychomotor reactions.

Overdosage

Symptoms: a single dose of 10–20 times the maximum therapeutic dose has been reported, including fatal cases. Overdose manifested symptoms, including nystagmus, ataxia, impaired consciousness and coma, as well as the expansion of the QRS complex on the ECG.
Treatment: hospitalization and maintenance therapy is recommended in accordance with the clinical picture or recommendations of the National Toxicological Center.