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Caspofungin Acetate Injection

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 

1. DESCRIPTION

Caspofungin is a sterile, lyophilized product for intravenous (IV) infusion that contains a semisynthetic lipopeptide (echinocandin) compound synthesized from a fermentation product of Glarea lozoyensis. Caspofungin is the first of a new class of antifungal drugs (echinocandins) that inhibit the synthesis of β (1,3)-D-glucan, an integral component of the fungal cell wall.

Caspofungin acetate is 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). The empirical formula is C52H88N10O15•2C2H4O2 and the formula weight is 1213.42. The structural formula is:

Caspofungin 50 mg also contains: 39 mg sucrose, 26 mg mannitol, glacial acetic acid, and sodium hydroxide. Caspofungin 70 mg also contains 54 mg sucrose, 36 mg mannitol, glacial acetic acid, and sodium hydroxide. Caspofungin acetate is a hygroscopic, white to off-white powder. It is freely soluble in water and methanol, and slightly soluble in ethanol. The pH of a saturated aqueous solution of caspofungin acetate is approximately 6.6.

2. INDICATIONS AND USAGE

Caspofungin is indicated in adults and pediatric patients (3 months 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. Caspofungin has not been studied in endocarditis, osteomyelitis, and meningitis due to Candida.

• Treatment of esophageal candidiasis.

• Treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies (i.e., amphotericin B, lipid formulations of amphotericin B, and/or itraconazole). Caspofungin has not been studied as initial therapy for invasive aspergillosis.

3. DOSAGE AND ADMINISTRATION

3.1 Instructions for Use in All Patients

Caspofungin should be administered by slow intravenous (IV) infusion over approximately 1 hour. Caspofungin should not be administered by IV bolus administration.

Do not mix or co-infuse caspofungin with other medications, as there are no data available on the compatibility of caspofungin with other intravenous substances, additives, or medications. DO NOT USE DILUENTS CONTAINING DEXTROSE (α-D-GLUCOSE), as caspofungin is not stable in diluents containing dextrose.

3.2 Recommended Dosing in Adult Patients [≥18 years of age]

The usual dose is 50 mg once daily (following a 70-mg loading dose for most indications). The safety and efficacy of a dose of 150 mg daily (range: 1 to 51 days; median: 14 days) have been studied in 100 adult patients with candidemia and other Candida infections. The efficacy of caspofungin at this higher dose was not significantly better than the efficacy of the 50-mg daily dose of caspofungin. The efficacy of doses higher than 50 mg daily in the other adult patients for whom caspofungin is indicated is not known.

Empirical Therapy

A single 70-mg loading dose should be administered on Day 1, followed by 50 mg daily thereafter. Duration of treatment should be based on the patient’s clinical response. Empirical therapy should be continued until resolution of neutropenia. Patients found to have a fungal infection should be treated for a minimum of 14 days; treatment should continue for at least 7 days after both neutropenia and clinical symptoms are resolved. If the 50-mg 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

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

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

A single 70-mg loading dose should be administered 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.

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

For all indications, a single 70-mg/m2 loading dose should be administered 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) X 70 mg/m2. The maintenance dose in milligrams should be calculated as BSA (m2) X 50 mg/m2.

Duration of treatment should be individualized to the indication, as described for each indication in adults [see Dosage and Administration]. 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).

3.4 Patients with Hepatic Impairment

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

3.5 Patients Receiving Concomitant Inducers of Drug Clearance

Adult patients on rifampin should receive 70 mg of caspofungin once daily. Adult patients on nevirapine, efavirenz, carbamazepine, dexamethasone, or phenytoin may require an increase in dose to 70 mg of caspofungin once daily [see Drug Interactions].

When caspofungin is co-administered to pediatric patients with inducers of drug clearance, such as rifampin, efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, a caspofungin dose of 70 mg/m2 once daily (not to exceed 70 mg) should be considered [see Drug Interactions].

3.6 Preparation and Reconstitution for Administration

Do not mix or co-infuse caspofungin with other medications, as there are no data available on the compatibility of caspofungin with other intravenous substances, additives, or medications. DO NOT USE DILUENTS CONTAINING DEXTROSE (α-D-GLUCOSE), as caspofungin is not stable in diluents containing dextrose.

Preparation of Caspofungin for Infusion

A. Equilibrate the refrigerated vial of caspofungin 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.

Each vial of caspofungin contains an intentional overfill of caspofungin. Thus, the drug concentration of the resulting solution is listed in Table 1 below.

TABLE 1. Information for Preparation of Caspofungin

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.

The reconstituted solution may be stored for up to one hour at ≤25°C (≤77°F).

Caspofungin vials are for single use only; the remaining solution should be discarded.

C. Aseptically transfer the appropriate volume (mL) of reconstituted caspofungin to an IV bag (or bottle) containing 250 mL of 0.9%, 0.45%, or 0.225% Sodium Chloride Injection or Lactated Ringers Injection. Alternatively, the volume (mL) of reconstituted caspofungin 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.

This infusion solution 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).

Special Considerations for Pediatric Patients >3 Months of Age

Follow the reconstitution procedures described above using either the 70-mg or 50-mg vial to create the reconstituted solution [see Dosage and Administration]. 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 50mg 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.

4. CONTRAINDICATIONS

Caspofungin is contraindicated in patients with hypersensitivity to any component of this product.

5. MECHANISM OF ACTION

Caspofungin acetate, the active ingredient of caspofungin, inhibits the synthesis of β (1,3)-D-glucan, an essential component of the cell wall of susceptible Aspergillus species and Candida species. β (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.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies with the use of caspofungin 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 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 doses 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.

6.2 Nursing Mothers

It is not known whether caspofungin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when caspofungin is administered to a nursing woman.

6.3 Pediatric Use

Safety and effectiveness in the pediatric population have not been established.

6.4 Geriatric Use

The safety and effectiveness of caspofungin in pediatric patients 3 months to 17 years of age are supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic data in pediatric patients, and additional data from prospective studies in pediatric patients 3 months to 17 years of age for the following indications [see Indications and Usage]:

• 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 (e.g., amphotericin B, lipid formulations of amphotericin B, itraconazole).

The efficacy and safety of caspofungin has not been adequately studied in prospective clinical trials involving neonates and infants under 3 months of age. Although limited pharmacokinetic data were collected in neonates and infants below 3 months of age, these data are insufficient to establish a safe and effective dose of caspofungin in the treatment of neonatal candidiasis. Invasive candidiasis in neonates has a higher rate of CNS and multi-organ involvement than in older patients; the ability of caspofungin to penetrate the blood-brain barrier and to treat patients with meningitis and endocarditis is unknown.

Caspofungin has not been studied in pediatric patients with endocarditis, osteomyelitis, and meningitis due to Candida. Caspofungin has also not been studied as initial therapy for invasive aspergillosis in pediatric patients.

In clinical trials, 171 pediatric patients (0 months to 17 years of age), including 18 patients who were less than 3 months of age, were given intravenous caspofungin. Pharmacokinetic studies enrolled a total of 66 pediatric patients, and an additional 105 pediatric patients received caspofungin in safety and efficacy studies. The majority of the pediatric patients received caspofungin at a once-daily maintenance dose of 50 mg/m2 for a mean duration of 12 days (median 9, range 1-87 days). In all studies, safety was assessed by the investigator throughout study therapy and for 14 days following cessation of study therapy. The most common adverse reactions in pediatric patients treated with caspofungin were pyrexia (29%), blood potassium decreased (15%), diarrhea (14%), increased aspartate aminotransferase (12%), rash (12%), increased alanine aminotransferase (11%), hypotension (11%), and chills (11%) [see Adverse Reactions].

Postmarketing hepatobiliary adverse reactions have been reported in pediatric patients with serious underlying medical conditions [see Warnings and Precautions].

6.5 Geriatric Use

Clinical studies of caspofungin did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Although the number of elderly patients was not large enough for a statistical analysis, no overall differences in safety or efficacy were observed between these and younger patients. Plasma concentrations of caspofungin in healthy older men and women (≥65 years of age) were increased slightly (approximately 28% in AUC) compared to young healthy men. A similar effect of age on pharmacokinetics was seen in patients with candidemia or other Candida infections (intra-abdominal abscesses, peritonitis, or pleural space infections). No dose adjustment is recommended for the elderly; however, greater sensitivity of some older individuals cannot be ruled out.

6.6 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 35 mg once daily is recommended based upon pharmacokinetic data. However, where recommended, a 70-mg loading dose should still be administered on Day 1 [see Dosage and Administration]. There is no clinical experience in adult patients with severe hepatic impairment (Child-Pugh score >9) and in pediatric patients 3 months to 17 years of age with any degree of hepatic impairment.

6.7 Patients with Renal Impairment

No dosage adjustment is necessary for patients with renal impairment. Caspofungin is not dialyzable; thus, supplementary dosing is not required following hemodialysis.

7. WARNINGS AND PRECAUTIONS

7.1 Hypersensitivity

Anaphylaxis has been reported during administration of caspofungin. If this occurs, caspofungin should be discontinued and appropriate treatment administered.

Possible histamine-mediated adverse reactions, including rash, facial swelling, angioedema, pruritus, sensation of warmth or bronchospasm have been reported and may require discontinuation and/or administration of appropriate treatment.

7.2 Concomitant Use with Cyclosporine

Concomitant use of caspofungin with cyclosporine should be limited to patients for whom the potential benefit outweighs the potential risk. In one clinical study, 3 of 4 healthy adult subjects who received caspofungin 70 mg on Days 1 through 10, and also received two 3 mg/kg doses of cyclosporine 12 hours apart on Day 10, developed transient elevations of alanine transaminase (ALT) on Day 11 that were 2 to 3 times the upper limit of normal (ULN). In a separate panel of adult subjects in the same study, 2 of 8 who received caspofungin 35 mg daily for 3 days and cyclosporine (two 3 mg/kg doses administered 12 hours apart) on Day 1 had small increases in ALT (slightly above the ULN) on Day 2. In both groups, elevations in aspartate transaminase (AST) paralleled ALT elevations, but were of lesser magnitude. In another clinical study, 2 of 8 healthy men developed transient ALT elevations of less than 2X ULN. In this study, cyclosporine (4 mg/kg) was administered on Days 1 and 12, and caspofungin was administered (70 mg) daily on Days 3 through 13. In one subject, the ALT elevation occurred on Days 7 and 9 and, in the other subject, the ALT elevation occurred on Day 19. These elevations returned to normal by Day 27. In all groups, elevations in AST paralleled ALT elevations but were of lesser magnitude. In these clinical studies, cyclosporine (one 4 mg/kg dose or two 3 mg/kg doses) increased the AUC of caspofungin by approximately 35%.

In a retrospective postmarketing study, 40 immunocompromised patients, including 37 transplant recipients, were treated with caspofungin 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 caspofungin and/or cyclosporine as well as to other possible causes.

In the prospective invasive aspergillosis and compassionate use studies, there were 4 adult patients treated with caspofungin (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, caspofungin 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.

7.3 Hepatic Effects

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

8. ADVERSE REACTIONS

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

• Hepatic effects [see Warnings and Precautions]

• Hypersensitivity [see Warnings and Precautions]

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. The adverse reaction information from clinical trials does provide a basis for identifying adverse reactions that appear to be related to drug use and for approximating rates.

8.1 Clinical Trials Experience in Adults

The overall safety of caspofungin was assessed in 1865 adult individuals who received single or multiple doses of caspofungin: 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

In the randomized, double-blinded empirical therapy study, patients received either caspofungin 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 and AmBisome groups, respectively. Also reported was an isolated, serious adverse reaction of hyperbilirubinemia considered possibly related to caspofungin. Adverse reactions occurring in ≥7.5% of the patients in either treatment group are presented in Table 2.

TABLE 2. Adverse Reactions Among Patients with Persistent Fever and Neutropenia*

Incidence ≥7.5% for at Least One Treatment Group by System Organ Class or Preferred Term

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

* Regardless of causality

† 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 (35%) than in the group treated with AmBisome (52%).

To evaluate the effect of caspofungin and AmBisome on renal function, nephrotoxicity was defined as doubling of serum creatinine relative to baseline or an increase of ≥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 >30 mL/min, the incidence of nephrotoxicity was significantly lower in the group treated with caspofungin (3%) than in the group treated with AmBisome (12%). Clinical renal events, regardless of causality, were similar between caspofungin (75/564, 13%) and AmBisome (85/547, 16%).

Candidemia and Other Candida Infections

In the randomized, double-blinded invasive candidiasis study, patients received either caspofungin 50 mg/day (following a 70-mg loading dose) or amphotericin B 0.6 to 1 mg/kg/day. Adverse reactions occurring in ≥10% 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 ≥10% for at Least One Treatment Group by System Organ Class or Preferred Term

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

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

† Regardless of causality

‡ Patients received caspofungin 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 (20%) than in the group treated with amphotericin B (49%).

To evaluate the effect of caspofungin and amphotericin B on renal function, nephrotoxicity was defined as doubling of serum creatinine relative to baseline or an increase of ≥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 >30 mL/min, the incidence of nephrotoxicity was significantly lower in the group treated with caspofungin than in the group treated with amphotericin B.

Esophageal Candidiasis and Oropharyngeal Candidiasis

Adverse reactions occurring in ≥10% of patients with esophageal and/or oropharyngeal candidiasis are presented in Table 4.

TABLE 4. Adverse Reactions Among Patients with Esophageal and/or Oropharyngeal Candidiasis*

Incidence ≥10% for at Least One Treatment Group by System Organ Class or Preferred Term

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

* Regardless of causality

† Derived from a comparator-controlled clinical study.

Invasive Aspergillosis

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

8.2 Clinical Trials Experience in Pediatric Patients (3 months to 17 years of age)

The overall safety of caspofungin was assessed in 171 pediatric patients who received single or multiple doses of caspofungin. 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 in pediatric patients is comparable to that in adult patients. Table 5 shows the incidence of adverse reactions reported in ≥7.5% of pediatric patients in clinical studies.

One patient (0.6%) receiving caspofungin, and three patients (12%) receiving AmBisome developed a serious drug-related adverse reaction. Two patients (1%) were discontinued from caspofungin 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 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% for at Least One Treatment Group by System Organ Class or Preferred Term

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

* Regardless of causality

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

8.3 Postmarketing Experience

The following additional adverse reactions have been identified during the post-approval use of caspofungin. 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, Stevens-Johnson, skin exfoliation

• Renal and urinary disorders: clinically significant renal dysfunction

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

9. OVERDOSAGE

In clinical studies the highest dose was 210 mg, administered as a single dose to 6 healthy subjects. This dose 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. The minimum lethal dose of caspofungin in rats was 50 mg/kg, a dose which is equivalent to 10 times the recommended daily dose based on relative body surface area comparison.

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.

10. DRUG INTERACTIONS

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.

Clinical studies in adult healthy volunteers show that the pharmacokinetics of caspofungin are not altered by itraconazole, amphotericin B, mycophenolate, nelfinavir, or tacrolimus. Caspofungin has no effect on the pharmacokinetics of itraconazole, amphotericin B, or the active metabolite of mycophenolate.

Cyclosporine: In two adult clinical studies, cyclosporine (one 4 mg/kg dose or two 3 mg/kg doses) increased the AUC of caspofungin by approximately 35%. Caspofungin did not increase the plasma levels of cyclosporine. There were transient increases in liver ALT and AST when caspofungin and cyclosporine were co-administered [see Warnings and Precautions].

Tacrolimus: For patients receiving caspofungin and tacrolimus, standard monitoring of tacrolimus blood concentrations and appropriate tacrolimus dosage adjustments are recommended.

Rifampin: Adult patients on rifampin should receive 70 mg of caspofungin daily.

Other inducers of drug clearance:

Adults: When caspofungin is co-administered to adult patients with inducers of drug clearance, such as efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, use of a daily dose of 70 mg of caspofungin should be considered.

Pediatric Patients: When caspofungin is co-administered to pediatric patients with inducers of drug clearance, such as rifampin, efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, a caspofungin dose of 70 mg/m2 daily (not to exceed an actual daily dose of 70 mg) should be considered.

11. PHARMACOKINETICS

Distribution

Plasma concentrations of caspofungin decline in a polyphasic manner following single 1-hour IV infusions. A short α-phase occurs immediately postinfusion, 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. 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, 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, 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.

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: CANCIDAS, by MERCK.

b) Generic drugs: None.

2) How Supplied:

No. 3822 — CANCIDAS 50 mg is a white to off-white powder/cake for infusion in a vial with a red aluminum band and a plastic cap.

NDC 0006-3822-10 supplied as one single-use vial.

No. 3823 — CANCIDAS 70 mg is a white to off-white powder/cake for infusion in a vial with a yellow/orange aluminum band and a plastic cap.

NDC 0006-3823-10 supplied as one single-use vial.

3) Storage:

Vials: The lyophilized vials should be stored refrigerated at 2° to 8°C (36° to 46°F).

Reconstituted Concentrate: Reconstituted CANCIDAS may be stored at ≤25°C (≤77°F) for one hour prior to the preparation of the patient infusion solution.

Diluted Product: The final patient infusion solution in the IV bag or bottle can be stored at ≤25°C (≤77°F) for 24 hours or at 2 to 8°C (36 to 46°F) for 48 hours.

Rx only

Rev 08/12