Control Number: 099642

(r) Registered Trademark of Merck & Co., Inc. Used under license.

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 DESCRIPTION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 6 DRUG INTERACTIONS 16 DOSAGE AND ADMINISTRATION 18 OVERDOSAGE 23 ACTION AND CLINICAL PHARMACOLOGY 23 STORAGE AND STABILITY 24 SPECIAL HANDLING INSTRUCTIONS 24 DOSAGE FORMS, COMPOSITION AND PACKAGING 24

PART II: SCIENTIFIC INFORMATION 25

PHARMACEUTICAL INFORMATION 25 CLINICAL TRIALS 26 DETAILED PHARMACOLOGY 32 MICROBIOLOGY 34 TOXICOLOGY 35 BIBLIOGRAPHY 37

PART III: CONSUMER INFORMATION 39

CANCIDAS(r)

caspofungin acetate for injection

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

DESCRIPTION

CANCIDAS(r) (caspofungin acetate) is a sterile, lyophilized product for intravenous (IV) infusion that contains a semisynthetic lipopeptide (echinocandin) compound synthesized from a fermentation product of Glarea lozoyensis. CANCIDAS(r) is a member of a class of antifungal drugs (echinocandins) that inhibits the synthesis of b (1,3)-D-glucan, an integral component of the fungal cell wall.

CONTRAINDICATIONS

CANCIDAS(r) (caspofungin acetate) is contraindicated in patients with hypersensitivity to any component of this product.

WARNINGS AND PRECAUTIONS

General

The efficacy of a 70-mg dose regimen in patients who are not clinically responding to the 50 mg daily dose is not known. Limited safety data suggest that an increase in dose to 70 mg daily is well tolerated. The safety and efficacy of doses above 70 mg have not been adequately studied. There is limited safety information on treatment for durations longer than 4 weeks, however, available data suggest that CANCIDAS(r) (caspofungin acetate) continues to be well tolerated with longer courses of therapy (up to 162 days of therapy). Concomitant use of CANCIDAS(r) (caspofungin acetate) with cyclosporine should be limited to patients for whom the potential benefit outweighs the potential risk. Elevated liver function tests have been observed in 5 of 12 healthy subjects who received concomitant CANCIDAS(r) and cyclosporine (see ADVERSE REACTIONS). In a retrospective study, 40 immunocompromised patients, including 37 transplant recipients, were treated during marketed use with CANCIDAS(r) and cyclosporine for 1 to 290 days (median 17.5 days). Fourteen patients (35%) developed transaminase elevations >5X upper limit of normal or >3X baseline during concomitant therapy or the 14-day follow-up period; five were considered possibly related to concomitant therapy. One patient had elevated bilirubin considered possibly related to concomitant therapy. No patient developed clinical evidence of hepatotoxicity or serious hepatic events. Discontinuations due to laboratory abnormalities in hepatic enzymes from any cause occurred in four patients. Of these, 2 were considered possibly related to therapy with CANCIDAS(r) and/or cyclosporine as well as to other possible causes. In the prospective invasive aspergillosis and compassionate use studies, there were 4 patients treated with CANCIDAS(r) (50 mg/day) and cyclosporine for 2 to 56 days. None of these patients experienced increases in hepatic enzymes. Given the limitations of these data, CANCIDAS(r) and cyclosporine should only be used concomitantly in those patients for whom the potential benefit outweighs the potential risk. Patients who develop abnormal liver function tests during concomitant therapy should be monitored and the risk/benefit of continuing therapy should be evaluated.

Special Populations

Pregnant Women: There are no adequate and well controlled studies in pregnant women. CANCIDAS(r) should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Caspofungin was shown to be embryotoxic in rats and rabbits. Findings included incomplete ossification of the skull and torso and an increased incidence of cervical rib in rats. An increased incidence of incomplete ossifications of the talus/calcaneus was seen in rabbits. Caspofungin also produced increases in resorptions in rats and rabbits and perimplantation losses in rats. These findings were observed at doses which produced exposures similar to those seen in patients treated with a 70-mg dose. Caspofungin crossed the placental barrier in rats and rabbits and was detected in the plasma of fetuses of pregnant animals dosed with CANCIDAS(r). Nursing Women: It is not known whether caspofungin is excreted in human milk. Caspofungin has been found in the milk of lactating laboratory animals. Women receiving CANCIDAS(r) should not breast-feed.

Pediatrics:

Safety and effectiveness in patients less than 18 years old have not been established.

Geriatrics (>=65 years of age): In a limited number of patients >=65 years of age, no overall differences in safety or efficacy have been observed between elderly and younger patients. Plasma concentrations of caspofungin in healthy older men and women (>=65 years of age) were increased slightly (approximately 28% in area under the curve [AUC]) compared to young healthy men. In patients who were treated empirically or who had invasive candidiasis, a similar modest effect of age was seen in older patients relative to younger patients. No dose adjustment is recommended for the elderly; however, greater sensitivity of some older individuals cannot be ruled out.

Patients with Special Diseases or Conditions Hepatic Insufficiency

Patients with mild hepatic insufficiency (Child-Pugh score 5 to 6) do not need a dosage adjustment. For patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9), CANCIDAS(r) 35 mg daily is recommended. 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) (see DOSAGE AND ADMINISTRATION and DETAILED PHARMACOLOGY, Pharmacokinetics, Special Populations).

Renal Insufficiency

Mild to advanced renal insufficiency does not alter significantly caspofungin plasma concentrations and does not require a change in dosing. Caspofungin is not dialyzable, thus supplementary dosing is not required following hemodialysis (see DETAILED PHARMACOLOGY, Renal Insufficiency).

DRUG INTERACTIONS

Overview

Studies in vitro show that caspofungin acetate is not an inhibitor of any enzyme in the cytochrome P450 (CYP) system at or up to 5 times the concentration expected in human use. In clinical studies, caspofungin did not induce the CYP3A4 metabolism of other drugs. Caspofungin is not a substrate for P-glycoprotein and is a poor substrate for cytochrome P450 enzymes. Studies in healthy volunteers show that the pharmacokinetics of caspofungin are not significantly altered by itraconazole, amphotericin B, mycophenolate, nelfinavir or tacrolimus. Caspofungin has no significant effect on the pharmacokinetics of itraconazole, amphotericin B, rifampin or the active metabolite of mycophenolate.

Drug-Drug Interactions

Tacrolimus

For patients receiving both caspofungin and tacrolimus, standard monitoring of tacrolimus blood concentrations and appropriate tacrolimus dosage adjustments are recommended. Caspofungin reduced the blood AUC of tacrolimus by approximately 20%, maximal blood concentration (Cmax) by 16%, and 12-hour blood concentration (C12hr) by 26% in healthy subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of CANCIDAS(r) 70 mg daily, as compared to results from a control period in which tacrolimus was administered alone.

Cyclosporine

In two clinical studies, cyclosporine (one 4 mg/kg dose or two 3 mg/kg doses) increased the AUC of caspofungin by approximately 35%. CANCIDAS(r) did not increase the plasma levels of cyclosporine. There were transient increases in liver ALT and AST when CANCIDAS(r) and cyclosporine were co-administered (see WARNINGS and ADVERSE REACTIONS).

Rifampin

Results from two clinical drug interaction studies indicate that rifampin both induces and inhibits caspofungin disposition with net induction at steady state. In one study, rifampin and caspofungin were co-administered for 14 days with both therapies initiated on the same day. In the second study, rifampin was administered alone for 14 days to allow the induction effect to reach steady state, and then rifampin and caspofungin were co-administered for an additional 14 days. When the induction effect of rifampin was at steady state, there was little change in caspofungin AUC or end-of-infusion concentration, but caspofungin trough concentrations were reduced by approximately 30%. The inhibitory effect of rifampin was demonstrated when rifampin and caspofungin treatments were initiated on the same day, and a transient elevation in caspofungin plasma concentrations occurred on Day 1 (approximately 60% increase in AUC). This inhibitory effect was not seen when caspofungin was added to preexisting rifampin therapy, and no elevation in caspofungin concentrations occurred. When CANCIDAS(r) is co-administered with rifampin (or other inducers of drug clearance - see Other Medications), use of a daily dose of 70 mg of CANCIDAS(r) may be considered (see DOSAGE AND ADMINISTRATION).

Other Medications

Results from population pharmacokinetic screening suggest that co-administration of inducers of drug clearance (efavirenz, nevirapine, phenytoin, dexamethasone or carbamazepine) with CANCIDAS(r) may result in clinically meaningful reductions in caspofungin concentrations. Available data suggest that the inducible drug clearance mechanism involved in caspofungin disposition is likely an uptake transport process, rather than metabolism. Therefore, when CANCIDAS(r) is co-administered with inducers of drug clearance, such as efavirenz, nevirapine, rifampin, dexamethasone, phenytoin, or carbamazepine, use of a daily dose of 70 mg of CANCIDAS(r) may be considered (see DOSAGE AND ADMINISTRATION).

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbs have not been established.

Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Do not mix or co-infuse CANCIDAS(r) (caspofungin acetate) with other medications. There are no data available on the compatibility of CANCIDAS(r) with other intravenous substances, additives, or medications. Do not use diluents containing dextrose (a-D-glucose), as CANCIDAS(r) is not stable in diluents containing dextrose.

CANCIDAS(r) should be administered by slow intravenous infusion over approximately 1 hour.

Recommended Dose and Dosage Adjustment

Empirical Therapy for presumed fungal infections in febrile, neutropenic patients A single 70-mg loading dose should be administered on Day 1, followed by 50 mg daily thereafter. CANCIDAS(r) should be administered by slow intravenous infusion over approximately 1 hour. 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 dose 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, limited 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. CANCIDAS(r) should be administered by slow intravenous infusion over approximately 1 hour. Duration of treatment of invasive candidiasis should be dictated 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 warrant a longer course of therapy pending resolution of the neutropenia.

Esophageal Candidiasis

Fifty (50) mg should be administered daily by slow intravenous infusion over approximately 1 hour. Duration of treatment should be dictated by the patient's clinical response. Because of the risk of relapse of oropharyngeal candidiasis in HIV-infected patients with esophageal and/or oropharyngeal candidiasis at baseline, suppressive oral therapy could be considered (see CLINICAL TRIALS). A 70-mg loading dose has not been studied with this indication.

Invasive Aspergillosis

A single 70 mg loading dose should be administered on Day 1, followed by 50 mg daily thereafter. CANCIDAS(r) should be administered by slow IV infusion over approximately 1 hour. Duration of treatment should be based upon the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response. Although there is no information to demonstrate an increase in efficacy with higher doses, available safety data suggests that an increase in dose to 70 mg daily may be considered in patients without evidence of clinical response in whom CANCIDAS(r) has been well tolerated.

Concomitant Therapy with Inducers of Drug Clearance

When CANCIDAS(r) is co-administered with inducers of drug clearance, such as efavirenz, nevirapine, rifampin, dexamethasone, phenytoin, or carbamazepine, use of a daily dose of 70 mg of CANCIDAS(r) may be considered (see DRUG INTERACTIONS). No dosage adjustment is necessary for elderly patients (65 years of age or older). No dosage adjustment is necessary based on gender, race, or renal impairment.

Hepatic Insufficiency

Patients with mild hepatic insufficiency (Child-Pugh score 5 to 6) do not need a dosage adjustment. For patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9), CANCIDAS(r) 35 mg daily is recommended. 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) (see DETAILED PHARMACOLOGY, Pharmacokinetics, Special Populations).

Missed Dose

The injection schedule will be set by the physician, who will monitor the response and condition to determine what treatment is needed.

Administration

DIRECTIONS FOR RECONSTITUTION AND DILUTION

Preparation of the 70 mg Day 1 loading-dose infusion

1. Equilibrate the refrigerated vial of CANCIDAS(r) to room temperature.

2. Aseptically add 10.5 mL of either 0.9% Sodium Chloride Injection, Sterile Water for Injection, Bacteriostatic Water for Injection with methylparaben and propylparaben, or Bacteriostatic Water for Injection with 0.9% benzyl alcohol to the vial.a Do not mix with diluents containing dextrose (a-D-glucose) as CANCIDAS(r) is not stable in diluents containing dextrose. This reconstituted solution may be stored for up to 1 hour at 15degC to 25degC.b

3. Aseptically transfer 10 mLc of reconstituted CANCIDAS(r) to an IV bag (or bottle) containing 250 mL 0.9%, 0.45%, or 0.225% Sterile Saline for Injection, or Lactated Ringer's Injection. Do not mix with diluents containing dextrose (a-D-glucose) as CANCIDAS(r) is not stable in diluents containing dextrose. This infusion solution should be used without delay. It can, however, be stored for up to 24 hours at 15degC to 25degC or for 48 hours refrigerated at 2degC to 8degC. (If a 70 mg vial is unavailable, see below: Alternative Infusion Preparation Methods, Preparation of 70 mg Day 1 loading dose from two 50 mg vials).

Preparation of the daily 50 mg infusion

1. Equilibrate the refrigerated vial of CANCIDAS(r) to room temperature.

2. Aseptically add 10.5 mL of either 0.9% Sodium Chloride Injection, Sterile Water for Injection, Bacteriostatic Water for Injection with methylparaben and propylparaben, or Bacteriostatic Water for Injection with 0.9% benzyl alcohol to the vial.a Do not mix with diluents containing dextrose (a-D-glucose) as CANCIDAS(r) is not stable in diluents containing dextrose. This reconstituted solution may be stored for up to 1 hour at 15degC to 25degC.b

3. Aseptically transfer 10 mLc of reconstituted CANCIDAS(r) to an IV bag (or bottle) containing 250 mL 0.9%, 0.45%, or 0.225% Sterile Saline for Injection, or Lactated Ringer's Injection. Do not mix with diluents containing dextrose (a-D-glucose) as CANCIDAS(r) is not stable in diluents containing dextrose. This infusion solution should be used without delay. It can, however, be stored for up to 24 hours at 15degC to 25degC or 48 hours refrigerated at 2degC to 8degC. (If a reduced infusion volume is medically necessary, see below: Alternative Infusion Preparation Methods, Preparation of 50 mg daily doses at reduced volume).

Alternative Infusion Preparation Methods

Preparation of 70 mg Day 1 loading dose from two 50 mg vials

Reconstitute two 50 mg vials with 10.5 mL of diluent each (see Preparation of the daily 50 mg infusion). Aseptically transfer a total of 14 mL of the reconstituted CANCIDAS(r) from the two vials to 250 mL 0.9%, 0.45%, or 0.225% Sterile Saline for Injection, or Lactated Ringer's Injection. Do not mix with diluents containing dextrose (a-D-glucose) as CANCIDAS(r) is not stable in diluents containing dextrose. This infusion solution should be used without delay. It can, however, be stored for up to 24 hours at 15degC to 25degC or 48 hours refrigerated at 2degC to 8degC.

Preparation of 50 mg daily doses at reduced volume

When medically necessary, the 50 mg daily doses can be prepared by adding 10 mL of reconstituted CANCIDAS(r) to 100 mL of 0.9%, 0.45%, or 0.225% Sterile Saline for Injection, or Lactated Ringer's Injection. Do not mix with diluents containing dextrose (a-D-glucose) as CANCIDAS(r) is not stable in diluents containing dextrose. This infusion solution should be used without delay. It can, however, be stored for up to 24 hours at 15degC to 25degC or 48 hours refrigerated at 2degC to 8degC (see Preparation of the daily 50 mg infusion).

Preparation of a 35 mg daily dose from a 70 mg vial for patients with moderate hepatic insufficiency

Reconstitute one 70 mg vial (see above: Preparation of the 70 mg Day 1 loading dose infusion). Aseptically transfer 5 mL of the reconstituted CANCIDAS(r) from the vial to 250 mL or, if medically necessary, to 100 mL of 0.9%, 0.45%, or 0.225% Sterile Saline for Injection, or Lactated Ringer's Injection. Do not mix with diluents containing dextrose (a-D-glucose) as CANCIDAS(r) is not stable in diluents containing dextrose. This infusion solution should be used without delay. It can however, be stored for up to 24 hours at 15degC to 25degC or 48 hours refrigerated at 2degC to 8degC.

Preparation of a 35 mg daily dose from a 50 mg vial for patients with moderate hepatic insufficiency

Reconstitute one 50 mg vial (see above: Preparation of the daily 50 mg infusion). Aseptically transfer 7 mL of the reconstituted CANCIDAS(r) from the vial to 250 mL of 0.9%, 0.45%, or 0.225% Sterile Saline for Injection, or Lactated Ringer's Injection or, if medically necessary, to 100 mL of 0.9%, 0.45%, or 0.225% Sterile Saline for Injection, or Lactated Ringer's Injection. Do not mix with diluents containing dextrose (a-D-glucose) as CANCIDAS(r) is not stable in diluents containing dextrose. This infusion solution should be used without delay. It can, however, be stored for up to 24 hours at 15degC to 25degC or 48 hours refrigerated at 2degC to 8degC.

Preparation notes:

1. The white to off-white compact powder will dissolve completely. Mix gently until a clear solution is obtained.

2. As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discolouration and leakage prior to administration whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should not be used.

3. CANCIDAS(r) is formulated to provide the full labeled vial dose (70 mg or 50 mg) when 10 mL is withdrawn from the vial.

TABLE 7

Preparation of the Patient Infusion Solutions

10.5 mL should be used for reconstitution of all vials

* * If a 70 mg vial is not available, the 70 mg dose can be prepared from two 50 mg vials.

OVERDOSAGE

In clinical studies, the highest dose was 210 mg, which was administered as a single dose to 6 healthy subjects, and was generally well tolerated. In addition, 100 mg once daily for 21 days has been administered to 15 healthy subjects and was generally well tolerated. Caspofungin is not dialyzable.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

CANCIDAS(r) (caspofungin acetate) is a sterile, lyophilized product for intravenous (IV) infusion that contains a semisynthetic lipopeptide (echinocandin) compound synthesized from a fermentation product of Glarea lozoyensis. CANCIDAS(r) is a member of a class of antifungal drugs (echinocandins) that inhibits the synthesis of b (1,3)-D-glucan, an integral component of the fungal cell wall.

Pharmacodynamics

Caspofungin acetate, inhibits the synthesis of b (1,3)-D-glucan, an essential component of the cell wall of many filamentous fungi and yeast. b (1,3)-D-glucan is not present in mammalian cells. Caspofungin has shown activity in regions of active cell growth of the hyphae of Aspergillus fumigatus. Caspofungin has in vitro activity against various pathogenic fungi of the Aspergillus and Candida species. Standardized susceptibility testing methods for echinocandins have not been established, and results of susceptibility studies do not correlate with clinical outcome.

Pharmacokinetics

Plasma concentrations of caspofungin decline in a polyphasic manner following single 1-hour intravenous infusions. A short a-phase occurs for 1 to 2 hours immediately post-infusion, followed by a b-phase with a half-life of 9 to 11 hours. An additional g-phase also occurs with a half-life of 27 hours. Distribution, rather than excretion or biotransformation, is the dominant mechanism influencing plasma clearance. Approximately 75% of a radioactive dose was recovered: 41% in urine and 34% in feces. Caspofungin is slowly metabolized by hydrolysis and N-acetylation. Caspofungin also undergoes spontaneous chemical degradation to an open-ring peptide compound. At later time points (>=5 days post-dose), there is a low level (<= 7 pmol/mg protein, or <=1.3% of administered dose) of covalent binding of radiolabel in plasma following single-dose administration of [3H] caspofungin acetate, which may be due to two reactive intermediates formed during the chemical degradation of caspofungin. There is little excretion or biotransformation of caspofungin during the first 30 hours after administration. Caspofungin is extensively bound to albumin (approximately 97%), and it is slowly metabolized by hydrolysis and N-acetylation. A small amount of caspofungin is excreted unchanged in urine (approximately 1.4% of dose). Renal clearance of parent drug is low (see DETAILED PHARMACOLOGY, Pharmacokinetics).

STORAGE AND STABILITY

Vials

The lyophilized single-dose vials should be stored at 2degC to 8degC. Discard unused portion.

Reconstituted Concentrate

Reconstituted CANCIDAS(r) may be stored at 15degC to 25degC for up to 1 hour prior to the preparation of the patient infusion solution.

Patient Infusion Solution

The final patient infusion solution in the IV bag or bottle should be used without delay. It can, however, be stored for up to 24 hours at 15degC to 25degC or 48 hours refrigerated at 2degC to 8degC.

SPECIAL HANDLING INSTRUCTIONS

DOSAGE FORMS, COMPOSITION AND PACKAGING

CANCIDAS(r) 50 mg is a white to off-white compact powder for infusion in a vial with a red aluminum seal and a plastic flip-off cap. Packaged as a single-dose vial in a carton. Each 50 mg vial of CANCIDAS(r) contains 50 mg caspofungin as caspofungin acetate. Inactive ingredients: 39.0 mg sucrose, 26.0 mg mannitol and 2.0 mg glacial acetic acid. The pH may have been adjusted with acetic acid and/or sodium hydroxide. CANCIDAS(r) 70 mg is a white to off-white compact powder for infusion in a vial with a yellow/orange aluminum seal and a plastic flip-off cap. Packaged as a single-dose vial in a carton. Each 70 mg vial of CANCIDAS(r) contains 70 mg caspofungin as caspofungin acetate. Inactive ingredients: 54.0 mg sucrose, 36.0 mg mannitol and 2.7 mg glacial acetic acid. The pH may have been adjusted with acetic acid and/or sodium hydroxide. CANCIDAS(r) does not contain any preservative agents.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: caspofungin acetate Chemical name: 1-[(4R,5S)-5-[(2-aminoethyl)amino]-N2-(10,12-dimethyl- 1-oxotetradecyl)-4-hydroxy-L-ornithine]-5-[(3R)-3- hydroxy-L-ornithine] pneumocandin B0 diacetate (salt). Molecular formula: C52H88N10O15 *2C2H4O2 Molecular mass: 1213.42 Structural formula: Physicochemical properties: Physical Form: Caspofungin acetate is a hygroscopic, white to off- white powder. It is freely soluble in water and methanol, and slightly soluble in ethanol. pH: The pH of a saturated aqueous solution of caspofungin acetate is approximately 6.6.

CLINICAL TRIALS

Empirical Therapy in febrile, neutropenic patients

A total of 1111 patients with persistent fever and neutropenia were enrolled in a clinical study and treated with either CANCIDAS(r) 50 mg once daily following a 70-mg loading dose or AmBisome(r) 3.0 mg/kg/day. Eligible patients had received chemotherapy for malignancy or had undergone hematopoietic stem-cell transplantation, and presented with neutropenia for at least 96 hours (<500 cells/mm3) and fever (>38.0degC) not responding to at least 96 hours of antibacterial therapy. Patients were to be treated until resolution of neutropenia, with a maximum duration of 28 days. However, patients found to have a documented fungal infection could be treated longer. If the drug was well tolerated but the patient's fever persisted and clinical condition deteriorated after 5 days of therapy, the dosage of study drug could be increased to 70 mg/day of CANCIDAS(r) (13.3% of patients treated) or to 5.0 mg/kg/day of AmBisome(r) (14.3% of patients treated). An overall favorable response required meeting each of 5 criteria: (1) successful treatment of any baseline fungal infection, (2) no breakthrough fungal infections during administration of study drug or within 7 days after completion of treatment, (3) survival for 7 days after completion of study therapy, (4) no discontinuation from the study drug because of drug-related toxicity or lack of efficacy, and (5) resolution of fever during the period of neutropenia. For baseline infections, complete response and partial response were considered favourable clinical outcomes. A partial response was defined as clinically meaningful improvement in attributable symptoms and signs, as well as in attributable abnormalities detected by radiography, bronchoscopy, endoscopy or other procedures. Unfavorable responses included stable disease and failure. There were 1095 patients included in the primary Modified Intention- To-Treat (MITT) efficacy analysis of overall favorable response. This trial was designed to establish noninferiority of CANCIDAS(r) to AmBisome(r) . The observed overall therapeutic success rates for CANCIDAS(r) and AmBisome(r) were 34.2% and 33.6%, respectively, with an estimated difference (95.2% CI) of 0.2% (-5.6%, 6.0%). Results are summarized in Table 8. The categories presented in Table 8 are not mutually exclusive. The therapeutic equivalence had no apparent relationship to the use of prestudy prophylaxis or baseline risk factors. CANCIDAS(r) had higher favorable response rates than AmBisome(r) for patients with a baseline fungal infection [14/27 (51.9%) and 7/27 (25.9%), respectively]; however the number of patients with baseline infections was small in both groups. Response rates for CANCIDAS(r) and AmBisome(r) for baseline infections caused by Aspergillus species were respectively, 41.7% (5/12) and 8.3% (1/12), and by Candida species were 66.7% (8/12) and 41.7% (5/12). Similarly, the proportion of patients not prematurely discontinued from study therapy due to toxicity or lack of efficacy was higher in the CANCIDAS(r) group (89.7%) compared with the AmBisome(r) group (85.5%). The proportion of patients who discontinued due to a drug-related clinical or drug- related laboratory abnormality was lower among patients treated with CANCIDAS(r) (4.9%) than among patients treated with AmBisome(r) (8.2%). Similar proportions of patients in each group were discontinued due to lack of efficacy (5.4% vs 6.3%). Also absence of breakthrough infections (94.8% vs 95.5%), resolution of fever for 48 hours during neutropenia (41.2% vs 41.4%), and survival to 7-day post-treatment (92.6% vs 89.2%) had similar incidences in both groups. Distribution of Probable or proven Breakthrough Infections is shown in Table 9.

Table 8

Favorable Response Rates in Febrile Neutropenic Patients

^The difference (95.2% CI) in the estimated favourable overall response was: 0.2% (-5.6, 6.0);

^ ^number of patients with favourable response/total number of MITT patients.

Table 9

Distribution of Probable or Proven Breakthrough Infections (MITT Population)

^Invasive fungal Infections were defined according to modified criteria of the European Organization for Research and Treatment

of the Cancer-Mycosis Study Group,

^ ^ in the CANCIDAS(r) group there were 30 breakthrough infections in 29 patients and in the AmBisome(r) group 25 breakthrough infections in 24 patients.

Invasive Candidiasis

Two hundred thirty-nine patients were enrolled in a study to compare CANCIDAS(r) and amphotericin B for the treatment of invasive candidiasis. The most frequent diagnoses were bloodstream infections (candidemia) (83%) and Candida peritonitis (10%). CANCIDAS(r) 50 mg once daily was administered following a 70-mg loading dose, while amphotericin B was administered at 0.6 to 0.7 mg/kg/day to non-neutropenic patients or 0.7 to 1.0 mg/kg/day to neutropenic patients. A favorable response required both symptom resolution and microbiological clearance of the Candida infection. Two hundred twenty-four patients were included in the primary efficacy analysis of response at the end of IV study therapy; favorable response rates for the treatment of invasive candidiasis were comparable for CANCIDAS(r) and amphotericin B. One hundred eighty-five patients who received at least 5 days of IV study therapy were included in a predefined efficacy analysis to support the primary analysis; in this analysis, CANCIDAS(r) was statistically superior to amphotericin B at the end of IV study therapy. Among patients with candidemia, CANCIDAS(r) was comparable to amphotericin B at the end of IV study therapy in both the primary efficacy analysis and in the predefined efficacy analysis to support the primary analysis. Favorable response rates at the end of IV study therapy are shown in Table10.

TABLE 10

Favorable Response Rates to IV Study Therapy Among Patients with Invasive Candidiasis and Candidemia

Patients received CANCIDAS(r) 70 mg on Day 1, then 50 mg daily for the remainder of their treatment.

* * Number of patients with favorable response at the end of IV study therapy/number of patients included in analysis

* * * The primary analysis population consisted of patients who received at least one dose of therapy and had a documented diagnosis of invasive candidiasis.

+

The supporting analysis population consisted of all patients who received at least 5 days of therapy, had a documented diagnosis

of invasive candidiasis, had an end-of-therapy evaluation, and did not commit any protocol violations that interfered with the assessment of efficacy.

++ 95.6% confidence interval.

+++ 95% confidence interval.

Esophageal Candidiasis (and information on oropharyngeal candidiasis)

One Phase III, randomized, double-blind, controlled, non-inferiorty, clinical trial and two small, comparative dose-ranging studies were conducted to evaluate the safety and efficacy of CANCIDAS(r) for the treatment of esophageal candidiasis. The Phase III clinical trial compared CANCIDAS(r) to intravenous fluconazole and the two dose-ranging studies compared different doses of CANCIDAS(r) to amphotericin B. In all three studies, patients were required to have symptoms and microbiological documentation of esophageal candidiasis. Most of the patients randomized in these studies had advanced AIDS (with CD4 counts < 50 cells/mm3). Candida isolates were obtained from esophageal biopsies or brushes in 166 of the 177 patients enrolled in the Phase III clinical trial. One hundred twenty infections were due to C. albicans alone; two to

C. tropicalis alone and the remainder were mixed infections with C. albicans and non-C. albicans species. In the randomized, double-blind study comparing CANCIDAS(r) 50 mg/day versus IV fluconazole 200 mg/day for the treatment of esophageal candidiasis, patients were treated for an average of 9 days (range 7 to 21 days). A favorable overall response required both complete resolution of symptoms and significant endoscopic improvement 5 to 7 days following discontinuation of study therapy. The definition of endoscopic response was based on severity of disease at baseline using a 4 grade scale and required at least a two grade reduction from baseline endoscopic score or reduction to grade 0 for patients with a baseline score of 2 or less. As shown in Table 11, the proportion of patients with a favorable overall response with CANCIDAS(r) was comparable to that seen with fluconazole (81.5% and 85.1%, respectively). The proportion of patients with a favorable symptom response was also comparable (90.1% and 89.4% for CANCIDAS(r) and fluconazole, respectively). In addition, the proportion of patients with a favorable endoscopic response (85.2% and 86.2% for CANCIDAS(r) and fluconazole, respectively) was comparable.

Table 11

Favorable Response Rates for Patients with Esophageal Candidiasis (MITT Analysis)

Number of patients with favorable response/number of patients with data at this time point.

* * Calculated as CANCIDAS(r)-fluconazole. The esophageal candidiasis relapse rates (Table12) at the Day 14 post-treatment visit were similar for the two groups. At the Day 28 post-treatment visit, the group treated with CANCIDAS(r) had a numerically higher incidence of relapse, however, the difference was not statistically significant.

Table 12

Relapse Rates for Patients with Esophageal Candidiasis (MITT Analysis)

Number of patients with favorable response/number of patients with data at this time point.

* * Calculated as CANCIDAS(r)-fluconazole. The results from the two dose-ranging studies corroborate the efficacy of CANCIDAS(r) for the treatment of esophageal candidiasis that was demonstrated in the Phase III study.

Oropharyngeal Candidiasis

Seventy percent (122) of the patients enrolled in the Phase III clinical study also had oropharyngeal candidiasis. A favorable response was defined as complete resolution of all symptoms of oropharyngeal candidiasis and all visible oropharyngeal lesions. The proportion of patients with favorable response was 71.4% for the CANCIDAS(r) group and 83.3% for the fluconazole group (Table 13). The relapse rates at Day 14 and 28 post-treatment (Table14) were statistically significantly greater in the CANCIDAS(r) group compared with the fluconazole group at both dates.

Table 13

Oropharyngeal Candidiasis Response Rates in Patients with Oropharyngeal and Esophageal Candidiasis at Baseline (MITT Analysis)

Number of patients with favorable response/number of patients with data at this time point.

* * Calculated as CANCIDAS(r)-fluconazole.

Table 14

Oropharyngeal Candidiasis Relapse Rates in Patients with Oropharyngeal and Esophageal Candidiasis at Baseline (MITT Analysis)

Number of patients with favorable response/number of patients with data at this time point.

* * Calculated as CANCIDAS(r)-fluconazole.

Invasive Aspergillosis

Patients between the ages of 18 and 80 with invasive aspergillosis were enrolled in an open-label, noncomparative study (n=69) to evaluate the safety, tolerability, and efficacy of CANCIDAS(r). Enrolled patients had previously been refractory to or intolerant of other antifungal therapy(ies). Refractory patients were classified as those who had disease progression or failed to improve despite therapy for at least 7 days with amphotericin B, lipid formulations of amphotericin B, itraconazole, or an investigational azole with reported activity against Aspergillus. Intolerance to previous therapy was defined as a doubling of creatinine (or creatinine > 2.5 mg/dL while on therapy), other acute reactions, or infusion-related toxicity. To be included in the study, patients with pulmonary disease must have had definite (positive tissue histopathology or positive culture from tissue obtained by an invasive procedure) or probable (positive radiographic or computed tomographic evidence with supporting culture from bronchoalveolar lavage or sputum, galactomannan enzyme-linked immunosorbent assay, and/or polymerase chain reaction) invasive aspergillosis. Patients with extrapulmonary disease had to have definite invasive aspergillosis. The definitions were modeled after the Mycoses Study Group Criteria. * * Patients were administered a single 70 mg loading dose of CANCIDAS(r) and subsequently dosed with 50 mg daily. The mean duration of therapy was 33.7 days, with a range of 1 to 162 days. An independent expert panel evaluated patient data, including diagnosis of invasive aspergillosis, response and tolerability to previous antifungal therapy, treatment course on CANCIDAS(r), and clinical outcome. A favorable response was defined as either complete resolution (complete response) or clinically meaningful improvement (partial response) of all signs and symptoms and attributable radiographic findings. Stable, nonprogressive disease was considered to be an unfavorable response. Among the 69 patients enrolled in the study, 63 met entry diagnostic criteria and had outcome data; and of these, 52 patients received treatment for >7 days. Fifty-three (84%) were refractory to previous antifungal therapy and 10 (16%) were intolerant. Forty-five patients had pulmonary disease and 18 had extrapulmonary disease. Underlying conditions were hematologic malignancy (n=24), allogeneic bone marrow transplant or stem cell transplant (n=18), organ transplant (n=8), solid tumor (n=3), or other conditions (n=10). All patients in the study received concomitant therapies for their other underlying conditions. Eighteen patients received tacrolimus and CANCIDAS(r) concomitantly, of whom 8 also received mycophenolate mofetil. Overall, the expert panel determined that 41% (26/63) of patients receiving at least one dose of CANCIDAS(r) had a favorable response (i.e. complete or partial response). For those patients who received >7 days of therapy with CANCIDAS(r), 50% (26/52) had a favorable response. The favorable response rates for patients who were either refractory to or intolerant of previous therapies were 36% (19/53) and 70% (7/10), respectively. The response rates among patients with pulmonary disease and extrapulmonary disease were 47% (21/45) and 28% (5/18), respectively.

* * Denning DW, Lee JY, Hostetler JS, et al. NIAID Mycoses Study Group multicenter trial of oral itraconazole therapy for invasive aspergillosis. Am J Med 1994; 97:135-44.

DETAILED PHARMACOLOGY

Pharmacokinetics Absorption

Absorption is not relevant since caspofungin acetate is administered intravenously.

Distribution

Plasma concentrations of caspofungin decline in a polyphasic manner following single 1-hour IV infusions. A short a-phase occurs immediately post-infusion, followed by a b-phase (half-life of 9 to 11 hours) that characterizes much of the profile and exhibits clear log-linear behavior from 6 to 48 hours post-dose during which the plasma concentration decreases by an order of magnitude. An additional, longer half-life phase, g-phase, also occurs with a half-life of 27 hours. Distribution, rather than excretion or biotransformation, is the dominant mechanism influencing plasma clearance. Caspofungin is extensively bound to albumin (~97%), and distribution into red blood cells is minimal. Mass balance results showed that approximately 92% of the [3H] label was found in tissues 36 to 48 hours after a single 70 mg dose of [3H] caspofungin acetate. There is little excretion or biotransformation of caspofungin during the first 30 hours after administration.

Metabolism

Caspofungin is slowly metabolized by hydrolysis and N-acetylation. Caspofungin also undergoes spontaneous chemical degradation to an open-ring peptide compound. At later time points (>= 5 days post-dose), there is a low level (<= 7 pmol/mg protein, or <= 1.3% of administered dose) of covalent binding of radiolabel in plasma following single-dose administration of [3H] caspofungin acetate, which may be due to two reactive intermediates formed during the chemical degradation of caspofungin. Additional metabolism involves hydrolysis into constitutive amino acids and their degradates, including dihydroxyhomotyrosine and N-acetyl- dihydroxyhomotyrosine. These two tyrosine derivatives are found only in urine, suggesting rapid clearance of these derivatives by the kidneys.

Elimination

Two single-dose radiolabeled pharmacokinetic studies were conducted. In one study, plasma, urine, and feces were collected over 27 days, and in the second study plasma was collected over 6 months. Approximately 75% of the radioactivity was recovered: 41% in urine and 34% in feces. Plasma concentrations of radioactivity and of caspofungin were similar during the first 24 to hours post-dose; thereafter drug levels fell more rapidly. In plasma, caspofungin concentrations fell below the limit of quantitation after 6 to 8 days post-dose, while radiolabel fell below the limit of quantitation at 22.3 weeks post-dose. A small amount of caspofungin is excreted unchanged in urine (~1.4% of dose). Renal clearance of parent drug is low (~0.15 mL/min; 2.5 uL/s *).

*International units

Special Populations

Gender

Plasma concentrations of caspofungin in healthy men and women were similar following a single 70 mg dose. After 13 daily 50 mg doses, caspofungin plasma concentrations in women were elevated slightly (approximately 20%) relative to men. No dosage adjustment is necessary based on gender.

Race

No clinically significant differences in the pharmacokinetics of caspofungin were seen among Caucasians, Blacks and Hispanics. No dosage adjustment is necessary on the basis of race.

Hepatic Insufficiency

Plasma concentrations of caspofungin after a single 70 mg dose (n=16) in patients with mild hepatic insufficiency (Child-Pugh score 5 to 6) were increased by approximately 55% compared to healthy historical control subjects. In a 14-day multiple-dose study (n=8) (70 mg on Day 1 followed by 50 mg daily thereafter), plasma concentrations in patients with mild hepatic insufficiency were increased modestly (19 to 25%) on Days 7 and 14 relative to healthy control subjects. No dosage adjustment is recommended for patients with mild hepatic insufficiency. Patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9) who received a single 70 mg dose of CANCIDAS(r) (caspofungin acetate) had an average plasma caspofungin increase of 76% compared to control subjects. A dosage reduction is recommended for patients with moderate hepatic insufficiency (see DOSAGE AND ADMINISTRATION, Hepatic Insufficiency). There is no clinical experience in patients with severe hepatic insufficiency (Child-Pugh score >9).

Renal Insufficiency

In a clinical study (n=36) of single 70 mg doses, caspofungin pharmacokinetics were similar in volunteers with mild renal insufficiency (creatinine clearance 50 to 80 mL/min; 0.83 to 1.33 mL/s *) and control subjects. After single-dose administration, caspofungin AUC plasma concentration increased by 30 to 49% in patients with moderate (creatinine clearance 31 to mL/min; 0.52 to 0.82 mL/s *), advanced (creatinine clearance 5 to 30 mL/min; 0.08 to 0.50 mL/s *), and end-stage (creatinine clearance <10 mL/min [<0.17 mL/s *] and dialysis dependent) renal insufficiency. However, in patients with invasive candidiasis (n=75) or invasive aspergillosis (n=69) who received multiple daily doses of CANCIDAS(r) 50 mg, there was no significant effect of mild to end-stage renal impairment on caspofungin concentrations. No dosage adjustment is necessary for patients with renal insufficiency. Caspofungin is not dialyzable, thus supplementary dosing is not required following hemodialysis.

*International units

MICROBIOLOGY

Activity in vitro

Standardized susceptibility testing methods for b(1,3)-D-glucan synthesis inhibitors have not been established, and results of susceptibility studies do not correlate with clinical outcome. Caspofungin has in vitro activity against Aspergillus species (including Aspergillus fumigatus,

Aspergillus flavus, Aspergillus niger, Aspergillus nidulans, Aspergillus terreus, and Aspergillus candidus) and Candida species (including Candida albicans, Candida dubliniensis, Candida

glabrata, Candida guilliermondii, Candida kefyr, Candida krusei, Candida lipolytica, Candida lusitaniae, Candida parapsilosis, Candida rugosa, and Candida tropicalis). Susceptibility testing was performed according to a modification of the National Committee for Clinical Laboratory Standards (NCCLS) method M38-P for Aspergillus species and method M27-A for Candida species.

Activity in vivo

Caspofungin, administered parenterally to immune-competent and immune-suppressed animals with disseminated infections of Aspergillus and Candida for which the endpoints were prolonged survival of infected animals (Aspergillus and Candida) and clearance of fungi from target organs (Candida). Caspofungin was also active in immunodeficient animals after disseminated infection with C. glabrata, C. krusei, C. lusitaniae, C. parapsilosis, or C. tropicalis in which the endpoint was clearance of Candida from target organs. In a lethal, rat pulmonary-infection model with A. fumigatus, caspofungin was highly active in the prevention and treatment of pulmonary aspergillosis.

Drug Resistance

Mutants of Candida with reduced susceptibility to caspofungin have been identified in some patients during treatment. MIC values for caspofungin should not be used to predict clinical outcome, since a correlation between MIC values and clinical outcome has not been established. The relevance to clinical outcome is unknown. In vitro drug resistance development to caspofungin in Aspergillus species has not been studied. In limited clinical experience, drug resistance in patients with invasive aspergillosis has not been observed. The incidence of drug resistance by various clinical isolates of Candida and Aspergillus species is unknown. Resistance development to caspofungin by Candida species occurs very rarely in the laboratory. Although increased MIC values could not be induced in Candida after serial passage in culture media containing caspofungin, prolonged exposure in a mouse model at subtherapeutic doses (approximately 1% or less of the human mg equivalent dose) suggests that there is a potential for resistance to develop.

Cross-resistance

Caspofungin acetate is active against strains of Candida with intrinsic or acquired resistance to fluconazole, amphotericin B, or flucytosine consistent with their different mechanisms of action. There are no data regarding the cross-resistance of caspofungin and other antifungal agents in treatment against Aspergillus species.

Drug Interactions

Studies in vitro and in vivo of caspofungin acetate, in combination with amphotericin B, demonstrate no antagonism of antifungal activity against A. fumigatus.

TOXICOLOGY

Animal Toxicology Acute Toxicity

The approximate intravenous lethal dose 50 (LD50) for female (male) mice and rats was calculated as 19(27) and 38 mg/kg, respectively.

Chronic Toxicity

Several treatment-related changes were noted in intravenous toxicity studies in rats and Rhesus monkeys. In these studies, signs of histamine release were observed in rats, serum transaminase levels were increased in monkeys, and injection-site irritation was seen in both species. In 5- and 14-week intravenous toxicity studies in rats, 5 mg/kg/day produced signs of histamine release consisting of hyperemia and swelling of the extremities, sluggish movement or ataxia, and recumbency. These signs occurred only during the first 7 to 9 days of dosing presumably due to endogenous histamine depletion. Overall, in the rat studies, 2 mg/kg/day was established as the no-effect level for histamine release. No signs of histamine release were reported in 5-, 14-, and 27-week intravenous dosing studies in monkeys. In ancillary pharmacology studies, a 20-minute infusion at 8 mg/kg produced no adverse effects in monkeys; however, bolus injections of 5 or 8 mg/kg did produce signs of histamine release. Similar signs of histamine release that were reversed upon injection of cyproheptadine were produced with structural analogs of caspofungin in monkeys. In 5-, 14- , and 27-week intravenous toxicity studies in monkeys, ALT and/or AST levels were increased slightly to moderately, but these levels returned to baseline or remained slightly elevated over the course of the studies. The increases in serum transaminase values did not always correlate with microscopic evidence of hepatic damage (subcapsular necrosis). However, in a 5-week intravenous toxicity study in monkeys, several animals in the mid- and high-dose groups had correlating microscopic subscapular necrosis. During the 5-, 14-, and 27-week intravenous toxicity studies in rats and monkeys, clinical and histopathological signs of injection-site irritation were observed. Concentration-dependent injection-site irritation was minimized by pre- and post-dose flushing of catheter lines. Overall, the no-effect dosage level for irritation at the injection site in rats was 1.8 mg/kg/day (0.18 mg/mL), and in monkeys it was 3 mg/kg/day (0.25 mg/mL) with effective pre- and post- dose flushing of catheter lines.

Carcinogenicity

No long-term studies in animals have been performed to evaluate the carcinogenic potential of caspofungin.

Mutagenesis

Caspofungin acetate was evaluated in the following series of in vitro assays and found to be neither mutagenic nor genotoxic: bacterial (Ames) and mammalian cell (V79 Chinese hamster lung fibroblasts) mutagenesis assays, the alkaline elution/rat hepatocyte DNA strand break test, and the chromosomal aberration assay in Chinese hamster ovary cells. Additionally, in the in vivo mouse bone marrow chromosomal test, caspofungin acetate was not genotoxic at doses up to 12.5 mg/kg, administered intravenously.

Reproduction and Teratology

Female rats administered 0.5, 2, and 5 mg/kg/day of caspofungin acetate IV for 16 days prior to cohabitation, during cohabitation, and through gestation Day 7 showed no drug-related effects on mating performance, fecundity, fertility, or embryonic survival. Male rats treated intravenously with 0.5, 2, and 5 mg/kg/day (maximum dosage tested) for 28 days prior to mating showed no effect on fertility. In rats, caspofungin caused decreases in fetal body weights and an increase in the incidence of incomplete ossification of the skull and torso at a maternally toxic dose of 5 mg/kg/day, which resulted in a plasma exposure approximately 1.5 times the plasma exposure seen in humans administered 70 mg. In addition, at this same maternally toxic dose, there was an increase in the incidence of cervical rib in rats. There were no developmental effects at a dose of 2 mg/kg/day. In rabbits, there were no treatment-related external, visceral, or skeletal fetal morphological findings in an IV toxicity study where caspofungin acetate was administered to pregnant rabbits at doses of 1, 3, and 6 mg/kg/day on gestation Days 7 through 20. Therefore, the no-effect level for developmental toxicity is >6 mg/kg/day. The no-effect level for maternal toxicity (based on minimal decreases in average maternal body weight gain and food consumption) was 3 mg/kg/day. Plasma exposures of approximately 1.5 times the human plasma exposure occurred in pregnant rabbits when administered caspofungin 5 mg/kg/day. Caspofungin has been shown to cross the placental barrier in animal studies. In two rat and one rabbit reproductive toxicity studies, incidental findings included slight increases in the percent of peri-implantation and post-implantation loss relative to concurrent controls but within the historical control range. These observations were considered unrelated to treatment.

BIBLIOGRAPHY

1. Bartizal K, Gill CJ, Abruzzo GK, Flattery AM, Kong L, Scott PM, Smith JG, Leighton CE, Bouffard A, Dropinski JF, Balkovec J. In vitro preclinical evaluation studies with the echinocandin antifungal MK-0991 (L-743,872). Antimicrob Agents Chemother 1997; 41(11):2326-32.

2. Del Poeta M, Schell WA, Perfect JR. In vitro antifungal activity of pneumocandin L- 743,872 against a variety of clinically important molds. Antimicrob Agents Chemother 1997; 41(8):1835-6.

3. De Lucca AJ, Walsh TJ. Antifungal peptides: Novel therapeutic compounds against emerging pathogens. Antimicrob Agents Chemother 1999; 45(1):1-11.

4. Espinel-Ingroff A. Comparison of in vitro activities of the new triazole SCH56592 and the echinocandins MK-0991 (L-743,872) and LY303366 against opportunistic filamentous and dimorphic fungi and yeasts. J Clin Microbiol 1998; 36(10):2950-6.

5. Kurtz MB, Heath IB, Marrinan J, Dreikorn S, Onishi J, Douglas C. Morphological effects of lipopeptides against Aspergillus fumigatus correlate with activities against (1,3)- -D-glucan synthase. Antimicrob Agents Chemother 1994; 38(7):1480-9.

6. Pfaller MA, Marco F, Messer SA, Jones RN. In vitro activity of two echinocandin derivatives, LY303366 and MK-0991 (L-743,872), against clinical isolates of Aspergillus, Fusarium, Rhizopus, and other filamentous fungi. Diagn Microbiol Infect Dis 1998; 30(4):251-5.

7. Keating GM, Jarvis B. Caspofungin. Drugs 2001; 61(8):1121-9.

8. Lomaestro BM. Caspofungin. An echinocandin antifungal for the treatment of invasive aspergillosis. Formulary 2001; 36:427-36.

9. Villanueva A, Arathoon EG, Gotuzzo E, Berman RS, DiNubile MJ, Sable CA. A randomized double-blind study of caspofungin versus amphotericin for the treatment of candidal esophagitis. Clin Infect Dis 2001; 33(9):1529-35.

10. Arathoon EG, Gotuzzo E, Noriega M, Berman RS, DiNubile M, Sable CA. Randomized, double-blind, multicenter study of caspofungin versus amphotericin B for treatment of oropharyngeal and esophageal candidiases. Antimicrob. Agents Chemother. 2002; 46: 451- 7.

11. Mora-Duarte J, Betts R, Rotstein C, Lopes Colombo A, Thompson-Moya L, Smietana J, Lupinacci R, Sable C, Kartsonis N, Perfect J, Caspofungin Invasive Candidiasis Study Group. Comparison of Caspofungin and Amphotericin B for Invasive Candidiasis. N Engl J Med 2002; 347(25):2020-9.

PART III: CONSUMER INFORMATION

CANCIDAS(r)

caspofungin acetate for injection

This leaflet is part III of a three-part "Product Monograph" published when CANCIDAS(r) was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about CANCIDAS(r). Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

Your doctor has prescribed CANCIDAS(r) to treat one of several types of fungal infections described below.

A serious fungal infection called invasive candidiasis. The infection is caused by fungal (yeast) cells called Candida. These yeast cells are normally found in the digestive tract, and do not cause an infection unless they enter the bloodstream (in which case the infection is referred to as candidemia) or other tissues or organs, such as the lining of the abdomen (peritonitis), the kidneys, the liver, bones, muscles, joints, spleen, or eyes. Persons at high risk for invasive candidiasis include surgical patients and those whose immune systems are deficient.

Fungal infections of the mouth, back of the throat, and the food tube connecting the mouth to the stomach. These infections are called oropharyngeal candidiasis (mouth and back of the throat) or esophageal (food tube) candidiasis. The infection is also caused by Candida. Healthy individuals usually have Candida in their mouth and throat without any ill effects. An infection occurs when the body's resistance to disease is lowered.

A serious fungal infection called invasive aspergillosis.

Invasive aspergillosis is a serious infection of the nose, nasal sinuses, and lungs. This infection may spread to other parts of the body. This kind of infection is caused by a number of

common fungi found in the environment called Aspergillus.

Most Aspergillus fungal infections begin in the respiratory system (in the nose, sinuses, or lungs) because the spores of the fungus are found in the air we breathe every day. In most healthy individuals, the natural ability to fight disease destroys the spores and removes them from the body. Some medical conditions lower the body's resistance to diseases. Also, certain medications prescribed for patients who are organ or bone marrow recipients lower the body's resistance to diseases. These are the patients who are most likely to develop these infections.

Also, your doctor may suspect that you have a fungal infection in the following situation, and prescribe

CANCIDAS(r) to treat it. Chemotherapy or other medical treatments or conditions can lower the body's resistance to disease by lowering counts of certain white blood cells. If you have persistent fever following chemotherapy or under other conditions as noted above, and your fever is not reduced by treatment with an antibiotic, you may have a fungal infection.

What it does:

CANCIDAS(r) is an antifungal drug that interferes with the production of a component (glucan polysaccharide) of the fungal

cell wall that is necessary if the fungus is to continue living and growing. Fungal cells exposed to CANCIDAS(r) have incomplete or defective cell walls, making them fragile and unable to grow.

When it should not be used:

Who should not receive CANCIDAS(r)?

CANCIDAS(r) should not be administered to you if you are allergic to any of its components (see "What the important

nonmedicinal ingredients are").

Use in children:

CANCIDAS(r) should not be used in patients under 18 years of age.

What the medicinal ingredient is:

Caspofungin acetate

What the important nonmedicinal ingredients are:

Glacial acetic acid

Mannitol

Sodium hydroxide Sucrose

This is a complete listing of all nonmedicinal ingredients.

What dosage forms it comes in:

Powder for injection, 50, 70 mg vials/cartons

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions:

The use of CANCIDAS(r) and cyclosporine at the same time is not recommended

Use in pregnancy and breast-feeding:

CANCIDAS(r) has not been studied in pregnant women. CANCIDAS(r) should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Women receiving CANCIDAS(r) should not breast-feed.

Consumer Information - DRUG(r) Page 39 of 41

Use in patients with Hepatic Insufficiency:

Some patients with liver problems may require a dosage adjustment. Be sure to tell you doctor if you have had or now have liver problems.

BEFORE you use CANCIDAS(r) talk to your doctor or pharmacist if:

• You are taking cyclosporine

• In addition, you should always tell your doctor about all other medications that you are taking or plan to take, including those obtained without a prescription. It is particularly important for your doctor to know if you are taking certain anti-HIV drugs (including efavirenz or nevirapine), the antiseizure (epilepsy) medications phenytoin and carbamazepine, the steroid dexamethasone, the antibiotic rifampin, and the immunosuppressant tacrolimus.

• You have liver problems

• You are pregnant

• You are breast feeding

• You are allergic to any component of CANCIDAS(r)

Missed Dose:

If you are concerned that you may have missed a dose, contact your doctor immediately.

No dosage adjustment is necessary for the elderly.

No dosage adjustment is necessary for patients with reduced kidney function.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

INTERACTIONS WITH THIS MEDICATION

Drugs that may interact with CANCIDAS(r) include

Carbamazepine

Cyclosporine

Dexamethasone

Efavirenz

Nevirapine

Phenytoin

Rifampin

Tacrolimus

PROPER USE OF THIS MEDICATION

Usual Adult dose:

The treatment schedule and dosage will be set by your doctor, who will monitor your response and condition. CANCIDAS(r) should be administered once daily by slow intravenous infusion of approximately 1 hour.

A single 70-mg loading dose should be administered on Day 1, followed by 50 mg daily thereafter.

If you are treated for fungal infections of the mouth, back of the throat, and the food tube connecting the mouth to the stomach, 50 mg should be administered on Day 1 and daily thereafter.

Overdose:

If you are concerned that you may have been given too much CANCIDAS(r), contact your doctor immediately.

Any medicine may have unintended or undesirable effects, so- called side effects.

The most common medication-related undesirable effects are fever and vein irritations at the infusion site (itching, redness, swelling, or clotting).

Other reported medication-related undesirable effects include: headache, pain, chills, rapid heartbeat, sweating, nausea, diarrhea, vomiting, flushing, rash, itching, trouble breathing, swelling of the hands, ankles, or feet, impaired liver function, and alterations in some laboratory blood tests. Life-threatening allergic reactions have been reported rarely during administration of CANCIDAS(r).

Other side effects may also occur rarely; and, as with any prescription medication, some side effects may be serious. Ask your doctor or pharmacist for more information. Tell your doctor [or pharmacist] promptly about these or any other unusual symptoms.

This is not a complete list of side effects. For any unexpected effects while taking CANCIDAS(r) contact your doctor or pharmacist.

HOW TO STORE IT

Unopened vials of CANCIDAS(r) should be stored refrigerated at 2degC to 8degC (36degF to 46degF).

Reconstituted CANCIDAS(r) should be used immediately because it does not contain any preservatives to prevent bacterial contamination. Only a trained healthcare professional who has access to the complete directions provided with each vial can properly prepare this medication for use.

REPORTING SUSPECTED SIDE EFFECTS

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals can be found at: http://www.merckfrosst.com

or by contacting the sponsor, Merck Frosst Canada Ltd., at: 1-800-567-2594,

This leaflet was prepared by Merck Frosst Canada Ltd. Last revised: January 26, 2006

To monitor drug safety, Health Canada collects information on serious and unexpected effects of drugs. If you suspect you have had a serious or unexpected reaction to this vaccine you may notify Health Canada by:

Toll-free telephone: 1-866-234-2345

Toll-free fax: 1-866-678-6789 By email: cadrmp @hc-sc.gc.ca

By regular mail: National AR Centre

Marketed Health Products Safety and Effectiveness Information Division

Marketed Health Products Directorate Tunney's Pasture, AL 0701C

Ottawa ON K1A 0K9

or Merck Frosst Canada Ltd. by: Toll-free telephone: 1-800-567-2594

Toll-free fax: 1-877-428-8675 By regular mail:

Merck Frosst Canada Ltd.

P.O. Box 1005

Pointe-Claire - Dorval, QC H9R 4P8

NOTE: Before contacting Health Canada or Merck Frosst, you should contact your physician or pharmacist.

CANCIDAS(r) is a Registered Trademark of Merck & Co., Inc. Used under license.