Caspolyn 50 mg/70 mg Solution

CASPOLYN is indicated in adults 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 in patients who are refractory to or intolerant of other therapies, including amphotericin B, lipid formulations of amphotericin B and itraconazole.

Paediatric use

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

General Recommendations in Adult Patients

CASPOLYN should be administered in adults (u2265 18 years of age) by slow intravenous infusion over approximately 1 hour.

Empirical therapy

A single 70 mg loading dose should be administered on Day 1 followed by 50 mg daily thereafter. Duration of treatment should be based on the patient's clinical response. Empirical therapy should be continued until resolution of neutropenia. 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 the 50 mg is well tolerated but does not provide an adequate clinical response, the daily dose can be increased to 70 mg. Although 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 well tolerated.

Invasive Candidiasis

A single 70 mg loading dose should be administered on Day 1, followed by 50 mg daily thereafter. Duration of treatment of invasive candidiasis should be dictated by the patientu2019s 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 warrant a longer course of therapy pending 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. Caspofungin, as contained in CASPOLYN was generally well tolerated in these patients receiving caspofungin at this higher dose; however, the efficacy of caspofungin at this higher dose was generally similar to patients receiving the 50 mg daily dose of caspofungin.

Oesophageal and Oropharyngeal Candidiasis

Fifty (50) mg should be administered daily.

Invasive Aspergillosis

A single 70 mg loading dose should be administered on Day 1, followed by 50 mg daily thereafter. Duration of treatment should be based upon the severity of the patientu2019s 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 dosage adjustment is necessary for elderly patients (65 years of age or more). No dosage adjustment is necessary based on gender, race or renal impairment. When co-administering CASPOLYN in adult patients with the metabolic inducers efavirenz, nevirapine, rifampicin, dexamethasone, phenytoin or carbamazepine, use of a daily dose of 70 mg of CASPOLYN, should be considered (see section 4.5).

Patients with Hepatic Insufficiency

Adult patients with mild hepatic insufficiency (Child-Pugh score 5 to 6) do not need a dosage adjustment. For adult patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9), CASPOLYN 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 adult patients with severe hepatic insufficiency (Child-Pugh score > 9) and in paediatric patients with any degree of hepatic insufficiency.

Paediatric Patients

CASPOLYN should be administered in children and adolescents (3 months to 17 years of age) by slow IV infusion over approximately 1 hour. Dosing in children and adolescents (3 months to 17 years of age) should be based on the patientu2019s body surface area (see u201cINSTRUCTIONS FOR USE IN PAEDIATRIC PATIENTS, 1 Mosteller Formulau201d). 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 (see General Recommendations in Adult Patients).

• CASPOLYN is contra-indicated in patients with hypersensitivity to caspofungin or any other component of this product (see section 6.1)
• CASPOLYN has not been studied in severe hepatic insufficiency.

Anaphylaxis has been reported during administration of caspofungin, as contained in CASPOLYN. If this occurs, CASPOLYN should be discontinued and appropriate treatment administered. Possibly 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 caspofungin. The efficacy of caspofungin against these fungal pathogens has not been established.

Concomitant use of caspofungin with ciclosporin has been evaluated in healthy adult volunteers and in adult patients. Some healthy adult volunteers who received two 3 mg/kg doses of ciclosporin with caspofungin 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. In a retrospective study of 40 patients treated during marketed use with caspofungin and ciclosporin for 1 to 290 days (median 17.5 days), no serious hepatic adverse reactions were noted. These data suggest that CASPOLYN can be used in patients receiving ciclosporin when the potential benefit outweighs the potential risk. Close monitoring of liver enzymes should be considered if CASPOLYN and ciclosporin are used concomitantly.

In adult patients with mild and moderate hepatic impairment, the AUC is increased about 20 % and 75 %, respectively. A reduction of the daily dose to 35 mg is recommended for adults with moderate hepatic impairment. 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 caspofungin should be used with caution in these patients (see sections 4.2 and 5.2).

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

Cases of Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported after post-marketing use of caspofungin, as contained in CASPOLYN. Caution should apply in patients with history of allergic skin reaction (see section 4.8).

CASPOLYN contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially 'sodium-free'.

Studies in vitro show that caspofungin, as contained in CASPOLYN is not an inhibitor of any enzyme in the cytochrome P450 (CYP) system. In clinical studies, caspofungin did not induce the CYP3A4 metabolism of other substances. Caspofungin is not a substrate for P-glycoprotein and is a poor substrate for cytochrome P450 enzymes. However, caspofungin has been shown to interact with other medicinal products in pharmacological and clinical studies (see below).

In two clinical studies performed in healthy adult subjects, ciclosporin A (one 4 mg/kg dose or two 3 mg/kg doses 12 hours apart) increased the AUC of caspofungin by approximately 35 %. These AUC increases are probably due to reduced uptake of caspofungin by the liver. Caspofungin did not increase the plasma levels of ciclosporin. There were transient increases in liver ALT and AST of less than or equal to 3-fold the upper limit of normal (ULN) when caspofungin and ciclosporin were co-administered, that resolved with discontinuation of the medicinal products. In a retrospective study of 40 patients treated during marketed use with caspofungin and ciclosporin for 1 to 290 days (median 17.5 days), no serious hepatic adverse reactions were noted (see section 4.4). Close monitoring of liver enzymes should be considered if the two medicinal products are used concomitantly.

Caspofungin reduced the trough concentration of tacrolimus by 26 % in healthy adult volunteers. For patients receiving both therapies, standard monitoring of tacrolimus blood concentrations and appropriate tacrolimus dosage adjustments are mandatory. Clinical studies in healthy adult volunteers show that the pharmacokinetics of caspofungin are not altered to a clinically relevant extent by itraconazole, amphotericin B, mycophenolate, nelfinavir, or tacrolimus. Caspofungin did not influence the pharmacokinetics of amphotericin B, itraconazole, rifampicin or mycophenolate mofetil. Although safety data are limited it appears that no special precautions are needed when amphotericin B, itraconazole, nelfinavir or mycophenolate mofetil are co-administered with caspofungin.

Rifampicin caused a 60 % increase in AUC and 170 % increase in trough concentration of caspofungin on the first day of co-administration when both medicinal products were initiated together in healthy adult volunteers. Caspofungin trough levels gradually decreased upon repeated administration. After two weeks' administration rifampicin had limited effect on AUC, but trough levels were 30 % lower than in adult subjects who received caspofungin alone. The mechanism of interaction could possibly be due to an initial inhibition and subsequent induction of transport proteins. A similar effect could be expected for other medicinal products that induce metabolic enzymes. Limited data from population pharmacokinetics studies indicate that concomitant use of caspofungin with the inducers efavirenz, nevirapine, rifampicin, dexamethasone, phenytoin, or carbamazepine may result in a decrease in caspofungin AUC. When co-administering inducers of metabolic enzymes, an increase in the daily dose of caspofungin to 70 mg, following the 70 mg loading dose, should be considered in adult patients (see section 4.2).

All adult medicine interaction studies described above were conducted at a 50 or 70 mg daily caspofungin dose. The interaction of higher doses of caspofungin with other medicinal products has not been formally studied. In paediatric patients, results from regression analyses of pharmacokinetic data suggest that co-administration of dexamethasone with caspofungin may result in clinically meaningful reductions in caspofungin trough concentrations. This finding may indicate that paediatric patients will have similar reductions with inducers as seen in adults. When caspofungin is co-administered to paediatric patients (12 months to 17 years of age) with inducers of medicine clearance, such as rifampicin, efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, a caspofungin dose of 70 mg/m2 daily (not to exceed an actual daily dose of 70 mg) should be considered.

Pregnancy

There are no or limited data from the use of caspofungin in pregnant women. CASPOLYN should not be used during pregnancy. Animal studies have shown developmental toxicity. Caspofungin has been shown to cross the placental barrier in animal studies.

Breastfeeding

It is unknown whether caspofungin is excreted in human milk. Available pharmacodynamic/ toxicological data in animals have shown excretion of caspofungin in milk. Women receiving CASPOLYN should not breastfeed.

Fertility

For caspofungin, there were no effects on fertility in studies conducted in male and female rats. There are no clinical data for caspofungin to assess its impact on fertility.

No studies on the effects on the ability to drive and use machines have been performed. However, CASPOLYN may cause dizziness, somnolence and blurred vision, which may influence the ability to perform these activities. Patients should be warned not to drive or operate machinery until they are aware of the measure to which CASPOLYN affects them or until such side effects subside.

a. Summary of the safety profile

Hypersensitivity reactions (anaphylaxis and possibly histamine-mediated adverse reactions) have been reported (see section 4.4). Also reported in patients with invasive aspergillosis were pulmonary oedema, adult respiratory distress syndrome (ARDS), and radiographic infiltrates

b. Tabulated list of adverse reactions

The following adverse reactions were reported during clinical studies and/or post-marketing use:

Table 1: ADRs reported during clinical studies and/or post-marketing use:

SYSTEM ORGAN CLASS INCIDENCE ADVERSE REACTION

Blood and lymphatic system disorders Frequent haemoglobindecreased,haematocritdecreased, whiteblood cell countdecreased Less frequent anaemia, thrombocytopaenia, coagulopathy,leukopaenia, eosinophil count increased, plateletcount decreased, platelet count increased,lymphocyte count decreased, white blood cell countincreased, neutrophil count decreased Frequent hypokalaemia

In clinical studies, the highest dose was 210 mg, which was administered as a single dose to 6 adult healthy subjects, and was generally well tolerated. In addition, a dose of 150 mg once daily up to 51 days has been administered to 100 adult patients and was generally well tolerated. Caspofungin is not dialysable.