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CANCIDAS * is a sterile, lyophilized product for intravenous (IV) infusion that contains a semisynthetic lipopeptide (echinocandin) compound synthesized from a fermentation product of Glarea lozoyensis . CANCIDAS is the first of a new class of antifungal drugs (glucan synthesis inhibitors) that inhibit the synthesis of (beta) (1,3)-D-glucan, an integral component of the fungal cell wall.
CANCIDAS (caspofungin acetate) is 1-[(4 R ,5 S )-5-[(2-aminoethyl)amino]- N 2 - (10,12-dimethyl-1-oxotetradecyl)-4 - hydroxy- L-ornithine]-5-[(3 R )-3-hydroxy-L-ornithine] pneumocandin B 0 diacetate (salt). In addition to the active ingredient caspofungin acetate, CANCIDAS contains the following inactive ingredients: sucrose, mannitol, 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. The empirical formula is C 52 H 88 N 10 O 15 ·2C 2 H 4 O 2 and the formula weight is 1213.42. The structural formula is:
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Distribution
Plasma concentrations of caspofungin decline in a polyphasic manner following single 1-hour IV infusions. A short (alpha)-phase occurs immediately postinfusion, followed by a (beta)-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, (gamma)-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 [ 3 H] caspofungin acetate. There is little excretion or biotransformation of caspofungin during the first 30 hours after administration.
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 to 20 days postdose), there is a low level (3 to 7 picomoles/mg protein, or 0.6 to 1.3% of administered dose) of covalent binding of radiolabel in plasma following single-dose administration of [ 3 H] 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.
In a single-dose radiolabeled pharmacokinetic study, plasma, urine, and feces were collected over 27 days. Plasma concentrations of radioactivity and of caspofungin were similar during the first 24 to 48 hours postdose; thereafter drug levels fell more rapidly. Radiolabel remained quantifiable through Day 27, whereas caspofungin concentrations fell below the limit of quantitation after 6 to 8 days postdose. After single intravenous administration of [ 3 H] caspofungin acetate, excretion of caspofungin and its metabolites in humans were 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
Plasma concentrations of caspofungin in healthy men and women were similar following a single 70-mg dose. After 13 daily 50-mg doses, caspofungin plasma concentrations in women were elevated slightly (approximately 22% in area under the curve [AUC]) relative to men. No dosage adjustment is necessary based on gender.
Geriatric
Plasma concentrations of caspofungin in healthy older men and women (>/=65 years of age) were increased slightly (approximately 28% in area under the curve [AUC]) compared to young healthy men after a single 70-mg dose of caspofungin. Age is not a significant determinant of caspofungin pharmacokinetics in patients with fungal infections. No dosage adjustment is necessary for the elderly (see PRECAUTIONS , Geriatric Use ).
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.
In a clinical study of single 70-mg doses, caspofungin pharmacokinetics were similar in volunteers with mild renal insufficiency (creatinine clearance 50 to 80 mL/min) and control subjects. Moderate (creatinine clearance 31 to 49 mL/min), advanced (creatinine clearance 5 to 30 mL/min), and end-stage (creatinine clearance <10 mL/min and dialysis dependent) renal insufficiency moderately increased caspofungin plasma concentrations after single-dose administration (range: 30 to 49% for AUC). However, in patients with invasive aspergillosis who received multiple daily doses of CANCIDAS 50 mg, there was no significant effect of mild to advanced renal impairment on caspofungin trough concentrations. No dosage adjustment is necessary for patients with renal insufficiency. Caspofungin is not dialyzable, thus supplementary dosing is not required following hemodialysis.
Plasma concentrations of caspofungin after a single 70-mg dose in patients with mild hepatic insufficiency (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 patients with mild hepatic insufficiency 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 insufficiency. Patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9) who received a single 70-mg dose of CANCIDAS had an average plasma caspofungin increase of 76% in AUC compared to control subjects. A dosage reduction is recommended for patients with moderate hepatic insufficiency (see DOSAGE AND ADMINISTRATION ). There is no clinical experience in patients with severe hepatic insufficiency (Child-Pugh score >9).
Pediatric Patients
CANCIDAS has not been adequately studied in patients under 18 years of age.
Caspofungin acetate, the active ingredient of CANCIDAS, inhibits the synthesis of (beta) (1,3)-D-glucan, an essential component of the cell wall of susceptible filamentous fungi. (beta) (1,3)-D-glucan is not present in mammalian cells. Caspofungin has shown activity in regions of active cell growth of the hyphae of Aspergillus fumigatus .
Activity in vitro
Caspofungin exhibits in vitro activity against Aspergillus fumigatus, Aspergillus flavus , and Aspergillus terreus . Susceptibility testing was performed according to the National Committee for Clinical Laboratory Standards (NCCLS) proposed method (M38-P). Standardized susceptibility testing methods for (beta) (1,3)-D-glucan synthesis inhibitors have not been established, and results of susceptibility studies do not correlate with clinical outcome.
Activity in vivo
Caspofungin, administered parenterally to immunocompetent and immunosuppressed rodents, as long as 24 hours after disseminated or pulmonary infection with Aspergillus fumigatus , has shown prolonged survival, which has not been consistently associated with a reduction in mycological burden.
In vitro resistance development to caspofungin by Aspergillus species has not been studied. In limited clinical experience, drug resistance in patients with invasive aspergillosis has not been observed. The incidence of drug resistance by various clinical isolates of Aspergillus species is unknown.
Studies in vitro and in vivo of caspofungin, in combination with amphotericin B, suggest no antagonism of antifungal activity against A. fumigatus . The clinical significance of these results is unknown.
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 CANCIDAS. 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. The definitions were modeled after the Mycoses Study Group Criteria. 1 Patients were administered a single 70-mg loading dose of CANCIDAS and subsequently dosed with 50 mg daily. The mean duration of therapy was 33.7 days, with a range of 1 to 162 days.
An independent expert panel evaluated patient data, including diagnosis of invasive aspergillosis, response and tolerability to previous antifungal therapy, treatment course on CANCIDAS, and clinical outcome.
A favorable response was defined as either complete resolution (complete response) or clinically meaningful improvement (partial response) of all signs and symptoms and attributable radiographic findings. Stable, nonprogressive disease was considered to be an unfavorable response.
Among the 69 patients enrolled in the study, 63 met entry diagnostic criteria and had outcome data; and of these, 52 patients received treatment for >7 days. Fifty-three (84%) were refractory to previous antifungal therapy and 10 (16%) were intolerant. Forty-five patients had pulmonary disease and 18 had extrapulmonary disease. Underlying conditions were hematologic malignancy (N=24), allogeneic bone marrow transplant or stem cell transplant (N=18), organ transplant (N=8), solid tumor (N=3), or other conditions (N=10). All patients in the study received concomitant therapies for their other underlying conditions. Eighteen patients received tacrolimus and CANCIDAS concomitantly, of whom 8 also received mycophenolate mofetil.
Overall, the expert panel determined that 41% (26/63) of patients receiving at least one dose of CANCIDAS had a favorable response. For those patients who received >7 days of therapy with CANCIDAS, 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 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.
There is substantial evidence that CANCIDAS is well tolerated and 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 CANCIDAS has not been evaluated in concurrently controlled clinical studies, with other antifungal therapies.
CANCIDAS is indicated for the 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).
CANCIDAS has not been studied as initial therapy for invasive aspergillosis.
CANCIDAS is contraindicated in patients with hypersensitivity to any component of this product.
Concomitant use of CANCIDAS with cyclosporine is not recommended unless the potential benefit outweighs the potential risk to the patient. In one clinical study, 3 of 4 healthy subjects who received CANCIDAS 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 subjects in the same study, 2 of 8 who received CANCIDAS 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 (see ADVERSE REACTIONS , Laboratory Abnormalities .) Hence, concomitant use of CANCIDAS with cyclosporine is not recommended until multiple-dose use in patients is studied.
General
The efficacy of a 70-mg dose regimen in patients who are not clinically responding to the 50 mg daily dose is not known. Limited safety data suggest that an increase in dose to 70 mg daily is well tolerated. The safety and efficacy of doses above 70 mg have not been adequately studied.
The safety information on treatment durations longer than 2 weeks is limited, however, available data suggest that CANCIDAS continues to be well tolerated with longer courses of therapy (68 patients received from 15 to 60 days of therapy; 12 patients received from 61 to 162 days of therapy).
Studies in vitro show that caspofungin acetate is not an inhibitor of any enzyme in the cytochrome P450 (CYP) system. In clinical studies, caspofungin did not induce the CYP3A4 metabolism of other drugs. Caspofungin is not a substrate for P-glycoprotein and is a poor substrate for cytochrome P450 enzymes.
Clinical studies in healthy volunteers show that the pharmacokinetics of CANCIDAS are not altered by itraconazole, amphotericin B, mycophenolate, or tacrolimus. CANCIDAS has no effect on the pharmacokinetics of itraconazole, amphotericin B, or the active metabolite of mycophenolate.
CANCIDAS reduced the blood AUC 0-12 of tacrolimus (FK-506, Prograf® 2 ) by approximately 20%, peak blood concentration (C max ) by 16%, and 12-hour blood concentration (C 12hr ) by 26% in healthy subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of CANCIDAS 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 blood concentrations and appropriate tacrolimus dosage adjustments are recommended.
In two clinical studies, cyclosporine (one 4 mg/kg dose or two 3 mg/kg doses) increased the AUC of caspofungin by approximately 35%. CANCIDAS did not increase the plasma levels of cyclosporine. There were transient increases in liver ALT and AST when CANCIDAS and cyclosporine were coadministered (see WARNINGS and ADVERSE EFFECTS , Laboratory Abnormalities ).
The results from regression analyses of patient pharmacokinetic data suggest that coadministration of inducers of drug clearance and/or mixed inducer/inhibitors with CANCIDAS may result in clinically meaningful reductions in caspofungin concentrations. This is based on results from a small number of patients who were administered the inducers and/or mixed inducer/inhibitors efavirenz, nelfinavir, nevirapine, phenytoin, rifampin, dexamethasone, or carbamazepine prior to and/or concomitant with caspofungin. There are presently no data from formal drug interaction studies to evaluate these regression analyses of patient pharmacokinetic data, and it is not known which drug clearance mechanism involved in caspofungin disposition may be inducible. When coadministering CANCIDAS with efavirenz, nelfinavir, nevirapine, phenytoin, rifampin, dexamethasone, or carbamazepine, an increase in the daily dose of CANCIDAS to 70 mg, following the usual 70-mg loading dose, should be considered in patients who are not clinically responding.
Carcinogenesis, Mutagenesis, and 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.
Pregnancy
Pregnancy Category C. CANCIDAS was shown to be embryotoxic in rats and rabbits. Findings included incomplete ossification of the skull and torso and an increased incidence of cervical rib in rats.
An increased incidence of incomplete ossifications of the talus/calcaneus was seen in rabbits. Caspofungin also produced increases in resorptions in rats and rabbits and periimplantation losses in rats. These findings were observed at doses which produced exposures similar to those seen in patients treated with a 70-mg dose. Caspofungin crossed the placental barrier in rats and rabbits and was detected in the plasma of fetuses of pregnant animals dosed with CANCIDAS. There are no adequate and well-controlled studies in pregnant women. CANCIDAS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
Caspofungin was found in the milk of lactating, drug-treated rats. 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.
Patients with Hepatic Insufficiency
Patients with mild hepatic insufficiency (Child-Pugh score 5 to 6) do not need a dosage adjustment. For patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9), after the initial 70-mg loading dose, CANCIDAS 35 mg daily is recommended. There is no clinical experience in patients with severe hepatic insufficiency (Child-Pugh score >9).
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of CANCIDAS 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. No dose adjustment is recommended for the elderly; however, greater sensitivity of some older individuals cannot be ruled out.
General
Possible histamine-mediated symptoms have been reported in clinical studies including isolated reports of rash, facial swelling, pruritus, or sensation of warmth. One case of anaphylaxis characterized by dyspnea, stridor, and worsening of rash during initial administration of CANCIDAS was reported.
Clinical Adverse Experiences
The overall safety of caspofungin was assessed in 623 individuals who received single or multiple doses of caspofungin acetate. Of the 623 individuals, 349 patients were enrolled in phase II and phase III clinical studies. Patients in clinical studies often had serious underlying medical conditions (e.g., HIV, bone marrow transplant, hematologic malignancy) requiring multiple concomitant medications. Sixty-nine patients with invasive aspergillosis were enrolled in an open-label noncomparative study; the majority of these patients had underlying hematologic malignancies.
Clinical adverse experiences with an incidence >/=2%, reported in patients treated with CANCIDAS in the noncomparative aspergillosis study are presented in Table 1.
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Also reported infrequently in this patient population were pulmonary edema, ARDS, and radiographic infiltrates.
Laboratory abnormalities with an incidence >/=2%, reported in patients treated with CANCIDAS in the noncomparative aspergillosis study are presented in Table 2.
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Drug-related clinical adverse experiences occurring in >/=2% of patients in 3 active-control studies for investigational indications other than aspergillosis are presented in Table 3.
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Laboratory abnormalities occurring in >/=2% of patients in 3 active-control studies for investigational indications other than aspergillosis are presented in Table 4.
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In one clinical study, 3 of 4 subjects who received CANCIDAS 70 mg daily 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 ALT on Day 11 that were 2 to 3 times the upper limit of normal (ULN). In a separate panel of subjects in the same study, 2 of 8 subjects who received CANCIDAS 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 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 CANCIDAS 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% (see WARNINGS ).
In clinical studies the highest dose was 100 mg, administered as a single dose to 5 patients. This dose was generally well tolerated. No overdosages have been reported. 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 one 5-week study in monkeys at doses which produced exposures approximately 4 to 6 times those seen in 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.
General Recommendations
A single 70-mg loading dose should be administered on Day 1, followed by 50 mg daily thereafter. CANCIDAS should be administered by slow IV infusion of approximately 1 hour. Duration of treatment should be based upon the severity of the patient' underlying disease, recovery from immunosuppression, and clinical response. Do not mix or co-infuse CANCIDAS with other medications. DO NOT USE DILUENTS CONTAINING DEXTROSE ((alpha)-D-GLUCOSE). The efficacy of a 70 mg dose regimen in patients who are not clinically responding to the 50 mg daily dose is not known. Limited safety data suggests that an increase in dose to 70 mg daily is well tolerated. The safety and efficacy of doses above 70 mg have not been adequately studied.
Patients with mild hepatic insufficiency (Child-Pugh score 5 to 6) do not need a dosage adjustment. However, for patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9), after the initial 70-mg loading dose, CANCIDAS 35 mg daily is recommended. There is no clinical experience in patients with severe hepatic insufficiency (Child-Pugh score >9) (see CLINICAL PHARMACOLOGY , Pharmacokinetics , Special Populations ).
Preparation of the 70-mg Day 1 loading-dose infusion
Preparation of the daily 50-mg infusion
Alternative Infusion Preparation Methods
Preparation of 70-mg Day 1 loading dose from two 50-mg vials
Reconstitute two 50-mg vials with 10.5 mL of diluent each (see Preparation of the daily 50-mg infusion ). Aseptically transfer a total of 14 mL of the reconstituted CANCIDAS from the two vials to 250 mL of 0.9% Sodium Chloride Injection.
Preparation of 50-mg daily doses at reduced volume
When medically necessary, the 50-mg daily doses can be prepared by adding 10 mL of reconstituted CANCIDAS to 100 mL of 0.9% Sodium Chloride Injection (see Preparation of the daily 50-mg infusion ).
Preparation of a 35-mg daily dose for patients with moderate Hepatic Insufficiency
Reconstitute one 50-mg vial (see above: Preparation of the daily 50-mg infusion ). Aseptically transfer 7 mL of the reconstituted CANCIDAS from the vial to 250 mL of 0.9% Sodium Chloride Injection or, if medically necessary, to 100 mL of 0.9% Sodium Chloride Injection.
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Preparation notes:
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No. 3822 -- CANCIDAS 50 mg is a white to off-white powder/cake for infusion in a vial labeled with a red aluminum band and a plastic cap.
NDC 0006-3822-10 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 one single-use vial.
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.
9344300 Issued January 2001
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