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DIETHYLCARBAMAZINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Diethylcarbamazine is a synthetic piperazine anthelmintic compound used in animals and humans for the treatment of Bancroft's filariasis, onchocerciasis, ascariasis, tropical eosinophilia, and loiasis.

Specific Substances

    1) Diethylcarbamazine acid citrate
    2) Diethylcarbamazine hydrogen citrate
    3) 1-Diethylcarbamoyl-4-methylpiperazine dihydrogen citrate
    4) N,N-diethyl-4-methyl-1-piperazine carboxamide citrate
    5) Diethylcarbamazini citras
    6) Ditrazini citras
    7) Molecular Formula: C10-H21-N3-O
    8) CAS 1642-54-2
    9) BANOCIDE
    10) CARBAMAZINE, DIETHYL
    11) CARICIDE
    12) CARITROL
    13) CYPIP
    14) DICAROCIDE
    15) DIETHYLCARBAMAZANE CITRATE
    16) DIETHYLCARBAMAZINE CITRATE
    17) DIROCIDE
    18) DITRAZIN
    19) DITRAZIN CITRATE
    20) DITRAZINE
    21) DITRAZINE CITRATE
    22) ETHODRYL CITRATE
    23) FILARIBITS
    24) FILAZINE
    25) FRANOCIDE
    26) FRANOZAN
    27) HEARTWORM PILL (COMMON NAME FOR VETERINARY MEDICATION)
    28) HETRAZAN
    29) LONGICID
    30) LOXURAN
    1.2.1) MOLECULAR FORMULA
    1) C10H21N3O

Available Forms Sources

    A) FORMS
    1) Diethylcarbamazine (Hetrazan(R)) is available as a 50 mg tablet for human use.
    2) Veterinary preparations include: Dirocide(R) 50 mg, 100 mg, 200 mg, 300 mg tablets.
    B) USES
    1) Diethylcarbamazine is used for the treatment of Bancroftian filariasis, onchocerciasis, ascariasis, tropical eosinophilia, and loiasis (Hetrazan package insert (Lederle-US), 2/82,; Rivas-Alcala AR, Taylor HR, Ruvalcaba-Macias AM, et al:, 1981.; Langham & Beltranena, 1985; Diethylcarbamazine., 1987;; Panel comments, Diethylcarbamazine (Systemic)., 3/31/88.).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH THERAPEUTIC USE
    1) Most of the severe clinical effects following diethylcarbamazine ingestion are due to allergic reactions to the protein substance elaborated by the dying microfilariae and not to diethylcarbamazine alone.
    2) The minimum toxic or lethal dose is not known. No deaths have been reported due to diethylcarbamazine citrate alone (i.e., in patients without infestation with microfilariae).
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Following IV injection a brief pressor response along with a mild tachycardia may be noted.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Although rare, headache, fever, fasciculations, seizure, encephalitis, and allergic reactions within 1/2 to 12 hours post ingestion may occur.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Nausea and vomiting may occur following oral ingestion.
    0.2.13) HEMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Leukocytosis and eosinophilia may be noted.
    0.2.19) IMMUNOLOGIC
    A) WITH THERAPEUTIC USE
    1) HYPERSENSITIVITY - Patients with onchocerciasis treated with diethylcarbamazine may develop a severe hypersensitivity reaction within 16 hours following the initial dose.
    0.2.20) REPRODUCTIVE
    A) Diethylcarbamazine was not teratogenic in rats and rabbits. It is unknown whether diethylcarbamazine is excreted in breast milk.
    0.2.22) OTHER
    A) WITH THERAPEUTIC USE
    1) Mazzotti reaction (rash, headache, myalgia, arthralgia, enlarged lymph nodes, fever, tachycardia and hypotension) may occur in patients with onchocerciasis following diethylcarbamazine therapy.

Laboratory Monitoring

    A) Diethylcarbamazine levels are not clinically useful.
    B) Monitor CBC in symptomatic patients.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    B) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 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) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 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).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    C) MONITOR ECG AND VITAL SIGNS closely in symptomatic patients.
    D) ALLERGIC REACTION: MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.

Range Of Toxicity

    A) The MINIMUM TOXIC AND LETHAL DOSE are not well established in the literature. Single oral doses of 1 to 1.5 grams are not uncommon. No ill effects were noted in one patient who ingested 3.5 grams within 4 hours. No deaths due to diethylcarbamazine citrate alone in patients without microfilariae infestation have been reported.

Clinical Effects

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) Most of the severe clinical effects following diethylcarbamazine ingestion are due to allergic reactions to the protein substance elaborated by the dying microfilariae and not to diethylcarbamazine alone.
    2) The minimum toxic or lethal dose is not known. No deaths have been reported due to diethylcarbamazine citrate alone (i.e., in patients without infestation with microfilariae).

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) FEVER may occur within 0.5 to 12 hours after ingestion, but is not a usual direct effect of the drug (JEF Reynolds , 2000).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) LOCAL EFFECTS - Diethylcarbamazine eyedrops have been used and are well tolerated (Ben-Sira & Aviel, 1970). Diethylcarbamazine has a low toxicity with no particular ocular toxicity when used by uninfected persons (Grant & Schuman, 1993).
    2) ONCHOCERCIASIS - When diethylcarbamazine is given orally or topically to infected patients, a severe reaction may occur secondary to local destruction of microfilariae. Corneal opacities, anterior uveitis, visual field restriction, optic atrophy, punctate keratitis, and chorioretinal changes have been observed (Bird & El Sheikh, 1980; Taylor & Green, 1981; Greene et al, 1983; Taylor et al, 1986; Grant & Schuman, 1993).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Following IV injection a brief pressor response along with a mild tachycardia may be noted.
    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) Brief pressor activity lasting a few minutes following IV injection, accompanied by a mild tachycardia has been noted.

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - Acute respiratory distress was noted within 30 minutes of ingestion of 12.5 mg in a child with onchocerciasis (Fuglsang & Anderson, 1974).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Although rare, headache, fever, fasciculations, seizure, encephalitis, and allergic reactions within 1/2 to 12 hours post ingestion may occur.
    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache, dizziness, and drowsiness may occur within minutes to a few hours and is directly attributable to diethylcarbamazine (JEF Reynolds , 2000).
    B) ENCEPHALITIS
    1) WITH THERAPEUTIC USE
    a) Following oral administration, fasciculations, seizures, and encephalitis may occur within a few hours but are unusual. Encephalitis in patients with loiasis may be exacerbated following diethylcarbamazine therapy (JEF Reynolds , 2000).
    C) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dose-related responses to diethylcarbamazine, when used for therapy of filariasis, include weakness, dizziness, lethargy, anorexia, and nausea. These effects generally occur within 1 to 2 hours following a dose and may persist for several hours (JEF Reynolds , 2000).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SEIZURES
    a) ANIMAL STUDIES - Seizures were seen following toxic doses in laboratory animals (Harned et al, 1948).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Nausea and vomiting may occur following oral ingestion.
    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH THERAPEUTIC USE
    a) Following oral exposures, nausea and vomiting, which is directly attributable to diethylcarbamazine, has been reported (USPDI, 1991; (JEF Reynolds , 2000).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ALBUMINURIA
    1) WITH THERAPEUTIC USE
    a) Proteinuria has been noted as a side effect during therapy of onchocerciasis (Greene et al, 1980; Ngu et al, 1980).

Hematologic

    3.13.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Leukocytosis and eosinophilia may be noted.
    3.13.2) CLINICAL EFFECTS
    A) LEUKOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) Leukocytosis and eosinophilia may be exhibited in patients being treated with this drug.

Immunologic

    3.19.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) HYPERSENSITIVITY - Patients with onchocerciasis treated with diethylcarbamazine may develop a severe hypersensitivity reaction within 16 hours following the initial dose.
    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) Many patients with onchocerciasis will develop an allergic reaction within approximately 16 hours following the initial dose (Bryceson et al, 1977).
    1) Clinical manifestations include hypotension, tachypnea, ocular disturbances, swelling and tenderness of lymphoid tissue, maculopapular rash, and mild hyperpyrexia.
    2) These symptoms may disappear after 3 to 5 days while the patient remains on the drug.
    b) ANAPHYLACTOID REACTIONS have been reported during therapeutic use (Mazzotti, 1951; Hawking, 1978).

Reproductive

    3.20.1) SUMMARY
    A) Diethylcarbamazine was not teratogenic in rats and rabbits. It is unknown whether diethylcarbamazine is excreted in breast milk.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) Diethylcarbamazine was not teratogenic in rats and rabbits (Fraser, 1972).
    3.20.3) EFFECTS IN PREGNANCY
    A) ABORTION
    1) Uterine hypermotility, mediated via prostaglandin synthesis, has been reported in animal studies following diethylcarbamazine therapy during pregnancy. This may explain previous human reports of an abortifacient action (JEF Reynolds , 2000).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is unknown whether diethylcarbamazine is excreted in breast milk (USPDI, 1991).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS1642-54-2 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Diethylcarbamazine levels are not clinically useful.
    B) Monitor CBC in symptomatic patients.

Methods

    A) OTHER
    1) The drug is assayed in a few laboratories with an interest in tropical diseases.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Diethylcarbamazine levels are not clinically useful.
    B) Monitor CBC in symptomatic patients.

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) There is no antidote for diethylcarbamazine poisoning. Treatment is SYMPTOMATIC and SUPPORTIVE.
    B) MONITORING OF PATIENT
    1) Monitor cardiac function closely.
    2) Obtain a baseline CBC.
    C) 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, 2009; 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).
    D) ANAPHYLAXIS
    1) Prednisolone or dexamethasone along with cyproheptadine or other antihistamines may be useful in controlling some of the hypersensitivity reactions.
    2) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    3) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    4) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    5) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    6) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    7) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    8) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    9) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    10) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    11) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    12) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    13) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).
    E) CORTICOSTEROID
    1) Prednisolone was reported to have been useful in the treatment of encephalitis following diethylcarbamazine exposure.

Range Of Toxicity

Summary

    A) The MINIMUM TOXIC AND LETHAL DOSE are not well established in the literature. Single oral doses of 1 to 1.5 grams are not uncommon. No ill effects were noted in one patient who ingested 3.5 grams within 4 hours. No deaths due to diethylcarbamazine citrate alone in patients without microfilariae infestation have been reported.

Therapeutic Dose

    7.2.1) ADULT
    A) DISEASE STATE
    1) ACUTE LYMPHATIC FILARIASIS
    a) The recommended dosage is 6 mg/kg/day given in divided doses after meals for 14 consecutive days for the treatment of filarial infections due to Wuchereria Bancrofti, Brugia Malayi, Brugia timori, Loa loa and Onchocerca volvulus and prophylaxis of bancroftian and malayan filariasis and loiasis (Prod Info diethylcarbamazine oral tablets, 2010).
    2) TROPICAL PULMONARY EOSINOPHILIA (TPE)
    a) The recommended dosage is 6 mg/kg/day for 21 days. If symptoms return, higher doses and repeat courses may be needed (6 to 12 mg/kg/day for 21 to 30 days) (Prod Info diethylcarbamazine oral tablets, 2010).
    3) ASYMPTOMATIC CARRIER
    a) The recommended cumulative dose is 72 mg/kg with doses given as 6 mg/kg over one day (Prod Info diethylcarbamazine oral tablets, 2010). The cumulative dose can be administered at different intervals as follows:
    1) 6 mg/kg weekly doses distributed over consecutive weeks (Prod Info diethylcarbamazine oral tablets, 2010).
    2) 6 mg/kg monthly doses, distributed over 12 consecutive months (Prod Info diethylcarbamazine oral tablets, 2010).
    3) 6 mg/kg every 6 months or yearly doses (Prod Info diethylcarbamazine oral tablets, 2010).
    7.2.2) PEDIATRIC
    A) DISEASE STATE
    1) ACUTE LYMPHATIC FILARIASIS
    a) CHILDREN 10 YEARS OF AGE AND OLDER: The recommended dosage is 6 mg/kg/day given in divided doses after meals for 14 consecutive days for the treatment of filarial infections due to Wuchereria Bancrofti, Brugia Malayi, Brugia timori, Loa loa and Onchocerca volvulus and prophylaxis of bancroftian and malayan filariasis and loiasis (Prod Info diethylcarbamazine oral tablets, 2010).
    b) CHILDREN UNDER 10 YEARS OF AGE: The recommended dosage is 3 mg/kg/day given in divided doses after meals for 14 consecutive days for the treatment of filarial infections due to Wuchereria Bancrofti, Brugia Malayi, Brugia timori, Loa loa and Onchocerca volvulus and prophylaxis of bancroftian and malayan filariasis and loiasis (Prod Info diethylcarbamazine oral tablets, 2010).
    2) TROPICAL PULMONARY EOSINOPHILIA (TPE)
    a) The recommended dosage is 6 mg/kg/day for 21 days. If symptoms return, higher doses and repeat courses may be needed (6 to 12 mg/kg/day for 21 to 30 days) (Prod Info diethylcarbamazine oral tablets, 2010; Anon, 1992).
    3) ASYMPTOMATIC CARRIER
    a) No pediatric dosing information is provided for this indication.

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) LETHAL DOSE is not known. No deaths due to Hetrazan(R) diethylcarbamazine citrate have been reported (Prod Info Hetrazan(R), 1976).

Maximum Tolerated Exposure

    A) ADULT
    1) One individual took 3.55 grams within 4 hours without ill effects. Single oral doses of 1 to 1.5 grams are not uncommon.
    2) In a study of almost 300,000 therapeutic administrations of the drug, approximately 29% of the patients experienced adverse reactions (Patel & Paranjpey, 1959).

Workplace Standards

    A) ACGIH TLV Values for CAS1642-54-2 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS1642-54-2 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS1642-54-2 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS1642-54-2 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) 240 mg/kg (RTECS, 2000)
    B) LD50- (ORAL)MOUSE:
    1) 660 mg/kg (Harned et al, 1948)
    C) LD50- (SUBCUTANEOUS)MOUSE:
    1) 608 mg/kg (RTECS, 2000)
    D) LD50- (ORAL)RAT:
    1) 1380 mg/kg (Harned et al, 1948)
    E) LD50- (SUBCUTANEOUS)RAT:
    1) 1136 mg/kg (RTECS, 2000)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) The drug appears to act by sensitizing various microfilariae so that they are more readily phagocytized.

Toxicologic Mechanism

    A) This drug has little toxic action in the human but it may cause a brief pressor response accompanied with tachycardia and mild peripheral vasoconstriction.
    B) The mechanism of toxicity in dogs was found to be a nicotine-like effect at the autonomic ganglia, adrenal medullae, and respiratory chemoreceptors. Effects were antagonized by hexamethonium and phentolamine (Forbes, 1972).

Physicochemical

Physical Characteristics

    A) Diethylcarbamazine is a white, crystalline, odorless, hygroscopic powder that has a bitter acidic taste and that is very soluble in water, soluble in ethanol (1 g/35 mL), and practically insoluble in acetone, chloroform, and ether (JEF Reynolds , 2000).

Molecular Weight

    A) 199.3 (Budavari, 1996)

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