Diethylcarbamazine Citrate
A white, crystalline, slightly hygroscopic powder, odourless
or with a slight odour. M.p. about 136Β° to 138Β° with decom-
pOlition. Very soluble in water; soluble or sparingly soluble
in alcohol; practically insoluble in acetone, in chloroform,
and in ether. Store in airtight container. Solutions should be
protected from light.
Adverse Effects
Adverse effects directly attributable to diethylcar-
bamazine include nausea and vomiting, Headache,
dizziness, and drowsiness may occur.
Hypersensitivity reactions arise from the death of
the microfilariae. These can be serious, especially in
onchocerciasis where there may also be sight-threat-
ening ocular toxicity; fatalities have been reported.
Encephalitis may be exacerbated in patients with
loiasis and fatalities have occurred.
Reactions occurring during diethylcarbamazine treatment of
lymphatic filariasis are basically of 2 types: pharmacological
close-dependent responses and a response of the infected host
to the destruction and death of parasites.' Reactions of the
first type include weakness, dizziness, lethargy, anorexia, and
nausea. They begin within 1 to 2 hours of taking dierhylcar-
bamazine, and persist for a few hours. Reactions of the sec-
ond type are less likely to occur and less severe in bancroftian
than in brugian filariasis. They may be systemic or local, both
wiih and without fever. Systemic reactions may occur a few
hours after the first oral dose of diethylcarbamazine and gen-
erally do not last for more than 3 days. They include head-
ache, aches in other parts of the body, joint pain. dizziness,
anorexia, malaise, transient haematuria, allergic reactions.
vomiting, and sometimes attacks of bronchial asthma in asth-
matic patients. Fever and systemic reactions are positively as-
sociated with microfilaraemia. Systemic reactions are
reduced if diethylcarbamazine is given in spaced doses or in
repeated small doses. They eventually cease spontaneously
and interruption of treatment is rarely necessary: symptomat-
ic treatment with antipyretics or analgesics may be helpful.
Local reactions tend to occur later in the course of treatment
and last longer, they also disappear spontaneously and inter-
ruption of treatment is not necessary. Local reactions include
lymphadenitis, abscess, ulceration. and transient lymphoede-
ma; funiculitis and epididymitis may also occur in bancroft-
ian filariasis.
In most patients with onchocerciasis the microfilaricidal ac-
tivity of diethylcarbamazine leads to a series of events with
dermal, ocular, and systemic components, known as the, Maz-
zotti reaction, within minutes to hours after its administration.
Clinical manifestations can be severe, dangerous, and
debilitating and WHO no longer recommends the use of di-
ethylcarbamazine in onchocerciasis. Systemic reactions in-
clude increased itching, rash, headache, aching muscles, joint
pain, painful swollen and tender lymph nodes, fever, tachy-
cardia and hypotension, and vertigo. Most patients experience
eye discomfort in the first few hours after diethylcarbamazine
treatment. Punctate keratitis can develop as can optic
neuritis and visual field loss.
It has been suggested that the release of interleukin-6 may
be implicated in diethylcarbamazine's adverse effects in
patients with lymphatic filariasis.
Precautions
Treatment with diethylcarbamazine should be close-
ly supervised since hypersensitivity reactions are
common and may be severe, especially in patients
with onchocerciasis or loiasis. Patients with on-
chocerciasis should be monitored for eye changes.
(The use of diethylcarbamazine to treat onchocer-
ciasis is no longer recommended.)
Infants, pregnant women, the elderly, and the debil-
Itated, especially those with cardiac or renal disease,
are normally excluded when diethylcarbamazine is
used in mass treatment schedules.
The use of diethylcarbamazine 2 mg per kg body-weight as a
Provocative day test for the detection of microfilariae of
nocturnally periodic Wucheria bancrofti in the blood, was not
Suitable in the presence of onchocerciasis or loiasis.
Pregnancy. Animal studies' suggest that the uterine hyper-
motility induced by diethylcarbamazine is mediated via prosta-
glandin synthesis: this might explain the mechanism of the
abortifacient action previously reported.
Phannacokinetics
Diethylcarbamazine citrate is readily absorbed from
the gastro-intestinal tract and also through the skin
and conjunctiva. It is widely distributed in tissues
and is excreted in the urine unchanged and as the N-
oxide metabolite. Urinary excretion and hence plas-
ma half-life is dependent on urinary pH.
A pharmacokinetic study in 6 patients with onchocerciasis'
indicating that diethylcarbamazine is absorbed quickly and
almost completely from the gastro-intestinal tract and is
eliminated largely as unchanged drug in urine with relatively
small amounts being excreted as the N-oxide metabolite. Fol-
lowing a simple radioactively labelled dose of diethylcar-
bamazine citrate 0.5 mg/kg body wt. administered by
mouth as an aqueous solution, peak plasma concentrations of
100 to 150 ng per mL were achieved in I io 2 hours, followed
by a sharp decline, then a marked secondary rise 3 to 6 hours
after dosing followed by a steady decline. The half-life
ranged from 9 to 13 hours. Urinary excretion of diethylcar-
bamazine and diethylcarbamazine N-oxide was complete
within 96 hours; between 4 and 5% of the dose was recovered
in the faeces. Disposition kinetics were similar in 5 healthy
subjects given a single 50-me tablet of diethylcarbamazine
citrate. Peak plasma concentrations were initially 80 to
200 ng per mL, with a secondary rise 3 to 9 hours after dos-
ing, the terminal half-life ranged from 5 to 13 hours, and
urinary excretion of unchanged diethylcarbamazine and the N-
oxide was complete within 48 hours.
When an alkaline urinary pH was maintained the elimination
half-life of diethylcarbamazine and the area under the plasma
concentration versus time curve were significantly increased
compared with values when an acidic urinary pH was main-
tained. However, alkalinisation of the urine in an attempt to
decrease the dose of diethylcarbamazine in onchocerciasis
was unlikely to be of practical value .
Renal impairment. Results in patients with chronic renal
impairment and healthy subjects, given a single 50-mg dose
of diethylcarbamazine citrate by mouth, indicating that the
plasma half-life of diethylcarbamazine is prolonged and its
24-hour urinary excretion considerably reduced in those with
moderate and severe degrees of renal impairment. Mean
plasma half-lives in 7 patients with severe renal impairment
(creatinine clearance less than 25 mL per minute). 5 patients
with moderate renal impairment (creatinine clearance be-
tween 25 and 60 mL per minute), and 4 healthy subjects were
15.1. 7.7, and 2.7 hours, respectively. The patient with the
longest plasma half-life of 32 hours did not have the poorest
renal function, but it was considered likely that the abnormal-
ly slow elimination of diethylcarbamazine was due to the high
urine pH (7) resulting from sodium bicarbonate therapy. A
further patient with a half-life longer than expected also had
a less acidic urine.
Uses and Administration
Diethylcarbamazine citrate is an anthelmintic used
in the treatment of lymphatic filariasis due to
Wuchereria bancrofti (bancrottian filariasis), Brugia
malayi, or B. timori (both known as brugian filaria-
sis and as Malayan and Timorian filariasis respec-
tively). It is also used in loiasis due to Loa loa. It was
used in onchocerciasis due to Onchocerca volvulus
before ivermectin became available. Diethylcar-
bamazine is active against both the microfilariae and
adult worms of W. bancrofti. B. malayi, and Loa loa,
but only against the microfilariae of 0. volvulus. It
has been tried in Mansonello infections and may be
most effective against M. streptocerca. Diethylcar-
bamazine is also used in the treatment of toxocaria-
sis (visceral larva migrans).
Diethylcarbamazine citrate is usually administered
bv mouth as tablets.
In the treatment of filarial infections due to W. ban-
cmfti, B. malayi. B. timori, and Loa loa the manu-
facturer recommends 6 mg per kg body-weight
daily in 3 divided doses for 3 weeks, given in an in-
itial dosage of I mg per kg daily, gradually in-
creased to 6 mg per kg daily over 3 days then
maintained for 3 weeks, to reduce the incidence and
severity of hypersensitivity reactions due to the de-
struction of microfilariae. However, in bancroftian
filariasis WHO recommends 6 mg per kg daily for
12 days, and in brugian filariasis a dose of 3 to 6 mg
per kg daily for 6 to 12 days. In the treatment of lo~
asis, WHO recommends a dose of I mg per kg as a
single dose initially, doubled on two successive days
and then adjusted to 2 to 3 mg per kg three times
daily for a further 18 days. A corticosteroid may be
given concurrently in the treatment of filarial infec-
tions. Similar doses are given for 3 weeks in the
treatment of toxocariasis.
In the prophylaxis of bancroftian filariasis a dose of
50 mg monthly has been recommended and in the
prophylaxis of loiasis a dose of 300 mg weekly.
In areas where lymphatic filariasis is endemic, mass
treatment campaigns can reduce the intensity of
transmission and incidence of disease. Diethylcar-
bamazine has been used in the form of medicated
salt in some countries to control lymphatic filariasis.
Administration. Diethylcarbamazine was first used as the
chloride, but is now produced as the dihydrogen citrate which
contains only half its weight as base. In reporting doses it is
therefore important to indicate whether they refer to a specific
sail or lo the base; unless otherwise stated, it can generally be
assumed that the dose refers to the citrate.
Loiasis. Diethylcarbamazine is the main drug used in the
management of loiasis .
Lymphatic filariasis. Diethylcarbamazine citrate is the
main drug used in the treatment of lymphatic filariasis .
In endemic areas where more than 5% of the population is
infected, mass treatment of the entire population (excluding
neonates, pregnant women, and debilitated individuals) can
reduce the intensity of transmission and the incidence of dis-
ease. However, compliance may be a problem with the usual
multidose treatment regimens. Administering the doses at
weekly intervals was shown to improve compliance and effi-
cacy. Single doses of 6 mg per kg body-weight clear micro-
filariae from the blood more slowly than the conventional
multiple-dose regimens, but microfilaraemia after 12 months
has been shown to be comparable with either regimen for both
bancroftian and brugian filariasis. Studies have shown that
single doses of 3 or 6 mg per kg body-weight repeated at in-
tervals of 6 or 12 months can maintain microfilaraemia at low
levels. In a study comparing a single dose every 6 months.
a low dose every month, and the use of medicated cooking
salt with the standard regimen, all three alternative regimens
were superior to the standard regimen and the use of medicat-
ed salt or low monthly doses were the most effective.67 The
effectiveness of medicated salt has been confirmed by other
investigators.89 Combination of diethylcarbamazine with
ivermectin has been reported to be more effective than cither
drug alone. Diethylcarbamazine with albendazole has
also shown promise.
Diethylcarbamazine has also been used diagnostically. De-
tecting microfilariae in lymphatic filariasis can be difficult
because of their nocturnal periodicity. Small doses of
diethylcarbamazine can stimulate the microfilariae thus aid-
ing their detection in the daytime in blood specimens."* For
cautions against using such a test in patients with loiasis or
onchocerciasis. see Precautions, above. Also it has been sug-
gested that measurements on finger-prick blood samples may
not be as accurate as those carried out on samples of venous
blood.