REZZAYO Powder for solution for injection Ref.[107368] Active ingredients: Rezafungin

5.1 Infusion-Related Reactions

Infusion-related reactions, including flushing, sensation of warmth, urticaria, nausea, and chest tightness have been observed in clinical trials with REZZAYO. If these reactions occur, slow or pause the infusion and restart at a lower rate [see Dosage and Administration (2.4)].

5.2 Photosensitivity

REZZAYO may cause photosensitivity. Patients should be advised to use protection from sun exposure and other sources of UV radiation during REZZAYO treatment.

5.3 Hepatic Adverse Reactions

Abnormalities in liver tests have been seen in clinical trial patients treated with REZZAYO [see Adverse Reactions (6.1)]. In some patients with serious underlying medical conditions who were receiving multiple concomitant medications along with REZZAYO, clinically significant hepatic abnormalities have occurred. Monitor patients who develop abnormal liver tests during REZZAYO therapy and evaluate patients for their risk/benefit of continuing REZZAYO therapy.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Infusion-related Reactions [see Warnings and Precautions (5.1)]
• Hepatic Adverse Reactions [see Warnings and Precautions (5.3)]

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

The safety of REZZAYO was assessed in 76 subjects in phase 1 studies and 232 patients with candidemia and invasive candidiasis in Trials 1 and 2, who received a 400 mg loading dose followed by a 200 mg dose once weekly or higher (please note that after the loading dose of 400 mg, weekly doses higher than 200 mg are not approved). A total of 151 patients received an initial 400 mg loading dose followed by a 200 mg dose once weekly thereafter (400 mg/200 mg dose); the maximum duration of dosing was 4 weekly doses (including the loading dose).

In the pooled Trial 1 and 2 safety database of REZZAYO patients treated with the 400 mg/200 mg dose, the age range was 19-91 years, the gender distribution was 64.9% male and 35.1% females, and the race distribution was 66.2% White, 7.9% Black, 17.9% Asian, 2.7% other, and 5.3% not reported.

Adverse Reactions Leading to Discontinuation in Patients with Candidemia and Invasive Candidiasis

The number of patients with an adverse reaction leading to discontinuation of study medication was 9.3% in the REZZAYO arm and 9.0% in the caspofungin arm. In Trial 2, patients with a history (or presenting with significant symptoms) of severe ataxia, tremor, or neuropathy or a diagnosis of multiple sclerosis or a movement disorder (including Parkinson’s Disease or Huntington’s Disease) or currently taking a known neurotoxic medication were excluded from the trial.

Most Common Adverse Reactions in Patients with Candidemia and Invasive Candidiasis

Selected adverse reactions occurring in 5% or more of the patients, who received a 400 mg loading dose followed by a 200 mg dose of REZZAYO once weekly are shown in Table 2.

Table 2. Adverse Reactions Reported in ≥5% of Adult Patients Receiving REZZAYO Therapy for Candidemia/Invasive Candidiasis:

Less Common Adverse Reactions in Patients with Candidemia and Invasive Candidiasis

The following selected adverse reactions occurred in <5% of patients receiving REZZAYO: infusion-related reactions, tremor, disseminated intravascular coagulation, dysphagia, gastrointestinal hemorrhage, fluid overload, insomnia, erythema, headache, dizziness, acute kidney injury, abnormal liver tests (including hypertransaminasemia and increased gamma-glutamyltransferase), peripheral neuropathy (includes neuropathy peripheral, polyneuropathy, and peroneal nerve palsy).

Tremors

Tremors were reported in 4/151 (2.6%) of REZZAYO-treated patients and none of the caspofungin-treated patients in Trials 1 and 2. All tremors developed in the second or third week after initiation of REZZAYO treatment and resolved within a month of onset.

Risk Summary

There are no data on the use of REZZAYO during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. No adverse embryofetal outcomes were observed when rezafungin was dosed intravenously to pregnant rats or rabbits during the period of organogenesis up to approximately 5 or 3 times the clinical exposure based on AUC comparison (see Data). In a pre- and post-natal study, there were no adverse effects on offspring growth, maturation, or measures of neurobehavioral or reproductive function in rats at doses up to about 5 times the recommended human dose based on AUC comparisons.

The background risk of major birth defects and miscarriage for the indicated population is 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 an embryofetal development study, intravenous rezafungin was administered at doses up to 45 mg/kg, once every 3 days to female rats one week prior to pairing with untreated males, and dosing was continued through mating to gestation day 17. Maternal toxicity included a transient histamine-release response (hypoactivity, ataxia, flushed extremities, dilated pupils and/or swollen facial area) at rezafungin doses of 15 mg/kg and above. No adverse embryofetal outcomes were observed in rat pups at rezafungin doses of 45 mg/kg, equivalent to 5 times the clinical exposure based on AUC comparisons.

No adverse outcomes were observed when rezafungin was dosed intravenously once every 3 days to pregnant rabbits during the period of organogenesis (GD 7 to 19) at doses up to 35 mg/kg (approximately 3 times the clinical exposure) despite maternal toxicity (reduced bodyweight gain).

In a pre- and post-natal study, there were no adverse effects on offspring growth, maturation, or measures of neurobehavioral or reproductive function in rats administered rezafungin intravenously once every 3 days from 1 week prior to mating through weaning (LD20), at doses up to 45 mg/kg/day (about 5 times the recommended human dose based on AUC comparisons).

Risk Summary

There are no data on the presence of rezafungin or its metabolite in human milk, the effects on the breastfed infant, or the effects on milk production. Rezafungin was present in rat milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for REZZAYO and any potential adverse effects on the breastfed infant from REZZAYO or from the underlying maternal condition.

Infertility

Males

Based on rat studies, rezafungin could lead to decreased sperm motility, decreased sperm numbers, and increased incidence of sperm with abnormal morphology. The effect of REZZAYO on human fertility is unknown [see Nonclinical Toxicology (13.1)].

The safety and effectiveness of REZZAYO have not been established in pediatric patients.

Of the 151 rezafungin-treated patients at the proposed dose in Trials 1 and 2, 64 patients (42%) were 65 years of age and older, while 26 patients (17%) were 75 years of age and older.

Clinical studies of REZZAYO did not include sufficient numbers of older adult patients to determine if patients 65 years and older respond differently than younger adult patients.