Casfolred 50 mg/70 mg Solution

CASFOLRED is indicated for:

• Empirical therapy for presumed fungal infections in febrile, neutropenic patients.
• Treatment of invasive candidiasis, including candidaemia.
• Treatment of oesophageal candidiasis where IV antifungal therapy is appropriate.
• Treatment of oropharyngeal candidiasis where IV antifungal therapy is appropriate.
• Treatment of invasive aspergillosis patients who are refractory to or intolerant of amphotericin B, lipid formulations of amphotericin B and itraconazole.

Paediatric Use

The safety and effectiveness of CASFOLRED in paediatric patients 3 months to 17 years old are supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic data in paediatric patients and additional data from studies in patients 3 months to 17 years old. The efficacy and safety of CASFOLRED have not been adequately studied in prospective clinical trials involving neonates and infants under 3 months of age. CASFOLRED has not been studied in paediatric patients with endocarditis, osteomyelitis, and meningitis due to Candida. CASFOLRED has also not been studied as initial therapy for invasive aspergillosis in paediatric patients.

Adults (u2265 18 years of age): CASFOLRED should be administered by a slow infusion over approximately 1 hour.

Empirical therapy

A single 70 mg loading dose should be administered on Day 1, thereafter followed by 50 mg daily. The patient's clinical response should determine the duration of treatment. Empirical therapy should be continued until the neutropenia is resolved. Patients found to have a fungal infection should be treated for a minimum of 14 days; treatment should continue for at least 7 days after both neutropenia and clinical symptoms are resolved. If 50 mg is well tolerated but does not provide an adequate clinical response, the daily dose can be increased to 70 mg. Even though an increase in efficacy with 70 mg daily has not been demonstrated, safety data suggest that an increase in dose to 70 mg daily is tolerated.

Invasive Candidiasis

A single 70 mg loading dose should be administered on Day 1, followed thereafter by 50 mg daily. Duration of treatment of invasive candidiasis should be determined by the patient's clinical and microbiological response. In general, antifungal therapy should continue for at least 14 days after the last positive culture. Patients who remain persistently neutropenic may require a longer course of therapy until the resolution of the neutropenia. The safety and efficacy of multiple doses up to 150 mg daily (range 1 to 51 days; median 14 days) have been studied in 100 adult patients with invasive candidiasis. CASFOLRED is generally well tolerated in these patients receiving CASFOLRED at this higher dose. The efficacy of CASFOLRED at this higher dose is generally similar to patients receiving the 50 mg daily dose.

Oesophageal and Oropharyngeal Candidiasis

50 mg should be given daily.

Invasive Aspergillosis

A single 70 mg loading dose should be administered on Day 1, followed thereafter by 50 mg daily. Duration of treatment should be based upon the severity of the patient's underlying disease, recovery from immunosuppression and clinical response. The efficacy of a 70 mg dose regimen in patients who are not clinically responding to the 50 mg daily dose is not known. Safety data suggests that an increase in dose to 70 mg daily is well tolerated. The efficacy of doses above 70 mg has not been adequately studied in patients with invasive aspergillosis. No dose adjustments are necessary for elderly patients (65 years of age or more). No dosage adjustment is necessary based on gender, race or renal impairment. When CASFOLRED is co-administered with the metabolic inducers such as efavirenz, nevirapine, rifampicin, dexamethasone, phenytoin or carbamazepine, use of a daily dose of 70 mg of CASFOLRED should be considered (see INTERACTIONS).

Patients with Hepatic Impairment

Patients with mild hepatic insufficiency (Child-Pugh score 5 to 6) do not need a dosage adjustment (see CONTRAINDICATIONS). For adult patients with moderate hepatic insufficiency (Child-Pugh-score 7 to 9), CASFOLRED 35 mg daily is recommended based upon pharmacokinetic data. However, where recommended, a 70 mg loading dose should still be administered on Day 1. There is no clinical experience in patients with severe hepatic insufficiency (Child-Pugh score > 9) and in paediatric patients with any degree of hepatic insufficiency (see CONTRAINDICATIONS).

Paediatric Patients

CASFOLRED should be administered in children and adolescents (3 months to 17 years old) by slow IV infusion over approximately 1 hour. Dosing in children and adolescents (3 months to 17 years old) should be based on the patient's body surface area (see INSTRUCTIONS FOR USE IN PAEDIATRIC PATIENTS, Mosteller 1 Formula). For all indications, a single 70 mg/m2 loading dose (not to exceed an actual dose of 70 mg) should be administered on Day 1, followed by 50 mg/m2 daily thereafter (not to exceed an actual dose of 70 mg daily). Duration of treatment should be individualised to the indication, as described for each indication in adults. If the 50 mg/m2 daily dose is well tolerated but does not provide an adequate clinical response, the daily dose can be increased to 70 mg/m2 daily (not to exceed an actual daily dose of 70 mg). Although an increase in efficacy with 70 mg/m2 daily has not been demonstrated, limited safety data suggest that an increase in dose to 70 mg/m2 daily is well tolerated. When CASFOLRED is co-administered to paediatric patients with inducers of drug clearance, such as rifampicin, efavirenz, nevirapine, phenytoin, dexamethasone or carbamazepine, use of a CASFOLRED dose of 70 mg/m2 daily (not to exceed an actual daily dose of 70 mg) should be considered.

u2022 CASFOLRED is contraindicated in patients with a hypersensitivity to caspofungin or to any of the excipients.

u2022 CASFOLRED has not been studied in patients with severe hepatic insufficiency.

Anaphylaxis has been reported during administration of CASFOLRED. Should this occur, CASFOLRED should be discontinued and appropriate treatment administered. Possible histamine-mediated adverse reactions, including rash, facial swelling, angioedema, pruritus, sensation of warmth, or bronchospasm have been reported and may require discontinuation and/or administration of appropriate treatment.

Limited data suggest that less common non-Candida yeasts and non-Aspergillus moulds are not covered by CASFOLRED. The efficacy of CASFOLRED against these fungal pathogens has not been established.

In adult patients with mild and moderate hepatic impairment, the AUC is increased about 20 % and 75 %, respectively. It is recommended for adults with moderate hepatic impairment that the daily dose be reduced to 35 mg. There is no clinical experience in adults with severe hepatic impairment or in paediatric patients with any degree of hepatic impairment. A higher exposure than in moderate hepatic impairment is expected and CASFOLRED should be used with caution in these patients (see CONTRAINDICATIONS, DOSAGE AND DIRECTIONS and Pharmacokinetic properties).

Laboratory abnormalities in liver function tests have been seen in healthy volunteers and adult and paediatric patients treated with CASFOLRED. In some adult and paediatric patients with serious underlying conditions who were receiving multiple concomitant medicines with CASFOLRED, cases of clinically significant hepatic dysfunction, hepatitis and hepatic failure have been reported. A causal relationship to CASFOLRED has not been established. Patients who develop abnormal liver function tests during CASFOLRED therapy should be monitored for evidence of worsening hepatic function and the risk/benefit of continuing CASFOLRED therapy.

Cases of Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported after post-marketing use of CASFOLRED. Caution should apply in patients with history of allergic skin reactions (see SIDE EFFECTS).

The use of CASFOLRED with ciclosporin showed transient increases in alanine transaminase (ALT) and aspartate transaminase (AST) of less than or equal to 3-fold the upper limit of normal (ULN) that resolved with discontinuation of the treatment. Close monitoring of liver enzymes should be considered.

There was also an increase of approximately 35 % in the area under the curve (AUC) of CASFOLRED when co-administered with ciclosporin; blood levels of ciclosporin remained unchanged.

CASFOLRED decreased the 12 hour blood concentration (C12hr) of tacrolimus (FK-506) by 26 % in healthy adult volunteers. For patients who are concomitantly treated with tacrolimus, blood concentrations have to be monitored and appropriate dosage adjustments of tacrolimus should be considered.

In vitro studies have shown that caspofungin is not an inhibitor of any enzyme in the cytochrome P450 (CYP) system. Clinical studies have shown that caspofungin did not induce the CYP3A4 metabolism of other medicines. Caspofungin is not a substrate for P-glycoprotein and is a poor substrate for cytochrome P450 enzymes.

In vitro and in vivo studies of caspofungin in combination with amphotericin B, does not result in antagonism of antifungal activity against either A. fumigatus or C. albicans. Results from in vitro studies suggest that there was some evidence of additive/indifferent or synergistic activity against A. fumigatus and additive/indifferent activity against C. albicans. The clinical significance of these results is unknown.

In two adult clinical studies, ciclosporin (one 4 mg/kg dose or two 3 mg/kg doses) increased the AUC of caspofungin by about 35 %. The AUC increases are probably due to reduced uptake of caspofungin by liver. CASFOLRED did not increase the plasma levels of ciclosporin. There were transient increases in liver ALT and AST when CASFOLRED and ciclosporin were co-administered. (See WARNINGS AND SPECIAL PRECAUTIONS).

Clinical studies in adult healthy volunteers show that medicines such as itraconazole, amphotericin B, mycophenolate, nelfinavir or tacrolimus do not alter the pharmacokinetics of caspofungin. CASFOLRED has no effect on the pharmacokinetics of itraconazole, amphotericin B, rifampicin, or the active metabolite of mycophenolate.

CASFOLRED decreased the 12 hour blood concentration (C12hr) of tacrolimus (FK-506) by 26 % in healthy adult volunteers. For patients who are concomitantly treated with tacrolimus, blood concentrations have to be monitored and appropriate dosage adjustments of tacrolimus should be considered.

Two clinical interaction studies indicate that rifampicin induces and inhibits caspofungin disposition with net induction at a steady state. Additionally results from population pharmacokinetic screening in adults suggest that co-administration of CASFOLRED with other inducers of medicine clearance (such as efavirenz, nevirapine, phenytoin, dexamethasone or carbamazepine) may also result in clinically meaningful reductions in caspofungin concentrations. Available data suggest that the inducible medicine clearance mechanism involved in caspofungin disposition is likely an uptake transport process, rather than metabolism. Therefore, when CASFOLRED is co-administered to adult patients with inducers of medicine clearance, such as efavirenz, nevirapine, rifampicin, dexamethasone, phenytoin or carbamazepine, use of a daily dose of 70 mg of CASFOLRED should be considered (see DOSAGE AND DIRECTIONS FOR USE).

In paediatric patients, results from regression analyses of pharmacokinetic data suggest that co-administration of dexamethasone with CASFOLRED may result in clinically meaningful reductions in CASFOLRED trough concentrations. This may indicate that paediatric patients will have similar reductions with inducers as seen in adults. When CASFOLRED is co-administered to paediatric patients with inducers of medicine clearance, such as rifampicin, efavirenz, nevirapine, phenytoin, dexamethasone or carbamazepine, a CASFOLRED dose of 70 mg/m2 daily (not to exceed an actual daily dose of 70 mg/m2) is recommended.

There are no data on the use of CASFOLRED in pregnant women, therefore, CASFOLRED should not be used during pregnancy. It is not known if CASFOLRED is excreted in the breast milk of humans, therefore, breast-feeding is not recommended.

No studies on the effects on the ability to drive and use machines have been performed. CASFOLRED contains sucrose. Patients with rare hereditary conditions such as fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not use CASFOLRED. CASFOLRED contains mannitol which, on rare occasions, may cause hypersensitivity reactions.

The following side effects were reported for adult patients:

Blood and lymphatic system disorders

• Frequent: haemoglobin decreased, haematocrit decreased, white blood cell count decreased.
• Less frequent: anaemia, thrombocytopenia, coagulopathy, leukopenia, eosinophil count increased, platelet count decreased, platelet count increased, lymphocyte count decreased, white blood cell count increased, neutrophil count decreased.

Metabolism and nutrition disorders

• Frequent: hypokalemia.
• Less frequent: fluid overload, hypomagnesaemia, anorexia, electrolyte imbalance, hyperglycaemia, hypocalcaemia, metabolic acidosis.

Psychiatric disorders

• Less frequent: anxiety, disorientation, insomnia.

Nervous system disorders

• Frequent: headache.
• Less frequent: dizziness, dysgeusia, paraesthesia, somnolence, tremor, hypoaesthesia.

Eye disorders

• Less frequent: ocular icterus, vision blurred, eyelid oedema, lacrimation increased.

Cardiac disorders

• Less frequent: palpitations, tachycardia, dysrhythmia, atrial fibrillation, cardiac failure congestive.

Vascular disorders

• Frequent: phlebitis.
• Less frequent: thrombophlebitis, flushing, hot flush, hypertension, hypotension.

Respiratory, thoracic and mediastinal disorders

• Frequent: dyspnoea.
• Less frequent: nasal congestion, pharyngolaryngeal pain, tachypnoea, bronchospasm, cough, dyspnoea paroxysmal nocturnal, hypoxia, rales, wheezing.

Gastrointestinal disorders

• Frequent: nausea, vomiting, diarrhoea.
• Less frequent: abdominal pain, abdominal pain upper, dry mouth, dyspepsia, stomach discomfort, abdominal distension, ascites, constipation, dysphagia, flatulence.

Hepatobiliary disorders

• Frequent: elevated liver values (alanine aminotransferase, aspartate aminotransferase, blood alkaline phosphatase, bilirubin conjugated, blood bilirubin).
• Less frequent: cholestasis, hepatomegaly, hyperbilirubinaemia, jaundice, hepatic function abnormal, hepatotoxicity, liver disorder, gamma-glutamyltransferase increased.

Skin and subcutaneous tissue disorders

• Frequent: rash, pruritus, hyperhidrosis, erythema.
• Less frequent: erythema multiforme, rash macular, rash maculo-papular, rash pruritic, urticaria, dermatitis allergic, pruritus generalised, rash erythematous, rash generalised, rash morbilliform, skin lesion.
• Frequency unknown: toxic epidermal necrolysis and Stevens-Johnson syndrome.

Musculoskeletal, connective tissue and bone disorders

• Frequent: arthralgia.
• Less frequent: back pain, pain in extremity, bone pain, muscular weakness, myalgia.

Renal and urinary disorders

• Less frequent: renal failure, renal failure acute.

General disorders and administration site conditions

• Frequent: pyrexia, chills, infusion-site pruritus.
• Less frequent: pain, catheter site pain, fatigue, feeling cold, feeling hot, infusion site erythema, infusion site induration, infusion site pain, infusion site swelling, injection site phlebitis, oedema peripheral, tenderness, chest discomfort, chest pain, face oedema, feeling of body temperature change, induration, infusion site extravasation, infusion site irritation, infusion site phlebitis, infusion site rash, infusion site urticaria, injection site erythema, injection site oedema, injection site pain, injection site swelling, malaise, oedema.

Investigations

• Frequent: blood potassium decreased, blood albumin decreased.
• Less frequent: blood creatinine increased, red blood cells urine positive, protein total decreased, protein urine present, prothrombin time prolonged, prothrombin time shortened, blood sodium decreased, blood sodium increased, blood calcium decreased, blood calcium increased, blood chloride decreased, blood glucose increased, blood magnesium decreased, blood phosphorus decreased, blood phosphorus increased, blood urea increased, activated partial thromboplastin time prolonged, blood bicarbonate decreased, blood chloride increased, blood potassium increased, blood pressure increased, blood uric acid decreased, blood urine present, breath sounds abnormal, carbon dioxide decreased, immunosuppressant drug level increased, international normalised ratio increased, urinary casts, white blood cells urine positive, and pH urine increased.

The following side effects were reported for paediatric patients:

Blood and lymphatic system disorders

• Frequent: increased eosinophil count.

Nervous system disorders

• Frequent: headache.

Cardiac disorders

• Frequent: tachycardia.

Vascular disorders

• Frequent: flushing, hypotension.
• Frequency unknown: swelling and peripheral oedema.

Hepatobiliary disorders

• Frequent: elevated liver enzyme levels (AST, ALT).
• Frequency unknown: hepatic dysfunction.

Skin and subcutaneous tissue disorders

• Frequent: rash, pruritus.
• Frequency unknown: histamine-mediated symptoms (rash, facial swelling, pruritus, sensation of warmth, bronchospasm), anaphylaxis.

General disorders and administration site conditions

• Frequent: fever, chills, catheter-site pain.

Investigations

• Frequent: increased liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), decreased potassium, hypomagnesaemia, increased glucose, decreased phosphorus, increased phosphorus.
• Frequency unknown: hypercalcaemia, increased eosinophils.

In one study 210 mg was the highest dose which was administered as a single dose to 6 healthy subjects and in another study 150 mg once a day for up to 51 days was administered to 100 subjects. CASFOLRED is not dialysable.