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ERAXIS (anidulafungin)

Indications

ERAXIS is indicated for the treatment of invasive candidiasis, including candidaemia, in adult patients.

Contraindications

Hypersensitivity to anidulafungin or to any of the excipients in ERAXIS.
Hypersensitivity to other medicinal products of the echinocandin class (e.g. caspofungin).
Pregnancy and lactation.
Use in patients under 18 years of age.

Warnings and Special Precautions

The infusion rate should not exceed the recommended infusion rate of 1,1 mg/minute. Infusion associated adverse events are infrequent when the rate of ERAXIS infusion does not exceed 1,1 mg/minute.

Hepatic effects

Laboratory abnormalities in liver function tests have been seen in healthy subjects and patients treated with ERAXIS. In some patients with serious underlying medical conditions who were receiving multiple concomitant medications along with ERAXIS, clinically significant hepatic abnormalities have occurred. Isolated cases of significant hepatic dysfunction, hepatitis, or worsening hepatic failure have been reported in patients; a causal relationship to ERAXIS has not been established. Patients who develop abnormal liver function tests during ERAXIS therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing ERAXIS therapy.

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

Side Effects

Nine hundred and twenty-nine (929) patients received intravenous ERAXIS in clinical trials (672 in Phase 2/3 studies and 257 in Phase I studies). Of the 669 Phase 2/3 patients for whom safety data are available, five hundred and five (505) received ERAXIS for ≥ 14 days.

Three studies (one comparative vs fluconazole, 2 non-comparative) assessed the efficacy of ERAXIS (100mg) in patients with candidaemia and other deep tissue Candida infections. In these three studies, a total of 204 patients received ERAXIS, 119 for ≥ 14 days. Adverse events were typically mild to moderate and seldom led to discontinuation. The medicine-related adverse events (MedDRA) listed below were reported with frequencies corresponding to Common (≥ 1/100, ≤ 1/10); Uncommon (≥ 1/1000, ≤ 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Infusion-related adverse events have been reported with ERAXIS, including rash, urticaria, flushing, pruritus, dyspnoea, and hypotension. These events can be minimised by infusing ERAXIS at a rate that does not exceed 1,1 mg/minute.

System Organ ClassFrequency Adverse Medicine Reactions
Infections and InfestationsUncommonFungaemia, candidiasis, pseudomembranous colitis, oral candidiasis
Blood and lymphatic system disordersCommonThrombocytopenia, coagulopathy
UncommonThrombocythaemia
Metabolism and nutrition disordersCommonHyperkalaemia, hypokalaemia, hypomagnesaemia
UncommonHyperglycaemia, hypercalcaemia, hypernatraemia
Nervous system disordersCommonConvulsion, headache
Eye disordersUncommonEye pain, visual disturbance, vision blurred
Cardiac disordersUncommonAtrial fibrillation, Sinus dysrhythmia, ventricular extrasystoles, bundle branch block right
Vascular disordersCommonFlushing
UncommonThrombosis, hypertension, hot flush
Gastrointestinal disordersCommonDiarrhoea
UncommonAbdominal pain upper, vomiting, faecal incontinence, nausea, constipation
Hepatobiliary disordersCommonGamma-glutamyltransferase increased, blood alkaline phosphatase increased, aspartate aminotransferase increased, alanine aminotransferase increased
UncommonLiver function test abnormal, Cholestasis, Hepatic enzyme increased, Transaminases increased
Skin and subcutaneous tissue disordersCommonRash, pruritus
UncommonUrticaria, generalised pruritus
Musculoskeletal and connective tissue disordersUncommonBack pain
General disorders and administration site conditionsUncommonInfusion site pain
InvestigationsCommonIncreased blood bilirubin, decreased platelet count, increased blood creatinine, prolonged electrocardiogram QT
UncommonIncreased blood amylase, decreased blood magnesium, decreased blood potassium, Electrocardiogram abnormal, increased lipase, increased platelet count, increased blood urea

In the safety assessment of the full Phase 2/3 patient population (N = 669), the following additional adverse events, all uncommon (≥ 1/1000, < 1/100), were of note: neutropenia, leukopenia, anaemia, hyperuricaemia, hypocalcaemia, hyponatraemia, hypoalbuminaemia, hypophosphataemia, anxiety, delirium, confusional state, auditory hallucination, dizziness, paraesthesia, central pontine myelinolysis, dysgeusia, Guillain-Barré syndrome, tremor, altered visual depth perception, unilateral deafness, phlebitis, superficial thrombophlebitis, hypotension, lymphangitis, dyspepsia, dry mouth, oesophageal ulcer, hepatic necrosis, angioedema, hyperhidrosis, myalgia, monoarthritis, renal failure, haematuria, pyrexia, chills, peripheral oedema, injection site reaction, increased blood creatine phosphokinase, increased blood lactate dehydrogenase, decreased lymphocyte count.

Interactions

Ciclosporin (CYP3A4 substrate):
In a study of 12 healthy adult subjects who received 100 mg/day ERAXIS following a 200 mg loading dose alone and in combination with 1,25 mg/kg oral ciclosporin twice daily, the steady state plasma peak concentration (Cmax) of ERAXIS was not significantly altered by ciclosporin; however the steady state area under the concentration-time curve (AUC) was increased by 22 %. An in vitro study has shown that ERAXIS has no effect on the metabolism of ciclosporin. Adverse events observed in this study were consistent with those observed in other studies where ERAXIS only was administered. No dosage adjustment of either medicine is required when they are co-administered.

Voriconazole (CYP2C19, CYP2C9, CYP3A4 inhibitor and substrate):
In a study of 17 healthy subjects who received 100 mg/day ERAXIS alone following a 200 mg loading dose, 200 mg twice daily oral voriconazole alone following 400 mg twice on the first day as loading doses, and both in combination, the steady state Cmax and AUC of ERAXIS and voriconazole were not significantly altered by co-administration. No dosage adjustment of either medicine is required when co-administered.

Tacrolimus (CYP3A4 substrate):
In a study of 35 healthy subjects who received a single oral dose of 5 mg tacrolimus alone, 100 mg/day ERAXIS alone following a 200 mg loading dose and both in combination, the steady state Cmax and AUC of ERAXIS and tacrolimus were not significantly altered by co-administration. No dosage adjustment of either medicine is required when co-administered.

Liposomal amphotericin B:
The pharmacokinetics of ERAXIS were examined in 27 patients (100 mg/day ERAXIS) who were co-administered with liposomal amphotericin B (doses up to 5 mg/kg/day). The population pharmacokinetic analysis showed that, the pharmacokinetics of ERAXIS were not significantly altered by co-administration with amphotericin B when compared to data from patients who did not receive amphotericin B. No dosage adjustment of ERAXIS is required.

Rifampicin (potent CYP450 inducer):
The pharmacokinetics of ERAXIS were examined in 27 patients (50 or 75 mg/day ERAXIS) who were co-administered with rifampicin (doses up to 600 mg/day). The population pharmacokinetic analysis showed that when compared to data from patients that did not receive rifampicin, the pharmacokinetics of ERAXIS was not significantly altered by co-administration with rifampicin. No dosage adjustment of ERAXIS is required.

Dosage and Directions for Use

Invasive candidiasis, including candidaemia, in adult patients

A single 200 mg loading dose should be administered on Day 1, followed by 100 mg daily thereafter. Duration of treatment should be based on the patient’s clinical response. In general, antifungal therapy should continue for at least 14 days after the last positive culture.

ERAXIS should be reconstituted with water for injections to a concentration of 3,33 mg/ml and subsequently diluted to a concentration of 0,77 mg/ml before use according to the instructions given below.

It is recommended that ERAXIS is administered at a maximum rate of infusion that does not exceed 1,1 mg/minute.

Use in renal and hepatic impairment

No dosing adjustments are required for patients with mild, moderate, or severe hepatic impairment. Hepatic function should be monitored.

No dosing adjustments are required for patients with any degree of renal insufficiency, including those on dialysis. ERAXIS can be given without regard to the timing of haemodialysis. (See Pharmacokinetic properties).

Use in other special populations

No dosing adjustments are required for adult patients based on patient gender, weight, ethnicity, HIV positivity, or geriatric status.

Use in children and adolescents

ERAXIS should not be used in children.

Reconstitution

ERAXIS must be reconstituted with water for injections and subsequently diluted with ONLY 9 mg/ml (0,9 %) sodium chloride for infusion or 50 mg/ml (5 %) glucose for infusion. The compatibility of reconstituted ERAXIS with intravenous substances, additives, or medications other than 9 mg/ml (0,9 %) sodium chloride for infusion or 50 mg/ml (5 %) glucose for infusion has not been established.

Aseptically reconstitute each vial with 30 ml water for injections to provide a concentration of 3,33 mg/ml. The reconstituted solution should be clear and free from visible particulates. The reconstituted solution must be further diluted within an hour.

Dilution and Infusion

Aseptically transfer the contents of the reconstituted vial(s) into an IV bag (or bottle) containing either 9 mg/ml (0,9 %) sodium chloride for infusion or 50 mg/ml (5 %) glucose for infusion to obtain the appropriate ERAXIS concentration. The table below provides the volumes required for each dose.

Dilution Requirements for ERAXIS Administration

DoseNumber of Vials RequiredTotal Reconstituted Volume RequiredInfusion Volume ATotal Infusion Volume BRate of InfusionMinimum Duration
100 mg1-100 mg30 ml100 ml130 ml1,4 ml/min90 min
200 mg2-100 mg60 ml200 ml260 ml1,4 ml/min180 min

A Either 9 mg/ml (0,9 %) sodium chloride for infusion or 50 mg/ml (5 %) glucose for infusion.
B Infusion solution concentration is 0,77 mg/ml.

Incompatibilities

ERAXIS must not be mixed or co-administered with other medicinal products or electrolytes except those mentioned above.

Parenteral medicine products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. If particulate matter or discolouration are identified, discard the solution.

If the infusion solution is not used immediately, it should be stored at 2 – 8 °C. Do not freeze. The infusion solution should be administered within 24 hours.

The rate of infusion should not exceed 1,1 mg/minute. The rate of infusion is equivalent to 1,4ml/min for the 100 mg and 200 mg doses.

For single use only.

Known Symptoms of Overdosage and Particulars of its Treatment

During clinical trials a single 400 mg dose of ERAXIS was inadvertently administered as a loading dose. No clinical adverse events were reported. In a study of 10 healthy subjects administered a loading dose of 260 mg followed by 130 mg daily, ERAXIS was well tolerated with no dose limiting toxicity; 3 of the 10 subjects experienced transient, asymptomatic transaminase elevations (≤ 3 x ULN).

In case of overdose, general supportive measures should be instituted as necessary.

ERAXIS is not dialysable.

Pharmacological Action

Pharmacodynamic properties

Mode of action

Anidulafungin is a semi-synthetic echinocandin, a lipopeptide synthesised from a fermentation product of Aspergillus nidulans.

Anidulafungin selectively inhibits 1,3-β-D glucan synthase, an enzyme present in fungal, but not mammalian cells. This results in inhibition of the formation of 1,3-β-D-glucan, an essential component of the fungal cell wall. Anidulafungin has shown fungicidal activity against Candida species and activity against regions of active cell growth of the hyphae of Aspergillus fumigatus.

Pharmacokinetic properties

General Pharmacokinetic Characteristics

The pharmacokinetics of anidulafungin have been characterised in healthy subjects, special populations and patients. A low intersubject variability in systemic exposure (coefficient of variation of approximately 25 %) was observed. The steady state was achieved on the first day after a loading dose (twice the daily maintenance dose).

Distribution

The pharmacokinetics of anidulafungin are characterised by a rapid distribution half-life (0,5 - 1 hour) and a volume of distribution of 30 - 50 ℓ that is similar to total body fluid volume. Anidulafungin is extensively bound (> 99 %) to human plasma proteins.

Biotransformation

Hepatic metabolism of anidulafungin has not been observed. Anidulafungin is not a clinically relevant substrate, inducer, or inhibitor of cytochrome P450 isoenzymes. It is unlikely that anidulafungin will have clinically relevant effects on the metabolism of medicines metabolised by cytochrome P450 isoenzymes.

Anidulafungin undergoes slow chemical degradation at physiologic temperature and pH to a ring-opened peptide that lacks antifungal activity. The in vitro degradation half-life of anidulafungin under physiologic conditions is approximately 24 hours. In vivo, the ring-opened product is subsequently converted to peptidic degradants and eliminated mainly through biliary excretion.

Elimination

The clearance of anidulafungin is about 1 ℓ/h. Anidulafungin has a predominant elimination half-life of approximately 24 hours that characterises the majority of the plasma concentration-time profile and a terminal half-life of 40 - 50 hours that characterises the terminal elimination phase of the profile.

In a single-dose clinical study, radiolabeled (14C) anidulafungin (~88 mg) was administered to healthy subjects. Approximately 30 % of the administered radioactive dose was eliminated in the faeces over 9 days, of which less than 10 % was intact medicine. Less than 1 % of the administered radioactive dose was excreted in the urine. Anidulafungin concentrations fell below the lower limits of quantitation 6 days post-dose. Negligible amounts of medicine-derived radioactivity were recovered in blood, urine, and faeces 8 weeks post-dose.

Linearity

Anidulafungin displays linear pharmacokinetics across a wide range of once daily doses (15 - 130 mg).

Special Populations

Patients with fungal infections

The pharmacokinetics of anidulafungin in patients with fungal infections are similar to those observed in healthy subjects based on population pharmacokinetic analyses. With the 200/100 mg daily dose regimen at an infusion rate of 1 mg/min, the steady state Cmax and trough concentrations Cmin could reach approximately 7 and 3 mg/ℓ, respectively, with an average steady state AUC of approximately 110 mg.h/ℓ.

Elderly

The population pharmacokinetic analysis showed that median clearance differed slightly between the elderly group (patients ≥ 65, median CL = 1,07 ℓ/h) and the non-elderly group (patients < 65, median CL = 1,22 ℓ/h), however, the range of clearance was similar.

Hepatic Insufficiency

Anidulafungin is not hepatically metabolised.

Renal Insufficiency

Anidulafungin has negligible renal clearance (< 1 %).

Paediatrics

Safety and efficacy in children have not been established.

Storage Instructions

Store in a refrigerator (2 – 8 °C). Do not freeze.

Reconstituted solution:

If not used immediately, the reconstituted solution should be stored at 2 – 8 °C for up to one hour. Do not freeze. Chemical and physical in-use stability of the reconstituted product has been demonstrated for 1 hour at 5 °C.

Infusion solution:

The infusion solution should be stored at 2 – 8 °C, and should be administered within 24 hours. Do not freeze. Chemical and physical in-use stability of the infusion solution has been demonstrated for 24 hours at 5 °C. From a microbiological point of view, the product should be used immediately. Keep out of reach of children.

Proprietary Name and Dosage Form

ERAXIS® 100 mg (Powder for solution for infusion)

Pregnancy and Lactation

Safety in pregnancy and lactation has not been established.

It is not known whether ERAXIS is excreted in human breast milk.

In animal studies, anidulafungin was found to be teratogenic and excreted in breastmilk.

Identification and Presentation

Identification

A white to off-white lyophilised solid in a 30 ml clear glass vial capped with a 20 mm grey stopper and an aluminium seal with a flip off top.

Presentation

A carton containing one clear glass vial of ERAXIS 100 mg lyophilised powder for solution for infusion.

References

ERAXIS® 100 mg MCC Approved package insert - 05 June 2014

Other

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
Pfizer Laboratories (Pty) Ltd.
85 Bute Lane
Sandton
2196
South Africa

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