Эраксис

Эраксис is indicated for use in adults for the treatment of the following fungal infections listed below. Specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained prior to therapy to isolate and identify causative organism(s). Therapy may be instituted before the results of the cultures and other laboratory studies known. However, once these results become available, antifungal therapy should be adjusted accordingly.

Candidemia And Other Forms Of Candida Infections (Intra-abdominal Abscess And Peritonitis)

Эраксис is indicated for the treatment of candidemia and the following Candida infections: intra-abdominal abscess and peritonitis.

Esophageal Candidiasis

Эраксис is indicated for the treatment of esophageal candidiasis.

Limitation Of Use

Эраксис has not been studied in endocarditis, osteomyelitis, and meningitis due to Candida, and has not been studied in sufficient numbers of neutropenic patients to determine efficacy in this group.

Recommended Dosing

Candidemia And Other Candida Infections (intra-abdominal abscess, and peritonitis)

The recommended dose is a single 200 mg loading dose of Эраксис on Day 1, followed by 100 mg daily dose thereafter. Duration of treatment should be based on the patient's clinical response. In general, antifungal therapy should continue for at least 14 days after the last positive culture.

Esophageal Candidiasis

The recommended dose is a single 100 mg loading dose of Эраксис on Day 1, followed by 50 mg daily dose thereafter. Patients should be treated for a minimum of 14 days and for at least 7 days following resolution of symptoms. Duration of treatment should be based on the patient's clinical response. Because of the risk of relapse of esophageal candidiasis in patients with HIV infections, suppressive antifungal therapy may be considered after a course of treatment.

Preparation For Administration

Эраксис for Injection must be reconstituted with sterile Water for Injection and subsequently diluted only with 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline). The compatibility of reconstituted Эраксис with intravenous substances, additives, or medications other than 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline) has not been established.

Reconstitution 50 mg/vial

Aseptically reconstitute each 50 mg vial with 15 mL of sterile Water for Injection to provide a concentration of 3.33 mg/mL. The reconstituted solution can be stored for up to 24 hours at temperatures up to 25°C (77°F) prior to dilution into the infusion solution.

Reconstitution 100 mg/vial

Aseptically reconstitute each 100 mg vial with 30 mL of sterile Water for Injection to provide a concentration of 3.33 mg/mL. The reconstituted solution can be stored for up to 24 hours at temperatures up to 25°C (77°F) prior to dilution into the infusion solution.

Dilution And Infusion

Aseptically transfer the contents of the reconstituted vial(s) into the appropriately sized IV bag (or bottle) containing either 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline). See Table 1 for the dilution and infusion instructions for each dose.

Table 1: Dilution Requirements for Эраксис Administration

Caution: The rate of infusion should not exceed 1.1 mg/minute (equivalent to 1.4 mL/minute or 84 mL/hour when reconstituted and diluted per instructions).

The infusion solution may be stored for up to 48 hours at temperatures up to 25°C (77°F), or stored frozen for at least 72 hours prior to administration.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter or discoloration is identified, discard the solution.

Эраксис is contraindicated in persons with known hypersensitivity to anidulafungin, any component of Эраксис, or other echinocandins.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hepatic Effects

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

Hypersensitivity

Anaphylactic reactions, including shock were reported with the use of Эраксис. If these reactions occur, Эраксис should be discontinued and appropriate treatment administered.

Infusion-related adverse reactions, possibly histamine-mediated, have been reported with Эраксис, including rash, urticaria, flushing, pruritus, bronchospasm, dyspnea, and hypotension. To reduce occurrence of these reactions, do not exceed a rate of Эраксис infusion of 1.1 mg/minute.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term animal carcinogenicity studies of anidulafungin have not been conducted.

Anidulafungin was not genotoxic in the following in vitro studies: bacterial reverse mutation assays, a chromosome aberration assay with Chinese hamster ovary cells, and a forward gene mutation assay with mouse lymphoma cells. Anidulafungin was not genotoxic in mice using the in vivo micronucleus assay.

Anidulafungin produced no adverse effects on fertility in male or female rats at intravenous doses of 20 mg/kg/day (equivalent to 2 times the proposed therapeutic maintenance dose of 100 mg/day on the basis of relative body surface area).

Use In Specific Populations

Pregnancy

Risk Summary

Based on findings from animal studies, Эраксис can cause fetal harm when administered to a pregnant woman. There are no available human data on the use of Эраксис in pregnant women to inform a drug-associated risk of adverse developmental outcomes. In animal reproduction studies fetal toxicity was observed in the presence of maternal toxicity when anidulafungin was administered to pregnant rabbits during organogenesis at 4 times the proposed therapeutic maintenance dose of 100 mg/day on the basis of relative body surface area. Inform pregnant woman of the risk to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20% respectively.

Data

Animal Data

In a combined fertility and embryo-fetal development study in rats dosed with anidulafungin for 4 weeks prior to cohabitation and through cohabitation for males or for 2 weeks prior to cohabitation and continuing through gestation day 19 for females, there was no maternal or embryo-fetal toxicity at intravenous doses up to 20 mg/kg/day (equivalent to 2 times the proposed therapeutic maintenance dose of 100 mg/day on the basis of relative body surface area).

In a rabbit embryo-fetal development study, intravenous administration of anidulafungin (0, 5, 10, and 20 mg/kg/day) from gestation day 7 through 19, resulted in reduced fetal weights and incomplete ossification in the presence of maternal toxicity (decreased body weight gain) at 20 mg/kg/day (equivalent to 4 times the proposed therapeutic maintenance dose of 100 mg/day on the basis of relative body surface area).

In a pre-and postnatal development study, pregnant rats were intravenously administered anidulafungin at doses of 2, 6, or 20 mg/kg/day from gestation day 7 through lactation day 20. Maternal toxicity was observed at ≥6 mg/kg/day (clinical signs at ≥6 mg/kg/day and reduced body weight gain and food consumption during gestation at 20 mg/kg/day group). There were no effects on the viability or growth and development of the offspring. In this study, anidulafungin was detected in fetal plasma, indicating that it crossed the placental barrier.

Lactation

Risk Summary

There are no data on the presence of anidulafungin in human milk, the effects on the breastfed infant or the effects on milk production. Anidulafungin was found in the milk of lactating rats. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Эраксис and any potential adverse effects on the breastfed child from Эраксис or from the underlying maternal condition.

Data

Animal Data

Pregnant rats were intravenously administered anidulafungin at doses of 2, 6, or 20 mg/kg/day from gestation day 7 through lactation day 20. Milk samples were collected from 5 rats per group on lactation day 14 at approximately 1 hours post dose. Approximately dose-proportional anidulafungin concentrations were found in the milk of lactating rats.

Pediatric Use

The safety and effectiveness of Эраксис in patients ≤16 years old has not been established.

Geriatric Use

Dosage adjustments are not required for geriatric patients.

Of the total number of subjects (N = 197) in the pivotal clinical studies of anidulafungin, 35% were 65 years and over, while 18% were 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Hepatic Insufficiency

No dosing adjustments are required for patients with any degree of hepatic insufficiency. Anidulafungin is not hepatically metabolized. Anidulafungin pharmacokinetics were examined in subjects with Child-Pugh class A, B or C hepatic insufficiency. Anidulafungin concentrations were not increased in subjects with any degree of hepatic insufficiency. Though a slight decrease in AUC was observed in patients with Child-Pugh C hepatic insufficiency, it was within the range of population estimates noted for healthy subjects.

Renal Insufficiency

Dosage adjustments are not required for patients with any degree of renal insufficiency including those on hemodialysis. Anidulafungin has negligible (<1%) renal clearance. In a clinical study of subjects with mild, moderate, severe or end stage (dialysis-dependent) renal insufficiency, anidulafungin pharmacokinetics were similar to those observed in subjects with normal renal function. Anidulafungin is not dialyzable and may be administered without regard to the timing of hemodialysis.

The most serious adverse reactions reported with Эраксис are:

• Hepatic effects
• Hypersensitivity

Clinical Trials Experience

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

The safety of Эраксис for Injection was assessed in 929 individuals, including 257 healthy subjects and 672 patients in clinical trials of candidemia, other forms of Candida infections, and esophageal candidiasis. A total of 633 patients received Эраксис at daily doses of either 50 mg or 100 mg. A total of 481 patients received Эраксис for ≥14 days.

Candidemia/Other Candida Infections

Three studies (one comparative vs. fluconazole, two non-comparative) assessed the efficacy and safety of Эраксис (100 mg) in patients with candidemia and other Candida infections.

The data described below reflect exposure to Эраксис and fluconazole in 127 and 118 patients, respectively, with candidemia and other forms of invasive candidiasis, in the randomized, comparative trial of the efficacy and safety of Эраксис to that of fluconazole. In Эраксис-treated patients, the age range was 16-89 years, the gender distribution was 51% male and 49% female, and the race distribution was 72% White, 18% Black/African American, 9% other races. Patients were randomized to receive once daily IV Эраксис (200 mg loading dose followed by 100 mg maintenance dose) or IV fluconazole (800 mg loading dose followed by 400 mg maintenance dose). Treatment was administered for at least 14 and not more than 42 days.

The number of patients with adverse reactions leading to discontinuation of study medication was 11.5% in the Эраксис arm and 21.6% in the fluconazole arm. The most common adverse reactions leading to study drug discontinuation were multi-organ failure and systemic Candida infection in the Эраксис arm.

Table 2 presents adverse reactions that were reported in ≥5% of subjects receiving Эраксис or fluconazole therapy in this trial.

Table 2: Adverse Reactions Reported in ≥5% of Subjects Receiving Эраксис or Fluconazole Therapy for Candidemia/other Candida Infections*, **

Esophageal Candidiasis

The data described below reflect exposure to Эраксис and fluconazole in 300 and 301 patients, respectively, with esophageal candidiasis in a randomized trial comparing the efficacy and safety of Эраксис to that of oral fluconazole. In Эраксис-treated patients, the age range was 18-68 years, the gender distribution was 42% male and 58% female and the race distribution was 15% White, 49% Black/African American, 15% Asian, 0.3 % Hispanic, 21% other races. Patients were randomized to receive IV Эраксис (100 mg on day 1, followed by 50 mg per day) or oral fluconazole (200 mg on day 1, followed by 100 mg per day) for 7 days beyond resolution of symptoms (range, 14-21 days).

Twenty eight (9%) patients in the Эраксис arm and 36 (12%) patients in the fluconazole arm had adverse reactions leading to discontinuation of study medication. The most common adverse reactions leading to study drug discontinuation were maculopapular rash for the Эраксис arm. The most common adverse reactions leading to discontinuation were rash and increased AST for the fluconazole arm.

Table 3 presents adverse reactions that were reported in ≥5% of subjects receiving Эраксис therapy.

Table 3 : Adverse Reactions Reported in ≥5% of Subjects Receiving Эраксис or Fluconazole Therapy for Esophageal Candidiasis*, **

Less Common Adverse Reactions

The following selected adverse reactions occurred in <2% of patients:

Blood and Lymphatic: coagulopathy, thrombocytopenia

Cardiac: atrial fibrillation, bundle branch block (right), sinus arrhythmia, ventricular extrasystoles

Eye: eye pain, vision blurred, visual disturbance

General and Administration Site: infusion related reaction, peripheral edema, rigors

Hepatobiliary: abnormal liver function tests, cholestasis, hepatic necrosis

Infections: clostridial infection

Investigations: amylase increased, bilirubin increased, CPK increased, electrocardiogram QT prolonged, gammaglutamyl transferase increased, lipase increased, potassium decreased, prothrombin time prolonged, urea increased

Nervous System: convulsion, dizziness

Respiratory, Thoracic and Mediastinal: cough

Skin and Subcutaneous Tissue: angioneurotic edema, erythema, pruritus, sweating increased, urticaria

Vascular: flushing, hot flushes, thrombophlebitis superficial

Post-marketing Experience

The following adverse reactions have been identified during post approval use of anidulafungin. 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.

Immune

Anaphylactic shock, anaphylactic reaction, bronchospasm.

During clinical trials a single 400 mg dose of Эраксис was inadvertently administered as a loading dose. No clinical adverse events were reported. In a study of 10 healthy subjects administered a loading dose of 260 mg followed by 130 mg daily, Эраксис was generally well tolerated; 3 of the 10 subjects experienced transient, asymptomatic transaminase elevations (≤3 x ULN).

Anidulafungin is not dialyzable.

The maximum non-lethal dose of anidulafungin in rats was 50 mg/kg, a dose which is equivalent to 10 times the recommended daily dose for esophageal candidiasis (50 mg/day) or equivalent to 5 times the recommended daily dose for candidemia and other Candida infections (100 mg/day), based on relative body surface area comparisons.

General Pharmacokinetic Characteristics

The pharmacokinetics of anidulafungin following intravenous (IV) administration have been characterized in healthy subjects, special populations and patients. Systemic exposures of anidulafungin are dose-proportional and have low intersubject variability (coefficient of variation <25%) as shown in Table 4. The steady state was achieved on the first day after a loading dose (twice the daily maintenance dose) and the estimated plasma accumulation factor at steady state is approximately 2.

Table 4: Mean (%CV) Steady State Pharmacokinetic Parameters of Anidulafungin Following IV Administration of Anidulafungin Once Daily for 10 Days in Healthy Adult Subjects

The clearance of anidulafungin is about 1 L/h and anidulafungin has a terminal elimination half-life of 40-50 hours.

Distribution

The pharmacokinetics of anidulafungin following IV administration are characterized by a short distribution half-life (0.5-1 hour) and a volume of distribution of 30-50 L that is similar to total body fluid volume. Anidulafungin is extensively bound (>99%) to human plasma proteins.

Metabolism

Hepatic metabolism of anidulafungin has not been observed. Anidulafungin is not a clinically relevant substrate, inducer, or inhibitor of cytochrome P450 (CYP450) isoenzymes. It is unlikely that anidulafungin will have clinically relevant effects on the metabolism of drugs metabolized by CYP450 isoenzymes.

Anidulafungin undergoes slow chemical degradation at physiologic temperature and pH to a ring-opened peptide that lacks antifungal activity. The in vitro degradation half-life of anidulafungin under physiologic conditions is about 24 hours. In vivo, the ring-opened product is subsequently converted to peptidic degradants and eliminated.

Excretion

In a single-dose clinical study, radiolabeled (¹⁴C) anidulafungin was administered to healthy subjects. Approximately 30% of the administered radioactive dose was eliminated in the feces over 9 days, of which less than 10% was intact drug. Less than 1% of the administered radioactive dose was excreted in the urine. Anidulafungin concentrations fell below the lower limits of quantitation 6 days post-dose. Negligible amounts of drug-derived radioactivity were recovered in blood, urine, and feces 8 weeks post-dose.