ERAXIS Solution for injection Ref.[10806] Active ingredients: Anidulafungin

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)].

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

• Hepatic Adverse Reactions [see Warnings and Precautions (5.1)]
• Anaphylactic and Hypersensitivity Reactions [see Warnings and Precautions (5.2)]

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^*,†:

^* 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.

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^*,†:

^* 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.

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^*,†:

^* 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.

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

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)].

7.1 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)].

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.

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.

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)].

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)].

8.7 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)].

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)].