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GLUTAMATE ANTAGONISTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Riluzole, a benzothiazole compound, act as a glutamate antagonists and exhibits neuroprotective properties by blocking glutamatergic neurotransmission in the CNS. Lubeluzole had been under investigation as a treatment for acute moderate-to-severe ischemic stroke, but has yet to be approved.

Specific Substances

    A) LUBELUZOLE
    1) R-87926
    RILUZOLE
    1) PK-26124
    2) RP-54274
    3) 2-Amino-6-(trifluoromethoxy)benzothiazole
    4) CAS 1744-22-5
    5) Molecular Formula: C8-H5-F3-N2-O-S

Available Forms Sources

    A) FORMS
    1) Riluzole is formulated as capsule-shaped, white, film-coated 50-mg tablets for oral administration (Prod Info RILUTEK(R) oral tablets, 2009).
    B) USES
    1) Riluzole has been FDA approved to treat patients with amyotrophic lateral sclerosis (ALS). It extends survival and/or time to tracheostomy (Prod Info RILUTEK(R) oral tablets, 2009). It has been studied for the treatment of Huntington's disease (Bodner et al, 2001), depression and cervical dystonia.

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Riluzole, a member of the benzothiazole class, is approved for use in the treatment of amyotrophic lateral sclerosis. Riluzole has also been studied in the treatment of depression, cervical dystonia and Huntington's disease.
    B) PHARMACOLOGY: Riluzole, a 2-amino-6-trifluoromethoxy benzothiazole, is a neuroprotective agent. The mode of action of riluzole is unknown. The pharmacological properties of riluzole include: an inhibitory effect on glutamate release; inactivation of voltage-dependent sodium channels, and ability to interfere with intracellular events that follow transmitter binding at excitatory amino acid receptors. Pharmacokinetics appear to be linear.
    C) EPIDEMIOLOGY: Overdose is uncommon.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EVENTS: Therapeutic administration of glutamate antagonists may cause dose-related adverse effects including: decreased lung function, asthenia, nausea, vomiting, anorexia, diarrhea, dizziness, somnolence, circumoral paresthesias and elevated liver enzymes. Hypertension and neutropenia are less common occurrences following therapeutic administration of riluzole.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Overdose ingestions have resulted in methemoglobinemia and severe cognitive and psychiatric disturbances.
    2) MILD TO MODERATE TOXICITY: Symptoms may be an extension of adverse events. The following events appear to be dose-related: asthenia, nausea, dizziness, decreased lung function, diarrhea, abdominal pain, pneumonia, vomiting and circumoral paraesthesia were dose-related.
    3) SEVERE TOXICITY: Toxic encephalopathy with stupor and coma, and methemoglobinemia have been reported in isolated cases following overdose.
    0.2.20) REPRODUCTIVE
    A) Decreased implantation rates and increased intrauterine death rates were seen in rats given oral riluzole during mating and throughout gestation and lactation. Impaired fertility was also seen in rats. Embryotoxicity was seen in rats and rabbits given oral riluzole.

Laboratory Monitoring

    A) Monitor blood pressure in symptomatic patients.
    B) Liver enzyme levels should be monitored after significant overdose.
    C) No other specific lab work (CBC, electrolytes, urinalysis) is needed unless otherwise clinically indicated.
    D) Serum levels of glutamate antagonists are not clinically useful for managing overdose or widely available.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Monitor fluid status in patients with significant gastrointestinal loss; treat with IV fluids and antiemetics as needed. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive; limited overdose data. Monitor neurologic function (events have been infrequent); overdose symptoms have included toxic encephalopathy, stupor and coma. Patients with a persistent fever should be evaluated for neutropenia. Methemoglobinemia has occurred infrequently following overdose; monitor methemoglobin as indicated. Treat with methylene blue.
    C) DECONTAMINATION
    1) PREHOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is alert and able to maintain their airway.
    2) HOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain their airway.
    D) ANTIDOTE
    1) None.
    E) AIRWAY MANAGEMENT
    1) Airway support or management is unlikely to be necessary following a mild to moderate exposure; patients with significant toxicity (ie, neurologic toxicity) may require mechanical intubation and ventilation.
    F) METHEMOGLOBINEMIA
    1) Initiate oxygen therapy. Treat with methylene blue if patient is symptomatic (usually at methemoglobin concentrations greater than 20% to 30% or at lower concentrations in patients with anemia, underlying pulmonary or cardiovascular disease). METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.
    G) ENHANCED ELIMINATION
    1) Hemodialysis is UNLIKELY to be of benefit due to the high protein binding (96%) of riluzole.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: An asymptomatic child with an inadvertent exposure (a single dose) can be managed at home with adult supervision. An adult with an inadvertent exposure of an extra dose can be managed at home.
    2) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite adequate treatment should be admitted.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    I) PHARMACOKINETICS
    1) Riluzole is approximately 90% absorbed with an oral bioavailability of about 60%. It is 96% bound to primarily albumin and lipoproteins and extensively metabolized by the liver with the metabolic pathways consisting of cytochrome P450-dependent hydroxylation and glucuronidation. Elimination half-life is 12 hours after multiple doses. Pharmacokinetics appear to be linear.
    J) DIFFERENTIAL DIAGNOSIS
    1) Underlying liver disease or insufficiency.

Range Of Toxicity

    A) TOXICITY: The toxic dose has not been established. Mild methemoglobinemia has been reported in adults after ingestion of 1.5 g and 2.8 g of riluzole. Circumoral paresthesia and dizziness/vertigo were associated with the oral administration of 250 to 300 mg of riluzole. In a safety and efficacy study, 2 patients experienced light-headedness and dizziness after receiving 25 mg of lubeluzole.
    B) THERAPEUTIC: RILUZOLE: ADULT: 50 mg orally every 12 hours. LUBELUZOLE: ADULT: 7.5 mg infused over 1 hour, followed by continuous infusion of 10 mg daily for 5 days. PEDIATRIC: Safety and efficacy have not been established in pediatric patients for either of these medications.

Clinical Effects

Summary Of Exposure

    A) USES: Riluzole, a member of the benzothiazole class, is approved for use in the treatment of amyotrophic lateral sclerosis. Riluzole has also been studied in the treatment of depression, cervical dystonia and Huntington's disease.
    B) PHARMACOLOGY: Riluzole, a 2-amino-6-trifluoromethoxy benzothiazole, is a neuroprotective agent. The mode of action of riluzole is unknown. The pharmacological properties of riluzole include: an inhibitory effect on glutamate release; inactivation of voltage-dependent sodium channels, and ability to interfere with intracellular events that follow transmitter binding at excitatory amino acid receptors. Pharmacokinetics appear to be linear.
    C) EPIDEMIOLOGY: Overdose is uncommon.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EVENTS: Therapeutic administration of glutamate antagonists may cause dose-related adverse effects including: decreased lung function, asthenia, nausea, vomiting, anorexia, diarrhea, dizziness, somnolence, circumoral paresthesias and elevated liver enzymes. Hypertension and neutropenia are less common occurrences following therapeutic administration of riluzole.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Overdose ingestions have resulted in methemoglobinemia and severe cognitive and psychiatric disturbances.
    2) MILD TO MODERATE TOXICITY: Symptoms may be an extension of adverse events. The following events appear to be dose-related: asthenia, nausea, dizziness, decreased lung function, diarrhea, abdominal pain, pneumonia, vomiting and circumoral paraesthesia were dose-related.
    3) SEVERE TOXICITY: Toxic encephalopathy with stupor and coma, and methemoglobinemia have been reported in isolated cases following overdose.

Vital Signs

    3.3.4) BLOOD PRESSURE
    A) Hypertension has been following therapeutic administration of riluzole (Prod Info RILUTEK(R) oral tablets, 2009; Bensimon et al, 1994).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) A mild-to-moderate increase in blood pressure was reported in 4 patients following riluzole therapy, 100 mg daily (Bensimon et al, 1994).
    b) During riluzole placebo-controlled clinical trials, hypertension was reported in 6.8%, 5.1%, and 3.3% of patients following therapeutic administration of 50 mg daily, 100 mg daily, and 200 mg daily of riluzole, respectively compared to 4.1% in the placebo group (Prod Info RILUTEK(R) oral tablets, 2009).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY FAILURE
    1) WITH THERAPEUTIC USE
    a) A decrease in lung function appeared to be dose-related adverse effect following riluzole therapy (Prod Info RILUTEK(R) oral tablets, 2009; Lacomblez et al, 1996; Miller et al, 1996; Wokke, 1996). A decrease in lung function may also be a consequence of amyotrophic lateral sclerosis (ALS), the disease for which riluzole was being given as treatment.

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) FATIGUE
    1) WITH THERAPEUTIC USE
    a) Asthenia has been reported as a common dose-related adverse effect in patients treated with riluzole (Prod Info RILUTEK(R) oral tablets, 2009; Bensimon et al, 1994; Anon, 1995; Lacomblez et al, 1996; Miller et al, 1996; Wokke, 1996), and is a common reason for withdrawal from therapy.
    1) Asthenia may also occur as a result of ALS itself, the disease being treated with riluzole.
    b) During riluzole placebo-controlled clinical trials, asthenia was reported in 14.8%, 19.2%, and 20.1% of patients following therapeutic administration of 50 mg daily, 100 mg daily, and 200 mg daily of riluzole, respectively compared to 12.2% in the placebo group (Prod Info RILUTEK(R) oral tablets, 2009).
    B) DROWSY
    1) WITH THERAPEUTIC USE
    a) Somnolence has occurred as a dose-related response to riluzole in clinical trials (Prod Info RILUTEK(R) oral tablets, 2009; Miller et al, 1996; Wokke, 1996).
    C) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness and vertigo have occurred as dose-related adverse effects following administration of riluzole (Prod Info RILUTEK(R) oral tablets, 2009; Anon, 1995; Lacomblez et al, 1996; Miller et al, 1996; Wokke, 1996; Liboux et al, 1997). Symptoms resolved after reducing the riluzole dose.
    b) In two safety studies, intravenous lubeluzole was administered to healthy volunteers. In the first study, 2 of 6 subjects complained of lightheadedness and dizziness 30 minutes after the end of a 10 mg lubeluzole infusion. The symptoms resolved spontaneously within 2 hours. In the second study, 4 of 5 subjects and all 5 subjects experienced lightheadedness and dizziness within 2 hours of receiving infusions of 15 mg and 20 mg lubeluzole, respectively. The lightheadedness and dizziness increased in intensity and severity with increasing doses of lubeluzole (Hantson et al, 1997).
    D) PARESTHESIA
    1) WITH THERAPEUTIC USE
    a) Circumoral paresthesias have been reported as a dose-related adverse effect following riluzole therapy (Prod Info RILUTEK(R) oral tablets, 2009; Lacomblez et al, 1996; Miller et al, 1996; Wokke, 1996; Liboux et al, 1997).
    E) SEIZURE
    1) WITH THERAPEUTIC USE
    a) During two studies to determine the safety of lubeluzole in patients with ischemic stroke, seizures were reported in 2 patients who received 10 mg lubeluzole infusions. EEG analysis revealed no epileptic discharges (De Keyser et al, 1997).
    b) Seizures have been reported infrequently with therapeutic use of riluzole (Prod Info RILUTEK(R) oral tablets, 2009)
    F) AMNESIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 38-year-old woman with Huntington's disease ingested 2.8 g of riluzole in a suicide attempt, and 4 days postingestion developed severe nausea, severe retrograde and antegrade amnesia, attentional deficits, short-term memory deficit, disorientation and dysphoria. All cognitive functions returned to baseline 10 weeks postingestion (Bodner et al, 2001).
    b) CASE REPORT: A 44-year-old woman with Huntington's disease developed delayed amnesic syndrome after ingesting 3 g of riluzole. She presented to the ED 7 hours after ingestion. The neurological exam upon presentation showed normal consciousness and orientation but with increased cognitive slowing, dysarthria, postural imbalance, and gait difficulties. Four days after presentation the patient experienced memory problems and attention deficits leading to a full amnesic syndrome including complete verbal and visuospatial antegrade amnesia, partial retrograde amnesia, and disorientation to time and place. The symptoms persisted. Testing one year postingestion showed irreversible effect with no improvement of orientation in time, immediate and delayed recognition of visual stimuli, and delayed reproduction of verbal items (Haaxma et al, 2006).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA, VOMITING AND DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Nausea, vomiting and diarrhea have been reported as dose-related adverse effects in patients receiving riluzole (Prod Info RILUTEK(R) oral tablets, 2009; Bodner et al, 2001; Bensimon et al, 1994; Anon, 1995; Lacomblez et al, 1996; Miller et al, 1996; Wokke, 1996).
    b) During a dose-ranging study, nausea was reported by 12% to 21% of riluzole-treated ALS patients and resulted in 1.4% of patients discontinuing treatment (Lacomblez et al, 1996).
    B) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) Anorexia appears to be a dose-related adverse effect following therapeutic administration of riluzole (Prod Info RILUTEK(R) oral tablets, 2009; Anon, 1995; Lacomblez et al, 1996; Miller et al, 1996).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Bensimon et al (1994) reported that abdominal pain occurred in 3 of 77 patients involved in a clinical trial to determine the safety and efficacy of riluzole in the treatment of ALS. Two of the 3 patients withdrew from the study (Bensimon et al, 1994a).
    b) Abdominal pain appears to be a dose-related adverse effect following administration of riluzole during clinical trials (Prod Info RILUTEK(R) oral tablets, 2009).
    D) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation was reported in 6 of 77 patients following riluzole therapy in a clinical trial (Bensimon et al, 1994).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) ABNORMAL LIVER FUNCTION
    1) WITH THERAPEUTIC USE
    a) Elevated serum transaminase (ALT/SGPT) levels have been reported as a dose-related adverse effect following administration of riluzole during clinical trials (Prod Info RILUTEK(R) oral tablets, 2009; Bensimon et al, 1994; Anon, 1995; Lacomblez et al, 1996; Miller et al, 1996; Wokke, 1996). Patients were withdrawn from the trials if the enzyme levels were greater than 5 times the upper limit of normal (ULN).
    b) According to the manufacturer, experience in 800 ALS patients indicates that 50% of riluzole-treated patients will experience at least one ALT/SGPT level above the ULN. About 8% of patients will have elevations greater than 3 times the ULN, and about 2% of the patients will have elevations greater than 5 times the ULN (Prod Info RILUTEK(R) oral tablets, 2009).
    1) Maximum increases in serum ALT of less than 5 times ULN usually occurred 3 months after the start of riluzole therapy. The levels usually returned to below 2 times ULN within 2 to 6 months after continuing riluzole therapy. If ALT levels exceeded 5 times ULN, riluzole treatment in studies was discontinued (Prod Info RILUTEK(R) oral tablets, 2009).
    c) CASE REPORT: A non-ALS patient with epilepsy, treated with carbamazepine and phenobarbital concurrently, experienced rapid elevations of liver enzymes with jaundice (ALT 26 times ULN, AST 17 times ULN, and bilirubin 11 times ULN) 4 months after beginning riluzole therapy. The enzyme levels returned to normal 7 weeks after discontinuing treatment (Prod Info RILUTEK(R) oral tablets, 2009).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Neutropenia (neutrophil counts less than 500/mm(3)) was reported in 3 of 4000 ALS patients within the first 2 months of riluzole treatment. In one patient, neutrophil counts increased with continuing riluzole treatment, and in another patient, the neutrophil counts increased when riluzole therapy was discontinued. In the third case, the patient developed moderate anemia and neutropenia; the etiology of these events were not known (Prod Info RILUTEK(R) oral tablets, 2009).
    b) CASE REPORT: Severe neutropenia occurred, with an absolute neutrophil count of 50/mm(3), in a 63-year-old woman following an inadvertent increase in her riluzole dosage from 100 mg/day to 200 mg/day. Bone marrow examination showed mildly hypocellular marrow with adequate megakaryocytic and erythroid precursors, indicative of drug-induced neutropenia (North et al, 2000).
    B) METHEMOGLOBINEMIA
    1) WITH POISONING/EXPOSURE
    a) SUMMARY: Methemoglobinemia has been reported in isolated cases following overdose (Prod Info RILUTEK(R) oral tablets, 2009)
    b) CASE REPORT: A 43-year-old woman with ALS presented with dyspnea, tachycardia, peripheral cyanosis and a Glasgow Coma score of 13 about 6 hours after an intentional ingestion of 2.8 g riluzole. Laboratory analysis showed an initial whole-blood methemoglobin concentration of 18.3% that peaked at 22% approximately 14 hours postingestion. The patient's methemoglobin level normalized following methylene blue administration, but she developed respiratory distress, progressing to respiratory failure, secondary to ALS, and subsequently died 7 days postingestion (Viallon et al, 2000).
    c) CASE REPORT: A 33-year-old woman with ALS developed methemoglobinemia after an intentional ingestion of 1.5 g of riluzole. Laboratory analysis revealed a methemoglobin level of 12.1% (1.48 g/dL calculated) with a hemoglobin level of 12.2 g/dL. Following supportive care, serial testing showed blood methemoglobin levels of 3.7% and 1.7%, 8 hours and 18 hours postingestion, respectively. She recovered completely and was discharged from the hospital 2 days after admission (Woolf et al, 2004).

Reproductive

    3.20.1) SUMMARY
    A) Decreased implantation rates and increased intrauterine death rates were seen in rats given oral riluzole during mating and throughout gestation and lactation. Impaired fertility was also seen in rats. Embryotoxicity was seen in rats and rabbits given oral riluzole.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) The oral administration of riluzole caused a decreases in fetal growth in rats at doses of 27 mg/kg (Prod Info RILUTEK(R) oral tablets, 2016).
    2) The oral administration of riluzole caused increased embryotoxicity in rabbits at doses of 60 mg/kg (Prod Info RILUTEK(R) oral tablets, 2016).
    3.20.3) EFFECTS IN PREGNANCY
    A) RISK SUMMARY
    1) No studies have been conducted of riluzole use during pregnancy, and case reports published to date cannot adequately inform the drug-associated risk during pregnancy (Prod Info RILUTEK(R) oral tablets, 2016).
    B) ANIMAL STUDIES
    1) The oral administration of riluzole to male and female rats prior to and during mating and to female rats throughout gestation and lactation was associated with decreased implantation rates and increased intrauterine death rates at doses of 15 mg/kg (Prod Info RILUTEK(R) oral tablets, 2016).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is unknown whether riluzole is excreted into human breast milk; therefore, the potential for adverse effects in the breastfeeding infant from riluzole exposure are unknown (Prod Info RILUTEK(R) oral tablets, 2016).
    2) Riluzole was detected in maternal rat milk (Prod Info RILUTEK(R) oral tablets, 2016).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Riluzole impaired fertility when orally administered to male and female rats prior to and during mating at a dose of 15 mg/kg (Prod Info RILUTEK(R) oral tablets, 2016).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor blood pressure in symptomatic patients.
    B) Liver enzyme levels should be monitored after significant overdose.
    C) No other specific lab work (CBC, electrolytes, urinalysis) is needed unless otherwise clinically indicated.
    D) Serum levels of glutamate antagonists are not clinically useful for managing overdose or widely available.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who remain symptomatic despite adequate treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) An asymptomatic child with an inadvertent exposure (a single dose) can be managed at home with adult supervision. An adult with an inadvertent exposure of an extra dose can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve.

Monitoring

    A) Monitor blood pressure in symptomatic patients.
    B) Liver enzyme levels should be monitored after significant overdose.
    C) No other specific lab work (CBC, electrolytes, urinalysis) is needed unless otherwise clinically indicated.
    D) Serum levels of glutamate antagonists are not clinically useful for managing overdose or widely available.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) In cases of a glutamate antagonist overdose, there is no specific treatment other than supportive care.
    B) MONITORING OF PATIENT
    1) Blood pressure should be monitored in symptomatic patients.
    2) Serum transaminase levels and methemoglobin concentration should be monitored after significant overdose.
    C) HYPERTENSIVE EPISODE
    1) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
    2) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
    3) SODIUM NITROPRUSSIDE/INDICATIONS
    a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.
    4) SODIUM NITROPRUSSIDE/DOSE
    a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).
    5) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION
    a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    6) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS
    a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    7) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS
    a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    8) NITROGLYCERIN/INDICATIONS
    a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).
    9) NITROGLYCERIN/ADULT DOSE
    a) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).
    10) NITROGLYCERIN/PEDIATRIC DOSE
    a) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).
    D) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    E) METHEMOGLOBINEMIA
    1) SUMMARY
    a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    2) METHYLENE BLUE
    a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
    b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
    c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
    d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).
    3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)
    a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
    b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
    c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is UNLIKELY to be of benefit due to the high protein binding of riluzole.

Range Of Toxicity

Summary

    A) TOXICITY: The toxic dose has not been established. Mild methemoglobinemia has been reported in adults after ingestion of 1.5 g and 2.8 g of riluzole. Circumoral paresthesia and dizziness/vertigo were associated with the oral administration of 250 to 300 mg of riluzole. In a safety and efficacy study, 2 patients experienced light-headedness and dizziness after receiving 25 mg of lubeluzole.
    B) THERAPEUTIC: RILUZOLE: ADULT: 50 mg orally every 12 hours. LUBELUZOLE: ADULT: 7.5 mg infused over 1 hour, followed by continuous infusion of 10 mg daily for 5 days. PEDIATRIC: Safety and efficacy have not been established in pediatric patients for either of these medications.

Therapeutic Dose

    7.2.1) ADULT
    A) AMYOTROPHIC LATERAL SCLEROSIS: 50 mg riluzole every 12 hours which should be taken at least one hour before or two hours after a meal in order to achieve maximum oral bioavailability (Prod Info RILUTEK(R) oral tablets, 2009).
    7.2.2) PEDIATRIC
    A) RILUZOLE: Safety and efficacy of riluzole in pediatric patients has not been established (Prod Info RILUTEK(R) oral tablets, 2009).

Maximum Tolerated Exposure

    A) SPECIFIC SUBSTANCE
    1) LUBELUZOLE: Two patients, involved in a safety and efficacy study of lubeluzole, experienced lightheadedness and dizziness after receiving 25 mg of lubeluzole in a 1-hour infusion (Hantson et al, 1997).
    2) RILUZOLE: Circumoral paresthesia and dizziness/vertigo have been associated with the oral administration of 300 mg of riluzole (Liboux et al, 1997).
    a) CASE REPORTS: One adult developed a peak methemoglobin concentration of 22% after ingestion of 2.8 g riluzole, and another developed a methemoglobin concentration of 12.2% after ingesting 1.5 g riluzole(Woolf et al, 2004; Viallon et al, 2000).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CASE REPORT
    a) The serum riluzole concentration peaked at 4998 ng/mL approximately 8 hours after a 43-year-old woman with ALS intentionally ingested 2.8 g riluzole (Viallon et al, 2000).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) RILUZOLE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 46 mg/kg (RTECS, 2002)
    2) LD50- (ORAL)MOUSE:
    a) 67 mg/kg (RTECS, 2002)
    3) LD50- (ORAL)RAT:
    a) 45 mg/kg (RTECS, 2002)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Glutamate is a neurotransmitter that is important for maintaining memory, cognition, movement, sensation, and possibly the plasticity of synaptic connections. Patients with neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS), may have increased glutamate concentrations because they lack glutamate dehydrogenase, the enzyme responsible for glutamate metabolism (Wagner & Landis, 1997).
    B) Riluzole, as a glutamate antagonist, may have several different mechanisms of action, including a noncompetitive blockade of excitatory amino acid receptors, inhibition of glutamic acid release, inactivation of voltage-dependent sodium channels, and stimulation of G-protein dependent signal transduction pathway. The mechanisms of action may act independently of each other thereby accounting for the various neuropharmacological properties of riluzole, or they may act synergistically at glutamatergic synapses to diminish neurotransmission (Doble, 1996).

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