Caspofungina Genfarma

Empirical Therapy for Presumed Fungal Infections in Febrile, Neutropenic Patients

Caspofungina Genfarma acetate for injection is indicated as empirical therapy for presumed fungal infections in febrile, neutropenic adult and pediatric patients (3 months of age and older).

Treatment of Candidemia and Other Candida Infections

Caspofungina Genfarma acetate for injection is indicated for the treatment of candidemia and the following Candida infections: intra-abdominal abscesses, peritonitis, and pleural space infections in adult and pediatric patients (3 months of age and older).

Limitation of Use: Caspofungina Genfarma acetate for injection has not been studied in endocarditis, osteomyelitis, and meningitis due to Candida.

Treatment of Esophageal Candidiasis

Caspofungina Genfarma acetate for injection is indicated for the treatment of esophageal candidiasis in adult and pediatric patients (3 months of age and older).

Limitation of Use: Caspofungina Genfarma acetate for injection has not been approved for the treatment of oropharyngeal candidiasis (OPC). In the study that evaluated the efficacy of Caspofungina Genfarma acetate for injection in the treatment of esophageal candidiasis, patients with concomitant OPC had higher relapse rate of the OPC.

Treatment of Invasive Aspergillosis in Patients Who Are Refractory to or Intolerant of Other Therapies

Caspofungina Genfarma acetate for injection is indicated for the treatment of invasive aspergillosis in adult and pediatric patients (3 months of age and older) who are refractory to or intolerant of other therapies.

Limitation of Use: Caspofungina Genfarma acetate for injection has not been studied as initial therapy for invasive aspergillosis.

Caspofungina Genfarma is an antifungal medicine that fights infections caused by fungus.

Caspofungina Genfarma is used to treat fungal infections of the stomach, lungs, esophagus, or other internal body areas.

Caspofungina Genfarma may also be used for purposes not listed in this medication guide.

Important Administration Instructions For Use In All Patients

Administer Caspofungina Genfarma by slow intravenous (IV) infusion over approximately 1 hour. Do not administer Caspofungina Genfarma by IV bolus administration.

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

The dosage and duration of Caspofungina Genfarma 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) 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 ]. 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), Caspofungina Genfarma 35 mg once daily is recommended based upon pharmacokinetic data 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 Caspofungina Genfarma once daily. W hen Caspofungina Genfarma 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 Caspofungina Genfarma should be considered.

Pediatric Patients

Pediatric patients on rifampin should receive 70 mg/m² of Caspofungina Genfarma daily (not to exceed an actual daily dose of 70 mg. W hen Caspofungina Genfarma is co-administered to pediatric patients with other inducers of hepatic CYP enzymes, such as efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, a Caspofungina Genfarma dose of 70 mg/m² once daily (not to exceed 70 mg) should be considered.

Preparation For Administration

Reconstitution Of Caspofungina Genfarma For

Intravenous Infusion

1. Equilibrate the refrigerated vial of Caspofungina Genfarma to room temperature.
2. Aseptically add 10.8 mL of 0.9% Sodium Chloride Injection, Sterile W ater for Injection, Bacteriostatic W ater for Injection with methylparaben and propylparaben, or Bacteriostatic W ater for Injection with 0.9% benzyl alcohol to the vial.
3. Each vial of Caspofungina Genfarma contains an intentional overfill of Caspofungina Genfarma. Thus, the drug concentration of the resulting solution is listed in Table 1 below.

   Table 1: Information for Preparation of Caspofungina Genfarma

   Caspofungina Genfarma vial	Total Drug Content (including overfill)	Reconstitution Volume to be added	Resulting Concentration following Reconstitution
   50 mg	54.6 mg	10.8 mL	5 mg/mL
   70 mg	75.6 mg	10.8 mL	7 mg/mL

4. 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.
5. The reconstituted solution of Caspofungina Genfarma 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.
6. Caspofungina Genfarma vials are for single use only. Discard unused portion.

Dilution Of The Reconstituted Solution In The

Intravenous Bag For Infusion

1. Aseptically transfer the appropriate volume (mL) of reconstituted Caspofungina Genfarma 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.
2. Alternatively, the volume (mL) of reconstituted Caspofungina Genfarma 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.
3. 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 ]. 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.

Drug Incompatibilities

Do not mix or co-infuse Caspofungina Genfarma with other medications, as there are no data available on the compatibility of Caspofungina Genfarma with other intravenous substances, additives, or medications.

Do not use diluents containing dextrose (α-D-glucose), as Caspofungina Genfarma is not stable in diluents containing dextrose.

How supplied

Dosage Forms And Strengths

Caspofungina Genfarma 50 mg is a white to off-white lyophilized cake or powder for reconstitution in a single-dose glass vial with a red aluminum band and a plastic cap. Caspofungina Genfarma 50-mg vial contains 54.6 mg of Caspofungina Genfarma.

Caspofungina Genfarma 70 mg is a white to off-white lyophilized cake or powder for reconstitution in a single-dose glass vial with a yellow/orange aluminum band and a plastic cap. Caspofungina Genfarma 70-mg vial contains 75.6 mg of Caspofungina Genfarma.

Storage And Handling

Caspofungina Genfarma 50 mg is a lyophilized white to off-white cake or powder for intravenous infusion supplied in single-dose vials with a red aluminum band and a plastic cap.

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

Caspofungina Genfarma 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. Storage and Handling

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

REFERENCES

1. Mosteller RD: Simplified Calculation of Body Surface Area. N Engl J Med 1987 Oct 22;317(17): 1098 (letter).

2. Clinical and Laboratory Standards Institute (CLSI). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard-Third Edition. CLSI document M27-A3. Clinical and Laboratory Standards Institute, 940 W est Valley Road, Suite 1400, W ayne, Pennsylvania 19087, USA, 2008.

3. Clinical and Laboratory Standards Institute (CLSI). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Third Informational Supplement. CLSI document M27-S3. Clinical and Laboratory Standards Institute, 940 W est Valley Road, Suite 1400, W ayne, Pennsylvania 19087, USA, 2008.

Distributed by: Merck Sharp & Dohme Corp., a subsidiary of MERCK & CO., INC., Whitehouse Station, NJ 08889, USA. Revised: Apr 2016

See also:
What is the most important information I should know about Caspofungina Genfarma?

You should not use Caspofungina Genfarma if you are allergic to it.

Before receiving Caspofungina Genfarma, tell your doctor if you have liver disease, or if you have recently had a kidney, heart, or liver transplant.

Use Caspofungina Genfarma for the full prescribed length of time. Your symptoms may improve before the infection is completely treated.

You may be given other medications to treat your infection. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice.

Use Caspofungina Genfarma as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Caspofungina Genfarma is usually given as an injection at your doctor's office, hospital, or clinic. If you will be using Caspofungina Genfarma at home, a health care provider will teach you how to use it. Be sure you understand how to use Caspofungina Genfarma. Follow the procedures you are taught when you use a dose. Contact your health care provider if you have any questions.
• Do not use Caspofungina Genfarma if it contains particles, is cloudy or discolored, or if the vial is cracked or damaged.
• Keep this product, as well as syringes and needles, out of the reach of children and pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.
• If you miss a dose of Caspofungina Genfarma, contact your doctor right away.

Ask your health care provider any questions you may have about how to use Caspofungina Genfarma.

Use: Labeled Indications

Aspergillosis, invasive: Treatment of invasive aspergillosis in patients ≥3 months of age who are refractory to or intolerant of other therapies (eg, amphotericin B, lipid formulations of amphotericin B, itraconazole).

Limitations of use: Has not been studied as initial therapy for invasive aspergillosis.

Candidemia and other Candida infections: Treatment of candidemia and the following candida infections in patients ≥3 months of age: Intra-abdominal abscesses, peritonitis, and pleural space infections.

Limitations of use: Has not been studied in endocarditis, osteomyelitis, and meningitis due to Candida.

Candidiasis, esophageal: Treatment of esophageal candidiasis in patients ≥3 months of age.

Limitations of use: Not approved for the treatment of oropharyngeal candidiasis (OPC).

Fungal infections, empiric therapy (neutropenic patients): Empiric therapy for presumed fungal infections in febrile, neutropenic patients ≥3 months of age.

Off Label Uses

Candida infection, prophylaxis in neutropenic cancer patients at substantial risk

Based on the Infectious Diseases Society of America (IDSA) guidelines for the use of antimicrobial agents in neutropenic patients with cancer, Caspofungina Genfarma is effective and recommended as an alternate agent in the prophylaxis against Candida infection in neutropenic cancer patients with substantial risk (eg, allogeneic transplant or undergoing induction therapy for acute leukemia).

Candidiasis, chronic disseminated (hepatosplenic)

Based on the Infectious Diseases Society of America (IDSA) clinical practice guidelines for the management of candidiasis, Caspofungina Genfarma is an effective and recommended treatment for patients with chronic disseminated (hepatosplenic) candidiasis.

Candidiasis, empiric therapy (non-neutropenic ICU patients)

Based on the Infectious Diseases Society of America (IDSA) clinical practice guidelines for the management of candidiasis, Caspofungina Genfarma is an effective and recommended agent for empiric therapy of suspected invasive candidiasis in non-neutropenic patients in the ICU.

Candidiasis, esophageal, in HIV-infected patients

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, Caspofungina Genfarma is an effective and recommended alternative agent for the treatment of esophageal candidiasis in adolescent and adult HIV-infected patients.

Candidiasis, intravascular infections

Based on the Infectious Diseases Society of America (IDSA) clinical practice guidelines for the management of candidiasis, Caspofungina Genfarma is an effective and recommended treatment for patients with Candida intravascular infections, including patients with endocarditis (native or prosthetic valve), infections of implantable cardiac devices (pacemaker, implantable cardiac defibrillator), and Candida suppurative thrombophlebitis.

Candidiasis, oropharyngeal (refractory disease)

Based on the Infectious Diseases Society of America (IDSA) clinical practice guidelines for the management of candidiasis, Caspofungina Genfarma may be considered as an alternative for patients with oropharyngeal candidiasis refractory to other antifungals.

Candidiasis, osteoarticular infections

Based on the Infectious Diseases Society of America (IDSA) clinical practice guidelines for the management of candidiasis, Caspofungina Genfarma is an effective and recommended treatment for patients with Candida osteoarticular infections, including Candida osteomyelitis and Candida septic arthritis.

Candidiasis, prophylaxis against invasive candidiasis (high-risk ICU patients in units with a high rate of invasive candidiasis)

Based on the Infectious Diseases Society of America (IDSA) clinical practice guidelines for the management of candidiasis, Caspofungina Genfarma may be considered as an alternative agent for prophylaxis against invasive candidiasis in high-risk patients in adult ICUs with a high rate of invasive candidiasis (>5%).

See also:
What other drugs will affect Caspofungina Genfarma?

Studies in vitro show that Caspofungina Genfarma acetate is not an inhibitor of any enzyme in the cytochrome P-450 (CYP) system. In clinical studies, Caspofungina Genfarma did not induce the CYP3A4 metabolism of other drugs. Caspofungina Genfarma is not a substrate for P-glycoprotein and is a poor substrate for cytochrome P-450 enzymes.

In 2 adult clinical studies, cyclosporine (one 4-mg/kg dose or two 3-mg/kg doses) increased the AUC of Caspofungina Genfarma by approximately 35%. These AUC increases are probably due to reduced uptake of Caspofungina Genfarma by the liver. Caspofungina Genfarma did not increase the plasma levels of cyclosporine. There were transient increases in liver ALT and AST when Caspofungina Genfarma and cyclosporine were co-administered. In a retrospective study of 40 patients treated during marketed use with Caspofungina Genfarma and/or cyclosporine for 1-290 days (median 17.5 days), no serious hepatic adverse events were noted.

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

Caspofungina Genfarma reduced the 12-hr blood concentration (C_{12 hr}) of tacrolimus (FK-506) by 26% in healthy adult volunteers. For patients receiving both therapies, standard monitoring of tacrolimus blood concentrations and appropriate tacrolimus dosage adjustments are recommended.

Results from 2 clinical drug interaction studies in healthy adult volunteers indicate that rifampicin both induces and inhibits Caspofungina Genfarma disposition with net induction at steady-state. In 1 study, rifampicin and Caspofungina Genfarma were co-administered for 14 days with both therapies initiated on the same day. In the 2nd study, rifampicin was administered alone for 14 days to allow the induction effect to reach steady state and then rifampicin and Caspofungina Genfarma were co-administered for an additional 14 days. When the induction effect of rifampicin was at steady state, there was little change in Caspofungina Genfarma AUC or end-of-infusion concentration, but Caspofungina Genfarma trough concentrations were reduced by approximately 30%. The inhibitory effect of rifampicin was demonstrated when rifampicin and Caspofungina Genfarma treatments were initiated on the same day, and a transient elevation in Caspofungina Genfarma plasma concentrations occurred on day 1 (approximately 60% increase in AUC). This inhibitory effect was not seen when Caspofungina Genfarma was added to preexisting rifampicin therapy and no elevation in Caspofungina Genfarma concentrations occurred. In addition, results from population pharmacokinetic screening in adults suggest that co-administration of other inducers of drug clearance (efavirenz, nevirapine, phenytoin, dexamethasone or carbamazepine) with Caspofungina Genfarma may also result in clinically meaningful reductions in Caspofungina Genfarma concentrations. Available data suggest that the inducible drug clearance mechanism involved in Caspofungina Genfarma disposition is likely an uptake transport process, rather than metabolism. Therefore, when Caspofungina Genfarma is co-administered to adult patients with inducers of drug clearance eg, efavirenz, nevirapine, rifampicin, dexamethasone, phenytoin or carbamazepine, use of a daily dose of Caspofungina Genfarma 70 mg should be considered.

In pediatric patients, results from regression analyses of pharmacokinetic data suggest that co-administration of dexamethasone with Caspofungina Genfarma may result in clinically meaningful reductions in Caspofungina Genfarma trough concentrations. This finding may indicate that pediatric patients will have similar reductions with inducers as seen in adults. When Caspofungina Genfarma is co-administered to pediatric patients with inducers of drug clearance eg, rifampin, efavirenz, nevirapine, phenytoin, dexamethasone or carbamazepine, a Caspofungina Genfarma dose of 70-mg/m² daily (not to exceed an actual daily dose of 70 mg) should be considered.

See also:
What are the possible side effects of Caspofungina Genfarma?

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

• Hypersensitivity
• Hepatic Effects
• Elevated Liver Enzymes During Concomitant Use With Cyclosporine

Clinical Trials Experience

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

Clinical Trials Experience In Adults

The overall safety of Caspofungina Genfarma was assessed in 1865 adult individuals who received single or multiple doses of Caspofungina Genfarma: 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 Caspofungina Genfarma 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 Caspofungina Genfarma 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 2.

Table 2: Adverse Reactions Among Patients with Persistent Fever and Neutropenia Incidence 7.5% or greater for at Least One Treatment Group

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

To evaluate the effect of Caspofungina Genfarma 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 Caspofungina Genfarma (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 Caspofungina Genfarma 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 3.

Table 3: Adverse Reactions Among Patients with Candidemia or other Candida Infections* Incidence 10% or Greater for at Least One Treatment Group

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 Caspofungina Genfarma (20%) than in the group treated with amphotericin B (49%).

To evaluate the effect of Caspofungina Genfarma 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 Caspofungina Genfarma than in the group treated with amphotericin B.

In a second randomized, double-blinded invasive candidiasis study, patients received either Caspofungina Genfarma 50 mg/day (following a 70-mg loading dose) or Caspofungina Genfarma 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 4.

Table 4: Adverse Reactions Among Patients with Candidemia or other Candida Infections* Incidence 5% or Greater for at Least One Treatment Group

Esophageal Candidiasis And Oropharyngeal Candidiasis

Adverse reactions occurring in 10% or greater of patients with esophageal and/or oropharyngeal candidiasis are presented in Table 5.

Table 5: Adverse Reactions Among Patients with Esophageal and/or Oropharyngeal Candidiasis Incidence 10% or Greater for at Least One Treatment Group

Invasive Aspergillosis

In an open-label, noncomparative aspergillosis study, in which 69 patients received Caspofungina Genfarma (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.

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

The overall safety of Caspofungina Genfarma was assessed in 171 pediatric patients who received single or multiple doses of Caspofungina Genfarma. 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 intraabdominal abscesses, peritonitis, or pleural space infections; 1 patient with esophageal candidiasis; and 10 patients with invasive aspergillosis. The overall safety profile of Caspofungina Genfarma in pediatric patients is comparable to that in adult patients. Table 6 shows the incidence of adverse reactions reported in 7.5% or greater of pediatric patients in clinical studies.

One patient (0.6%) receiving Caspofungina Genfarma, and three patients (12%) receiving AmBisome developed a serious drug-related adverse reaction. Two patients (1%) were discontinued from Caspofungina Genfarma 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 Caspofungina Genfarma and 35% in the group treated with AmBisome.

Table 6: Adverse Reactions Among Pediatric Patients (0 months to 17 years of age) Incidence 7.5% or Greater for at Least One Treatment Group

Overall Safety Experience Of Caspofungina Genfarma In Clinical Trials

The overall safety of Caspofungina Genfarma 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 Caspofungina Genfarma, 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 Caspofungina Genfarma in these trials are shown in Table 7.

Overall, 1665 of the 1951 (85%) patients/volunteers who received Caspofungina Genfarma experienced an adverse reaction.

Table 7: Adverse Reactions* in Patients Who Received Caspofungina Genfarma in Clinical Trials† Incidence 5% or Greater for at Least One Treatment Group

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

The following additional adverse reactions have been identified during the post-approval use of Caspofungina Genfarma. 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

Caspofungina Genfarma (Caspofungina Genfarma 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). It also contains the following inactive ingredients: Sucrose, mannitol, acetic acid and sodium hydroxide.

Caspofungina Genfarma 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 Caspofungina Genfarma acetate is approximately 6.6. The empirical formula is C₅₂H₈₈N₁₀O₁₅·2C₂H₄O₂ and the formula weight is 1213.42.

Caspofungina Genfarma is a sterile, lyophilized product for IV infusion that contains a semisynthetic lipopeptide (echinocandin) compound synthesized from a fermentation product of Glarea lozoyensis. Caspofungina Genfarma 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.

Before reconstitution, Caspofungina Genfarma appears to be solid, white to off-white compact powder.

After reconstitution, Caspofungina Genfarma appears to be a clear, colorless solution, leaving no visible residue as undissolved matter and free from particles of foreign matter that can be observed on visual inspection.