2.1 Dose and Schedule

Administer CYFENDUS by intramuscular injection as a series of two doses (0.5 mL each) two weeks apart (at Week 0 and 2) post-exposure combined with antibacterial therapy.

2.2 Administration

Gently swirl or roll the vial to ensure that the vaccine is a homogeneous milky-white suspension. To avoid foaming DO NOT shake.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If either of these conditions exist, do not administer the vaccine.

Administer CYFENDUS intramuscularly.

Do not mix CYFENDUS with any other product in the same syringe or vial.

5.1 Management of Acute Allergic Reactions

Appropriate medical treatment must be available to manage possible anaphylactic reactions following administration of CYFENDUS.

5.2 Altered Immunocompetence

Immunocompromised persons, including those receiving immunosuppressive therapy, may have a diminished immune response to CYFENDUS.

5.3 Pregnancy

CYFENDUS can cause fetal harm when administered to a pregnant individual. In an observational study, there were more birth defects in infants born to individuals vaccinated with BioThrax (a licensed anthrax vaccine with the same active ingredient as CYFENDUS; BioThrax does not contain CPG 7909 adjuvant) in the first trimester compared to infants born to individuals vaccinated post pregnancy or individuals never vaccinated with BioThrax. [See Use in Specific Populations (8.1)]

If CYFENDUS is administered during pregnancy, the vaccinated individual should be apprised of the potential hazard to a fetus.

6.1 Clinical Trials Experience

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

The safety of CYFENDUS was evaluated in 4 clinical studies, in which a total of 3,276 participants 18 through 65 years of age received at least one dose of CYFENDUS and were included in a pooled safety population.

Study 1 (NCT01263691) evaluated the safety and immunogenicity of different vaccine formulations administered intramuscularly two weeks apart in participants between 18 and 50 years of age. Seventeen participants received at least one 0.5 mL dose of CYFENDUS.

Study 2 (NCT01770743) evaluated the safety and immunogenicity of different dosing regimens of CYFENDUS in participants between 18 and 50 years of age. Forty-four participants received two doses of CYFENDUS via the intramuscular route two weeks apart.

Study 3 (NCT04067011) investigated potential interactions of intramuscularly administered CYFENDUS with the antibacterials ciprofloxacin or doxycycline, when administered concomitantly in participants between 18 and 45 years of age. Sixty-four participants received only CYFENDUS in the control arm.

Study 4 (NCT03877926) evaluated the safety and immunogenicity of CYFENDUS in participants between 18 and 65 years of age. CYFENDUS was administered intramuscularly as two doses at Weeks 0 and 2, with saline placebo given at Week 4. BioThrax was administered subcutaneously as three doses at Weeks 0, 2, and 4. The number of participants receiving at least one dose of CYFENDUS was 3151, while 2898 participants received the complete two dose regimen. [See Clinical Studies (14.1)]

The mean age for the pooled safety population across Studies 1-4 was 39 years; 32.1% of participants (n=1050) were between 18-30 years of age, 44.2% (n=1447) were between 31 to 50 years of age, and 23.8% (n=779) were between 51-65 years of age. Females comprised 57.8% (n=1895) of the population, with 40.4% (n=1325) being women of childbearing potential. The race distribution was as follows: 77.9% White, 17.1% Black or African American, 1.8% Asian, 1.7% Multiracial, 0.4% American Indian or Alaskan Native, 0.3% Native Hawaiian or Other Pacific Islander, 0.5% Other, and 0.2% Unknown. Most participants (83.9%) were not Hispanic or Latino.

Study 4 Solicited Local and Systemic Adverse Reactions

In Study 4, an active-controlled study, the licensed anthrax vaccine, BioThrax (Anthrax Vaccine Adsorbed), was used as the comparator. Solicited local and systemic adverse reactions reported following administration of any dose of CYFENDUS or BioThrax are presented in Table 1. CYFENDUS was administered intramuscularly as two doses at Weeks 0 and 2, with saline placebo given at Week 4. BioThrax was administered subcutaneously as three doses at Weeks 0, 2, and 4. The number of participants receiving at least one dose of CYFENDUS was 3151, while 2898 participants received the complete two dose regimen of CYFENDUS. There was no notable difference in the frequency of solicited local or systemic adverse reactions after the first or second dose of CYFENDUS, with the exception of itching (10.3% after first CYFENDUS dose vs. 16.8% after second dose), erythema/redness (7.4% after first CYFENDUS dose vs. 14.8% after second dose), swelling (10.2% after first CYFENDUS dose vs. 15.9% after second dose) and fever (2.7% after first CYFENDUS dose vs. 5.0% after second dose).

Serious Adverse Events (SAEs) and Deaths

In the pooled safety population, serious adverse events including deaths were monitored for up to one year following the last vaccination. None of the reported deaths (n=6, 0.2%) or SAEs (n=62, 1.9%) were determined to be related to the administration of CYFENDUS.

Potentially Immune-mediated Adverse Events

In the pooled safety population, participants were monitored for the occurrence of new-onset potentially immune-mediated adverse events for 12 months after the first dose of vaccine. Events were adjudicated as to whether they were of autoimmune etiology by an external expert blinded to treatment assignment. As determined by the adjudicator, three events of autoimmune etiology in three participants were considered possibly related to the administration of CYFENDUS: (1) a case of ulcerative colitis that occurred 208 days after the administration of CYFENDUS, (2) a case of chronic idiopathic urticaria that occurred 76 days after the administration of CYFENDUS and (3) a case of diffuse alopecia that occurred 17 days after the administration of CYFENDUS.

6.2 Postmarketing Experience

There is no postmarketing experience following administration of CYFENDUS. However, the postmarketing safety experience with BioThrax is relevant because BioThrax and CYFENDUS contain the same active ingredient and are manufactured similarly. BioThrax does not contain CPG 7909 adjuvant.

The following adverse events have been spontaneously reported during the postmarketing use of BioThrax and may occur in people receiving CYFENDUS. Because these events 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 vaccine exposure. Adverse events included below are listed due to one or more of the following factors: (1) seriousness of the event, (2) number of reports, or (3) strength of causal relationship to BioThrax.

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Blood and lymphatic system disorders: Lymphadenopathy

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Gastrointestinal disorders: Nausea

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Immune system disorders: Allergic reactions (including anaphylaxis, angioedema, rash, urticaria, pruritus, erythema multiforme, anaphylactoid reaction, and Stevens-Johnson syndrome)

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Nervous system disorders: Paresthesia, syncope, dizziness, tremor, ulnar nerve neuropathy

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Musculoskeletal, connective tissue, and bone disorders: Arthralgia, arthropathy, myalgia, rhabdomyolysis, alopecia

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General disorders and administration site conditions: Malaise, pain, cellulitis, flu-like symptoms

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Psychiatric disorders: Insomnia

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Skin and subcutaneous tissue disorders: Pruritus, rash, urticaria

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Vascular disorders: Flushing

Reports of the following were also received: multisystem disorder defined as chronic symptoms involving at least two of the following three categories: fatigue, mood-cognition, and musculoskeletal system.

8.1 Pregnancy

Risk Summary

All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In clinically recognized pregnancies in the US general population, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20%.

There are no adequate and well-controlled studies of CYFENDUS in pregnant individuals.

Available human data on CYFENDUS administered to pregnant individuals do not establish the presence or absence of vaccine-associated risks in pregnancy (see Human Data). However, available data on BioThrax (a licensed anthrax vaccine), administered to pregnant individuals are relevant to CYFENDUS because BioThrax and CYFENDUS contain the same active ingredient and are manufactured similarly. BioThrax does not contain CPG 7909 adjuvant. Data are available from a BioThrax observational study and pregnancy exposure registry.

In the observational study there were more birth defects in infants born to individuals vaccinated with BioThrax in the first trimester compared to individuals vaccinated post pregnancy or individuals never vaccinated with BioThrax. Data from the BioThrax pregnancy exposure registry do not establish the presence or absence of vaccine-associated risks in pregnancy (see Human Data).

In a developmental study with an embryo-fetal development toxicity phase, female rats were administered a full human dose (0.5 mL) of CYFENDUS twice prior to mating and once during gestation. This study revealed no evidence of harm to the fetus, changes in reproductive performance, or adverse effects on post-natal development due to the vaccine (see Animal Data).

Data

Human Data

In pre-licensure clinical studies of CYFENDUS, women underwent pregnancy testing immediately prior to administration of each dose of CYFENDUS. Despite this pregnancy screening regimen, some subjects were vaccinated with CYFENDUS very early in pregnancy before human chorionic gonadotropin was detectable (n=10) or in the 30 days prior to pregnancy onset (n=1). Of the 11 pregnancies (one twin pregnancy), 1 (9.1%) resulted in miscarriage and there were 2 infants (18.2%) born with major birth defects.

An observational study examined the rate of birth defects among 37,140 infants born to US military service personnel who received BioThrax during pregnancy between 1998 and 2004. In this study, birth defects were slightly more common in first trimester-exposed infants (4.68%) when compared with infants of individuals vaccinated post pregnancy (3.85%) (odds ratio = 1.20; 95% confidence interval: 1.005, 1.43) or when compared to individuals never vaccinated with BioThrax (4.03%) (odds ratio = 1.20; 95% confidence interval: 1.02, 1.42)1.

A pregnancy exposure registry was conducted in individuals who received BioThrax. Of 91 individuals who reported pregnancy outcomes, the majority of exposures were in the first trimester (n=89), and there were two infants with major birth defects (2.2%) and no miscarriages.

Animal Data

In a pre- and post-natal developmental study with an embryo-fetal development toxicity phase performed in female rats, a full human dose (0.5 mL) of CYFENDUS was administered by intramuscular injection on three occasions: 14 days prior to start of cohabitation, on the day of cohabitation, and on Gestation Day 7. No vaccine-related adverse effects on fetal development, reproductive performance, or pre- and post-natal development up to post-natal day 21 in the offspring were reported.

8.2 Lactation

Risk Summary

It is not known whether CYFENDUS is excreted in human milk. Human data are not available to assess the impact of the vaccine on milk production, its presence in breast milk, or its effects on the breastfed child. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for CYFENDUS and any potential adverse effects on the breastfed child, or from the underlying maternal condition. For preventive vaccines, the underlying maternal condition is susceptibility to disease prevented by the vaccine.

8.4 Pediatric Use

Safety and effectiveness of CYFENDUS in individuals younger than 18 years of age have not been established.

8.5 Geriatric Use

Safety and effectiveness of CYFENDUS in individuals older than 65 years of age have not been established.

12.1 Mechanism of Action

Anthrax is an infectious disease caused by the Gram-positive, spore-forming bacterium B. anthracis.

CYFENDUS induces antibodies against protective antigen protein that may contribute to protection by neutralizing the activities of the cytotoxic lethal toxin and edema toxin of B. anthracis.

13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility

CYFENDUS has not been evaluated for carcinogenicity, mutagenic potential, or male infertility in animals. CYFENDUS administered to female rats had no effect on fertility [see Use in Specific Populations (8.1)].

13.2 Animal Toxicology and/or Pharmacology

Animal Pharmacology

Because it is not feasible or ethical to conduct controlled clinical trials with anthrax, the efficacy of CYFENDUS is based on animal studies with CYFENDUS and BioThrax. Pre-exposure prophylaxis studies conducted in animal models were used to derive protective antibody thresholds to bridge animal efficacy and human immunogenicity data and predict efficacy in humans.

Pivotal efficacy animal studies with BioThrax were conducted in rabbits and nonhuman primates (NHPs). Animals received two intramuscular vaccinations four weeks apart with serial dilutions of BioThrax and were subjected to lethal challenge on study day 70 with aerosolized B. anthracis spores at a target dose exceeding the 50% lethal dose by 200-fold. Serum samples were collected at various time points prior to challenge for immune response analysis via anthrax lethal toxin neutralizing antibody (TNA) assay. The relationship between pre-challenge serum TNA levels and survival was evaluated. Logistic regression analysis demonstrated that a 70% probability of survival was associated with a TNA NF50 (50% neutralization factor) level of 0.56 in rabbits and 0.29 in NHPs.

Efficacy studies for CYFENDUS were conducted in guinea pigs and cynomolgus macaques. Animals received two intramuscular vaccinations two weeks apart with various dilutions of CYFENDUS and were challenged with a lethal dose of aerosolized B. anthracis spores on Day 28 or 70. The studies demonstrated a strong correlation between pre-challenge serum TNA levels and survival.

The ability of CYFENDUS to increase survival after the cessation of the post-exposure antibacterial treatment, as compared with antibacterial treatment alone, was investigated in a guinea pig post-exposure prophylaxis study. In this study, guinea pigs were challenged with a lethal dose of aerosolized B. anthracis spores on Day 0 and treated with ciprofloxacin (7.5 mg/kg three times daily) for two weeks after the challenge. Various dilutions of the vaccine were administered on Days 1 and 8 after the challenge. Post-exposure vaccination increased animal survival in the 21-day period following cessation of antibacterial drugs, compared to antibacterial treatment alone, in a dose-dependent manner.

14.1 Post-Exposure Prophylaxis

The efficacy of CYFENDUS is based on studies of both CYFENDUS and BioThrax in animals [see Animal Toxicology and/or Pharmacology (13.2)].

Based on the animal model-derived TNA thresholds from studies of BioThrax, a multicenter, randomized, active-controlled, double-blind, parallel-group clinical study (Study 4; NCT03877926) was conducted to evaluate the immunogenicity and safety of a post-exposure administration schedule of two doses (0.5 mL) of CYFENDUS intramuscularly two weeks apart in adults ages 18 through 65 years. In the study, 3151 participants received at least one dose of CYFENDUS, and 533 participants received at least one dose (0.5 mL) of the comparator licensed anthrax vaccine, BioThrax. Participants were followed for immunogenicity up to Day 64 (7 weeks after last CYFENDUS vaccination, 5 weeks after last BioThrax vaccination) [see Adverse Reactions (6.1)].

The mean age of participants in the per protocol (PP) population receiving CYFENDUS (n=2543) was 39.4 years. Of these, 57.8% of participants were female, 78.1% were White, 17.0% were Black or African American, 1.7% were Multiracial, 1.6% were Asian, 0.5% were Other, 0.4% were American Indian or Alaskan Native, and 0.4% were Native Hawaiian or Pacific Islander. There were 13.8% Hispanic or Latino participants.

The primary immunogenicity objectives were to assess CYFENDUS vaccine-induced TNA 50% neutralization factor (NF50) response at Day 64 and non-inferiority to BioThrax following two doses of CYFENDUS administered intramuscularly two weeks apart (Week 0 and 2) and three doses of BioThrax administered subcutaneously two weeks apart (Week 0, 2, and 4). The two co-primary immunogenicity endpoints and statistical evaluation criteria were:

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Percentage of CYFENDUS recipients achieving a threshold TNA NF50 value ≥0.56 at Day 64 (with the lower bound of the 2-sided 95% confidence interval [CI] for the proportion ≥40%) and,

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The percent difference between participants achieving a threshold TNA NF50 value ≥0.29 at Day 64 in those who received CYFENDUS and those who received BioThrax (with the lower bound of the 2-sided 95% CI for the difference being greater than -15%).

The TNA NF50 thresholds of 0.56 and 0.29 were based on the TNA NF50 values in rabbits and nonhuman primates, respectively, that were associated with 70% probability of survival in pre-exposure prophylaxis studies, in which animals were immunized with BioThrax and subsequently challenged with aerosolized B. anthracis spores [see Animal Toxicology and/or Pharmacology (13.2)].

Overall, 66.3% of CYFENDUS participants from the PP population achieved threshold TNA NF50 value ≥0.56 on Day 64 in the study; the lower bound of the 95% CI was 64.4% (Table 2).

The percent of participants with a threshold TNA NF50 of ≥0.29 at Day 64 was 86.6% in the CYFENDUS group compared with 61.4% in the BioThrax group, corresponding to a difference of 25.2%. The lower bound of the 2-sided 95% CI for the difference was 20.5%, thereby demonstrating non-inferiority of CYFENDUS to BioThrax (Table 3).

14.2 Concomitant Administration with Ciprofloxacin or Doxycycline

A randomized, open-label, multicenter study (Study 3; NCT04067011) was conducted in males and females, age 18 to 45 years, to investigate the potential interactions of concomitant intramuscular administration of CYFENDUS with oral administration of ciprofloxacin or doxycycline. The potential effect of CYFENDUS vaccination on ciprofloxacin or doxycycline serum levels was assessed by evaluating steady-state pharmacokinetic profiles of ciprofloxacin or doxycycline before and after vaccination with a two-dose series of CYFENDUS.

Concomitant administration of 0.5 mL of CYFENDUS intramuscularly with oral ciprofloxacin or doxycycline in participants did not have a clinically relevant impact on the pharmacokinetics of ciprofloxacin and doxycycline, or the immunogenicity of CYFENDUS as measured by the TNA assay.