Monograph: |
SODIUM ANTIMONY GLUCONATE
Pentavalent Antimony Compounds
A pentavalent antimony compound of indefinite composition
containing, when dried, 30 to 34% of pentavalent antimony. It
has been represented by the formula C6H,Na209Sb but usual-
ly there are less than 2 atoms of Na for each atom of Sb.
It is a colourless, odourless or almost odourless, mostly amor-
phous powder. Very soluble in water: practically insoluble in
alcohol and in ether. A solution containing 10% of pentava-
lent antimony has a pH of 5.0 to 5.6 after autoclaving. Solu-
tions may be sterilized by autoclaving.
Adverse Effects, Treatment, and Precautions
As for Trivalent Antimony Compounds.
Adverse effects are generally less frequent and less
severe with the pentavalent antimony compounds
sodium stibogluconate and meglumine antimonate
than with trivalent compounds such as antimony so-
dium tartrate. Nevertheless, similar precautions
should be observed, especially in patients on high-
dose therapy.
Intramuscular injections of sodium stibogluconate
can be painful and intravenous administration has
been associated with thrombophlebitis.
On a weight-for-weight basis children require more pentava-
lent antimony than adults and tolerate it better, but in both
adults and children tolerance is adversely affected by im-
paired renal function. Common side-effects are anorexia.
vomiting, nausea, malaise, myalgia, headache, and lethargy.
ECG changes are dose-dependent and most commonly T-
wave inversion and prolonged QT interval. Renal damage is a
rarely reported toxic effect. Pentavalent antimony is usually
well tolerated. Serious side-effects when they occur usually
involve the liver or the heart when it is prudent to interrupt
the course temporarily.
Breast feeding. There was some distribution of antimony
into breast milk following administration of sodium stiboglu-
conate to one patient. The authors considered that the
amount present did not constitute a hazard and oral absorp-
tion was not detected in an animal study. Verschoyle in com-
menting on the report felt more safety evaluation was
required before pronouncing on the safety of antimony to
breast-feeding infants.
Effects on the blood. Although thrombocytopenia is asso-
ciated with leishmaniasis, there are case reports of it also be-
ing associated with sodium stibogluconate.
Effects on the heart. The ECG was monitored during 65
courses of treatment with sodium stibogluconate in 59 Ken-
yan patients with leishmaniasis. ECG abnormalities devel-
oped during 35 treatment courses. They were qualitatively
similar to those previously described during treatment with
trivalent antimonial drugs, but occurred less frequently and
later during the course of treatment. The most common ab-
normality was inversion and/or decreased amplitude of T
waves. Incidence was related to total daily dose and duration
of treatment. One patient died suddenly during the 4th week
of treatment with 60 mg of antimony per kg body-weight dai-
ly. Other deaths probably related to cardiac toxicity have been
reported in patients receiving 60 mg per kg daily and 30 mg
per kg daily. Guidelines for monitoring during treatment
with sodium stibogluconate include the recommendation that
ECGs be obtained every 3 to 4 days in patients receiving
20 mg of antimony per kg daily for more than 20 days or a
higher dose for more than 10 days. If Stokes-Adams attacks
or ventricular tachyarrhythmias develop, sodium stibogluco-
nate should be stopped and treatment should be instituted for
the cardiac toxicity.
Effects on the kidneys. Sodium stibogluconate given to 16
young men with cutaneous leishmaniasis, but otherwise
healthy, for 10 days had no apparent adverse effect on glomer-
ular or tubular renal function. However, evidence of renal tu-
bular dysfunction has been reported in patients with
mucocutaneous leishmaniasis given meglumine antimonate
or sodium stibogluconate for 30 days or more and acute renal
failure occurred in a patient with pre-existing renal impair-
ment.
Effects on the liver. The WHO has reported that when se-
rious side-effects occur with sodium stibogluconate they usu-
ally involve the liver or the heart. There have been reports of
disturbed liver function?Β·3 in patients given sodium stiboglu-
conate, although there has also been a report that signs of
altered liver function improved during treatment with sodium
stibogluconate and may be a feature of visceral leishmaniasis.
Effects on the musculoskeletal system. Arthralgia is
common with pentavalent antimony compounds. It is usually
dose-dependent' but a patient has been described who experi-
enced symptoms early in treatment. Palindromic arthropathy
with effusion was associated with sodium stibogluconate
treatment in one patient.
Effects on the pancreas. Pancreatitis has been associated
with sodium stibogluconate treatment. Withdrawing treat-
ment usually resulted in resolution of pancreatitis.
Pharmacokinetics
The pentavalent antimony compounds are poorly
absorbed from the gastro-intestinal tract. After intra-
venous administration an initial distribution phase is
followed by biexponential elimination by the kid-
neys. The elimination half-life of the initial phase is
about 1.7 hours and that of the slow terminal phase
is about 33 hours. The corresponding half-lives after
intramuscular administration are 2 hours and 766
hours respectively. The slow elimination phase may
reflect reduction to trivalent antimony. Accumula-
tion occurs on daily administration and maximum
tissue concentrations may not be reached for 7 days
or more. Antimony has been detected in breast milk
(see Breast Feeding in Precautions, above).
Uses and Administration
Pentavalent antimony, as sodium stibogluconate or
meglumine antimonate. is the treatment of choice
for all forms of leishmaniasis except Leishmania ae-
thiopica infections.
Sodium stibogluconate is administered by intrave-
nous or intramuscular injection as a solution con-
taining the equivalent of 100 mg of pentavalent antimony per mL.
Intravenous injections must be administered very slowly (over at
least 5 minutes)and preferably through a fine needle to avoid
thrombophlebitis: as with trivalent antimony compounds
they should be discontinued immediately if cough-
ing, vomiting, or substemal pain occurs. Meglumine
antimonate is administered by deep intramuscular
injection as a solution containing the equivalent of
85 mg of pentavalent antimony per mL. Doses are
expressed in terms of the equivalent amount of pen-
tavalent antimony. Local variations exist in treat-
ment schedules but WHO recommends the
following regimens.
In visceral leishmaniasis initial treatment is based
on a daily injection of 20 mg of pentavalent antimo-
ny per kg body-weight to a maximum of 850 mg(but see
below) for at least' 20 days. The length of
treatment varies from one endemic area to another.
but is continued until no parasites are detected in
consecutive splenic aspirates taken at 14-day inter-
vals. Patients who relapse are re-treated at the same
dose.
Early non-inflamed lesions of cutaneous leishmani-
asis due to all forms of Leishmania except L. aethi-
opica. L. amawnensis, and L. braziliensis may be
treated by infiltration with intralesional injections of
I to 3 mL of sodium stibogluconate or meglumine
antimonate (approximately 100 to 300 mg of pen-
tavalent antimony), repeated once or twice if neces-
sary at intervals of I to 2 days. Systemic therapy
with 10 to 20 mg of pentavalent antimony per kg
daily is given if the lesions are more severe and con-
tinued until a few days after clinical and parasitolog-
ical cure is achieved. Cutaneous leishmaniasis due
to L. aethiopica is not responsive to antimonials at
conventional doses. In cutaneous leishmaniasis due
to L. hrcr=ilierrsis, prolonged systemic treatment
with 20 mg of pentavalent antimony per kg daily for
a minimum of 4 weeks is indicated to prevent the
later development of mucocutaneous leishmaniasis.
Similar doses are required for diffuse cutaneous
leishmaniasis due to L. anwzonensis and are contin-
ued for several months after clinical improvement
occurs.
In mucocutaneous leishmaniasis daily doses of
20 mg of pentavalent antimony per kg are given for
a minimum of 4 weeks; if toxic effects develop or the response
is poor, 10 to 15 mg per kg may be giv-
en every 12 hours. Relapses are well known and
have generally been associated with inadequate or
interrupted treatment: they are treated with the same
drug given for at least twice as long as the original
treatment. Only when that fails should alternative
treatment be given.
Leishmaniasis. The main treatment for leishmaniasis
is a pentavalent antimony compound such as sodium
stibogluconate. Higher doses of antimony compounds than
those recommended by WHO (see above) have been tried in
order to overcome the unresponsiveness of leishmaniasis to
therapy. Drug-resistant strains of Leishmania infantum have
been associated with unresponsiveness to treatment with
meglumine antimonate. Grogi and colleagues suggested
that the use of suboptimal doses may be increasing the prev-
alence of drug-resistant strains of the parasite. The Centers
for Disease Control (CDC) in the USA recommend the use of
20 mg per kg body-weight per day of pentavalent antimony
without restriction to the 850-mg maximum daily dose. At
this dose the most common adverse effects are musculoskel-
etal disorders, elevated liver enzyme values, and T-wave
changes on the ECG. and the CDC recommends that the
ECG. blood chemistry, and blood count should be monitored
throughout therapy if resources permit. Severe cardiotoxicity
is rare at 20 mg per kg per day but fatal cardiac toxicity has
been reported with doses of up to 60 mg per kg per day (see
under Effects on the Heart, above).
PROPHYLAXIS. Sodium stibogluconate or megluminr anti-
monate given once a month provided effective secondary
prophylaxis against visceral leishmaniasis in patients with
HIV infection.
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