Caspofungin Acetate (Page 4 of 7)
8.5 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 and older) 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.
8.6 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 [see Clinical Pharmacology (12.3)]. However, where recommended, a 70 mg loading dose should still be administered on Day 1 [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. There is no clinical experience in adult patients with severe hepatic impairment (Child-Pugh score greater than 9) and in pediatric patients 3 months to 17 years of age with any degree of hepatic impairment.
8.7 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 [see Clinical Pharmacology (12.3)].
10 OVERDOSAGE
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.
11 DESCRIPTION
Caspofungin acetate for injection 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 acetate is an echinocandin antifungal that inhibits 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). Caspofungin acetate for injection 50 mg vial contains 50 mg of caspofungin equivalent to 55.5 mg of caspofungin acetate. Caspofungin acetate for injection 50 mg vial also contains 39 mg sucrose, 26 mg mannitol, 2 mg glacial acetic acid added as a buffering agent, and sodium hydroxide added as a pH adjuster ingredient. Caspofungin acetate for injection 70 mg vial contains 70 mg of caspofungin equivalent to 77.7 mg of caspofungin acetate. Caspofungin acetate for injection 70 mg vial also contains 54 mg sucrose, 36 mg mannitol, 2.7 mg glacial acetic acid added as a buffering agent, and sodium hydroxide added as a pH adjuster ingredient.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. The empirical formula is C52 H88 N10 O15 •2C2 H4 O2 and the formula weight is 1213.42. The structural formula is:
Caspofungin-SPL-Chemical-Structure
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Caspofungin is an echinocandin antifungal drug [see Microbiology (12.4)].
12.3 Pharmacokinetics
Adult and pediatric pharmacokinetic parameters are presented in Table 8.
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 to 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.
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 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 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 Dosage and Administration (2.4)].
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 [see Use in Specific Populations (8.5)].
Pediatric Patients Caspofungin 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)]
[ see Use in Specific Populations
(8.4) ].
Pharmacokinetic parameters following multiple doses of caspofungin in pediatric and adult patients are presented in Table 8.
Table 8: Pharmacokinetic Parameters Following Multiple Doses of Caspofungin in Pediatric (3 months to 17 years) and Adult Patients
| Population | N | Daily Dose | Pharmacokinetic Parameters (Mean ± Standard Deviation) | |||||
| AUC0-24hr ( mcg∙hr/mL) | C1hr ( mcg/mL) | C24hr ( mcg/mL) | t1/2 (hr)* | CI (mL/min) | ||||
| PEDIATRIC PATIENTS | ||||||||
| Adolescents, Aged 12-17 years | 8 | 50 mg/m2 | 124.9 ± 50.4 | 14.0 ± 6.9 | 2.4 ± 1.0 | 11.2 ± 1.7 | 12.6 ± 5.5 | |
| Children, Aged 2-11 years | 9 | 50 mg/m2 | 120.0 ± 33.4 | 16.1 ± 4.2 | 1.7 ± 0.8 | 8.2 ± 2.4 | 6.4 ± 2.6 | |
| Young Children, Aged 3-23 months | 8 | 50 mg/m2 | 131.2 ± 17.7 | 17.6 ± 3.9 | 1.7 ± 0.7 | 8.8 ± 2.1 | 3.2 ± 0.4 | |
| ADULT PATIENTS | ||||||||
| Adults with Esophageal Candidiasis | 6† | 50 mg | 87.3 ± 30.0 | 8.7 ± 2.1 | 1.7 ± 0.7 | 13.0 ± 1.9 | 10.6 ± 3.8 | |
| Adults receiving Empirical Therapy | 119‡ | 50 mg § | — | 8.0 ± 3.4 | 1.6 ± 0.7 | — | — | |
| * Harmonic Mean ± jackknife standard deviation † N=5 for C1hr and AUC0-24hr ; N=6 for C24hr ‡ N=117 for C24hr ; N=119 for C1hr § Following an initial 70 mg loading dose on day 1 | ||||||||
Drug Interactions [see Drug Interactions (7)]
Studies in vitro show that caspofungin acetate is not an inhibitor of any enzyme in the cytochrome P (CYP) system. Caspofungin is not a substrate for P-glycoprotein and is a poor substrate for CYP enzymes.
In clinical studies, caspofungin did not induce the CYP3A4 metabolism of other drugs. Clinical studies in adult healthy volunteers also demonstrated 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 (5.2)].
Tacrolimus: Caspofungin reduced the blood AUC0 — 12 of tacrolimus (FK-506, Prograf®) by approximately 20%, peak blood concentration (Cmax ) by 16%, and 12-hour blood concentration (C12hr ) by 26% in healthy adult subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of caspofungin 70 mg daily, as compared to results from a control period in which tacrolimus was administered alone. For patients receiving both therapies, standard monitoring of tacrolimus whole blood trough concentrations and appropriate tacrolimus dosage adjustments are recommended.
Rifampin: A drug-drug interaction study with rifampin in adult healthy volunteers has shown a 30% decrease in caspofungin trough concentrations [see Dosage and Administration (2.5)].
Other Inducers of Hepatic CYP Enzymes
Adults: Results from regression analyses of adult patient pharmacokinetic data suggest that co-administration of other hepatic CYP enzyme inducers (e.g., efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine) with caspofungin may result in clinically meaningful reductions in caspofungin concentrations. It is not known which drug clearance mechanism involved in caspofungin disposition may be inducible [see Dosage and Administration (2.5)].
Pediatric patients : In pediatric patients, results from regression analyses of pharmacokinetic data suggest that co-administration of dexamethasone with caspofungin may result in clinically meaningful reductions in caspofungin trough concentrations. This finding may indicate that pediatric patients will have similar reductions with inducers as seen in adults [see Dosage and Administration (2.5)].
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