PENTOSTAM

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

ןולעב )תוחיטב ןולעב )תוחיטב

ל

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אפור אפור

ןכדועמ( ןכדועמ(

05.2013

05.2013

ךיראת

:

14/7/2013

םושירה רפסמו תילגנאב רישכת םש

:

PENTOSTAM , 102-10-24710

םושירה לעב םש

GlaxoSmithKline (ISRAEL) Ltd

:

ספוט

הז

דעוימ

טורפל

תורמחהה

דבלב

אפורל ןולעב אפורל ןולעב תורמחהה

תושקובמה

ןולעב קרפ

יחכונ טסקט

שדח טסקט

Special Warnings and

Special Precautions

for Use

There have been some reports of cardiac

arrhythmias and sudden death when

amphotericin B deoxycholate is

administered soon after sodium

stibogluconate for retreatment of visceral

leishmaniasis. Electrolyte imbalances

should be corrected prior to

administration of amphotericin B

deoxycholate, and patients appropriately

monitored.

ב"צמ

ובש ,ןולעה

נמוסמ תו

תורמחהה

שקובמה תו

לע

עקר

בוהצ

.

ונמוס תורמחה רדגב םניאש םייוניש ןולעב

עבצב קורי

The format of this leaflet was determined by the Ministry of Health

and its content was checked and approved in July 2013

PENTOSTAM

TM

TITLE

Sodium stibogluconate

SCOPE

Trade Name

PENTOSTAM

TM

Formulation and Strength

Injection solution.

Injections of sodium stibogluconate containing the equivalent of 100 mg/ml

pentavalent antimony.

Excipients

Chlorocresol

Gluconolactone

Water for injection

CLINICAL INFORMATION

Indications

Sodium stibogluconate is indicated for the following diseases:

Visceral leishmaniasis (Kala Azar);

Cutaneous leishmaniasis;

South American mucocutaneous leishmaniasis.

Sodium stibogluconate may also be of value in the treatment of leishmaniasis

recidivans and diffuse cutaneous leishmaniasis in the New World.

Note: Cutaneous and diffuse cutaneous leishmaniasis caused by Leishmania

aethiopica infections are unresponsive to treatment with pentavalent antimony

compounds, including sodium stibogluconate injection, at conventional

dosage, but may respond slowly at higher dosage.

Dosage and Administration

Except where otherwise stated, all doses should be given by the intravenous

or intramuscular route (see Warnings and Precautions).

Due to the presence of particulates (size range 20 to 300 microns) sodium

stibogluconate solution should be drawn up through a sterile filter immediately

prior to administration. These particulates are insoluble complexes formed

by an interaction between product preservative and the antioxidant in the

rubber stopper. Filters of pore size 5 microns or less and membrane types

polyvinylidene difluoride, polyethersulphone, polysulphone, nylon, surfactant-

free cellulose acetate and mixed cellulose esters have been shown to be suitable.

Where sterile filters are not available the risks and benefits of administering

unfiltered sodium stibogluconate therapy should be assessed by the clinician

on an individual basis.

All dosage recommendations are based on the findings of the WHO Expert

Committee on leishmaniasis, which met in 1984. There are no special

recommendations for different age groups.

Visceral Leishmaniasis

10 to 20 mg pentavalent antimony (0.1-0.2 ml sodium stibogluconate injection)

per kg bodyweight to a maximum of 850 mg (8.5 ml sodium stibogluconate

injection) daily for a minimum period of 20 days.

Patients should be examined for evidence of relapse after 2 and 6 months,

and in Africa after twelve months.

Cutaneous Leishmaniasis not caused by L. aethiopica

The dosage regimen outlined for visceral leishmaniasis is recommended.

Alternatively, single, non-inflamed nodular lesions known not to be due to

L. braziliensis may be treated with intralesional injections of 100 to 300 mg

pentavalent antimony (1-3 ml sodium stibogluconate injection) repeated once

or twice if necessary at intervals of 1 to 2 days. Infiltration must be thorough

and produce complete blanching of the base of the lesion.

Individuals with cutaneous leishmaniasis due to L. braziliensis should be treated

systemically for several days after the lesion is healed.

Note: After successful treatment of L. braziliensis, anti-leishmania antibody

titres decline steadily over 4-24 months.

Mucocutaneous leishmaniasis

Patients with parasitologically confirmed leishmaniasis should be treated

with 20 mg pentavalent antimony (0.2 ml sodium stibogluconate injection)

per kg bodyweight to a maximum of 850 mg (8.5 ml sodium stibogluconate

injection) daily, continuing this dosage for several days longer than it takes

to achieve parasitological and clinical cure.

In the event of relapse, a further course should be given for at least twice

the previous duration.

Diffuse cutaneous leishmaniasis in the New World and leishmaniasis

recidivans

Owing to the rarity of these conditions, precise data on dosage are not

available. A dose of 10 to 20 mg pentavalent antimony (0.1-0.2 ml sodium

stibogluconate injection) per kg bodyweight to a maximum of 850 mg (8.5

ml sodium stibogluconate injection) may be given daily for 2-3 weeks. If there

is a response then treatment should be maintained until several days after

clinical cure of leishmaniasis recidivans and for several months after clinical

and parasitological cure of diffuse cutaneous leishmaniasis.

Populations

Elderly

There is little information on the effects of sodium stibogluconate on elderly

individuals. If treatment of cutaneous leishmaniasis is necessary then local

infiltration is preferred. The normal precautions should be strictly adhered to

when treating older patients for visceral leishmaniasis.

Contraindications

- Sodium stibogluconate injection should not be given to any patient with

significantly impaired renal function.

- Sodium stibogluconate injection should not be given to any patient who

has experienced a serious adverse reaction to a previous dose.

Warnings and Precautions

Intravenous injection should be filtered immediately prior to use (see Dosage

and Administration). Administer very slowly over 5 min to reduce the risk of

local thrombosis. In the unlikely event of coughing, vomiting or substernal

pain occurring, administration should be discontinued immediately. In such

cases, extreme care should be taken if sodium stibogluconate is re-administered

by this route.

Successful treatment of mucocutaneous leishmaniasis may induce severe

inflammation around the lesion. In cases of pharyngeal or tracheal involvement,

this may be life-threatening. Under such circumstances, corticosteroids may

be used.

Very rarely, anaphylactic shock may develop during treatment, for which

adrenalin injection and appropriate supportive measures should be given

immediately.

Prolongation of the QTc interval has been observed in some patients taking

sodium stibogluconate and appears to be dose-related. There have also

been reports of fatal cardiac arrhythmias in patients receiving higher dose

antimonial therapy for visceral leishmaniasis. Therefore, ECG monitoring

is recommended before and during therapy with sodium stibogluconate.

Where ECG monitoring is not available, the risks and benefits of sodium

stibogluconate therapy should be assessed on an individual basis.

If clinically significant prolongation of QTc interval occurs, sodium stibogluconate

should be discontinued. Electrocardiographic changes, notably alterations in

T-wave amplitude may be expected in the majority of patients given sodium

stibogluconate. These appear to be reversible on cessation of therapy and

are not of serious significance.

Sodium stibogluconate should be used cautiously in patients with cardiovascular

disease, a history of ventricular arrhythmias or other risk factors known to

predispose towards QT prolongation: for example, those with congenital QTc

prolongation or taking concomitant drugs known to significantly prolong the

QT interval (e.g. class

anti-arrhythmics such as sotalol and amiodarone).

As there appears to be a dose relationship in the development of ECG

abnormalities, prior exposure to antimonial therapy should be considered

when assessing a patient’s suitability for initiating or continuing therapy with

sodium stibogluconate.

Patients who have recently received other antimonial drugs should be monitored

closely for signs of antimony intoxication such as bradycardia and cardiac

arrhythmias during administration of sodium stibogluconate.

There have been some reports of cardiac arrhythmias and sudden death when

amphotericin B deoxycholate is administered soon after sodium stibogluconate

for retreatment of visceral leishmaniasis. Electrolyte imbalances should be

corrected prior to administration of amphotericin B deoxycholate, and patients

appropriately monitored.

Intercurrent infections, such as pneumonia, should be sought and treated

concurrently.

High concentrations of antimony are found in the livers of animals after

repeated dosage with pentavalent antimony.

Sodium stibogluconate should therefore be used with caution in patients

with hepatic disease. However, some abnormalities of liver function may be

expected in cases of visceral leishmaniasis. In such patients the benefit of

pentavalent antimony treatment outweighs the risk. Sodium stibogluconate

may induce mild elevation of hepatic enzymes in serum which later return

to normal.

Interactions

No interactions with sodium stibogluconate have been reported.

There is no information on whether sodium stibogluconate interferes with

the accuracy of routine biochemical tests.

Pregnancy and Lactation

Pregnancy

Although no effects on the foetus have been reported, sodium stibogluconate

should be withheld during pregnancy unless the potential benefits to the

patient outweigh the possible risk to the foetus.

Lactation

Children should not be breast-fed by mothers receiving sodium

stibogluconate.

Ability to perform tasks that require judgement, motor or

cognitive skills

No data.

Adverse Reactions

Approximately 1 to 2% of patients complain of nausea, vomiting and/or

diarrhoea and a slightly higher number of abdominal pain.

Other common side effects include anorexia, malaise, myalgia, arthralgia,

headache and lethargy.

ECG changes, including reduction in T-wave amplitude, T-wave inversion and

QT prolongation have been observed (see Warnings and Precautions).

Transient coughing immediately following injection was reported with varying

frequency during several trials.

Intravenous injection of sodium stibogluconate may cause transient pain along

the course of the vein and eventually thrombosis of that vein.

Transient rises in serum lipase and amylase may occur during treatment with

sodium stibogluconate. Symptomatic pancreatitis has also been reported.

During some early trials of sodium stibogluconate, pneumonia occurred in a

small number of patients treated for visceral leishmaniasis and this occasionally

proved fatal. Pneumonia is a feature of the visceral leishmaniasis disease

process; however it has been associated with the toxicity profile of trivalent

antimony. It is, therefore, not possible to determine whether these cases were

due to the disease or to sodium stibogluconate.

Other (rarely reported) side effects include fever, rigor, sweating, vertigo,

facial flushing, worsening of lesions on the cheek, bleeding from the nose

or gum, substernal pain, jaundice and rash.

Transient reductions in platelets, white blood cells and haemoglobin have

been reported.

Overdosage

Symptoms and Signs

The main symptoms of antimony overdosage are gastro-intestinal disturbances

(nausea, vomiting and severe diarrhoea). Haemorrhagic nephritis and hepatitis

may also occur.

Treatment

There is only limited information on the use of chelating agents in the treatment

of intoxication by antimony compounds.

Dimercaprol has been reported to be effective; a dose of 200 mg by i.m.

injection every six hours until recovery is complete has been suggested.

2,3-Dimercaptosuccinic acid (DMSA) may also be effective treatment.

Clinical Pharmacology

Pharmacodynamics

Mechanism of Action

The mode of action of sodium stibogluconate is unknown. In vitro exposure

of amastigotes to 500 mg pentavalent antimony/ml results in a greater

than 50% decrease in parasite DNA, RNA protein and purine nucleoside

triphosphate levels. It has been postulated that the reduction in ATP (adenosine

triphosphate) and GTP (guanosine triphosphate) synthesis contributes to

decreased macromolecular synthesis.

Pharmacokinetics

Distribution

During daily administration there is a slow accumulation of sodium stibogluconate

into the central compartment so that tissue concentrations reach a theoretical

maximum level after at least 7 days.

Elimination

Following i.v. or i.m. administration of sodium stibogluconate, antimony is

excreted rapidly via the kidneys, the majority of the dose being detected in

the first twelve-hour urine collection. This rapid excretion is reflected by a

marked fall in serum or whole blood antimony levels to approximately 1 to

4% of the peak level by 8 h after an i.v. dose.

NON-CLINICAL INFORMATION

No data.

PHARMACEUTICAL INFORMATION

Shelf-Life

The expiry date of the product is indicated on the label and packaging.

Storage

Store below 25

C. Protect from light.

Do not freeze.

100 ml vial: The contents should not be used more than one month after

removing the first dose.

Keep out of the reach of children.

Nature and Contents of Container

Neutral, amber glass vial sealed with a chlorobutyl rubber closure and aluminium

collar with polypropylene flip-top cover.

Pack size: 100 ml

Incompatibilities

No data.

Use and Handling

Sodium stibogluconate should be filtered immediately prior to use (see

Dosage and Administration).

Manufacturer

Glaxo Operations (UK) Limited, Barnard Castle, UK.

License Holder and Importer

GlaxoSmithKline (Israel) Ltd., 25 Basel St., Petach Tikva

License Number

102-10-24710

Pen DR v2 21824