Caspofungin acetate for Injection is indicated in adults and pediatric patients (3 months of age and older) for:

• Empirical therapy for presumed fungal infections in febrile, neutropenic patients.

• Treatment of candidemia and the following Candida infections: intra-abdominal abscesses,

  peritonitis and pleural space infections.

• Treatment of esophageal candidiasis.

• Treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies.

1. Important Administration Instructions for Use in All Patients

   Administer Caspofungin acetate for Injection by slow intravenous (IV) infusion over approximately 1 hour. Do not administer Caspofungin acetate for Injection by IV bolus administration.

    

   Posology

   Recommended Dosage in Adult Patients [18 years of age and older]

   The dosage and duration of Caspofungin acetate for Injection treatment for each indication are as follows:

   Empirical Therapy for Presumed Fungal Infections in Febrile Neutropenic Patients Administer a single 70-mg loading dose on Day 1, followed by 50 mg once daily thereafter. Duration of treatment should be based on the patient's clinical response. Continue empirical therapy until resolution of neutropenia. In general, treat patients found to have a fungal infection for a minimum of 14 days after the last positive culture and continue treatment 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.

   Candidemia and Other Candida Infections

   Administer a single 70-mg loading dose on Day 1, followed by 50 mg once daily thereafter. Duration of treatment should be dictated by the patient's clinical and microbiological response. In general, continue antifungal therapy for at least 14 days after the last positive culture. Patients with neutropenia who remain persistently neutropenic may warrant a longer course of therapy pending resolution of the neutropenia.

   Esophageal Candidiasis

   The dose is 50 mg once daily for 7 to 14 days after symptom resolution. A 70-mg loading dose has not been studied for this indication. Because of the risk of relapse of oropharyngeal candidiasis in patients with HIV infections, suppressive oral therapy could be considered.

   Invasive Aspergillosis

   Administer a single 70-mg loading dose on Day 1, followed by 50 mg once daily thereafter. Duration of treatment should be based upon the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response.

   Recommended Dosing in Pediatric Patients [3 months to 17 years of age]

   For all indications, administer a single 70 mg/m² loading dose on Day 1, followed by 50 mg/m² once daily thereafter. The maximum loading dose and the daily maintenance dose should not

    

   exceed 70 mg, regardless of the patient's calculated dose. Dosing in pediatric patients (3 months to 17 years of age) should be based on the patient's body surface area (BSA) as calculated by the Mosteller Formula.

   

    

    

   Following calculation of the patient's BSA, the loading dose in milligrams should be calculated as BSA (m²) × 70 mg/m². The maintenance dose in milligrams should be calculated as BSA (m²) × 50 mg/m².

   Duration of treatment should be individualized 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 70 mg).

   Dosage Adjustments in Patients with Hepatic Impairment

   Adult patients with mild hepatic impairment (Child-Pugh score 5 to 6) do not need a dosage adjustment.

   For adult patients with moderate hepatic impairment (Child-Pugh score 7 to 9), Caspofungin acetate for Injection 35 mg once daily is recommended based upon pharmacokinetic data (see section 5.2) with a 70-mg loading dose administered on Day 1 where appropriate. There is no clinical experience in adult patients with severe hepatic impairment (Child-Pugh score greater than 9) and in pediatric patients with any degree of hepatic impairment.

   Dosage Adjustments in Patients Receiving Concomitant Inducers of Hepatic CYP Enzymes

   Adult Patients:

   Adult patients on rifampin should receive 70 mg of Caspofungin acetate for Injection once daily. When Caspofungin acetate for Injection is coadministered to adult patients with other inducers of hepatic CYP enzymes such as nevirapine, efavirenz, carbamazepine, dexamethasone, or phenytoin, administration of a daily dose of 70 mg of Caspofungin acetate for Injection should be considered (see section 4.5).

    

   Pediatric Patients:

   Pediatric patients on rifampin should receive 70 mg/m² of Caspofungin acetate for Injection daily (not to exceed an actual daily dose of 70 mg). When Caspofungin acetate for Injection is co-administered to pediatric patients with other inducers of hepatic CYP enzymes, such as efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, a Caspofungin acetate for Injection dose of 70 mg/m² once daily (not to exceed 70 mg) should be considered (see section 4.5).

Hypersensitivity

Anaphylaxis and other hypersensitivity reactions have been reported during administration of Caspofungin acetate for Injection.

Possible histamine-mediated adverse reactions, including rash, facial swelling, angioedema, pruritus, sensation of warmth or bronchospasm have been reported.

Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some with a fatal outcome, have been reported with use of Caspofungin acetate for Injection (see section 4.6)

Discontinue Caspofungin acetate for Injection at the first sign or symptom of a hypersensitivity reaction and administer appropriate treatment.

Hepatic Effects

Laboratory abnormalities in liver function tests have been seen in healthy volunteers and in adult and pediatric patients treated with Caspofungin acetate for Injection. In some adult and pediatric patients with serious underlying conditions who were receiving multiple concomitant medications with Caspofungin acetate for Injection, isolated cases of clinically significant hepatic dysfunction, hepatitis, and hepatic failure have been reported; a causal relationship to Caspofungin acetate for Injection has not been established. Monitor patients who develop abnormal liver function tests during Caspofungin acetate for Injection therapy for evidence of worsening hepatic function and evaluated for risk/benefit of continuing Caspofungin acetate

for Injection therapy.

Elevated Liver Enzymes During Concomitant Use with Cyclosporine

Elevated liver enzymes have occurred in patients receiving Caspofungin acetate for Injection and cyclosporine concomitantly. Only use Caspofungin acetate for Injection and cyclosporine in those patients for whom the potential benefit outweighs the potential risk. Patients who develop abnormal liver enzymes during concomitant therapy should be monitored and the risk/benefit of continuing therapy should be evaluated.

Cyclosporine: In two adult clinical studies, cyclosporine (one 4 mg/kg dose or two 3 mg/kg doses) increased the AUC of Caspofungin acetate for Injection. Caspofungin acetate for Injection did not increase the plasma levels of cyclosporine.

There were transient increases in liver ALT and AST when Caspofungin acetate for Injection and cyclosporine were coadministered. Monitor patients who develop abnormal liver enzymes during concomitant therapy and evaluate the risk/benefit of continuing therapy (see section 4.4 and 5).

Tacrolimus: For patients receiving Caspofungin acetate for Injection and tacrolimus, standard monitoring of tacrolimus trough whole blood concentrations and appropriate tacrolimus dosage adjustments are recommended.

Inducers of Hepatic CYP Enzymes

Rifampin: Rifampin is a potent CYP3A4 inducer and concomitant administration with Caspofungin acetate for Injection is expected to reduce the plasma concentrations of Caspofungin acetate for Injection. Therefore, adult patients on rifampin

should receive 70 mg of Caspofungin acetate for Injection daily and pediatric patients on rifampin should receive 70 mg/m² of Caspofungin acetate for Injection daily (not to exceed an actual daily dose of 70 mg) (see section 4.2 and 5.2).

Other Inducers of Hepatic CYP Enzymes

Adults: When Caspofungin acetate for Injection is co-administered to adult patients with other inducers of hepatic CYP enzymes, such as efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, administration of a daily dose of 70 mg of Caspofungin acetate for Injection should be considered (see section 4.2 and 5.2).

Pediatric Patients: When Caspofungin acetate for Injection is co-administered to pediatric patients with other inducers of hepatic CYP enzymes, such as efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, administration of a daily dose of 70 mg/m² Caspofungin acetate for Injection (not to exceed an actual daily dose of 70 mg) should be considered (see section 4.2 and 5.2).

Pregnancy

There are no adequate and well-controlled studies with the use of Caspofungin acetate for Injection in pregnant women. In animal studies, caspofungin caused embryofetal toxicity, including increased resorptions, increased peri-implantation loss, and incomplete ossification at multiple fetal sites. Caspofungin acetate for Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In offspring born to pregnant rats treated with caspofungin at doses comparable to the human dose based on body surface area comparisons, there was incomplete ossification of the skull and torso and increased incidences of cervical rib. There was also an increase in resorptions and peri-implantation losses. In pregnant rabbits treated with caspofungin at dose comparable to 2 times the human dose based on body surface area comparisons, there was an increased incidence of incomplete ossification of the talus/calcaneus in offspring and increases in fetal resorptions. Caspofungin crossed the placenta in rats and rabbits and was detectable in fetal plasma.

Nursing Mothers

It is not known whether caspofungin is present in human milk. Caspofungin was found in the milk of lactating, drug-treated rats. Because many drugs are excreted in human milk, caution should be exercised when caspofungin is administered to a nursing woman.

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

The following serious adverse reactions are discussed in detail in another section of the labeling:

·       Hypersensitivity [see Special warnings and precautions for use – section 4.4]

·       Hepatic Effects [see Special warnings and precautions for use – section 4.4]

·       Elevated Liver Enzymes During Concomitant Use with Cyclosporine [see Interaction with other medicinal products and other forms of interaction – section 4.5]

Clinical Trials Experience

·       Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of caspofungin cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice

Adults

The overall safety of Caspofungin acetate for Injection was assessed in 1865 adult individuals who received single or multiple doses of Caspofungin acetate for Injection : 564 febrile, neutropenic patients (empirical therapy study); 382 patients with candidemia and/or intra-abdominal abscesses, peritonitis, or pleural space infections (including 4 patients with chronic disseminated candidiasis); 297 patients with esophageal and/or oropharyngeal candidiasis; 228 patients with invasive aspergillosis; and 394 individuals in phase I studies. In the empirical therapy study patients had undergone hematopoietic stem-cell transplantation or chemotherapy. In the studies involving patients with documented Candida infections, the majority of the patients had serious underlying medical conditions (e.g., hematologic or other malignancy, recent major surgery, HIV) requiring multiple concomitant medications. Patients in the noncomparative Aspergillus studies often had serious predisposing medical conditions (e.g., bone marrow or peripheral stem cell transplants, hematologic malignancy, solid tumors or organ transplants) requiring multiple concomitant medications.

Empirical Therapy for Presumed Fungal Infections in Febrile Neutropenic Patients

In the randomized, double-blinded empirical therapy study, patients received either Caspofungin acetate for Injection 50 mg/day (following a 70-mg loading dose) or AmBisome (amphotericin B liposome for injection, 3 mg/kg/day). In this study clinical or laboratory hepatic adverse reactions were reported in 39% and 45% of patients in the Caspofungin acetate for Injection and AmBisome groups, respectively. Also reported was an isolated, serious adverse reaction of hyperbilirubinemia. Adverse reactions occurring in 7.5% or greater of the patients in either treatment group are presented in Table 1.

Table 1: Adverse Reactions Among Patients with Persistent Fever and Neutropenia Incidence 7.5% or greater for at Least One Treatment Group

Within any system organ class, individuals may experience more than 1 adverse reaction.

* 70 mg on Day 1, then 50 mg once daily for the remainder of treatment; daily dose was increased to 70 mg for 73 patients.

^† 3 mg/kg/day; daily dose was increased to 5 mg/kg for 74 patients.

The proportion of patients who experienced an infusion-related adverse reaction (defined as a systemic event, such as pyrexia, chills, flushing, hypotension, hypertension, tachycardia, dyspnea, tachypnea, rash, or anaphylaxis, that developed during the study therapy infusion and one hour following infusion) was significantly lower in the group treated with Caspofungin acetate for Injection (35%) than in the group treated with AmBisome (52%).

To evaluate the effect of Caspofungin acetate for Injection and AmBisome on renal function, nephrotoxicity was defined as doubling of serum creatinine relative to baseline or an increase of greater than or equal to 1 mg/dL in serum creatinine if baseline serum creatinine was above the upper limit of the normal range. Among patients whose baseline creatinine clearance was greater than 30 mL/min, the incidence of nephrotoxicity was significantly lower in the group treated with Caspofungin acetate for Injection (3%) than in the group treated with AmBisome (12%).

Candidemia and Other Candida Infections

In the randomized, double-blinded invasive candidiasis study, patients received either Caspofungin acetate for Injection 50 mg/day (following a 70-mg loading dose) or amphotericin B 0.6 to 1 mg/kg/day. Adverse reactions occurring in 10% or greater of the patients in either treatment group are presented in Table 2.

Table 2: Adverse Reactions Among Patients with Candidemia or Other Candida Infections Incidence 10% or Greater for at Least One Treatment Group

Within any system organ class, individuals may experience more than 1 adverse reaction.

* Intra-abdominal abscesses, peritonitis and pleural space infections.

† Patients received Caspofungin acetate for Injection 70 mg on Day 1, then 50 mg once daily for the remainder of their treatment.

The proportion of patients who experienced an infusion-related adverse reaction (defined as a systemic event, such as pyrexia, chills, flushing, hypotension, hypertension, tachycardia, dyspnea, tachypnea, rash, or anaphylaxis, that developed during the study therapy infusion and one hour following infusion) was significantly lower in the group treated with Caspofungin acetate for Injection (20%) than in the group treated with amphotericin B (49%).

To evaluate the effect of Caspofungin acetate for Injection and amphotericin B on renal function, nephrotoxicity was defined as doubling of serum creatinine relative to baseline or an increase of greater than or equal to 1 mg/dL in serum creatinine if baseline serum creatinine was above the upper limit of the normal range. In a subgroup of patients whose baseline creatinine clearance was greater than 30 mL/min, the incidence of nephrotoxicity was significantly lower in the group treated with Caspofungin acetate for Injection than in the group treated with amphotericin B.

In a second randomized, double-blinded invasive candidiasis study, patients received either Caspofungin acetate for Injection 50 mg/day (following a 70-mg loading dose) or Caspofungin acetate for Injection 150 mg/day. The proportion of patients who experienced any adverse reaction was similar in the 2 treatment groups; however, this study was not large enough to detect differences in rare or unexpected adverse reactions. Adverse reactions occurring in 5 % or greater of the patients in either treatment group are presented in Table 3.

Table 3: Adverse Reactions Among Patients with Candidemia or other Candida Infections Incidence 5% or Greater for at Least One Treatment Group

Within any system organ class, individuals may experience more than 1 adverse reaction.

* Derived from a comparator-controlled clinical study.

Invasive Aspergillosis

In an open-label, noncomparative aspergillosis study, in which 69 patients received Caspofungin acetate for Injection (70-mg loading dose on Day 1 followed by 50 mg daily), the following adverse reactions were observed with an incidence of 12.5% or greater: blood alkaline phosphatase increased (22%), hypotension (20%), respiratory failure (20%), pyrexia (17%), diarrhea (15%), nausea (15%), headache (15%), rash (13%), alanine aminotransferase increased (13%), aspartate aminotransferase increased (13%), blood bilirubin increased (13%), and blood potassium decreased (13%). Also reported in this patient population were pulmonary edema, ARDS (adult respiratory distress syndrome), and radiographic infiltrates.

Pediatric Patients (3 months to 17 years of age)

The overall safety of Caspofungin acetate for Injection was assessed in 171 pediatric patients who received single or multiple doses of Caspofungin acetate for Injection. The distribution among the 153 pediatric patients who were over the age of 3 months was as follows: 104 febrile, neutropenic patients; 38 patients with candidemia and/or intra-abdominal abscesses, peritonitis, or pleural space infections; 1 patient with esophageal candidiasis; and 10 patients with invasive aspergillosis. The overall safety profile of Caspofungin acetate for Injection in

pediatric patients is comparable to that in adult patients. Table 5 shows the incidence of adverse reactions reported in 7.5% or greater of pediatric patients in clinical studies.

One patient (0.6%) receiving Caspofungin acetate for Injection, and three patients (12%) receiving AmBisome developed a serious drug-related adverse reaction. Two patients (1%) were discontinued from Caspofungin acetate for Injection and three patients (12%) were discontinued from AmBisome due to a drug-related adverse reaction. The proportion of patients who experienced an infusion-related adverse reaction (defined as a systemic event, such as pyrexia, chills, flushing, hypotension, hypertension, tachycardia, dyspnea, tachypnea, rash, or anaphylaxis, that developed during the study therapy infusion and one hour following infusion) was 22% in the group treated with Caspofungin acetate for Injection and 35% in the group treated with AmBisome.

Table 5: Adverse Reactions Among Pediatric Patients (0 months to 17 years of age) Incidence 7.5% or Greater for at Least One Treatment Group

Within any system organ class, individuals may experience more than 1 adverse reaction.

*70 mg/m on Day 1, then 50 mg/m² once daily for the remainder of the treatment.

Overall Safety Experience of Caspofungin acetate for Injection in Clinical Trials

The overall safety of Caspofungin acetate for Injection was assessed in 2036 individuals (including 1642 adult or pediatric patients and 394 volunteers) from 34 clinical studies. These individuals received single or multiple (once daily) doses of Caspofungin acetate for Injection, ranging from 5 mg to 210 mg. Full safety data is available from 1951 individuals, as the safety data from 85 patients enrolled in 2 compassionate use studies was limited solely to serious adverse reactions. Adverse reactions which occurred in 5% or greater of all individuals who received Caspofungin acetate for Injection in these trials are shown in Table 6.

Overall, 1665 of the 1951 (85%) patients/volunteers who received Caspofungin acetate for Injection experienced an adverse reaction.

Table 6: Adverse Reactions in Patients Who Received Caspofungin acetate for Injection in Clinical Trials^† Incidence 5% or Greater for at Least One Treatment Group

*Defined as an adverse reaction, regardless of causality, while on Caspofungin acetate for Injection or during the 14 -day post- Caspofungin acetate for Injection follow-up period.

† Incidence for each preferred term is 5% or greater among individuals who received at least 1 dose of Caspofungin acetate for Injection.

^‡ Within any system organ class, individuals may experience more than 1 adverse event.

Clinically significant adverse reactions, regardless of causality or incidence which occurred in less than 5% of patients are listed below.

·       Blood and lymphatic system disorders: anemia, coagulopathy, febrile neutropenia, neutropenia, thrombocytopenia

·       Cardiac disorders: arrhythmia, atrial fibrillation, bradycardia, cardiac arrest, myocardial infarction, tachycardia

·       Gastrointestinal disorders: abdominal distension, abdominal pain upper, constipation, dyspepsia

·       General disorders and administration site conditions: asthenia, fatigue, infusion site pain/pruritus/swelling, mucosal inflammation, edema

·       Hepatobiliary      disorders:      hepatic     failure, hepatomegaly,     hepatotoxicity, hyperbilirubinemia, jaundice

·       Infections and infestations: bacteremia, sepsis, urinary tract infection

·       Metabolic and nutrition disorders: anorexia, decreased appetite, fluid overload, hypomagnesemia, hypercalcemia, hyperglycemia, hypokalemia

·       Musculoskeletal, connective tissue, and bone disorders: arthralgia, back pain, pain in extremity

·       Nervous system disorders: convulsion, dizziness, somnolence, tremor

·       Psychiatric disorders: anxiety, confusional state, depression, insomnia

·       Renal and urinary disorders: hematuria, renal failure

·       Respiratory, thoracic, and mediastinal disorders: dyspnea, epistaxis, hypoxia, tachypnea

·       Skin and subcutaneous tissue disorders: erythema, petechiae, skin lesion, urticaria

·       Vascular disorders: flushing, hypertension, phlebitis

Postmarketing Experience of Caspofungin acetate for Injection

The following additional adverse reactions have been identified during the post-approval use of Caspofungin acetate for Injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

·       Gastrointestinal disorders: pancreatitis

·       Hepatobiliary disorders: hepatic necrosis

·       Skin and subcutaneous tissue disorders: erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, and skin exfoliation

·       Renal and urinary disorders: clinically significant renal dysfunction

·       General disorders and administration site conditions: swelling and peripheral edema

·       Laboratory abnormalities: gamma-glutamyltransferase increased

To reports any side effect(s):

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to the competent authority in Saudi Arabia as per details below:

-          The National Pharmacovigilance and Drug Safety Centre (NPC)

o Fax: +966-11-205-7662

o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.

o   Toll free phone: 8002490000

o   E-mail: npc.drug@sfda.gov.sa

o   Website: www.sfda.gov.sa/npc

To report the Adverse event in other GCC States - Please contact the relevant competent authority

In 6 healthy subjects who received a single 210-mg dose, no significant adverse reactions were reported. Multiple doses above 150 mg daily have not been studied. Caspofungin is not dialyzable.

In clinical trials, one pediatric patient (16 years of age) unintentionally received a single dose of caspofungin of 113 mg (on Day 1), followed by 80 mg daily for an additional 7 days. No clinically significant adverse reactions were reported.

Pharmacotherapeutic group: antimycotics for systemic use, ATC code: J02AX04

Mechanism of Action

Caspofungin, an echinocandin, inhibits the synthesis of beta (1,3)-D-glucan, an essential component of the cell wall of susceptible Aspergillus species and Candida species. Beta (1,3)- D-glucan is not present in mammalian cells. Caspofungin has shown activity against Candida species and in regions of active cell growth of the hyphae of Aspergillus fumigatus.

Resistance

There have been reports of clinical failures in patients receiving caspofungin therapy due to the development of drug resistant Candida or Aspergillus species. Some of these reports have identified specific mutations in the Fks subunits, encoded by the fks1 and/or fks2 genes, of the glucan synthase enzyme. These mutations are associated with higher MICs and breakthrough infection. Candida species that exhibit reduced susceptibility to caspofungin as a result of an increase in the chitin content of the fungal cell wall have also been identified, although the significance of this phenomenon in vivo is not well known.

Interaction with Other Antimicrobials

Studies in vitro and in vivo of caspofungin, in combination with amphotericin B, suggest no antagonism of antifungal activity against either A. fumigatus or C. albicans. The clinical significance of these results is unknown.

Antimicrobial Activity

Caspofungin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections (see section 4.1)

Aspergillus flavus Aspergillus fumigatus Aspergillus terreus Candida albicans Candida glabrata Candida guilliermondii Candida krusei Candida parapsilosis Candida tropicalis

Susceptibility Testing Methods

The interpretive standards for caspofungin against Candida species are applicable only to tests performed using Clinical Laboratory and Standards Institute (CLSI) microbroth dilution reference methods. ^2,3 for MIC (partial inhibition endpoint) read at 24 hours. No interpretive criteria have been established for Aspergillus species or other filamentous fungi.

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of pathogens. These reports should aid the physician in selecting an antifungal drug product for treatment. The techniques for Broth Microdilution are described below.

Broth Microdilution Techniques

Quantitative methods are used to determine antifungal minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of Candida spp. to antifungal agents. MICs should be determined using a standardized procedure at 24 hours^2,3. Standardized

procedures are based on a microdilution method (broth) with standardized inoculum concentrations and standardized concentrations of caspofungin powder. The MIC values should be interpreted according to the criteria provided in Table 7.

Table 7: Susceptibility Interpretive Criteria for Caspofungin

* A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable

Quality Control

Quality Control Standardized susceptibility test procedures require the use of quality control organisms to control the technical aspects of the test procedures. Standard caspofungin powder should provide the following range of values noted in Table 8³. Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within fungi; the specific strains used for microbiological control are not clinically significant.

Table 8: Acceptable Quality Control Ranges for Caspofungin to be used in Validation of Susceptibility Test Results

* The MIC for caspofungin is the lowest concentration at which a score of 2 (prominent decrease in turbidity [greater than 50% inhibition of growth as compared to the growth control]; see CLSI document M27-A3², Section 7.6.3) is observed after 24 hours of incubation.

Clinical efficacy and safety

Empirical Therapy in Febrile, Neutropenic Patients

A double-blind study enrolled 1111 febrile, neutropenic (<500 cells/mm³) patients who were randomized to treatment with daily doses of Caspofungin acetate for Injection (50 mg/day following a 70-mg loading dose on Day 1) or AmBisome (3 mg/kg/day). Patients were stratified based on risk category (high-risk patients had undergone allogeneic stem cell

transplantation or had relapsed acute leukemia) and on receipt of prior antifungal prophylaxis. Twenty-four percent of patients were high risk and 56% had received prior antifungal prophylaxis. Patients who remained febrile or clinically deteriorated following 5 days of therapy could receive 70 mg/day of Caspofungin acetate for Injection or 5 mg/kg/day of AmBisome. Treatment was continued to resolution of neutropenia (but not beyond 28 days unless a fungal infection was documented).

An overall favorable response required meeting each of the following criteria: no documented breakthrough fungal infections up to 7 days after completion of treatment, survival for 7 days after completion of study therapy, no discontinuation of the study drug because of drug-related toxicity or lack of efficacy, resolution of fever during the period of neutropenia, and successful treatment of any documented baseline fungal infection.

Based on the composite response rates, Caspofungin acetate for Injection was as effective as AmBisome in empirical therapy of persistent febrile neutropenia (see Table 9).

Table 9: Favorable Response of Patients with Persistent Fever and Neutropenia

*Caspofungin acetate for Injection: 70 mg on Day 1, then 50 mg once daily for the remainder of treatment (daily dose increased to 70 mg for 73 patients); AmBisome: 3 mg/kg/day (daily dose increased to 5 mg/kg for 74 patients).

^†Overall Response: estimated % difference adjusted for strata and expressed as Caspofungin acetate for Injection

– AmBisome (95.2% CI); Individual criteria presented above are not mutually exclusive. The percent difference calculated as Caspofungin acetate for Injection – AmBisome.

^‡Analysis population excluded subjects who did not have fever or neutropenia at study entry.

The rate of successful treatment of documented baseline infections, a component of the primary endpoint, was not statistically different between treatment groups.

The response rates did not differ between treatment groups based on either of the stratification variables: risk category or prior antifungal prophylaxis.

Candidemia and the Following other Candida Infections: Intra-Abdominal Abscesses, Peritonitis and Pleural Space Infections

In a randomized, double-blind study, patients with a proven diagnosis of invasive candidiasis received daily doses of Caspofungin acetate for Injection (50 mg/day following a 70-mg loading dose on Day 1) or amphotericin B deoxycholate (0.6 to 0.7 mg/kg/day for non- neutropenic patients and 0.7 to 1 mg/kg/day for neutropenic patients). Patients were stratified by both neutropenic status and APACHE II score. Patients with Candida endocarditis, meningitis, or osteomyelitis were excluded from this study.

Patients who met the entry criteria and received one or more doses of IV study therapy were included in the modified intention-to-treat [MITT] analysis of response at the end of IV study therapy. A favorable response at this time point required both symptom/sign resolution/improvement and microbiological clearance of the Candida infection.

Two hundred thirty-nine patients were enrolled. Patient disposition is shown in Table 10.

Table 10: Disposition in Candidemia and Other Candida Infections (Intra-abdominal abscesses, peritonitis, and pleural space infections)

*Patients received Caspofungin acetate for Injection 70 mg on Day 1, then 50 mg once daily for the remainder of their treatment.

^†Study defined as study treatment period and 6-8 week follow-up period.

^‡Determined by the investigator to be possibly, probably, or definitely drug-related.

Of the 239 patients enrolled, 224 met the criteria for inclusion in the MITT population (109 treated with Caspofungin acetate for Injection and 115 treated with amphotericin B). Of these 224 patients, 186 patients had candidemia (92 treated with Caspofungin acetate for Injection and 94 treated with amphotericin B). The majority of the patients with candidemia were non- neutropenic (87%) and had an APACHE II score less than or equal to 20 (77%) in both arms. Most candidemia infections were caused by C. albicans (39%), followed by C. parapsilosis (20%), C. tropicalis (17%), C. glabrata (8%), and C. krusei (3%).

At the end of IV study therapy, Caspofungin acetate for Injection was comparable to amphotericin B in the treatment of candidemia in the MITT population. For the other efficacy time points (Day 10 of IV study therapy, end of all antifungal therapy, 2-week post-therapy follow-up, and 6- to 8-week post-therapy follow-up), Caspofungin acetate for Injection was as effective as amphotericin B.

Outcome, relapse and mortality data are shown in Table 11.

Table 11: Outcomes, Relapse, & Mortality in Candidemia and Other Candida Infections (Intra-abdominal abscesses, peritonitis, and pleural space infections)

*Patients received Caspofungin acetate for Injection 70 mg on Day 1, then 50 mg once daily for the remainder of their treatment.

^†Calculated as Caspofungin acetate for Injection – amphotericin B

^‡95% CI for candidemia, 95.6% for all patients

^§Modified intention-to-treat

^¶Includes all patients who either developed a culture-confirmed recurrence of Candida infection or

required antifungal therapy for the treatment of a proven or suspected Candida infection in the follow-up period.

^#Study defined as study treatment period and 6-8 week follow-up period.

In this study, the efficacy of Caspofungin acetate for Injection in patients with intra-abdominal abscesses, peritonitis and pleural space Candida infections was evaluated in 19 non- neutropenic patients. Two of these patients had concurrent candidemia. Candida was part of a polymicrobial infection that required adjunctive surgical drainage in 11 of these 19 patients. A favorable response was seen in 9 of 9 patients with peritonitis, 3 of 4 with abscesses (liver, parasplenic, and urinary bladder abscesses), 2 of 2 with pleural space infections, 1 of 2 with mixed peritoneal and pleural infection, 1 of 1 with mixed abdominal abscess and peritonitis, and 0 of 1 with Candida pneumonia.

Overall, across all sites of infection included in the study, the efficacy of Caspofungin acetate for Injection was comparable to that of amphotericin B for the primary endpoint.

In this study, the efficacy data for Caspofungin acetate for Injection in neutropenic patients with candidemia were limited. In a separate compassionate use study, 4 patients with hepatosplenic candidiasis received prolonged therapy with Caspofungin acetate for Injection following other long-term antifungal therapy; three of these patients had a favorable response.

In a second randomized, double-blind study, 197 patients with proven invasive candidiasis received Caspofungin acetate for Injection 50 mg/day (following a 70-mg loading dose on Day 1) or Caspofungin acetate for Injection 150 mg/day. The diagnostic criteria, evaluation time

points, and efficacy endpoints were similar to those employed in the prior study. Patients with Candida endocarditis, meningitis, or osteomyelitis were excluded. Although this study was designed to compare the safety of the two doses, it was not large enough to detect differences in rare or unexpected adverse events [see Undesirable effects – section 4.8]. The efficacy of Caspofungin acetate for Injection at the 150 mg daily dose was not significantly better than the efficacy of the 50-mg daily dose of Caspofungin acetate for Injection. The efficacy of doses higher than 50 mg daily in the other adult patients for whom Caspofungin acetate for Injection is indicated has not been evaluated.

Esophageal Candidiasis (and information on oropharyngeal candidiasis)

The safety and efficacy of Caspofungin acetate for Injection in the treatment of esophageal candidiasis was evaluated in one large, controlled, noninferiority, clinical trial and two smaller dose-response studies.

In all 3 studies, patients were required to have symptoms and microbiological documentation of esophageal candidiasis; most patients had advanced AIDS (with CD4 counts <50/mm³).

Of the 166 patients in the large study who had culture-confirmed esophageal candidiasis at baseline, 120 had Candida albicans and 2 had Candida tropicalis as the sole baseline pathogen whereas 44 had mixed baseline cultures containing C. albicans and one or more additional Candida species.

In the large, randomized, double-blind study comparing Caspofungin acetate for Injection 50 mg/day versus intravenous fluconazole 200 mg/day for the treatment of esophageal candidiasis, patients were treated for an average of 9 days (range 7-21 days). Favorable overall response at 5 to 7 days following discontinuation of study therapy required both complete resolution of symptoms and significant endoscopic improvement. 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. The proportion of patients with a favorable overall response was comparable for Caspofungin acetate for Injection and fluconazole as shown in Table 12.

Table 12: Favorable Response Rates for Patients with Esophageal Candidiasis*

*Analysis excluded patients without documented esophageal candidiasis or patients not receiving at least 1 day of study therapy.

^†Calculated as Caspofungin acetate for Injection – fluconazole

The proportion of patients with a favorable symptom response was also comparable (90.1% and 89.4% for Caspofungin acetate for Injection and fluconazole, respectively). In addition, the proportion of patients with a favorable endoscopic response was comparable (85.2% and 86.2% for Caspofungin acetate for Injection and fluconazole, respectively).

As shown in Table 13, the esophageal candidiasis relapse rates at the Day 14 post-treatment visit were similar for the two groups. At the Day 28 post-treatment visit, the group treated with Caspofungin acetate for Injection had a numerically higher incidence of relapse; however, the difference was not statistically significant.

Table 13: Relapse Rates at 14- and 28-Days Post-Therapy in Patients with Esophageal Candidiasis at Baseline

*Calculated as Caspofungin acetate for Injection – fluconazole

In this trial, which was designed to establish noninferiority of Caspofungin acetate for Injection to fluconazole for the treatment of esophageal candidiasis, 122 (70%) patients also had oropharyngeal candidiasis. A favorable response was defined as complete resolution of all symptoms of oropharyngeal disease and all visible oropharyngeal lesions. The proportion of patients with a favorable oropharyngeal response at the 5- to 7-day post-treatment visit was numerically lower for Caspofungin acetate for Injection; however, the difference was not statistically significant. Oropharyngeal candidiasis relapse rates at Day 14 and Day 28 posttreatment visits were statistically significantly higher for Caspofungin acetate for Injection than for fluconazole. The results are shown in Table 14.

Table 14: Oropharyngeal Candidiasis Response Rates at 5 to 7 Days Post-Therapy and Relapse Rates at 14 and 28 Days Post-Therapy in Patients with Oropharyngeal and

Esophageal Candidias is at Baseline

*Calculated as Caspofungin acetate for Injection – fluconazole

The results from the two smaller dose-ranging studies corroborate the efficacy of Caspofungin acetate for Injection for esophageal candidiasis that was demonstrated in the larger study.

Caspofungin acetate for Injection was associated with favorable outcomes in 7 of 10 esophageal C. albicans infections refractory to at least 200 mg of fluconazole given for 7 days, although the in vitro susceptibility of the infecting isolates to fluconazole was not known.

Invasive Aspergillosis

Sixty-nine patients between the ages of 18 and 80 with invasive aspergillosis were enrolled in an open label, noncomparative study to evaluate the safety, tolerability, and efficacy of Caspofungin acetate for Injection. 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 tomography 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. Patients were administered a single 70-mg loading dose of Caspofungin acetate for Injection 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 Caspofungin acetate for Injection, 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 greater than 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 Caspofungin acetate for Injection 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 Caspofungin acetate for Injection had a favorable response. For those patients who received greater than 7 days of therapy with Caspofungin acetate for Injection, 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. Among patients with extrapulmonary disease, 2 of 8 Calculated as Caspofungin acetate for Injection – fluconazole patients who also had definite, probable, or possible CNS involvement had a favorable response. Two of these 8 patients had progression of disease and manifested CNS involvement while on therapy.

Caspofungin acetate for Injection is effective for the treatment of invasive aspergillosis in patients who are refractory to or intolerant of itraconazole, amphotericin B, and/or lipid formulations of amphotericin B. However, the efficacy of Caspofungin acetate for Injection for initial treatment of invasive aspergillosis has not been evaluated in comparator-controlled clinical studies.

Pediatric Patients

The safety and efficacy of Caspofungin acetate for Injection were evaluated in pediatric patients 3 months to 17 years of age in two prospective, multicenter clinical trials.

The first study, which enrolled 82 patients between 2 to 17 years of age, was a randomized, double-blind study comparing Caspofungin acetate for Injection (50 mg/m IV once daily

following a 70-mg/m loading dose on Day 1 [not to exceed 70 mg daily]) to AmBisome (3 mg/kg IV daily) in a 2:1 treatment fashion (56 on caspofungin, 26 on AmBisome) as empirical therapy in pediatric patients with persistent fever and neutropenia. The study design and criteria for efficacy assessment were similar to the study in adult patients. Patients were stratified based on risk category (high-risk patients had undergone allogeneic stem cell transplantation or had relapsed acute leukemia). Twenty-seven percent of patients in both treatment groups were high risk. Favorable overall response rates of pediatric patients with persistent fever and neutropenia are presented in Table 15.

Table 15: Favorable Overall Response Rates of Pediatric Patients with Persistent Fever

and Neutropenia

^*One patient excluded from analysis due to no fever at study entry.

The second study was a prospective, open-label, non-comparative study estimating the safety and efficacy of caspofungin in pediatric patients (ages 3 months to 17 years) with candidemia and other Candida infections, esophageal candidiasis, and invasive aspergillosis (as salvage therapy). The study employed diagnostic criteria which were based on established EORTC/MSG criteria of proven or probable infection; these criteria were similar to those criteria employed in the adult studies for these various indications. Similarly, the efficacy time points and endpoints used in this study were similar to those employed in the corresponding adult studies. All patients received Caspofungin acetate for Injection at 50 mg/m IV once daily following a 70-mg/m loading dose on Day 1 (not to exceed 70 mg daily). Among the 49 enrolled patients who received Caspofungin acetate for Injection, 48 were included in the efficacy analysis (one patient excluded due to not having a baseline Aspergillus or Candida infection). Of these 48 patients, 37 had candidemia or other Candida infections, 10 had invasive aspergillosis, and 1 patient had esophageal candidiasis. Most candidemia and other Candida infections were caused by C. albicans (35%), followed by C. parapsilosis (22%), C. tropicalis (14%), and C. glabrata (11%). The favorable response rate, by indication, at the end

of caspofungin therapy was as follows: 30/37 (81%) in candidemia or other Candida

infections, 5/10 (50%) in invasive aspergillosis, and 1/1 in esophageal candidiasis.

Distribution

Plasma concentrations of caspofungin decline in a polyphasic manner following single 1 hour IV infusions. A short α-phase occurs immediately post infusion, followed by a β-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 postdose during which the plasma concentration decreases 10- fold. An additional, longer half-life phase, γ-phase, (half-life of 40-50 hours), also occurs. 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 administered radioactivity was distributed to tissues by 36 to 48 hours after a single 70-mg dose of [³H] Caspofungin acetate for Injection. 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, L-747969. At later time points (≥5 days postdose), there is a low level (≤7 picomoles/mg protein, or ≤1.3% of administered dose) of covalent binding of radiolabel in plasma following single-dose administration of [³H] Caspofungin acetate for Injection, which may be due to two reactive intermediates formed during the chemical degradation of caspofungin to L-747969. 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.

Excretion

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. Plasma concentrations of radioactivity and of caspofungin were similar during the first 24 to 48 hours postdose; thereafter drug levels fell more rapidly. In plasma, caspofungin concentrations fell below the limit of quantitation after 6 to 8 days postdose, while

radiolabel fell below the limit of quantitation at 22.3 weeks postdose. After single intravenous administration of [³H] Caspofungin acetate for Injection, excretion of caspofungin and its metabolites in humans was 35% of dose in feces and 41% of dose in urine. 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) and total clearance of caspofungin is 12 mL/min.

Special Populations

Renal Impairment

In a clinical study of single 70-mg doses, caspofungin pharmacokinetics were similar in healthy adult volunteers with mild renal impairment (creatinine clearance 50 to 80 mL/min) and control subjects. Moderate (creatinine clearance 31 to 49 mL/min), severe (creatinine clearance 5 to 30 mL/min), and end-stage (creatinine clearance less than 10 mL/min and dialysis dependent) renal impairment moderately increased caspofungin plasma concentrations after single-dose administration (range: 30 to 49% for AUC). However, in adult patients with invasive aspergillosis, candidemia, or other Candida infections (intra-abdominal abscesses, peritonitis, or pleural space infections) who received multiple daily doses of Caspofungin acetate for Injection 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 impairment. Caspofungin is not dialyzable, thus supplementary dosing is not required following hemodialysis.

Hepatic Impairment

Plasma concentrations of caspofungin after a single 70-mg dose in adult patients with mild hepatic impairment (Child-Pugh score 5 to 6) were increased by approximately 55% in AUC compared to healthy control subjects. In a 14-day multiple-dose study (70 mg on Day 1 followed by 50 mg daily thereafter), plasma concentrations in adult patients with mild hepatic impairment were increased modestly (19 to 25% in AUC) on Days 7 and 14 relative to healthy control subjects. No dosage adjustment is recommended for patients with mild hepatic impairment.

Adult patients with moderate hepatic impairment (Child-Pugh score 7 to 9) who received a single 70-mg dose of Caspofungin acetate for Injection had an average plasma caspofungin increase of 76% in AUC compared to control subjects. A dosage reduction is recommended

for adult patients with moderate hepatic impairment based upon these pharmacokinetic data. (see section 4.2).

There is no clinical experience in adult patients with severe hepatic impairment (Child-Pugh score greater than 9) or in pediatric patients with any degree of hepatic impairment.

Gender

Plasma concentrations of caspofungin in healthy adult 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 22% in area under the curve [AUC]) relative to men. No dosage adjustment is necessary based on gender.

Race

Regression analyses of patient pharmacokinetic data indicated that 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.

Geriatric Patients

Plasma concentrations of caspofungin in healthy older men and women (65 years of age and older) were increased slightly (approximately 28% AUC) compared to young healthy men after a single 70-mg dose of caspofungin. In patients who were treated empirically or who had candidemia or other Candida infections (intra-abdominal abscesses, peritonitis, or pleural space infections), a similar modest effect of age was seen in older patients relative to younger patients. No dosage adjustment is necessary for the elderly.

Pediatric Patients

Caspofungin acetate for Injection has been studied in five prospective studies involving pediatric patients under 18 years of age, including three pediatric pharmacokinetic studies [initial study in adolescents (12-17 years of age) and children (2-11 years of age) followed by a study in younger patients (3-23 months of age) and then followed by a study in neonates and infants (less than 3 months of age)].

Pharmacokinetic parameters following multiple doses of Caspofungin acetate for Injection in pediatric and adult patients are presented in Table 16.

Table 16: Pharmacokinetic Parameters Following Multiple Doses of Caspofungin acetate for Injection in Pediatric (3 months to 17 years) and Adult Patients

*Harmonic Mean ± jackknife standard deviation

† N=5 for C_1hr and AUC_0-24hr; N=6 for C_24hr

‡N=117 for C_24hr; N=119 for C_1hr

^§Following an initial 70-mg loading dose on day 1

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies in animals have been performed to evaluate the carcinogenic potential of caspofungin.
Caspofungin did not show evidence of mutagenic or genotoxic potential when evaluated in the following in vitro assays: bacterial (Ames) and mammalian cell (V79 Chinese hamster lung fibroblasts) mutagenesis assays, the alkaline elution/rat hepatocyte DNA strand break test, and the chromosome aberration assay in Chinese hamster ovary cells. Caspofungin was not genotoxic when assessed in the mouse bone marrow chromosomal test at doses up to 12.5 mg/kg (equivalent to a human dose of 1 mg/kg based on body surface area comparisons), administered intravenously.
Fertility and reproductive performance were not affected by the intravenous administration of caspofungin to rats at doses up to 5 mg/kg. At 5 mg/kg exposures were similar to those seen in patients treated with the 70-mg dose.

Animal Toxicology and/or Pharmacology

In one 5-week study in monkeys at doses which produced exposures approximately 4 to 6 times those seen in adult patients treated with a 70-mg dose, scattered small foci of subcapsular necrosis were observed microscopically in the livers of some animals (2/8 monkeys at 5 mg/kg and 4/8 monkeys at 8 mg/kg); however, this histopathological finding was not seen in another study of 27 weeks duration at similar doses.

No treatment-related findings were seen in a 5-week study in infant monkeys at doses which produced exposures approximately 3 times those achieved in pediatric patients receiving a maintenance dose of 50 mg/m daily.

Mannitol
Sucrose
Glacial acetic acid
Sodium Hydroxide (to adjust the pH)

Do not mix or co-infuse Caspofungin acetate for Injection with other medications, as there are no data available on the compatibility of Caspofungin acetate for Injection with other intravenous substances, additives, or medications.
Do not use diluents containing dextrose (α-D-glucose), as Caspofungin acetate for Injection is not stable in diluents containing dextrose.

Store Refrigerated at 2°C – 8°C (36 °F– 46 °F).

The container closure system for Caspofungin acetate for Injection is listed below. Caspofungin acetate for Injection, 50 mg/vial, 10 mL clear glass tubular Lyo vial

10 mL USP Type-I clear glass tubular Lyo vials with 20 mm ready to sterilize bromobutyl double slotted Lyo rubber stoppers and 20 mm aluminum flip-off seals with button.

Caspofungin acetate for Injection, 70 mg/vial, 10 mL clear glass tubular Lyo vial

10 mL USP Type-I clear glass tubular Lyo vials with 20 mm ready to sterilize bromobutyl double slotted Lyo rubber stoppers and 20 mm aluminum flip-off seals with button.

5.1  Preparation for Administration

Reconstitution of Caspofungin acetate for Injection for Intravenous Infusion

A.   Equilibrate the refrigerated vial of Caspofungin acetate for Injection to room temperature.

B.    Aseptically add 10.8 mL of 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.

C.    Each vial of Caspofungin acetate for Injection contains an intentional overfill of Caspofungin acetate for Injection. Thus, the volume of diluent to be added to each vial and the drug concentration of the resulting solution is listed in Table 17 below.

Table 17: Information for Preparation of Caspofungin acetate for Injection

*Reconstitution volume of diluent to be added is based on the overfill amount of caspofungin (54 .6 mg and 75.6 mg, respectively).

D.  The white to off-white cake will dissolve completely. Mix gently until a clear solution is obtained. Visually inspect the reconstituted solution for particulate matter or discoloration during reconstitution and prior to infusion. Do not use if the solution is cloudy or has precipitated.

E.  The reconstituted solution of Caspofungin acetate for Injection in the vial may be stored for up to one hour at ≤25°C (≤77°F) prior to the preparation of the infusion solution in the intravenous bag or bottle.

F.  Caspofungin acetate for Injection vials are for single-dose only. Discard unused portion.

Dilution of the Reconstituted Solution in the Intravenous Bag for Infusion

A.  Aseptically transfer the appropriate volume (mL) of reconstituted Caspofungin acetate for Injection to an intravenous (IV) bag (or bottle) containing 250 mL of 0.9%, 0.45%, or

0.225% Sodium Chloride Injection or Lactated Ringers Injection.

B.  Alternatively, the volume (mL) of reconstituted Caspofungin acetate for Injection can be added to a reduced volume of 0.9%, 0.45%, or 0.225% Sodium Chloride Injection or Lactated Ringers Injection, not to exceed a final concentration of 0.5 mg/mL.

C.  This diluted infusion solution in the intravenous bag or bottle must be used within 24 hours if stored at ≤25°C (≤77°F) or within 48 hours if stored refrigerated at 2 to 8°C (36 to 46°F).

Important Reconstitution and Dilution Instructions for Pediatric Patients 3 Months of Age and Older

Follow the reconstitution procedures described above using either the 70-mg or 50-mg vial to create the reconstituted solution (see section 4.2). From the reconstituted solution in the vial, remove the volume of drug equal to the calculated loading dose or calculated maintenance dose based on a concentration of 7 mg/mL (if reconstituted from the 70-mg vial) or a concentration of 5 mg/mL (if reconstituted from the 50-mg vial).

The choice of vial should be based on total milligram dose of drug to be administered to the pediatric patient. To help ensure accurate dosing, it is recommended for pediatric doses less than 50 mg that 50-mg vials (with a concentration of 5 mg/mL) be used if available. The 70- mg vial should be reserved for pediatric patients requiring doses greater than 50 mg.

The maximum loading dose and the daily maintenance dose should not exceed 70 mg, regardless of the patient's calculated dose.