PALFORZIA Initial Dose Escalation: Package Insert and Label Information

PALFORZIA INITIAL DOSE ESCALATION- peanut
PALFORZIA (LEVEL 1)- peanut powder
PALFORZIA (LEVEL 2)- peanut powder
PALFORZIA (LEVEL 3)- peanut
PALFORZIA (LEVEL 4)- peanut powder
PALFORZIA (LEVEL 5)- peanut powder
PALFORZIA (LEVEL 6)- peanut powder
PALFORZIA (LEVEL 7)- peanut
PALFORZIA (LEVEL 8)- peanut
PALFORZIA (LEVEL 9)- peanut powder
PALFORZIA (LEVEL 10)- peanut
PALFORZIA (LEVEL 11)- peanut powder
Aimmune Therapeutics

1 INDICATIONS AND USAGE

PALFORZIA is an oral immunotherapy indicated for the mitigation of allergic reactions, including anaphylaxis, that may occur with accidental exposure to peanut. PALFORZIA is approved for use in patients with a confirmed diagnosis of peanut allergy. Initial Dose Escalation may be administered to patients aged 4 through 17 years. Up-Dosing and Maintenance may be continued in patients 4 years of age and older [see Dosage and Administration (2.4)] .

PALFORZIA is to be used in conjunction with a peanut-avoidant diet.

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

2 DOSAGE AND ADMINISTRATION

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.

Table 1: Dosing Configuration for Initial Dose Escalation (Single Day Dose Escalation)

Dose Level	Total Dose	Dose Configuration
Initial Dose Escalation supplied as a single card consisting of 5 blisters containing a total of 13 capsules.
A	0.5 mg	One 0.5 mg capsule
B	1 mg	One 1 mg capsule
C	1.5 mg	One 0.5 mg capsule; One 1 mg capsule
D	3 mg	Three 1 mg capsules
E	6 mg	Six 1 mg capsules

Table 2: Daily Dosing Configuration for Up-Dosing

Dose Level	Total Daily Dose	Daily Dose Configuration	Dose Duration (weeks)
1	3 mg	Three 1 mg capsules	2
2	6 mg	Six 1 mg capsules	2
3	12 mg	Two 1 mg capsules; One 10 mg capsule	2
4	20 mg	One 20 mg capsule	2
5	40 mg	Two 20 mg capsules	2
6	80 mg	Four 20 mg capsules	2
7	120 mg	One 20 mg capsule; One 100 mg capsule	2
8	160 mg	Three 20 mg capsules; One 100 mg capsule	2
9	200 mg	Two 100 mg capsules	2
10	240 mg	Two 20 mg capsules; Two 100 mg capsules	2
11	300 mg	One 300 mg sachet	2

Table 3: Daily Dosing Configuration for Maintenance

Dose Level	Total Daily Dose	Daily Dose Configuration
11	300 mg	One 300 mg sachet

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.

Initial Dose Escalation

Initial Dose Escalation is administered on a single day under the supervision of a health care professional in a health care setting with the ability to manage potentially severe allergic reactions, including anaphylaxis.

Initial Dose Escalation is administered in sequential order on a single day beginning at Level A (5 Levels A-E, 0.5-6 mg; Table 1).

Each dose should be separated by an observation period of 20 to 30 minutes.

No dose level should be omitted.

Observe patients after the last dose for at least 60 minutes until suitable for discharge.

Discontinue PALFORZIA if symptoms requiring medical intervention (e.g., use of epinephrine) occur with any dose during Initial Dose Escalation [see Dosage and Administration (2.5)] .

Patients who tolerate at least the 3 mg single dose (Level D) of PALFORZIA during Initial Dose Escalation must return to the health care setting for initiation of Up-Dosing.

If possible, begin Up-Dosing the day after Initial Dose Escalation.

Repeat Initial Dose Escalation in a health care setting if the patient is unable to begin Up-Dosing within 4 days.

Up-Dosing

Complete Initial Dose Escalation before starting Up-Dosing.

Up-Dosing consists of 11 dose levels and is initiated at a 3 mg dose (Level 1).

The first dose of each new Up-Dosing level is administered under the supervision of a health care professional in a health care setting with the ability to manage potentially severe allergic reactions, including anaphylaxis.

Observe patients after administering the first dose of a new Up-Dosing level for at least 60 minutes until suitable for discharge.

If the patient tolerates the first dose of the increased dose level, the patient may continue that dose level at home. Each dose should be consumed daily with a meal at approximately the same time each day, preferably in the evening.

Administer all the dose levels in Table 2 in sequential order at 2-week intervals if tolerated.

No dose level should be omitted.

Do not progress through Up-Dosing more rapidly than shown in Table 2.

No more than 1 dose should be consumed per day. Instruct patients not to consume a dose at home on the same day as a dose consumed in the clinic.

Consider dose modification or discontinuation for patients who do not tolerate Up-Dosing as described in Table 2 [see Dosage and Administration (2.5)] .

Maintenance

Complete all dose levels of Up-Dosing before starting Maintenance.

The Maintenance dose of PALFORZIA is 300 mg daily.

Daily Maintenance is required to maintain the effect of PALFORZIA.

During Maintenance, contact patient at regular intervals to assess for adverse reactions to PALFORZIA.

2.5 Schedule Modification and Product Discontinuation

Dose Modification

Dose modifications are not appropriate during Initial Dose Escalation.

Temporary dose modification of PALFORZIA may be required for patients who experience allergic reactions during Up-Dosing or Maintenance, for patients who miss doses, or for practical reasons of patient management. Allergic reactions, including gastrointestinal reactions, that are severe, recurrent, bothersome, or last longer than 90 minutes during Up-Dosing or Maintenance should be actively managed with dose modifications. Use clinical judgment to determine the best course of action, which can include maintaining the dose level for longer than 2 weeks, reducing, withholding, or discontinuing PALFORZIA doses.

Management of Consecutive Missed Doses

Following 1 to 2 consecutive days of missed doses, patients may resume PALFORZIA at the same dose level. Data are insufficient to inform resumption of PALFORZIA following 3 or more consecutive days of missed doses. Patients who miss 3 or more consecutive days of PALFORZIA should consult their healthcare providers; resumption of PALFORZIA should be done under medical supervision.

Discontinuation of PALFORZIA

Discontinue treatment with PALFORZIA for:

• Patients who are unable to tolerate doses up to and including the 3 mg dose during Initial Dose Escalation
• Patients with suspected eosinophilic esophagitis [see Warnings and Precautions (5.4 and 5.5)]
• Patients unable to comply with the daily dosing requirements
• Patients with recurrent asthma exacerbations or persistent loss of asthma control

3 DOSAGE FORMS AND STRENGTHS

PALFORZIA powder description and dosage strengths are as follows:

• 0.5 mg: white to off-white fine granular oral powder (may contain clumps) in white opaque capsules with Aimmune printed on the body and 0.5 mg printed on the cap in grey ink
• 1 mg: white to off-white fine granular oral powder (may contain clumps) in red opaque capsules with Aimmune printed on the body and 1 mg printed on the cap in white ink
• 10 mg: white to off-white fine granular oral powder (may contain clumps) in blue opaque capsules with Aimmune printed on the body and 10 mg printed on the cap in white ink
• 20 mg: off-white to light beige fine granular oral powder (may contain clumps) in white opaque capsules with Aimmune printed on the body and 20 mg printed on the cap in grey ink
• 100 mg: beige fine oral powder (may contain clumps) in red opaque capsules with Aimmune printed on the body and 100 mg printed on the cap in white ink
• 300 mg: beige fine oral powder (may contain clumps) in white foil-laminate sachets with printed information

Combinations of capsules for doses are described in Dosage and Administration (2.2).

4 CONTRAINDICATIONS

PALFORZIA is contraindicated in patients with the following:

• Uncontrolled asthma [see Warnings and Precautions (5.3)]
• A history of eosinophilic esophagitis and other eosinophilic gastrointestinal disease [see Warnings and Precautions (5.4 and 5.5)]

5 WARNINGS AND PRECAUTIONS

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)] .