Label: ERAXIS- anidulafungin injection, powder, lyophilized, for solution

  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: New Drug Application

Drug Label Information

Updated February 12, 2021

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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use ERAXIS safely and effectively. See full prescribing information for ERAXIS.

    ERAXIS® (anidulafungin) for injection, for intravenous use
    Initial U.S. Approval: 2006

    RECENT MAJOR CHANGES

    Indications and Usage (1)9/2020
    Dosage and Administration (2)9/2020
    Contraindications (4)9/2020
    Warnings and Precautions (5)9/2020

    INDICATIONS AND USAGE

    ERAXIS is an echinocandin antifungal indicated for the treatment of the following infections:

    • Candidemia and other forms of Candida infections (intra-abdominal abscess and peritonitis) in adults and pediatric patients (1 month of age and older) (1.1)
    • Esophageal candidiasis in adults (1.2)

    Limitations of use

    • ERAXIS has not been studied in adult and pediatric patients with endocarditis, osteomyelitis, and meningitis due to Candida or in sufficient numbers of neutropenic patients. The dosage of ERAXIS for the treatment of Candida dissemination into the CNS and the eye has not been established. (1.3, 5.3, 8.4)
    • ERAXIS is associated with high relapse rates in esophageal candidiasis. (1.3, 14.2)

    DOSAGE AND ADMINISTRATION

    AdultsPediatric Patients 1 Month of Age and Older
    Candidemia and other forms of Candida infections
    200 mg loading dose on Day 1, followed by 100 mg once daily maintenance dose thereafter for at least 14 days after the last positive culture (2.1)3 mg/kg (not to exceed 200 mg) loading dose on Day 1, followed by 1.5 mg/kg (not to exceed 100 mg) once daily maintenance dose thereafter for at least 14 days after the last positive culture (2.2)
    Esophageal candidiasis
    100 mg loading dose on Day 1, followed by 50 mg once daily maintenance dose thereafter for a minimum of 14 days and for at least 7 days following resolution of symptoms (2.1)Not Approved

    Rate of Infusion for Adults and Pediatric Patients

    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] (2.3, 2.4)

    DOSAGE FORMS AND STRENGTHS

    For injection: 50 mg, and 100 mg as a lyophilized powder in a single-dose vial for reconstitution (3)

    CONTRAINDICATIONS

    • Known hypersensitivity to anidulafungin, any component of ERAXIS, or other echinocandins (4, 5.2)
    • Known or suspected Hereditary Fructose Intolerance (HFI) (4, 5.4)

    WARNINGS AND PRECAUTIONS

    • Hepatic Effects: Risk of abnormal liver tests, hepatitis, hepatic failure; monitor hepatic function during therapy. (5.1, 13.2)
    • Hypersensitivity: Anaphylaxis, including shock has been reported. Risk of infusion-related adverse reactions, possibly histamine-mediated, including rash, urticaria, flushing, pruritus, bronchospasm, dyspnea, and hypotension; to reduce occurrence, do not exceed a rate of infusion of 1.1 mg/minute. (2.4, 5.2)
    • Risk of Neonatal Toxicity Associated with Polysorbates: ERAXIS contains polysorbate 80, an inactive ingredient. Thrombocytopenia, renal dysfunction, hepatomegaly, cholestasis, ascites, hypotension and metabolic acidosis haves been reported in low-birth weight infants receiving high doses of polysorbate. ERAXIS is not approved in pediatric patients younger than 1 month of age. (5.3, 8.4)
    • Hereditary Fructose Intolerance (HFI): ERAXIS contains fructose. Risk of metabolic crisis with life-threatening hypoglycemia, hypophosphatemia, lactic acidosis, and hepatic failure. Obtain history of HFI symptoms in pediatric patients before ERAXIS administration. (5.4, 8.4)

    ADVERSE REACTIONS

    Adults

    • Candidemia and other forms of Candida infections: Most common adverse reactions (≥15%) are hypokalemia, nausea, diarrhea, vomiting, pyrexia, insomnia, hypotension. (6.1)
    • Esophageal candidiasis: Most common adverse reactions (≥5%) are diarrhea, pyrexia, anemia, headache, vomiting, nausea, dyspepsia, oral candidiasis, and hypokalemia. (6.1)

    Pediatric Patients (1 month and older)

    Candidemia and other forms of Candida infections: Most common adverse reactions (≥ 5%): diarrhea, vomiting, pyrexia, abdominal pain, anemia, thrombocytopenia, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increased, hypoglycemia, epistaxis, and rash. (6.1)


    To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

    USE IN SPECIFIC POPULATIONS

    • Pregnancy: Based on findings from animal studies, ERAXIS can cause fetal harm when administered to a pregnant woman. Inform pregnant woman of the risk to the fetus. (8.1)
    • Pediatric Use: The safety and effectiveness in patients younger than 1 month of age has not been established. (8.4)

    See 17 for PATIENT COUNSELING INFORMATION.

    Revised: 9/2020

  • Table of Contents

    FULL PRESCRIBING INFORMATION: CONTENTS*

    1 INDICATIONS AND USAGE

    1.1 Candidemia and Other Forms of Candida Infections (Intra-abdominal Abscess and Peritonitis)

    1.2 Esophageal Candidiasis

    1.3 Limitations of Use

    1.4 Usage

    2 DOSAGE AND ADMINISTRATION

    2.1 Recommended Dosage in Adults

    2.2 Recommended Dosage in Pediatric Patients (1 Month of Age and Older)

    2.3 Preparation for Administration

    2.4 Dilution and Administration of the Infusion

    3 DOSAGE FORMS AND STRENGTHS

    4 CONTRAINDICATIONS

    5 WARNINGS AND PRECAUTIONS

    5.1 Hepatic Adverse Reactions

    5.2 Anaphylactic and Hypersensitivity Reactions

    5.3 Risk of Neonatal Toxicity Associated with Polysorbates

    5.4 Risk in Patients with Hereditary Fructose Intolerance (HFI)

    6 ADVERSE REACTIONS

    6.1 Clinical Trials Experience

    6.2 Post-marketing Experience

    7 DRUG INTERACTIONS

    7.1 Cyclosporine

    7.2 Voriconazole

    7.3 Tacrolimus

    7.4 Rifampin

    7.5 Amphotericin B Liposome for Injection

    8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    8.2 Lactation

    8.4 Pediatric Use

    8.5 Geriatric Use

    8.6 Hepatic Insufficiency

    8.7 Renal Insufficiency

    10 OVERDOSAGE

    11 DESCRIPTION

    12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    12.3 Pharmacokinetics

    12.4 Microbiology

    13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    13.2 Animal Toxicology and/or Pharmacology

    14 CLINICAL STUDIES

    14.1 Candidemia and Other Candida Infections (Intra-abdominal Abscess and Peritonitis)

    14.2 Esophageal Candidiasis

    16 HOW SUPPLIED/STORAGE AND HANDLING

    16.1 How Supplied

    16.2 Storage

    17 PATIENT COUNSELING INFORMATION

    *
    Sections or subsections omitted from the full prescribing information are not listed.
  • 1 INDICATIONS AND USAGE

    1.1 Candidemia and Other Forms of Candida Infections (Intra-abdominal Abscess and Peritonitis)

    ERAXIS is indicated for the treatment of candidemia and the following Candida infections: intra-abdominal abscess and peritonitis in adults and pediatric patients 1 month of age and older [see Clinical Studies (14.1) and Microbiology (12.4)].

    1.2 Esophageal Candidiasis

    ERAXIS is indicated for the treatment of esophageal candidiasis in adults [see Indications and Usage (1.3), Clinical Studies (14.2)].

    1.3 Limitations of Use

    • ERAXIS has not been studied in adult and pediatric patients with endocarditis, osteomyelitis, and meningitis due to Candida, and has not been studied in sufficient numbers of neutropenic patients to determine efficacy in this group. The dosage of ERAXIS for the treatment of Candida dissemination into the CNS and the eye has not been established [see Warning and Precautions (5.3), Use in Specific Populations (8.4)].
    • ERAXIS is associated with high relapse rates in esophageal candidiasis [see Clinical Studies (14.2)].

    1.4 Usage

    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 are known. However, once these results become available, antifungal therapy should be adjusted accordingly.

  • 2 DOSAGE AND ADMINISTRATION

    2.1 Recommended Dosage in Adults

    Candidemia and other Candida infections (intra-abdominal abscess and peritonitis)

    The recommended dose is a single 200 mg loading dose of ERAXIS on Day 1, followed by a 100 mg once daily maintenance 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 ERAXIS on Day 1, followed by a 50 mg once daily maintenance 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 infection, suppressive antifungal therapy may be considered after a course of treatment.

    2.2 Recommended Dosage in Pediatric Patients (1 Month of Age and Older)

    Candidemia and other Candida infections (intra-abdominal abscess and peritonitis)

    The recommended dose is a single loading dose of 3 mg/kg (not to exceed 200 mg) of ERAXIS on Day 1, followed by a once daily maintenance dose of 1.5 mg/kg (not to exceed 100 mg) of ERAXIS thereafter. Overall antifungal treatment should continue for at least 14 days after the last positive culture.

    2.3 Preparation for Administration

    ERAXIS 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), prior to administration.

    The compatibility of reconstituted ERAXIS 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. Do NOT dilute with other solutions or co-infuse with other medications or electrolytes. The infusion solution must not be frozen.

    Reconstitution of the 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.

    Reconstitution of the 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.

    Storage of the Reconstituted Solution

    ERAXIS reconstituted solution can be stored at 25°C (77°F) for up to 24 hours prior to dilution into the infusion solution. Chemical and physical in-use stability of the reconstituted solution has been demonstrated for 24 hours at 25°C (77°F). From a microbiological point of view, following good aseptic practices, the reconstituted solution can be utilized for up to 24 hours when stored at 25°C.

    2.4 Dilution and Administration of the Infusion

    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.

    Adult Patients

    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 to a concentration of 0.77 mg/mL for the final infusion solution and infusion instructions for each dose. 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) [see Warnings and Precautions (5.2)].

    Table 1: Dilution Requirements for ERAXIS Administration
    DoseNumber of Vials RequiredTotal Reconstituted Volume RequiredInfusion Volume*Total Infusion VolumeRate of InfusionMinimum Duration of Infusion
    *
    Either 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline)
    Infusion solution concentration is 0.77 mg/mL
    50 mg1–50 mg15 mL50 mL65 mL1.4 mL/min or 84 mL/ hour45 min
    100 mg2–50 mg or 1–100 mg30 mL100 mL130 mL1.4 mL/min or 84 mL/ hour90 min
    200 mg4–50 mg or 2–100 mg60 mL200 mL260 mL1.4 mL/min or 84 mL/ hour180 min

    Pediatric Patients

    The volume of infusion solution required to deliver the dose is dependent on the weight of the child. The reconstituted solution must be further diluted to a concentration of 0.77 mg/mL for the final infusion solution. A programmable syringe or infusion pump is recommended. 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) [see Warnings and Precautions (5.2)].

    Steps for the Preparation of Pediatric Doses below 50 mg

    1. Calculate pediatric patient dose and aseptically reconstitute vial(s) required according to reconstitution instructions to provide a concentration of 3.33 mg/mL (if dose is 50 mg or above, see preparation instructions for Adult Patients above) [see Dosage and Administration (2.2, 2.3)].
    2. Calculate the volume (mL) of reconstituted ERAXIS required:
      [Volume of reconstituted ERAXIS (mL) = Dose of ERAXIS (mg) ÷ 3.33 mg/mL]
    3. Calculate the total volume of the infusion solution (mL) that contains a final concentration of 0.77 mg/mL:
      [Total volume of infusion solution (mL) = Dose of ERAXIS (mg) ÷ 0.77 mg/mL]
    4. Calculate the volume of diluent [5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline)] required to prepare the infusion solution: [Volume of diluent (mL) = Total volume of final infusion solution (mL) – Volume of reconstituted ERAXIS (mL)]
    5. Prepare the infusion solution by aseptically transferring the required volumes (mL) of the reconstituted ERAXIS and diluent [5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline)] into an infusion syringe or IV infusion bag needed for administration.

    Storage of the Infusion Solution

    ERAXIS infusion solution can be stored at temperatures up to 25°C (77°F) for up to 48 hours. Do not freeze. Chemical and physical in-use stability of the infusion solution has been demonstrated for 48 hours at 25°C (77°F). From a microbiological point of view, following good aseptic practices, the infusion solution can be utilized for up to 48 hours from preparation when stored at 25°C.

  • 3 DOSAGE FORMS AND STRENGTHS

    For injection: 50 mg, and 100 mg of anidulafungin as a white to off-white sterile lyophilized powder in a single-dose vial for reconstitution.

  • 4 CONTRAINDICATIONS

    ERAXIS is contraindicated in:

  • 5 WARNINGS AND PRECAUTIONS

    5.1 Hepatic Adverse Reactions

    Laboratory abnormalities in liver tests have been seen in healthy volunteers and pediatric patients treated with ERAXIS. In some patients with serious underlying medical conditions who were receiving multiple concomitant medications along with ERAXIS, 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 ERAXIS has not been established [see Adverse Reactions (6.1) and Nonclinical Toxicology (13.2)]. Patients who develop abnormal liver tests during ERAXIS therapy should be monitored for evidence of worsening hepatic tests and evaluated for risk/benefit of continuing ERAXIS therapy.

    5.2 Anaphylactic and Hypersensitivity Reactions

    Anaphylactic reactions, including shock were reported with the use of ERAXIS. If these reactions occur, ERAXIS should be discontinued and appropriate treatment administered [see Adverse Reactions (6)].

    Infusion-related adverse reactions, possibly histamine-mediated, have been reported with ERAXIS, including rash, urticaria, flushing, pruritus, bronchospasm, dyspnea, and hypotension [see Adverse Reactions (6)]. To reduce occurrence of these reactions, do not exceed a rate of ERAXIS infusion of 1.1 mg/minute [see Dosage and Administration (2.4)].

    5.3 Risk of Neonatal Toxicity Associated with Polysorbates

    ERAXIS contains polysorbate 80, an inactive ingredient. Thrombocytopenia, renal dysfunction, hepatomegaly, cholestasis, ascites, hypotension, and metabolic acidosis have been reported in low-birth weight infants receiving high doses of polysorbate. Polysorbate toxicity has not been reported with ERAXIS. ERAXIS is not approved in pediatric patients younger than 1 month of age [see Indications and Usage (1.1, 1.3), Use in Specific Populations (8.4)].

    5.4 Risk in Patients with Hereditary Fructose Intolerance (HFI)

    ERAXIS contains fructose, an inactive ingredient, and may precipitate a metabolic crisis that may include, but is not limited to life-threatening hypoglycemia, hypophosphatemia, lactic acidosis, and hepatic failure in patients with HFI. Obtain careful history of HFI symptoms (nausea, vomiting, abdominal pain) with fructose/sucrose exposure prior to ERAXIS administration because a diagnosis of HFI may not yet be established in pediatric patients [see Contraindications (4) and Use in Specific Populations (8.4)].

  • 6 ADVERSE REACTIONS

    The following most serious adverse reactions are described elsewhere in other labeling sections:

    6.1 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.

    Clinical Trials Experience in Adults

    The safety of ERAXIS 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 ERAXIS at daily doses of either 50 mg or 100 mg. A total of 481 patients received ERAXIS for ≥14 days.

    Candidemia/other Candida Infections

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

    The data described below reflect exposure to ERAXIS 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 ERAXIS to that of fluconazole. In ERAXIS-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 ERAXIS (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 ERAXIS arm and 21.6% in the fluconazole arm. The most common adverse reactions leading to study drug discontinuation were multi-organ failure (2.3%) and systemic Candida infection (1.5%) in the ERAXIS arm.

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

    Table 2: Adverse Reactions Reported in ≥5% of Adult Patients Receiving ERAXIS or Fluconazole Therapy for Candidemia/other Candida Infections*,
    Adverse ReactionERAXIS
    100 mg
    N=131
    Fluconazole
    400 mg
    N=125
    N (%)N (%)
    *
    A patient who experienced multiple reactions within a Body System or preferred term was counted one time for that class, one time for the preferred term and one time for "subjects with at least one adverse reaction".
    This trial was not designed to support comparative claims for ERAXIS for the adverse reactions reported in this table.
    Subjects with a least one adverse reaction130 (99)122 (98)
     
    Gastrointestinal disorders81 (62)72 (58)
      Nausea32 (24)15 (12)
      Diarrhea24 (18)23 (18)
      Vomiting23 (18)12 (10)
      Constipation11 (8)14 (11)
      Abdominal pain8 (6)16 (13)
    General disorders and administration site conditions70 (53)76 (61)
      Pyrexia23 (18)23 (18)
      Edema peripheral14 (11)16 (13)
      Chest pain7 (5)6 (5)
    Respiratory, thoracic, and mediastinal disorders67 (51)55 (44)
      Dyspnea15 (12)4 (3)
      Pleural effusion13 (10)11 (9)
      Cough9 (7)7 (6)
      Respiratory distress8 (6)2 (2)
    Investigations66 (50)46 (37)
      Blood alkaline phosphatase increased15 (12)14 (11)
      White blood cell increased11 (8)3 (2)
      Hepatic enzyme increased7 (5)14 (11)
      Blood creatinine increased7 (5)1 (1)
    Metabolism and nutrition disorders61 (47)61 (49)
      Hypokalemia33 (25)24 (19)
      Hypomagnesemia15 (12)14 (11)
      Hypoglycemia9 (7)10 (8)
      Hyperkalemia8 (6)14 (11)
      Hyperglycemia8 (6)8 (6)
      Dehydration8 (6)2 (2)
    Vascular disorders50 (38)41 (33)
      Hypotension19 (15)18 (14)
      Hypertension15 (12)5 (4)
      Deep vein thrombosis13 (10)9 (7)
    Psychiatric disorders48 (37)45 (36)
      Insomnia20 (15)12 (10)
      Confusional state10 (8)10 (8)
      Depression8 (6)5 (4)
    Blood and lymphatic system disorders34 (26)36 (29)
      Anemia12 (9)20 (16)
      Thrombocythemia8 (6)1 (1)
      Leukocytosis7 (5)6 (5)
    Skin and subcutaneous tissue disorders30 (23)32 (26)
      Decubitus ulcer7 (5)10 (8)
    Nervous system disorders27 (21)31 (25)
      Headache11 (8)10 (8)
    Musculoskeletal and connective tissue disorders27 (21)25 (20)
      Back pain7 (5)13 (10)

    Esophageal Candidiasis

    The data described below reflect exposure to ERAXIS and fluconazole in 300 and 301 patients, respectively, with esophageal candidiasis in a randomized trial comparing the efficacy and safety of ERAXIS to that of oral fluconazole. In ERAXIS-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 ERAXIS (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 ERAXIS arm and 36 (12%) patients in the fluconazole arm had adverse reactions related to study medication. The most common adverse reactions leading to study discontinuation were maculopapular rash (1 patient) for the ERAXIS arm. The most common adverse reactions leading to discontinuation were rash (1 patient) and increased AST (1 patient) for the fluconazole arm.

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

    Table 3: Adverse Reactions Reported in ≥5% of Adult Patients Receiving ERAXIS or Fluconazole Therapy for Esophageal Candidiasis*,
    Adverse ReactionERAXIS
    50 mg
    N=300
    Fluconazole
    100 mg
    N=301
    N (%)N (%)
    *
    A patient who experienced multiple reactions within a Body System or preferred term was counted one time for that class, one time for the preferred term and one time for "subjects with at least one adverse reaction".
    This trial was not designed to support comparative claims for ERAXIS for the adverse reactions reported in this table.
    Subjects with a least one adverse reaction239 (80)227 (75)
     
    Infections and infestations115 (38)99 (33)
      Oral candidiasis15 (5)10 (3)
    Gastrointestinal disorders106 (35)113 (38)
      Diarrhea27 (9)26 (9)
      Vomiting27 (7)30 (10)
      Nausea20 (7)23 (8)
      Dyspepsia20 (7)21 (7)
    Blood and lymphatic system disorders55 (18)50 (17)
      Anemia25 (8)22 (7)
    Metabolism and nutrition disorders50 (17)46 (15)
      Hypokalemia14 (5)17 (6)
    General disorders and administration site condition49 (16)54 (18)
      Pyrexia27 (9)28 (9)
    Nervous system disorders39 (13)36 (12)
      Headache25 (8)20 (7)

    Less Common Adverse Reactions in Adult Patients with Candidemia/other Candida Infections and Esophageal Candidiasis

    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, gamma-glutamyl 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

    Clinical Trials Experience in Pediatric Patients with Candidemia/Invasive Candidiasis

    The safety of ERAXIS was investigated in 68 pediatric patients from 1 month to less than 18 years of age with candidemia/invasive candidiasis in a prospective, open-label, non-comparative pediatric trial [see Clinical Studies (14.1)]. Overall, the safety profile of ERAXIS in the pediatric patients 1 month and older was similar to that of adults.

    Most Common Adverse Reactions

    The most common adverse reactions occurring in ≥5% of pediatric patients receiving ERAXIS therapy in the clinical trial are displayed by body system in Table 4.

    Table 4 Adverse Reactions Occurring in ≥5% of Pediatric Patients Receiving ERAXIS Therapy for Candidemia/other Candida Infections*,
    Adverse Reaction1 month to <2 years
    N=19
    2 to <5 years
    N=19
    5 to <18 years
    N=30
    Overall
    N=68
    n (%)n (%)n (%)n (%)
    *
    Reflects adverse reactions including those that started on or after first dose of anidulafungin through 6-week follow-up for patients who did not receive oral fluconazole, and those that started between first dose and last dose of anidulafungin for patients who received oral fluconazole.
    A patient who experienced multiple reactions within a Body System or preferred term was counted one time for that class, one time for the preferred term and one time for "subjects with at least one adverse reaction".
    Includes such terms as: abdominal pain and abdominal pain upper.
    §
    Includes such terms as: rash and rash generalized.
    Subjects with a least one adverse reaction17 (90)14 (74)24 (80)55 (81)
     
    Blood and lymphatic system disorders9 (47)3 (16)4 (13)16 (24)
      Anemia5 (26)2 (11)07 (10)
      Thrombocytopenia2 (11)1 (5)1 (3)4 (6)
    Gastrointestinal disorders8 (42)8 (42)12 (40)28 (41)
      Diarrhea4 (21)2 (11)5 (17)11 (16)
      Vomiting4 (21)5 (26)2 (7)11 (16)
      Abdominal pain04 (21)2 (7)6 (9)
    General disorders and administration site condition5 (26)6 (32)9 (30)20 (29)
      Pyrexia4 (21)3 (16)5 (17)12 (18)
    Laboratory Investigations4 (21)4 (21)8 (27)16 (24)
      Alanine aminotransferase increased2 (11)2 (11)2 (7)6 (9)
      Aspartate aminotransferase increased2 (11)1 (5)1 (3)4 (6)
    Metabolism and nutrition disorders3 (16)4 (21)6 (20)13 (19)
      Hypoglycemia1 (5)2 (11)1 (3)4 (6)
    Respiratory, thoracic and mediastinal disorders5 (26)5 (26)5 (17)15 (22)
      Epistaxis1 (5)2 (11)3 (10)6 (9)
    Skin and subcutaneous tissue disorders6 (32)5 (26)5 (17)16 (24)
      Rash§3 (16)1 (5)2 (7)6 (9)

    Other adverse reactions were reported in 2 or more pediatric patients and in less than 5% of the 68 pediatric patients treated with ERAXIS in the clinical trial:

    Blood and Lymphatic System Disorders: pancytopenia, thrombocytosis, febrile neutropenia, leukopenia, neutropenia

    Eye Disorders: Periorbital edema

    Gastrointestinal Disorders: gastroesophageal reflux disease, abdominal distension, nausea, stomatitis, dry mouth

    General Disorders and Administrative Site Conditions: chest pain, edema peripheral

    Infections and Infestations: bacteremia, device related infection, gastroenteritis, lower respiratory tract infection, upper respiratory tract infection, urinary tract infection

    Laboratory Investigations: gamma-glutamyltransferase increased, transaminases increased

    Metabolism and Nutrition Disorders: hypocalcemia, hypokalemia, hyponatremia, hypoproteinemia

    Musculoskeletal and Connective Tissue Disorders: back pain, pain in extremity

    Nervous System Disorders: headache, tremor, seizure

    Psychiatric Disorders: agitation

    Respiratory, Thoracic and Mediastinal Disorders: hemoptysis

    Vascular Disorders: hypotension

    6.2 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 [see Warnings and Precautions (5.2)].

  • 7 DRUG INTERACTIONS

    7.1 Cyclosporine

    Administration of multiple doses of anidulafungin and cyclosporine to healthy subjects resulted in no significant alteration in the steady state pharmacokinetics of either drug. No dosage adjustment of cyclosporine or anidulafungin is needed when the two drugs are co-administered [see Clinical Pharmacology (12.3)].

    7.2 Voriconazole

    Administration of multiple doses of anidulafungin and voriconazole to healthy subjects resulted in no significant alteration in the steady state pharmacokinetics of either drug. No dosage adjustment of voriconazole or anidulafungin is needed when the two drugs are co-administered [see Clinical Pharmacology (12.3)].

    7.3 Tacrolimus

    Administration of multiple doses of anidulafungin and a single-dose of tacrolimus to healthy subjects resulted in no significant alteration in the steady state pharmacokinetics of either drug. No dosage adjustment of tacrolimus or anidulafungin is needed when the two drugs are co-administered [see Clinical Pharmacology (12.3)].

    7.4 Rifampin

    Administration of multiple doses of anidulafungin and rifampin to patients resulted in no significant alteration in the steady state pharmacokinetics of anidulafungin. No dosage adjustment of anidulafungin is needed when it is co-administered with rifampin [see Clinical Pharmacology (12.3)].

    7.5 Amphotericin B Liposome for Injection

    Administration of multiple doses of anidulafungin and liposomal amphotericin B to patients resulted in no significant alteration in the steady state pharmacokinetics of anidulafungin. No dosage adjustment of anidulafungin is needed when it is co-administered with liposomal amphotericin B [see Clinical Pharmacology (12.3)].

  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Risk Summary

    Based on findings from animal studies, ERAXIS can cause fetal harm when administered to a pregnant woman. There are no available human data on the use of ERAXIS 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 (see Data). 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. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 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.

    8.2 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. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Anidulafungin was found in the milk of lactating rats (see Data).

    The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ERAXIS and any potential adverse effects on the breastfed child from ERAXIS 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.

    8.4 Pediatric Use

    The safety and effectiveness of ERAXIS for the treatment of candidemia and the following Candida infections: intra-abdominal abscess and peritonitis, have been established in pediatric patients 1 month of age and older. Use of ERAXIS for this indication in this age group is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic, safety data in pediatric patients 1 month of age and older [see Indications and Usage (1), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)].

    The safety and effectiveness of ERAXIS in patients younger than 1 month of age with candidemia/invasive candidiasis has not been established.

    Candidemia/invasive candidiasis in pediatric patients younger than 1 month of age has a higher rate of central nervous system (CNS) and multi-organ dissemination than in older patients. In addition, in patients younger than 1 month of age ERAXIS carries a potential risk of life-threatening toxicity associated with high doses of polysorbate 80, an inactive ingredient in ERAXIS [see Warnings and Precautions (5.3)].

    The safety and effectiveness of ERAXIS in pediatric patients with esophageal candidiasis has not been established.

    ERAXIS is contraindicated in adult and pediatric patients with HFI. Because a diagnosis of HFI may not yet be established in pediatric patients, obtain a careful history of HFI symptoms with fructose/sucrose exposure prior to administration of ERAXIS [see Warnings and Precautions (5.4)].

    8.5 Geriatric Use

    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.

    Dosage adjustments are not required for geriatric patients [see Clinical Pharmacology (12.3)].

    8.6 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 [see Clinical Pharmacology (12.3)].

    8.7 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 [see Clinical Pharmacology (12.3)].

  • 10 OVERDOSAGE

    During clinical trials a single 400 mg dose of ERAXIS 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; 3 of the 10 subjects experienced transient, asymptomatic transaminase elevations (≤3 × ULN) [see Warnings and Precautions (5.1)].

    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.

  • 11 DESCRIPTION

    ERAXIS for Injection is a sterile, lyophilized product for intravenous (IV) infusion that contains anidulafungin. ERAXIS (anidulafungin) is a semi-synthetic lipopeptide synthesized from a fermentation product of Aspergillus nidulans. Anidulafungin is an echinocandin, a class of antifungal drugs that inhibits the synthesis of 1,3-β-D-glucan, an essential component of fungal cell walls.

    ERAXIS (anidulafungin) is 1-[(4R,5R)-4,5-dihydroxy-N2-[[4"-(pentyloxy)[1,1':4',1"-terphenyl]-4-yl]carbonyl]-L-ornithine]echinocandin B. Anidulafungin is a white to off-white powder that is practically insoluble in water and slightly soluble in ethanol. In addition to the active ingredient, anidulafungin, ERAXIS for Injection contains the following inactive ingredients:

    50 mg/vial – fructose (50 mg), mannitol (250 mg), polysorbate 80 (125 mg), tartaric acid (5.6 mg), and sodium hydroxide and/or hydrochloric acid for pH adjustment.

    100 mg/vial – fructose (100 mg), mannitol (500 mg), polysorbate 80 (250 mg), tartaric acid (11.2 mg), and sodium hydroxide and/or hydrochloric acid for pH adjustment.

    The empirical formula of anidulafungin is C58H73N7O17 and the formula weight is 1140.3.

    The structural formula is:

    Chemical Structure

    Prior to administration, ERAXIS for Injection requires reconstitution with sterile Water for Injection and subsequent dilution with either 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline).

  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    Anidulafungin is an anti-fungal drug [see Microbiology (12.4)].

    12.3 Pharmacokinetics

    General Pharmacokinetic Characteristics

    The pharmacokinetics of anidulafungin following intravenous (IV) administration of ERAXIS have been characterized in healthy subjects, special populations and patients. Systemic exposures of anidulafungin are dose-proportional and have low inter-subject variability (coefficient of variation <25%) as shown in Table 5. 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 5: Mean (%CV) Steady State Pharmacokinetic Parameters of Anidulafungin Following IV Administration of ERAXIS Once Daily for 10 Days in Healthy Adult Subjects
    Anidulafungin IV Dosing Regimen (LD/MD, mg)*
    PK Parameter70/35,§
    (N=6)
    200/100
    (N=10)
    260/130§,
    (N=10)
    Cmax, ss = the steady state peak concentration
    AUCss = the steady state area under concentration vs. time curve
    CL = clearance
    t1/2 = the terminal elimination half-life
    *
    LD/MD: loading dose/maintenance dose once daily
    Parameters were obtained from separate studies
    Data were collected on Day 7
    §
    Safety and efficacy of these doses has not been established
    See OVERDOSAGE
    Cmax, ss [mg/L]3.55 (13.2)8.6 (16.2)10.9 (11.7)
    AUCss [mg∙h/L]42.3 (14.5)111.8 (24.9)168.9 (10.8)
    CL [L/h]0.84 (13.5)0.94 (24.0)0.78 (11.3)
    t1/2 [h]43.2 (17.7)52.0 (11.7)50.3 (9.7)

    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.

    Specific Populations

    Patients with fungal infections

    Population pharmacokinetic analyses from four clinical trials including 107 male and 118 female patients with fungal infections showed that the pharmacokinetic parameters of anidulafungin are not affected by age, race, or the presence of concomitant medications which are known metabolic substrates, inhibitors or inducers.

    The pharmacokinetics of anidulafungin in patients with fungal infections are similar to those observed in healthy subjects. The pharmacokinetic parameters of anidulafungin estimated using population pharmacokinetic modeling following IV administration of a maintenance dose of 50 mg/day or 100 mg/day (following a loading dose) of ERAXIS are presented in Table 6.

    Table 6: Mean (%CV) Steady State Pharmacokinetic Parameters of Anidulafungin Following IV Administration of ERAXIS in Patients with Fungal Infections Estimated Using Population Pharmacokinetic Modeling
    PK Parameter*ERAXIS IV Dosing Regimen (LD/MD, mg)
    100/50200/100
    *
    All the parameters were estimated by population modeling using a two-compartment model with first order elimination; AUCss, Cmax,ss and Cmin,ss (steady state trough plasma concentration) were estimated using individual PK parameters and infusion rate of 1 mg/min to administer recommended doses of 50 and 100 mg/day.
    LD/MD: loading dose/daily maintenance dose.
    t1/2, β is the predominant elimination half-life that characterizes the majority of the concentration-time profile.
    Cmax, ss [mg/L]4.2 (22.4)7.2 (23.3)
    Cmin, ss [mg/L]1.6 (42.1)3.3 (41.8)
    AUCss [mg∙h/L]55.2 (32.5)110.3 (32.5)
    CL [L/h]1.0 (33.5)
    t1/2, β [h] 26.5 (28.5)

    Gender

    Dosage adjustments are not required based on gender. Plasma concentrations of anidulafungin in healthy men and women were similar. In multiple-dose patient studies, drug clearance was slightly faster (approximately 22%) in men.

    Geriatric

    Dosage adjustments are not required for geriatric patients. The population pharmacokinetic analysis showed that median clearance differed slightly between the elderly group (patients ≥65, median CL=1.07 L/h) and the non-elderly group (patients <65, median CL=1.22 L/h) and the range of clearance was similar.

    Race

    Dosage adjustments are not required based on race. Anidulafungin pharmacokinetics were similar among Whites, Blacks, Asians, and Hispanics.

    HIV Status

    Dosage adjustments are not required based on HIV status, irrespective of concomitant anti-retroviral therapy.

    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 [see Use in Specific Populations (8.6)].

    Renal Insufficiency

    Anidulafungin has negligible 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 [see Use in Specific Populations (8.7)].

    Pediatric

    The pharmacokinetics of anidulafungin after daily doses were investigated in immunocompromised pediatric (2 through 11 years) and adolescent (12 through 17 years) patients with neutropenia. The steady state was achieved on the first day after administration of the loading dose (twice the maintenance dose), and the Cmax and AUCss increased in a dose-proportional manner. Concentrations and exposures following administration of maintenance doses of 0.75 and 1.5 mg/kg/day in this population were similar to those observed in adults following maintenance doses of 50 and 100 mg/day, respectively (as shown in Table 7).

    Table 7: Mean (%CV) Steady State Pharmacokinetic Parameters of Anidulafungin Following IV Administration of ERAXIS Once Daily in Pediatric Patients

    PK Parameter*
    ERAXIS IV Dosing Regimen
    (LD/MD, mg/kg)
    1.5/0.753.0/1.5
    Age Group2–11 years
    (N = 6)
    12–17 years
    (N = 6)
    2–11 years
    (N = 6)
    12–17 years
    (N = 6)
    *
    Data were collected on Day 5
    LD/MD: loading dose/daily maintenance dose
    Cmax, ss [mg/L]3.32 (50.0)4.35 (22.5)7.57 (34.2)6.88 (24.3)
    AUCss [mg∙h/L]41.1 (38.4)56.2 (27.8)96.1 (39.5)102.9 (28.2)

    The pharmacokinetics of anidulafungin were also investigated in 66 pediatric patients (1 month to <18 years) with candidemia/invasive candidiasis (ICC) in a prospective, open-label, non-comparative pediatric study following administration of ERAXIS of 3 mg/kg loading dose on Day 1 and followed by 1.5 mg/kg once daily maintenance dose [see Clinical Studies (14.1)]. Based on population pharmacokinetic analysis of combined data from adult and pediatric patients with ICC, the mean steady state exposure parameters (AUC0–24,,ss Cmin,,ss and Cmax,ss) across age groups in the overall pediatric patients (Table 8) were comparable to those in adults receiving 200 mg loading dose and 100 mg once daily maintenance dose.

    Table 8: Mean (%CV) Steady State Pharmacokinetic Parameters of Anidulafungin Following IV Administration of ERAXIS in Pediatric Patients with Candidemia/Invasive Candidiasis Estimated Using Population Pharmacokinetic Modeling
    PK ParameterERAXIS IV Dosing Regimen
    (3 mg/kg LD/1.5 mg/kg MD)*
    Age Group1 month to <2 years
    (N = 17)
    2 to < 5 years
    (N = 19)
    5 to <18 years
    (N = 30)
    *
    LD/MD: loading dose on Day 1/ once daily maintenance dose.
    Cmax, ss [mg/L]6.7 (28.3)7.1 (39.4)6.5 (29.2)
    Cmin, ss [mg/L]2.0 (29)2.5 (44)2.5 (38.4)
    AUCss [mg∙h/L]69.9 (25.3)82.8 (38.5)86.8 (35.8)

    Drug Interactions

    In vitro studies showed that anidulafungin is not metabolized by human cytochrome P450 or by isolated human hepatocytes and does not significantly inhibit the activities of human CYP isoforms (1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A) in clinically relevant concentrations. No clinically relevant drug-drug interactions were observed with drugs likely to be co-administered with anidulafungin.

    Cyclosporine (CYP3A4 substrate)

    In a study in which 12 healthy adult subjects received 100 mg/day maintenance dose of anidulafungin following a 200 mg loading dose (on Days 1 to 8) and in combination with 1.25 mg/kg oral cyclosporine twice daily (on Days 5 to 8), the steady state Cmax of anidulafungin was not significantly altered by cyclosporine; the steady state AUC of anidulafungin was increased by 22%. A separate in vitro study showed that anidulafungin has no effect on the metabolism of cyclosporine [see Drug Interactions (7.1)].

    Voriconazole (CYP2C19, CYP2C9, CYP3A4 inhibitor and substrate)

    In a study in which 17 healthy subjects received 100 mg/day maintenance dose of anidulafungin following a 200 mg loading dose, 200 mg twice daily oral voriconazole (following two 400 mg loading doses) and both in combination, the steady state Cmax and AUC of anidulafungin and voriconazole were not significantly altered by co-administration [see Drug Interactions (7.2)].

    Tacrolimus (CYP3A4 substrate)

    In a study in which 35 healthy subjects received a single oral dose of 5 mg tacrolimus (on Day 1), 100 mg/day maintenance dose of anidulafungin following a 200 mg loading dose (on Days 4 to 12) and both in combination (on Day 13), the steady state Cmax and AUC of anidulafungin and tacrolimus were not significantly altered by co-administration [see Drug Interactions (7.3)].

    Rifampin (potent CYP450 inducer)

    The pharmacokinetics of anidulafungin were examined in 27 patients that were co-administered anidulafungin and rifampin. The population pharmacokinetic analysis showed that when compared to data from patients that did not receive rifampin, the pharmacokinetics of anidulafungin were not significantly altered by co-administration with rifampin [see Drug Interactions (7.4)].

    Amphotericin B liposome for injection

    The pharmacokinetics of anidulafungin were examined in 27 patients that were co-administered liposomal amphotericin B. The population pharmacokinetic analysis showed that when compared to data from patients that did not receive amphotericin B, the pharmacokinetics of anidulafungin were not significantly altered by co-administration with amphotericin B [see Drug Interactions (7.5)].

    12.4 Microbiology

    Mechanism of Action

    Anidulafungin is a semi-synthetic echinocandin with antifungal activity. Anidulafungin inhibits glucan synthase, an enzyme present in fungal, but not mammalian cells. This results in inhibition of the formation of 1,3-β-D-glucan, an essential component of the fungal cell wall.

    Resistance

    Echinocandin resistance is due to point mutations within the genes (FKS1 and FKS2) encoding for subunits in the glucan synthase enzyme complex. There have been reports of Candida isolates with reduced susceptibility to anidulafungin, suggesting a potential for development of drug resistance. The clinical significance of this observation is not fully understood.

    Antimicrobial Activity

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

    Candida albicans
    Candida glabrata
    Candida parapsilosis
    Candida tropicalis

    The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following fungi exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for anidulafungin against isolates of the following Candida species. However, the effectiveness of anidulafungin in treating clinical infections due to these fungi has not been established in adequate and well-controlled clinical trials:

    Candida guilliermondii
    Candida krusei

    Susceptibility Testing

    For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

  • 13 NONCLINICAL TOXICOLOGY

    13.1 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).

    13.2 Animal Toxicology and/or Pharmacology

    In 3 month studies, liver toxicity, including single cell hepatocellular necrosis, hepatocellular hypertrophy and increased liver weights were observed in monkeys and rats at doses equivalent to 5–6 times human exposure. For both species, hepatocellular hypertrophy was still noted one month after the end of dosing.

  • 14 CLINICAL STUDIES

    14.1 Candidemia and Other Candida Infections (Intra-abdominal Abscess and Peritonitis)

    Adults Candidemia and Other Candida Infections (Intra-abdominal Abscess and Peritonitis) Trial

    The safety and efficacy of ERAXIS were evaluated in a Phase 3, randomized, double-blind study of patients with candidemia and/or other forms of invasive candidiasis. Patients were randomized to receive once daily IV ERAXIS (200 mg loading dose followed by 100 mg maintenance dose) or IV fluconazole (800 mg loading dose followed by 400 mg maintenance dose). Patients were stratified by APACHE II score (≤20 and >20) and the presence or absence of neutropenia. Patients with Candida endocarditis, osteomyelitis or meningitis, or those with infection due to C. krusei, were excluded from the study. Treatment was administered for at least 14 and not more than 42 days. Patients in both study arms were permitted to switch to oral fluconazole after at least 10 days of intravenous therapy, provided that they were able to tolerate oral medication, were afebrile for at least 24 hours, and the last blood cultures were negative for Candida species.

    Patients who received at least one dose of study medication and who had a positive culture for Candida species from a normally sterile site before entry into the study (modified intent-to-treat [MITT] population) were included in the analysis of global response at the end of IV therapy. A successful global response required clinical cure or improvement (significant, but incomplete resolution of signs and symptoms of the Candida infection and no additional antifungal treatment), and documented or presumed microbiological eradication. Patients with an indeterminate outcome were analyzed as failures in this population.

    Two hundred and fifty-six patients in the intent-to-treat (ITT) population were randomized and received at least one dose of study medication. In ERAXIS-treated patients, the age range was 16–89 years, the gender distribution was 50% male and 50% female, and the race distribution was 71% White, 20% Black/African American, 7% Hispanic, 2% other races. The median duration of IV therapy was 14 and 11 days in the ERAXIS and fluconazole arms, respectively. For those who received oral fluconazole, the median duration of oral therapy was 7 days for the ERAXIS arm and 5 days for the fluconazole arm.

    Patient disposition is presented in Table 9.

    Table 9: Patient Disposition and Reasons for Discontinuation in Candidemia and other Candida Infections Study
    ERAXISFluconazole
    n (%)n (%)
    Treated patients131125
    Patients completing study through 6 week follow-up94 (72)80 (64)
    DISCONTINUATIONS FROM STUDY MEDICATION
    Total discontinued from study medication34 (26)48 (38)
      Discontinued due to adverse events12 (9)21 (17)
      Discontinued due to lack of efficacy11 (8)16 (13)

    Two hundred and forty-five patients (127 ERAXIS, 118 fluconazole) met the criteria for inclusion in the MITT population. Of these, 219 patients (116 ERAXIS, 103 fluconazole) had candidemia only. Risk factors for candidemia among patients in both treatment arms in this study were: presence of a central venous catheter (78%), receipt of broad-spectrum antibiotics (69%), recent surgery (42%), recent hyperalimentation (25%), and underlying malignancy (22%). The most frequent species isolated at baseline was C. albicans (62%), followed by C. glabrata (20%), C. parapsilosis (12%) and C. tropicalis (11%). The majority (97%) of patients were non-neutropenic (ANC >500) and 81% had APACHE II scores less than or equal to 20.

    Global success rates in patients with candidemia and other Candida infections are summarized in Table 10.

    Table 10: Efficacy Analysis: Global Success in patients with Candidemia and other Candida Infections (MITT Population)
    Time-pointERAXIS
    (N=127)
    n (%)
    Fluconazole
    (N=118)
    n (%)
    Treatment Difference*, %
    (95% C.I.)
    *
    Calculated as ERAXIS minus fluconazole
    33 patients in each study arm (26% ERAXIS and 29% fluconazole-treated) switched to oral fluconazole after the end of IV therapy.
    98.3% confidence intervals, adjusted post hoc for multiple comparisons of secondary time points
    End of IV Therapy96 (75.6)71 (60.2)15.4
    (3.9, 27.0)
    End of All Therapy94 (74.0)67 (56.8)17.2
    (2.9, 31.6)
    2 Week Follow-up82 (64.6)58 (49.2)15.4
    (0.4, 30.4)
    6 Week Follow-up71 (55.9)52 (44.1)11.8
    (-3.4, 27.0)

    Table 11 presents global response by patients with candidemia or multiple sites of Candida infection and mortality data for the MITT population.

    Table 11: Global Response and Mortality in Candidemia and other Candida Infections
    ERAXISFluconazoleBetween group difference *
    (95% CI)
    *
    Calculated as ERAXIS minus fluconazole
    No. of MITT patients127118
    Global Success (MITT) At End Of IV Therapy
     
    Candidemia88/116 (75.9%)63/103 (61.2%)14.7 (2.5, 26.9)
    Neutropenic
    1/22/4-
    Non neutropenic87/114 (76.3%)61/99 (61.6%)-
     
    Multiple sites
    Peritoneal fluid/ intra-abdominal abscess4/65/6-
    Blood/ peritoneum (intra-abdominal abscess)2/20/2-
    Blood /bile-1/1-
    Blood/renal-1/1-
    Pancreas-0/3-
    Pelvic abscess-1/2-
    Pleural fluid1/1--
    Blood/ pleural fluid0/1--
    Blood/left thigh lesion biopsy1/1--
    Total8/11 (72.7%)8/15 (53.3%)-
    Mortality
    Overall study mortality29/127 (22.8 %)37/118 (31.4%)-
    Mortality during study therapy10/127 (7.9%)17/118 (14.4%)-
    Mortality attributed to Candida2/127 (1.6%)5/118 (4.2%)-

    Pediatric Candidemia/Invasive Candidiasis Trial

    A prospective, open-label, non-comparative, multinational trial (National Clinical Trial (NCT) number 00761267) assessed the safety and efficacy of ERAXIS in 68 pediatric patients aged 1 month to <18 years with candidemia/invasive candidiasis. Patients were stratified by age (1 month to <2 years, 2 to <5 years, and 5 to <18 years) and received once daily intravenous ERAXIS (3 mg/kg loading dose on Day 1, and 1.5 mg/kg daily maintenance dose thereafter) followed by an optional switch to oral fluconazole (6–12 mg/kg/day, maximum 800 mg/day) up to Day 49. Patients were followed at 2 and 6 weeks after EOT.

    Among 68 ERAXIS-treated patients, 64 had microbiologically confirmed Candida infection and were evaluated for efficacy in the modified intent-to-treat (MITT) population. Overall, 59 patients (92.2%) had Candida isolated from blood only. The most commonly isolated pathogens were Candida albicans (25 [39.1%] patients), followed by Candida parapsilosis (17 [26.6%] patients), and Candida tropicalis (9 [14.1%] patients). A successful global response was defined as having both successful clinical (cure or improvement) and microbiological (eradication or presumed eradication) response. The overall rates of successful global response in the MITT population are presented in Table 12 below.

    Table 12: Summary of Successful Global Response by Age Group, MITT Population
    Successful Global Response, n (%)
    TimepointGlobal Response1 month to <2 years
    (N = 16)
    n (n/N, %)
    2 to <5 years
    (N=18)
    n (n/N, %)
    5 to <18 years
    (N=30)
    n (n/N, %)
    Overall
    (N=64)
    n (n/N, %)
    95% CI = exact 95% confidence interval for binomial proportions using Clopper-Pearson method; EOIVT = end of intravenous treatment; EOT = end of treatment; FU = follow-up; MITT = modified intent-to-treat; N = number of subjects in the population; n = number of subjects with responses.
    EOIVTSuccess11 (68.8)14 (77.8)20 (66.7)45 (70.3)
    95% CI (41.3, 89.0)(52.4, 93.6)(47.2, 82.7)(57.6, 81.1)
    EOTSuccess11 (68.8)14 (77.8)21 (70.0)46 (71.9)
    95% CI (41.3, 89.0)(52.4, 93.6)(50.6, 85.3)(59.2, 82.4)
    2-week FUSuccess11 (68.8)13 (72.2)22 (73.3)46 (71.9)
    95% CI (41.3, 89.0)(46.5, 90.3)(54.1, 87.7)(59.2, 82.4)
    6-week FUSuccess11 (68.8)12 (66.7)20 (66.7)43 (67.2)
    95% CI (41.3, 89.0)(41.0, 86.7)(47.2, 82.7)(54.3, 78.4)

    14.2 Esophageal Candidiasis

    ERAXIS was evaluated in a double-blind, double-dummy, randomized Phase 3 study. Three hundred patients received ERAXIS (100 mg loading dose IV on Day 1 followed by 50 mg/day IV) and 301 received oral fluconazole (200 mg loading dose on Day 1 followed by 100 mg/day). Treatment duration was 7 days beyond resolution of symptoms for a minimum of 14 and a maximum of 21 days.

    Of the 442 patients with culture confirmed esophageal candidiasis, most patients (91%) had C. albicans isolated at the baseline.

    Treatment groups were similar in demographic and other baseline characteristics. In ERAXIS-treated patients, the age range was 16–69 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.

    In this study, of 280 patients tested, 237 (84.6%) tested HIV positive. In both groups the median time to resolution of symptoms was 5 days and the median duration of therapy was 14 days.

    Efficacy was assessed by endoscopic outcome at end of therapy (EOT). Patients were considered clinically evaluable if they received at least 10 days of therapy, had an EOT assessment with a clinical outcome other than 'indeterminate', had an endoscopy at EOT, and did not have any protocol violations prior to the EOT visit that would affect an assessment of efficacy.

    An endoscopic success, defined as cure (endoscopic grade of 0 on a 4-point severity scale) or improvement (decrease of one or more grades from baseline), was seen in 225/231 (97.4%) ERAXIS-treated patients and 233/236 (98.7%) fluconazole-treated patients (Table 13). The majority of these patients were endoscopic cures (grade=0). Two weeks after completing therapy, the ERAXIS group had significantly more endoscopically-documented relapses than the fluconazole group, 120/225 (53.3%) vs. 45/233 (19.3%), respectively (Table 13).

    Table 13: Endoscopy Results in Patients with Esophageal Candidiasis (Clinically Evaluable Population)
    *
    Calculated as ERAXIS minus fluconazole
    Endoscopic Response at End of Therapy
    ResponseERAXIS
    N=231
    Fluconazole
    N=236
    Treatment Difference*95% CI
    Endoscopic Success, n (%)225 (97.4)233 (98.7)-1.3%-3.8%, 1.2%
    Cure204 (88.3)221 (93.6)
    Improvement 21 (9.1)12 (5.1)
    Failure, n (%)6 (2.6)3 (1.3)
     
    Endoscopic Relapse Rates at Follow-Up, 2 Weeks Post-Treatment
    ERAXISFluconazoleTreatment Difference*95% CI
    Endoscopic Relapse, n/N (%)120/225 (53.3%)45/233 (19.3%)34.0%25.8%, 42.3%

    Clinical success (cure or improvement in clinical symptoms including odynophagia/dysphagia and retrosternal pain) occurred in 229/231 (99.1%) of the ERAXIS-treated patients and 235/236 (99.6%) of the fluconazole-treated patients at the end of therapy. For patients with C. albicans, microbiological success occurred in 142/162 (87.7%) of the ERAXIS-treated group and 157/166 (94.6%) of the fluconazole-treated group at the end of therapy. For patients with Candida species other than C. albicans, success occurred in 10/12 (83.3%) of the ERAXIS-treated group and 14/16 (87.5%) of the fluconazole-treated group.

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    16.1 How Supplied

    ERAXIS (anidulafungin) for Injection is supplied in a single-dose vial of sterile, lyophilized, preservative-free, white to off-white powder. ERAXIS (anidulafungin) is available in the following packaging configuration:

    Single-Dose Vial of ERAXIS 50 mg
    NDC 0049-0114-28One - 50 mg vial
    Single-Dose Vial of ERAXIS 100 mg
    NDC 0049-0116-28One - 100 mg vial

    16.2 Storage

    ERAXIS vials

    ERAXIS (unreconstituted) vials should be stored in a refrigerator at 2°C – 8°C (36°F – 46°F). Do not freeze.

    Excursions for 96 hours up to 25°C (77°F) are permitted, and the vial can be returned to storage at 2°C – 8°C (36°F – 46°F).

    Reconstituted solution

    ERAXIS reconstituted solution can be stored at up to 25°C (77°F) for up to 24 hours [see Dosage and Administration (2.3)].

    Infusion Solution

    ERAXIS infusion solution can be stored at temperatures up to 25°C (77°F) for up to 48 hours. Do not freeze [see Dosage and Administration (2.4)].

  • 17 PATIENT COUNSELING INFORMATION

    Hepatic Adverse Reactions

    Inform patients about the risk of developing abnormal liver function tests and/or hepatic dysfunction. Advise the patient that liver function tests may be monitored during treatment.

    Anaphylactic and Hypersensitivity Reactions

    Inform the patient that anaphylactic reactions, including shock were reported with ERAXIS. Inform the patient if these reactions occur, ERAXIS may be discontinued and appropriate treatment administered.

    Inform the patient that ERAXIS is also known to cause infusion-related adverse reactions, possibly histamine-mediated. Inform the patient to report symptoms including rash, urticaria, flushing, pruritus, dyspnea, and hypotension to their healthcare provider.

    Embryo-Fetal Toxicity

    Advise pregnant women and females of reproductive potential of the potential risk of ERAXIS to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy.

    Patients with Hereditary Fructose Intolerance (HFI)

    Inform patients and caregivers that ERAXIS contains fructose and can be life-threatening when administered to patients with hereditary fructose intolerance (HFI) [see Warnings and Precautions (5.4)]. Inquire for symptoms of fructose and/or sucrose intolerance.

  • SPL UNCLASSIFIED SECTION

    This product's prescribing information may have been updated. For current full prescribing information, please visit www.pfizer.com.

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    LAB-0336-15.0

  • PRINCIPAL DISPLAY PANEL - 50 mg Vial Label

    1 Sterile Single-dose Vial

    Eraxis®
    (anidulafungin)
    for Injection

    50 mg/vial

    For Intravenous Infusion Only

    Pfizer Injectables

    Distributed by: Roerig
    Division of Pfizer Inc
    NY, NY 10017

    Rx only

    PRINCIPAL DISPLAY PANEL - 50 mg Vial Label
  • PRINCIPAL DISPLAY PANEL - 50 mg Vial Carton

    NDC 0049-0114-28

    Unit Pack Contains:
    1 Sterile Single-dose Vial
    Eraxis
    ® 50 mg

    Eraxis®
    (anidulafungin)
    for Injection

    50 mg/vial

    For Intravenous Infusion Only

    Store Vial in Refrigerator
    at 2 - 8° C (36 - 46° F).
    Do Not Freeze.

    Pfizer Injectables

    Distributed by: Roerig
    Division of Pfizer Inc
    NY, NY 10017

    Rx only

    PRINCIPAL DISPLAY PANEL - 50 mg Vial Carton
  • PRINCIPAL DISPLAY PANEL - 100 mg Vial Label

    1 Sterile Single-dose Vial

    Eraxis®
    (anidulafungin)
    for Injection

    100 mg/vial

    For Intravenous Infusion Only

    Pfizer Injectables

    Distributed by: Roerig
    Division of Pfizer Inc
    NY, NY 10017

    Rx only

    PRINCIPAL DISPLAY PANELPANEL - 100 mg Vial Label
  • PRINCIPAL DISPLAY PANEL - 100 mg Vial Carton

    NDC 0049-0116-28

    Unit Pack Contains:
    1 Sterile Single-dose Vial
    Eraxis
    ® 100 mg

    Eraxis®
    (anidulafungin)
    for Injection

    100 mg/vial

    For Intravenous Infusion Only

    Store Vial in Refrigerator
    at 2 - 8° C (36 - 46° F).
    Do Not Freeze.

    Pfizer Injectables

    Distributed by: Roerig
    Division of Pfizer Inc
    NY, NY 10017

    Rx only

    PRINCIPAL DISPLAY PANEL - 100 mg Vial Carton
  • INGREDIENTS AND APPEARANCE
    ERAXIS 
    anidulafungin injection, powder, lyophilized, for solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:0049-0114
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    ANIDULAFUNGIN (UNII: 9HLM53094I) (ANIDULAFUNGIN - UNII:9HLM53094I) ANIDULAFUNGIN50 mg  in 15 mL
    Inactive Ingredients
    Ingredient NameStrength
    FRUCTOSE (UNII: 6YSS42VSEV) 50 mg  in 15 mL
    MANNITOL (UNII: 3OWL53L36A) 250 mg  in 15 mL
    POLYSORBATE 80 (UNII: 6OZP39ZG8H) 125 mg  in 15 mL
    TARTARIC ACID (UNII: W4888I119H) 5.6 mg  in 15 mL
    SODIUM HYDROXIDE (UNII: 55X04QC32I)  
    HYDROCHLORIC ACID (UNII: QTT17582CB)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:0049-0114-2815 mL in 1 VIAL, SINGLE-USE; Type 0: Not a Combination Product02/17/2006
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA02163202/17/2006
    ERAXIS 
    anidulafungin injection, powder, lyophilized, for solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:0049-0116
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    ANIDULAFUNGIN (UNII: 9HLM53094I) (ANIDULAFUNGIN - UNII:9HLM53094I) ANIDULAFUNGIN100 mg  in 30 mL
    Inactive Ingredients
    Ingredient NameStrength
    FRUCTOSE (UNII: 6YSS42VSEV) 100 mg  in 30 mL
    MANNITOL (UNII: 3OWL53L36A) 500 mg  in 30 mL
    POLYSORBATE 80 (UNII: 6OZP39ZG8H) 250 mg  in 30 mL
    TARTARIC ACID (UNII: W4888I119H) 11.2 mg  in 30 mL
    SODIUM HYDROXIDE (UNII: 55X04QC32I)  
    HYDROCHLORIC ACID (UNII: QTT17582CB)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:0049-0116-2830 mL in 1 VIAL, SINGLE-USE; Type 0: Not a Combination Product02/17/2006
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA02163202/17/2006
    Labeler - Roerig (829076996)
    Registrant - Pfizer Inc (113480771)
    Establishment
    NameAddressID/FEIBusiness Operations
    Pharmacia & Upjohn Company LLC618054084ANALYSIS(0049-0114, 0049-0116) , MANUFACTURE(0049-0114, 0049-0116) , API MANUFACTURE(0049-0114, 0049-0116) , PACK(0049-0114, 0049-0116) , LABEL(0049-0114, 0049-0116)
    Establishment
    NameAddressID/FEIBusiness Operations
    Eurofins Lancaster Laboratories, Inc069777290ANALYSIS(0049-0114, 0049-0116)