Terisom 50 mg Sterile, Powder for dispersion for infusion

TERISOM is indicated for:

• Empirical treatment of presumed fungal infection in febrile neutropaenic adults and children unresponsive to anti-bacterial treatment.
• The treatment of severe systemic and/or deep mycoses in adults and children in whom toxicity (particularly nephrotoxicity) precludes the use of conventional systemic amphotericin B, or in patients who are resistant to conventional amphotericin B. Fungal infections successfully treated with amphotericin B include: disseminated candidiasis, aspergillosis, mucormycosis, chronic mycetoma and cryptococcal meningitis.
• Cryptococcal meningitis in HIV-infected patients. This medicine should not be used to treat the common clinically inapparent forms of fungal disease which show only positive skin or serologic tests.
• Primary therapy of visceral leishmaniasis in immunocompetent adults and children and immunocompromised adults (e.g. HIV positive).

Posology

Adults

The recommended dosage of TERISOM for each indication is provided in the table below:

*A large randomised controlled study of amphotericin B as in TERISOM reported that a dose of 3 mg/kg/day was optimal for invasive pulmonary aspergillosis.

Elderly Population: No alteration in dose or frequency of dosing is required.

Renal Impairment: Amphotericin B as in TERISOM has been successfully administered to patients with pre-existing renal impairment at doses of 1-5 mg/kg/day in reported studies and no adjustment in dose or frequency of administration was required.

Paediatric Population: Amphotericin B as in TERISOM has been studied in paediatric patients aged one month to 18 years old. Dosage should be calculated on the same per Kg body weight basis as for adults. The safety and efficacy of amphotericin B as in TERISOM has not been established in infants under one month old.

Method of administration

TERISOM should be administered by intravenous infusion over a 30 - 60 minute period. For doses greater than 5 mg/kg/day, intravenous infusion over a 2 hour period is recommended (see Section 4.4). The recommended concentration for intravenous infusion is 0,20 mg/mL to 2,00 mg/mL amphotericin B as TERISOM (see section 6.6).

• TERISOM is contraindicated in patients who have shown hypersensitivity to amphotericin B or any of its constituents unless, in the opinion of the medical practitioner, the condition requiring treatment is life-threatening and amenable only to TERISOM therapy (see Section 6.1).
• Safety in pregnancy and lactation has not been established.

Anaphylaxis and anaphylactoid reactions

Anaphylaxis and anaphylactoid reactions have been reported in association with amphotericin B infusion as in TERISOM. If a severe anaphylactic/ anaphylactoid reaction occurs, the infusion should be immediately discontinued and the patient should not receive further infusion of TERISOM.

Infusion - related reactions

Severe infusion-related reactions can occur during administration of TERISOM (See section 4.8). Consideration of precautionary measures for the prevention or treatment of these reactions should be given to patients who receive TERISOM therapy. Slower infusion rates (over two hours) or routine doses of diphenhydramine, paracetamol, pethidine, and/or hydrocortisone have been reported as successful in their prevention or treatment.

Renal toxicity

Liposomal amphotericin B as in TERISOM has been reported to be substantially less toxic than conventional amphotericin B, particularly with respect to nephrotoxicity; however, renal adverse reactions may still occur. In reported studies comparing amphotericin B as in TERISOM, 3 mg/kg daily with higher doses (5, 6 or 10 mg/kg daily), it was reported that the incidence rates of increased serum creatinine, hypokalaemia and hypomagnesaemia have been notably higher in the high dose groups.

Prolonged therapy

Adverse events may occur and caution should be exercised when prolonged therapy is required. Regular laboratory evaluation of renal, hepatic and haematopoietic function should be performed. This is particularly important in patients receiving concomitant nephrotoxic medications (See section 4.5). Due to the risk of hypokalaemia, appropriate potassium supplementation may be required during the course of TERISOM infusion administration. If clinically significant reduction in renal function or worsening of other parameters occurs, consideration should be given to dose reductions, treatment interruption or discontinuation.

Acute pulmonary toxicity

Acute pulmonary toxicity has been reported in patients given amphotericin B (as sodium deoxycholate complex) during or shortly after leukocyte transfusions. It is recommended these infusions are separated by as long a period as possible and pulmonary function should be monitored.

In the treatment of diabetic patients:

Excipients

Sucrose: It should be noted that TERISOM contains approximately 900 mg of sucrose in each vial. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Sodium: TERISOM contains 27 mg sodium succinate dibasic per vial.

No specific interaction studies have been reported with amphotericin B as in TERISOM. However, the following medicines are known to interact with amphotericin B and may interact with TERISOM.

Nephrotoxic medications:

Concurrent administration of amphotericin B as in TERISOM with other nephrotoxic medicines, for example cyclosporine, aminoglycosides and pentamidine, may enhance the potential for medicine-induced renal toxicity. However, in patients receiving concomitant ciclosporin and/or aminoglycosides, TERISOM has relatively less nephrotoxicity. Regular monitoring of renal function is recommended in patients receiving amphotericin B with any nephrotoxic medications.

Corticosteroids, corticotrophin (ACTH) and diuretics:

Concurrent use of corticosteroids, corticotrophin (ACTH) and diuretics (loop and thiazide) may potentiate hypokalaemia.

Digitalis glycosides:

TERISOM infusion-induced hypokalaemia may potentiate digitalis toxicity.

Skeletal muscle relaxants:

TERISOM-induced hypokalaemia may enhance the curariform effect of skeletal muscle relaxants (e.g. tubocurarine).

Antifungals:

No evidence of benefit from the use of flucytosine with amphotericin B as in TERISOM has been reported. Whilst synergy between amphotericin and flucytosine has been reported. Concurrent use with flucytosine may increase the toxicity of flucytosine by possible increasing its cellular uptake and/or impairing its renal excretion.

Antineoplastic medicines:

Concurrent use of antineoplastic medicines may enhance the potential for renal toxicity, bronchospasm and hypotension. Antineoplastic medicines should be given concomitantly with caution.

Leucocyte transfusions:

Acute pulmonary toxicity has been reported in patients given amphotericin B (as sodium deoxycholate complex) during or shortly after leukocyte transfusions. It is recommended that these infusions are separated by as long a period as possible and pulmonary function should be monitored.

Pregnancy

The safety of TERISOM in pregnant women has not been established. Systemic fungal infections have been successfully treated in pregnant women with conventional amphotericin B without obvious effect on the foetus, but the number of cases reported is insufficient to draw any conclusions on the safety of TERISOM in pregnancy.

Breast-feeding

It is unknown whether TERISOM is excreted in human breast milk. The safety of taking TERISOM during breastfeeding has not been established.

Fertility

Reported animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

No studies on the effects on the ability to drive and use machines have been reported. Some of the undesirable effects of TERISOM presented below may impact the ability to drive and use machines.

Summary of adverse reactions:

Fever and chills/rigors are the most frequent infusion-related reactions expected to occur during amphotericin B as in TERISOM administration. Less frequent infusion-related reactions may consist of one or more of the following symptoms: back pain, chest tightness or pain, dyspnoea, bronchospasm, flushing, tachycardia, and hypotension. These resolved rapidly on stopping the infusion and may not occur with every subsequent dose or when slower infusion rates (over 2 hours) are used.

In addition, infusion-related reactions may also be prevented by the use of premedication. However, severe infusion-related reactions may necessitate the permanent discontinuation of TERISOM.

The following adverse reactions have reported with amphotericin B as in TERISOM, based on clinical trial data and post-marketing experience. The frequency is based on analysis from pooled clinical studies of amphotericin B treated patients. The frequency of adverse reactions identified from post-marketing experience is not known.

Adverse reactions are listed below by body system organ class and are sorted by frequency.

Description of selected adverse reactions

Infusion-related reactions

It has been reported that, amphotericin B as in TERISOM treated patients experienced a significantly lower incidence of infusion-related reactions, as compared to patients treated with conventional amphotericin B or amphotericin B lipid complex.

Renal toxicity

Nephrotoxicity occurs to some degree with conventional amphotericin B in most patients receiving the product intravenously. In reported study, the incidence of nephrotoxicity with amphotericin B (as measured by serum creatinine increase greater than 2,0 times baseline measurement), was approximately half that for conventional amphotericin B. In another reported study, the incidence of nephrotoxicity with amphotericin B (as measured by serum creatinine increase greater than 2,0 times baseline measurement) was approximately half that for amphotericin B lipid complex.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

The toxicity of TERISOM due to overdose has not been defined. If overdose should occur, cease administration immediately. Carefully monitor clinical status including renal and hepatic function, serum electrolytes and haematologic status. Haemodialysis or peritoneal dialysis does not appear to enhance the elimination of TERISOM.