Diethylcarbamazine (Systemic)


VA CLASSIFICATION
Primary: AP200

Commonly used brand name(s): Hetrazan.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Anthelmintic (systemic){16}

Indications

Accepted

Filariasis, Bancroft's (treatment)—Diethylcarbamazine is indicated as a primary agent in the treatment of Bancroft's filariasis caused by Wuchereria bancrofti . {01} {03} {08} {12}

Loiasis (treatment)—Diethylcarbamazine is indicated as a primary agent in the treatment of loiasis caused by Loa loa . {01} {03} {12}

Onchocerciasis (treatment)—Diethylcarbamazine is indicated as a secondary agent in the curative treatment, given before and after suramin therapy, of onchocerciasis (river blindness) caused by Onchocerca volvulus . Ivermectin is considered to be the primary agent in the treatment of onchocerciasis. {01} {02} {05} {06} {12}

Tropical eosinophilia (treatment)—Diethylcarbamazine is indicated as a primary agent in the treatment of tropical eosinophilia (eosinophilic lung; tropical pulmonary eosinophilia). {01} {12}

Unaccepted
Diethylcarbamazine has been used for the treatment of ascariasis. However, in the opinion of most USP medical experts, it has been superseded by newer, safer, and more effective anthelmintics. {12}


Pharmacology/Pharmacokinetics

Mechanism of action/Effect:

Filariasis; loiasis—Microfilaricidal and macrofilaricidal. {03} {06}

Onchocerciasis—Microfilaricidal; diethylcarbamazine reduces the number of intrauterine Onchocerca volvulus microfilariae by inhibiting the rate of embryogenesis; this agent also increases the rate of loss of O. volvulus microfilariae from nematodes and nodules; diethylcarbamazine has no sterilizing effect on adult worms. {05} {06} {07} {12}

Absorption:

Readily absorbed following oral administration. {06} {07}

Distribution:

Widely distributed throughout all body compartments, except adipose tissue. {19}

Biotransformation:

Partially metabolized to diethylcarbamazine N-oxide. {04}

Half-life:

Approximately 8 hours. {19}

Time to peak serum concentration

1 to 2 hours. {04} {19}

Peak serum concentration

80 to 200 nanograms per mL after a single 50-mg dose. {04}

Elimination:
    Renal—Excreted in urine, largely unchanged and as N-oxide metabolite, within 48 hours. {06}
    Fecal—Approximately 4 to 5% eliminated in feces. {04}


Precautions to Consider

Pregnancy/Reproduction

Treatment of pregnant patients with diethylcarbamazine should be deferred until after delivery. {06} {12} However, problems in humans have not been documented.

Breast-feeding

It is not known whether diethylcarbamazine is distributed into breast milk. However, problems in humans have not been documented.

Pediatrics

Appropriate studies on the relationship of age to the effects of diethylcarbamazine have not been performed in the pediatric population. However, no pediatrics-specific problems have been documented to date. {01} {17} {18}


Geriatrics


No information is available on the relationship of age to the effects of diethylcarbamazine in geriatric patients.

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problem exists
Hypersensitivity to diethylcarbamazine
Note: In ocular onchocerciasis, prolonged administration of diethylcarbamazine may result in inflammation and subsequent degenerative changes in the optic disc and retina. {02} {06}



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):


For Bancroft's filariasis and loiasis
Microfilarial blood concentrations    (may be required prior to and periodically during therapy with diethylcarbamazine; in loiasis, retinal hemorrhage and encephalopathy may occur with very high microfilarial blood concentrations {12})


For onchocerciasis
» Ophthalmologic examinations, including examinations for visual acuity, visual fields, and ophthalmoscopy    (ophthalmologic examinations for visual acuity and visual fields may be required routinely prior to and {12} periodically during therapy with diethylcarbamazine; slit-lamp examinations may be required prior to, periodically during, and following treatment with diethylcarbamazine to assess the number of intraocular microfilariae and adverse reactions such as iridocyclitis {02} {06} {12})


» Skin snips    (may be required prior to and every 6 to 12 {12} months following treatment with diethylcarbamazine to assess the number of intradermal microfilariae {02})




Side/Adverse Effects

Note: In heavily infected patients with onchocerciasis, severe reactions may occur following a single dose of diethylcarbamazine. The Mazzotti reaction, a complex, acute inflammatory response characterized by fever, tachycardia, hypotension, adenitis, and an ocular inflammatory response, usually results from the death of microfilariae. The intensity of the reaction depends on the dose and the microfilarial load. However, it is sometimes difficult to determine whether these reactions are caused by the death of microfilariae or by diethylcarbamazine itself. {01} {03} {06}
In very heavily infected patients with loiasis, encephalopathy and retinal hemorrhage may occur following treatment with diethylcarbamazine. {12}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Itching and swelling of face, especially eyes{01}

Incidence less frequent
    
Fever{02}{06}
    
lymphadenopathy (painful and tender glands in neck, armpits, or groin){06}
    
skin rash{01}{02}{06}

With prolonged use in onchocerciasis {06}
    
Visual disturbances (loss of vision; night blindness; tunnel vision)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Arthralgia (joint pain){02}{06}
    
headache{01}{02}{06}
    
malaise (unusual tiredness or weakness){01}

Incidence less frequent
    
Dizziness{02}{06}
    
nausea or vomiting{01}





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Diethylcarbamazine (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:

Pregnancy—Treatment of pregnant patients should be deferred until after delivery; however, problems in humans have not been documented

Proper use of this medication
Taking immediately after meals

» Compliance with full course of therapy; second course may be required in some patients

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
Checking with physician if no improvement within a few days

For river blindness
Regular visits to physician to check progress, as well as ophthalmologic examinations

» Caution if dizziness, loss of vision, night blindness, or tunnel vision occurs

Concurrent administration with systemic corticosteroids to reduce inflammatory response to death of microfilariae


Side/adverse effects
Signs of potential side effects, especially itching and swelling of face, particularly eyes; fever; lymphadenopathy; skin rash; and visual disturbances


General Dosing Information
Diethylcarbamazine should be taken immediately after meals. {01}

Diethylcarbamazine should be administered with caution (e.g., gradually increasing doses) to prevent or minimize allergic reactions. Most side effects of diethylcarbamazine are not serious and do not generally require discontinuation of therapy. However, it may be necessary to discontinue therapy if severe allergic reactions, in conjunction with skin rash, occur. {01}

Patients who are more heavily infected may require more prolonged treatment. {01} {03}

For Bancroft's filariasis, loiasis, or onchocerciasis
In the acute and chronic stages of these infections, treatment should be continued for 2 to 4 weeks. Recurrences require retreatment. {01} {12}

In Bancroft's filariasis, treatment should preferably be given before irreparable damage is done to the lymphatic system and its valves. {03}

In the curative treatment of onchocerciasis, diethylcarbamazine is administered before and after suramin therapy. Diethylcarbamazine is recommended in low initial doses concurrently with systemic corticosteroids to suppress the inflammatory response to the death of microfilariae caused by diethylcarbamazine, especially in moderate to heavy infections with ocular involvement. {02} {05} {06} {12}

In severe onchocerciasis, severe allergic reactions may develop following the administration of a single dose of diethylcarbamazine. Gradually increasing doses are recommended as follows: 25 mg daily, gradually increased to the usual maintenance dose over a period of 7 to 14 days. {13} If very severe allergic reactions occur, diethylcarbamazine should be discontinued and corticosteroids should be given. {12} If severe allergic reactions occur again, diethylcarbamazine should not be used in these patients. {01} {12}

In the suppressive treatment of onchocerciasis, diethylcarbamazine is recommended in low, intermittent doses to preserve eyesight and to relieve pruritus by reducing the microfilarial load. {06} {12}

For treatment of adverse effects
Recommended treatment consists of the following:

   • Systemic corticosteroids for very severe allergic reactions. {01} {02} {05} {06} {12}


Oral Dosage Forms

DIETHYLCARBAMAZINE CITRATE TABLETS USP

Usual adult dose
Bancroft's filariasis; or
Loiasis; or
Onchocerciasis
Oral, 2 to 3 mg per kg of body weight three times a day. {01} {03} {12}

Tropical eosinophilia
Oral, 6 mg per kg of body weight once a day for four to seven days. {01} {12}


Usual adult prescribing limits
Onchocerciasis—Up to 9 mg per kg of body weight a day. {05} {12}

Tropical eosinophilia—Up to 13 mg per kg of body weight a day. {01}

Usual pediatric dose
Dosage has not been established in the treatment of Bancroft's filariasis, loiasis, onchocerciasis, or tropical eosinophilia. However, doses of 50 mg to 250 mg daily, based on the patient's age, have been used in children between the ages of 1 and 15 years of age. {17} {18}

Strength(s) usually available
U.S.—


50 mg (Rx) [Hetrazan{01}{09}{10}{14}]


200 mg (Rx)[Generic]{11}


400 mg (Rx)[Generic]{11}

Note: The 50-mg tablet is available only through the manufacturer upon request (tel. no.: 914-735-2815). {09} {10} {14}


Canada—


50 mg (Rx) [Hetrazan (scored){15}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container.

Auxiliary labeling:
   • Take immediately after meals.
   • May cause dizziness or vision problems.
   • Continue medication for full time of treatment.



Revised: 08/11/1995



References
  1. Hetrazan package insert (Lederle—US), Rev 2/82, Rec 9/87, Rec 6/95.
  1. Rivas-Alcala AR, Taylor HR, Ruvalcaba-Macias AM, et al. Chemotherapy of onchocerciasis: a controlled comparison of mebendazole, levamisole, and diethylcarbamazine. Lancet 1981; 485-90.
  1. Duke BOL. Lymphatic and other filariases. Br Med J 1981; 283: 1036-7.
  1. Edwards G, Awadzi K, Breckenridge AM, et al. Diethylcarbamazine disposition in patients with onchocerciasis. Clin Pharmacol Ther 1981; 30(4): 551-7.
  1. Langham ME, Beltranena F. The Onchocerca volvulus micro- and macrofilarial responses in onchocerciasis patients to increased dosage of diethylcarbamazine. Trop Med Parasitol 1985; 36: 175-9.
  1. Diethylcarbamazine. WHO Drug Info 1987; 1(2): 83-5.
  1. Taylor HR, Greene BM. Ocular changes with oral and transepidermal diethylcarbamazine therapy of onchocerciasis. Br J Ophthalmol 1981; 65: 494-502.
  1. Partono F, Purnomo, Oemijati S, et al. The long term effects of repeated diethylcarbamazine administration with special reference to microfilaraemia and elephantiasis. Acta Tropica 1981; 38: 217-25.
  1. Lederle letter to Mark Bonner, 4/2/84.
  1. Sklaver L, Murray C. Availability of diethylcarbamazine citrate. Am J Hosp Pharm 1986; 43: 2987.
  1. Diethylcarbamazine (generic). In: Red book 1991. Montvale, NJ: Medical Economics Data, 1991: 246.
  1. Panel comments, Diethylcarbamazine (Systemic), 3/31/88.
  1. Review comments, Diethylcarbamazine (Systemic), Vol. 9, No. 1.
  1. Katzung BG, editor. Basic and clinical pharmacology. Norwalk, CT: Appleton and Lange, 1992: 763.
  1. Hetrazan (Lederle). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 23rd ed. Ottawa: Canadian Pharmaceutical Association, 1988: 389.
  1. Fleeger CA, editor. USAN 1989. USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1988: 180.
  1. Wijers DJB, Kaleli N. Bancroftian filariasis in Kenya, V. Mass treatment given by members of the local community. Ann Trop Med Parasitol 1984; 78(4): 383-94.
  1. Dreyer G, de Andrade L. Inappropriateness of the association of diphenhydramine with diethylcarbamazine for the treatment of lymphatic filariasis. J Trop Med Hygiene 1989; 92: 32-4.
  1. Mandell GL, Douglas RG, Bennett JE, editors. Principles and practice of infectious diseases. New York: Churchill Livingstone, Inc., 1990: 418-9, 2142-4.
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