Limitation of Use: Not indicated for the emergency treatment of allergic reactions, including anaphylaxis.

2.1 Important Considerations Prior to Initiation and During Therapy

Verify that the patient has injectable epinephrine and instruct patient on its appropriate use [see Warnings and Precautions (5.2)] .

2.2 Dosage

Treatment with PALFORZIA is administered in 3 sequential phases: Initial Dose Escalation, Up-Dosing, and Maintenance.

The dose configurations for each phase of dosing are provided in Table 1 through Table 3.

2.3 Preparation and Handling

PALFORZIA is to be administered orally.

• Open capsule(s) or sachet and empty the entire dose of PALFORZIA powder onto a few spoonfuls of refrigerated or room temperature semisolid food (e.g., applesauce, yogurt, pudding). Do not use liquid (e.g., milk, water, juice) to prepare.
• Mix well.
• Consume the entire volume of the prepared mixture promptly.
• Dispose of the opened capsule(s) or sachet.
• Wash hands immediately after handling PALFORZIA capsule(s) or sachets.
• Dispose of all unused PALFORZIA.

2.4 Administration

• For oral administration only.
• Do not swallow capsule(s).
• Do not inhale powder.

2.5 Schedule Modification and Product Discontinuation

5.1 Anaphylaxis

PALFORZIA can cause anaphylaxis, which may be life-threatening.

Anaphylaxis has been reported during all phases of PALFORZIA dosing, including Maintenance and in subjects who have undergone recommended Up-Dosing and dose modification procedures.

In 709 PALFORZIA-treated subjects and 292 placebo-treated subjects in the placebo-controlled population in Studies 1 and 2 combined [see Adverse Reactions (6.1)] , anaphylaxis was reported in 9.4% of PALFORZIA-treated subjects compared with 3.8% of placebo-treated subjects during Initial Dose Escalation and Up-Dosing combined, and in 8.7% of PALFORZIA-treated subjects compared with 1.7% of placebo-treated subjects during Maintenance in Study 1. Epinephrine use for any reason was reported in 10.4% of PALFORZIA-treated subjects compared with 4.8% of placebo-treated subjects during Initial Dose Escalation and Up-Dosing combined, and in 7.7% of PALFORZIA-treated subjects compared with 3.4% of placebo-treated subjects during Maintenance dosing in Study 1. Time to onset of anaphylaxis occurred within 2 hours after dosing in 70% of reactions, greater than 2 hours and up to 10 hours in 18% of reactions, and greater than 10 hours in 12% of reactions among PALFORZIA-treated subjects.

Do not initiate PALFORZIA treatment in a patient who has had severe or life-threatening anaphylaxis within the previous 60 days. PALFORZIA may not be suitable for patients with certain medical conditions that may reduce the ability to survive anaphylaxis, including but not limited to markedly compromised lung function, severe mast cell disorder, or cardiovascular disease. In addition, PALFORZIA may not be suitable for patients taking medications that can inhibit or potentiate the effects of epinephrine.

All Initial Dose Escalation doses and the first dose of each Up-Dosing level must be administered under observation in a health care setting [see Dosage and Administration (2.5)] . Prior to initiating PALFORZIA treatment, educate patients to recognize the signs and symptoms of anaphylaxis. Prescribe injectable epinephrine, instruct and train patients on its appropriate use, and instruct patients to seek immediate medical care upon its use. Instruct patients to contact their health care professional before administering the next dose of PALFORZIA if anaphylaxis or symptoms of an escalating or persistent allergic reaction occur as dose modification may be necessary [see Dosage and Administration (2.4)] .

Patients may be more likely to experience allergic reactions following PALFORZIA administration in the presence of cofactors such as exercise, hot water exposure, intercurrent illness (e.g., viral infection), or fasting. Other potential cofactors may include menstruation, sleep deprivation, nonsteroidal anti-inflammatory drug use, or uncontrolled asthma. Patients should be proactively counseled about the potential for the increased risk of anaphylaxis in the presence of these cofactors. If possible, adjust the time of dosing to avoid these cofactors. If it is not possible to avoid these cofactors, consider withholding PALFORZIA temporarily.

If appropriate to re-start administering PALFORZIA in patients who experienced anaphylaxis while on PALFORZIA or who had doses withheld to avoid increased risk of anaphylaxis, consider a dose reduction and dose re-escalation based on clinical judgment [see Dosage and Administration (2.5)] .

PALFORZIA is available only through a restricted program under a REMS [see Warnings and Precautions (5.2)] .

5.2 PALFORZIA REMS Program

PALFORZIA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the PALFORZIA REMS because of the risk of anaphylaxis [see Warnings and Precautions (5.1)] .

Notable requirements of the PALFORZIA REMS include the following:

• Health care providers who prescribe PALFORZIA must be certified with the program by enrolling.
• Health care settings must be certified in the program, have on-site access to equipment and personnel trained to manage anaphylaxis, and establish policies and procedures to verify that patients are monitored during and after the Initial Dose Escalation and first dose of each Up-Dosing level.
• Patients must be enrolled in the program prior to initiation of PALFORZIA treatment and must be informed of the need to have injectable epinephrine available for immediate use at all times, the need for monitoring with the Initial Dose Escalation and first dose of each Up-Dosing level, the need for continued dietary peanut avoidance, and how to recognize the signs and symptoms of anaphylaxis.
• Pharmacies must be certified with the program and must only dispense PALFORZIA to health care settings that are certified or to patients who are enrolled depending on the treatment phase.

Further information, including a list of certified prescribers, health care settings, and pharmacies, is available at www.PALFORZIAREMS.com or 1-844-PALFORZ (1-844-725-3679).

5.3 Asthma

Uncontrolled asthma is a risk factor for a serious outcome, including death, in anaphylaxis. Ensure patients with asthma have their asthma under control prior to initiation of PALFORZIA.

PALFORZIA should be temporarily withheld if the patient is experiencing an acute asthma exacerbation. Following resolution of the exacerbation, resumption of PALFORZIA should be undertaken cautiously [see Dosage and Administration (2.5)] . Re-evaluate patients who have recurrent asthma exacerbations and consider discontinuation of PALFORZIA. PALFORZIA has not been studied in subjects with severe asthma, persistently uncontrolled asthma, or patients on long-term systemic corticosteroid therapy.

5.4 Eosinophilic Gastrointestinal Disease

In clinical studies, 28 of 1050 (2.7%) subjects were referred for a gastroenterology evaluation and 17 of these 28 subjects reported undergoing an esophagogastroduodenoscopy (EGD). Of subjects who underwent an EGD, 12 were diagnosed with biopsy-confirmed eosinophilic esophagitis while receiving PALFORZIA compared with 0 of 292 (0%) subjects receiving placebo. After discontinuation of PALFORZIA, symptomatic improvement was reported in 12 of 12 subjects. In 8 subjects with available follow-up biopsy results, eosinophilic esophagitis was resolved in 6 subjects and improved in 2 subjects [see Contraindications (4)] .

Discontinue PALFORZIA and consider a diagnosis of eosinophilic esophagitis in patients who experience severe or persistent gastrointestinal symptoms, including dysphagia, vomiting, nausea, gastroesophageal reflux, chest pain, or abdominal pain [see Warnings and Precautions (5.5)] .

5.5 Gastrointestinal Adverse Reactions

Gastrointestinal adverse reactions, including abdominal pain, vomiting, nausea, oral pruritus, and oral paresthesia, were commonly reported in PALFORZIA-treated subjects in the placebo-controlled clinical study population [see Adverse Reactions (6, Table 4)] . Dose modification should be considered for patients who report these reactions [see Dosage and Administration (2.5)]. For severe or persistent gastrointestinal symptoms consider a diagnosis of eosinophilic esophagitis [see Warnings and Precautions (5.4)] .

6.1 Clinical Trial Experience

Use of PALFORZIA has been associated with:

• Anaphylaxis [see Warnings and Precautions (5.1)]
• Eosinophilic esophagitis [see Warnings and Precautions (5.4)]

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

The clinical data for PALFORZIA reflect exposure in 709 peanut-allergic subjects enrolled in two phase 3, double-blind, placebo-controlled trials (Study 1 and Study 2), and in long-term, open-label, follow-on studies. In Study 1, subjects were Up-Dosed for 20-40 weeks followed by Maintenance dosing for 24-28 weeks. In Study 2 subjects were Up-Dosed for 20-40 weeks up to a 300 mg daily dose with no extended Maintenance dosing. In these studies, subjects recorded adverse reactions daily in an electronic diary card throughout the study duration.

Study 1 (NCT02635776) was a randomized, double-blind, placebo-controlled efficacy and safety study conducted in the United States, Canada, and Europe evaluating PALFORZIA versus placebo in 555 subjects aged 4 through 55 years with peanut allergy. Subjects were required to have serum IgE to peanut ≥ 0.35 kUA/L within 12 months before study entry and/or a mean wheal diameter on skin prick test to peanut ≥ 3 mm greater than the negative control. The primary analysis population was aged 4 through 17 years, 78% white and 57% male. At study entry, subjects reacted at 100 mg or less of peanut protein in a double-blind, placebo-controlled food challenge (DBPCFC). The primary analysis was conducted in 496 subjects aged 4 through 17 years (PALFORZIA, N = 372; placebo, N = 124). Of the subjects aged 4 through 17 years treated with PALFORZIA, 72% had a medical history of anaphylactic reactions to peanut, 66% reported multiple food allergies, 63% had a medical history of atopic dermatitis, and 53% had a present or previous diagnosis of asthma. Subjects with severe persistent or uncontrolled asthma were excluded.

Study 2 (NCT03126227) was a randomized, double-blind, placebo-controlled safety study conducted in the United States and Canada evaluating PALFORZIA versus placebo in 506 subjects aged 4 through 17 years with peanut allergy. Subjects were required to have a clinical history of peanut allergy including onset of characteristic allergic signs and symptoms within 2 hours of known oral exposure to peanut, serum IgE to peanut of ≥ 14 kUA/L and a mean wheal diameter on skin prick test ≥ 8 mm greater than the negative control at screening. Subjects were not required to complete a DBPCFC for study entry. The study duration was approximately 6 months and compared the safety and tolerability of PALFORZIA (N = 337) with placebo (N = 168). Most subjects were male (63%) and white (79%). Of the subjects treated with PALFORZIA, 60.5% had a medical history of anaphylactic reactions, 65.0% reported multiple food allergies, 57.9% had a medical history of atopic dermatitis, and 52.2% had a present or previous diagnosis of asthma. Subjects with severe persistent or uncontrolled asthma were excluded.

Across these two phase 3, double-blind, placebo-controlled, randomized clinical studies the most common adverse reactions in subjects treated with PALFORZIA (incidence ≥ 5% and at least 5 percentage points greater than in subjects treated with placebo) were gastrointestinal, respiratory, and skin symptoms commonly associated with allergic reactions, as shown in Table 4.

A total of 155 (21.9%) PALFORZIA-treated subjects and 19 (6.5%) placebo-treated subjects discontinued for any reason in Studies 1 and 2. Adverse reactions led to study discontinuation in 9.2% PALFORZIA-treated subjects and 1.7% placebo-treated subjects during Initial Dose Escalation and Up-Dosing combined in Studies 1 and 2, and 1.0% PALFORZIA-treated subjects and no placebo-treated subjects during Maintenance dosing in Study 1. Gastrointestinal reactions were the most common reason leading to discontinuation of study product during Initial Dose Escalation and Up-Dosing combined (6.5% PALFORZIA, 1.0% placebo), followed by respiratory disorders (2.3% PALFORZIA, 1.0% placebo) in Studies 1 and 2.

The timing of symptoms relative to exposure to PALFORZIA was evaluated for dosing that occurred within a clinical setting during Initial Dose Escalation and on the day of initiation of each new dose level during the Up-Dosing phase (every 2 weeks) and during monthly Maintenance visits. Symptoms occurring in the clinic following any dose of PALFORZIA had a median time to onset of 4 minutes for 502 subjects (70.8%). The median time to resolution of the last symptom was 37 minutes.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness of PALFORZIA have not been established in persons younger than 4 years of age.

12.1 Mechanism of Action

The mechanism of action of PALFORZIA has not been established.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

PALFORZIA has not been evaluated for carcinogenicity, genotoxicity, mutagenic potential, or impairment of male or female fertility in animals.

Store PALFORZIA at room temperature or in a refrigerator at 2° to 25°C (36° to 77°F). Avoid excessive heat. Do not freeze. Store in the original packaging until use to protect from moisture.

Allergic Reactions

Advise patient, parent, or guardian that PALFORZIA may cause allergic reactions, including anaphylaxis that may be life-threatening. Educate patient, parent, or guardian to recognize the signs and symptoms of an allergic reaction [see Warnings and Precautions (5.1)] . The signs and symptoms of a severe allergic reaction may include syncope, dizziness, hypotension, tachycardia, dyspnea, wheezing, bronchospasm, chest discomfort, cough, abdominal pain, vomiting, diarrhea, rash, pruritus, flushing, and urticaria.

Ensure patient has injectable epinephrine and instruct patient, parent, or guardian on its proper use and that injectable epinephrine must be available for immediate use at all times. Instruct patient, parent, or guardian that if patient experiences a severe allergic reaction to seek immediate medical care, discontinue PALFORZIA, and resume treatment only when advised by their health care professional [see Warnings and Precautions (5.1)] .

Advise patient, parent, or guardian to read the patient information for epinephrine.

Inform patient, parent, or guardian that the first dose of each dose level of PALFORZIA must be administered in a health care setting under the supervision of a health care professional, and that after consuming PALFORZIA, patient will be monitored for signs and symptoms of an allergic reaction [see Warnings and Precautions (5.1)] .

Advise patient, parent, or guardian that if patient experiences an escalating or persistent allergic reaction or becomes intolerant to PALFORZIA at home to contact their health care professional immediately.

Administration of PALFORZIA to young patients should be under adult supervision [see Dosage and Administration (2)] .

PALFORZIA Risk Evaluation and Mitigation Strategy (REMS) Program

Advise patient that due to the risk of anaphylaxis, PALFORZIA is only available through a restricted program called the PALFORZIA REMS Program [see Warnings and Precautions (5.2)] .

Inform patient, parent, or guardian of the following requirements:

• Patient must be enrolled in the PALFORZIA REMS Program.
• Patient, parent or guardian must be educated on the need for monitoring with the Initial Dose Escalation and first dose of each Up-Dosing level and how to recognize the signs and symptoms of anaphylaxis.
• Patient must continue dietary peanut avoidance.
• Injectable epinephrine must be available to patient for immediate use at all times.

Asthma

Instruct patient, parent, or guardian that patients with asthma should stop taking PALFORZIA and contact their health care professional immediately if they have difficulty breathing or if their asthma becomes difficult to control [see Warnings and Precautions (5.3)] .

Eosinophilic Esophagitis

Because of the risk of eosinophilic esophagitis, instruct patient, parent or guardian that patients with severe or persistent symptoms of esophagitis or gastrointestinal intolerance should discontinue PALFORZIA and contact their health care professional [see Warnings and Precautions (5.4 and 5.5)] .

Handling Instructions

Advise patient, parent, or guardian of the following:

• To store PALFORZIA in a refrigerator.
• That patient must not swallow capsule(s) or inhale the powder.
• To open capsule(s) or sachet and empty the entire dose onto a few spoonfuls of refrigerated or room temperature semisolid food (e.g., applesauce, yogurt, pudding) and to mix well. Do not use liquid (e.g., milk, water, juice) to prepare PALFORZIA for consumption.
• That patient should consume the entire prepared mixture.
• To dispose of all unused PALFORZIA [see Dosage and Administration (2.3)].
• To dispose of the opened capsule(s) or sachet and wash hands immediately after handling.

Dosing Instructions

Advise patient, parent, or guardian of the following:

• The importance of taking each dose daily to avoid loss of treatment effect.
• That each dose should be consumed with a meal, at approximately the same time each day, preferably in the evening.
• To observe the patient for at least 60 minutes after administering PALFORZIA for any signs of intolerability.
• To contact their health care professional for advice on how to resume PALFORZIA if doses are missed.
• That the risk of an allergic reaction following PALFORZIA administration may be increased in the presence of cofactors such as:
  • Exercise or hot water exposure (e.g. a hypermetabolic state)
  • A medical event such as an intercurrent illness (e.g., viral infection)
  • Fasting
  • Menstruation
  • Sleep deprivation
  • Nonsteroidal anti-inflammatory drug use
  • Uncontrolled asthma
  Temporarily withholding or decreasing PALFORZIA doses may be required in the presence of these cofactors.

Patient should delay consuming PALFORZIA after strenuous exercise until signs of a hypermetabolic state (e.g., flushing, sweating, rapid breathing, rapid heart rate) have subsided and avoid taking hot showers or baths immediately prior to or within 3 hours after consuming PALFORZIA.