CANCIDAS® (caspofungin acetate) for injection

CANCIDAS® (caspofungin acetate) for injection

CANCIDAS® (caspofungin acetate) for injection

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 an echinocandin antifungal that inhibits the synthesis of β (1,3)-D-glucan, an integral component of the fungal cell wall.

CANCIDAS (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).

CANCIDAS 50 mg contains 50 mg of caspofungin equivalent to 55.5 mg of caspofungin acetate.

CANCIDAS 50 mg 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.

CANCIDAS 70 mg contains 70 mg of caspofungin equivalent to 77.7 mg of caspofungin acetate.

CANCIDAS 70 mg 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.

INDICATIONS AND USAGE

Empirical Therapy for Presumed Fungal Infections in Febrile, Neutropenic Patients

CANCIDAS® 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

CANCIDAS 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).

Limitations of Use: CANCIDAS has not been studied in endocarditis, osteomyelitis, and meningitis due to Candida.

Treatment of Esophageal Candidiasis

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

Limitations of Use: CANCIDAS has not been approved for the treatment of oropharyngeal candidiasis (OPC). In the study that evaluated the efficacy of caspofungin 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

CANCIDAS 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.

Limitations of Use: CANCIDAS has not been studied as initial therapy for invasive aspergillosis.

Mechanism of Action

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

Antimicrobial Activity

Caspofungin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections:

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

DOSAGE AND ADMINISTRATION

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

The dosage and duration of CANCIDAS 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 ad equate 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.

CONTRAINDICATIONS

CANCIDAS is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis) to any component of this product

WARNINGS AND PRECAUTIONS

Hypersensitivity

Anaphylaxis and other hypersensitivity reactions have been reported during administration of CANCIDAS. Possible histamine-mediated adverse reactions, including rash, facial swelling, angioedema, pruritus, sensation of warmth or bronchospasm have been reported.

Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some with a fatal outcome, have been reported with use of CANCIDAS.

Discontinue CANCIDAS at the first sign or symptom of a hypersensitivity reaction and administer appropriate treatment.

Hepatic Effects

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

Elevated Liver Enzymes During Concomitant Use with Cyclosporine

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

ADVERSE REACTIONS

  • 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

DRUG INTERACTIONS

Cyclosporine: In two adult clinical studies, cyclosporine (one 4mg/kg dose or two 3 mg/kg doses) increased the AUC of CANCIDAS. CANCIDAS did not increase the plasma levels of cyclosporine. There were transient increases in liver ALT and AST when CANCIDAS and cyclosporine were co-administered.

Monitor patients who develop abnormal liver enzymes during concomitant therapy and evaluate the risk/benefit of continuing therapy.

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

Rifampin: Rifampin is a potent CYP3A4 inducer and concomitant administration with CANCIDAS is expected to reduce the plasma concentrations of CANCIDAS. Therefore, adult patients on rifampin should receive 70 mg of CANCIDAS daily and pediatric patients on rifampin should receive 70 mg/m2 of CANCIDAS daily (not to exceed an actual daily dose of 70 mg).

Adults: When CANCIDAS is co-administered to adult patients with other inducers of hepatic CYP enzymes, such as efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, administration of a daily dose of 70 mg of CANCIDAS should be considered.

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

USE IN SPECIFIC POPULATIONS

Pregnancy: Based on animal data, CANCIDAS may cause fetal harm (see Data). There are insufficient human data to establish whether there is a drug-associated risk for major birth defects, miscarriage, or ad verse maternal or fetal outcomes with CANCIDAS use in pregnant women.

Lactation: There are no data on the presence of caspofungin in human milk, the effects on the breast-fed child,or the effects on milk production. Caspofungin was found in the milk of lactating, drug-treated rats.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CANCIDAS and any potential adverse effects on the breastfed child from CANCIDAS or from the underlying maternal condition.

Pediatric Use: The safety and effectiveness of CANCIDAS in pediatric patients 3 months to 17 years of ag e are

supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic data in pediatric patients, and additional data from prospective studies.

Patients with Hepatic Impairment: Adult patients with mild hepatic impairment (Child-Pugh score 5 to 6) do not need a dosageadjustment. For adult patients with moderate hepatic impairment (Child-Pugh score 7 to 9), CANCIDAS 35 mg once daily is recommended based upon pharmacokinetic data.

However, where recommended, a 70-mg loading dose should still be administered on Day1. 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.

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.

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.

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