Palynziq

The following serious adverse reactions are discussed below and in other sections of labeling:

• Anaphylaxis [see WARNINGS AND PRECAUTIONS]
• Other Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

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.

The data described below reflect a total treatment exposure of 580 patient-years in 285 patients who received Palynziq in an induction/titration/maintenance regimen in clinical trials [see Clinical Studies]. Of the 285 patients, 229 patients were exposed to Palynziq for 24 weeks, 209 patients were exposed for 1 year, 137 patients were exposed for 2 years, and 85 patients were exposed for 3 years or longer. The patient population was evenly distributed between male and female patients, the mean age was 29 years (range: 16 to 56 years), and 98% of patients were White.

The most common adverse reactions (at least 20% of patients in either treatment phase) were injection site reactions, arthralgia, hypersensitivity reactions, headache, generalized skin reactions lasting at least 14 days, pruritus, nausea, abdominal pain, oropharyngeal pain, vomiting, cough, diarrhea, and fatigue.

Of the 285 patients exposed to Palynziq in an induction/titration/maintenance regimen in clinical trials, 31 (11%) patients discontinued treatment due to adverse reactions. The most common adverse reactions leading to treatment discontinuation were hypersensitivity reactions (6% of patients) including anaphylaxis (3% of patients) and angioedema (1% of patients), arthralgia (4% of patients), generalized skin reactions lasting at least 14 days (2% of patients), and injection site reactions (1% of patients).

The most common adverse reactions leading to dosage reduction were arthralgia (14% of patients), hypersensitivity reactions (9% of patients), injection site reactions (4% of patients), alopecia (3% of patients), and generalized skin reactions lasting at least 14 days (2% of patients).

The most common adverse reactions leading to temporary drug interruption were arthralgia (13% of patients), hypersensitivity reactions (13% of patients), anaphylaxis (4% of patients), and injection site reactions (4% of patients).

Table 2 lists adverse reactions reported in at least 15% of patients treated with Palynziq in an induction/titration/maintenance dosage regimen in clinical trials, and illustrates the adverse reaction rates over time by treatment phase. Table 3 lists laboratory abnormalities reported in at least 10% of patients treated with Palynziq in an induction/titration/maintenance dosage regimen in clinical trials.

For these analyses, the induction/titration phase was defined as the time prior to reaching a stable dose (completing an 8-week phase at the same dose level). Once a stable dosage was reached, patients were considered to be in the maintenance phase thereafter. Safety data for patients who reached the maintenance phase are included within either the induction/titration or maintenance phases depending on the onset date of the adverse reaction. Safety data for patients who did not reach the maintenance phase are included within the induction/titration phase. The maintenance phase includes data for patients who were previously on Palynziq and transitioned to placebo during the randomized withdrawal period of Study 302 [see Clinical Studies].

Rates of adverse reactions (adjusted for duration of exposure) generally decreased over time and for some stayed relatively stable. In the maintenance phase, the rate of adverse reactions (adjusted for duration of exposure) in patients who reached the maintenance phase was comparable across dosages evaluated. The types and rate of adverse reactions reported during the maintenance phase in patients who received 20 mg once daily and 40 mg once daily were similar.

Rates of laboratory abnormalities (adjusted for duration of exposure) stayed relatively stable over time, except for complement C4 below lower limit of normal (LLN) and hs-CRP above 0.287 mg/dL over a 6 month period (both decreased over time) and hypophenylalaninemia (blood phenylalanine concentration below 30 micromol/L) on a single measurement (increased over time). The types and rates of laboratory abnormalities (adjusted for duration of exposure) reported during the maintenance phase in patients receiving 20 mg once daily and 40 mg once daily were similar with the exception of hs-CRP above 0.287 mg/dL over a 6 month period (exposure-adjusted event rates 0.04 and 0.08 in patients on 20 mg once daily and 40 mg once daily, respectively).

Table 2: Adverse Reactions* Reported in at least 15% of PKU Patients Treated with Palynziq in an Induction/Titration/Maintenance Regimen in Clinical Trials - Incidence and Exposure-Adjusted Rates

Table 3: Laboratory Abnormalities Reported in at least 10% of PKU Patients Treated with Palynziq in an Induction/Titration/Maintenance Regimen in Clinical Trials - Incidence and Exposure-Adjusted Rates

Arthralgia

In clinical trials, 235 out of 285 (83%) patients experienced episodes consistent with arthralgia (includes back pain, musculoskeletal pain, pain in extremity, and neck pain). Arthralgia episodes were more frequent during the induction/titration phase (7.6 episodes/patient-year) and decreased over time (1.5 episodes/patient-year in the maintenance phase). Thirty-nine out of 285 (14%) patients had one episode of arthralgia, 32 (11%) patients had 2 episodes of arthralgia, 18 (6%) had 3 episodes of arthralgia, and 146 (51%) had 4 or more episodes of arthralgia. Arthralgia occurred as early as after the first dose of Palynziq and occurred at any time during treatment. The mean duration of arthralgia was 14 days (median: 3 days, range: 1 to 580 days), and 19% of arthralgia episodes had a duration of at least 14 days. Severe arthralgia (severe pain limiting self-care activities of daily living) was reported by 14 (5%) patients. In addition to arthralgia, other joint-related signs and symptoms reported were: joint swelling (22 patients; 8%), joint stiffness (22 patients; 8%), and musculoskeletal stiffness (19 patients; 7%). Arthralgia episodes were managed with medications (e.g., nonsteroidal anti-inflammatory drugs, glucocorticoids, and acetaminophen), Palynziq dosage reduction (4% of episodes), Palynziq interruption (4% of episodes), or Palynziq withdrawal (0.6% of episodes). 97% of arthralgia episodes were reported as resolved at the time of last observation (up to 59 months of follow-up).

Injection Site Reactions

Injection site reactions were reported as early as after the first dose of Palynziq and occurred at any time during treatment. Injection site reactions were more frequent during the induction/titration phase (21.9 episodes/patient-years) and decreased over time (4 episodes/patient-years in the maintenance phase). The mean duration of injection site reaction was 8 days (median: 2 days, range: 1 to 970 days), and 7% of injection site reactions had a duration of at least 14 days. 99% of injection site reactions were reported as resolved at the time of last observation (up to 59 months of follow-up).

Three injection site reactions consistent with granulomatous skin lesions were reported (each reaction occurring in one patient): granulomatous dermatitis (occurred after 464 days of Palynziq treatment and lasted 16 days), xanthogranuloma (occurred after 378 days of Palynziq treatment and lasted 638 days) was treated with a topical antihistamine, corticosteroid, and Palynziq treatment was discontinued, and necrobiosis lipoidica diabeticorum (occurred after 281 days of Palynziq treatment and lasted 281 days). Necrobiosis lipoidica diabeticorum was treated with steroid injections and complicated by Pseudomonas infection. All three injection site reactions resolved.

One patient reported soft tissue infection (occurred after 196 days of Palynziq treatment and lasted 8 days) associated with mesenteric panniculitis treated with antibiotics, which resulted in treatment discontinuation.

Generalized Skin Reactions (Not Limited To The Injection Site) Lasting At Least 14 Days

In clinical trials, 125 out of 285 (44%) patients treated with Palynziq experienced generalized skin reactions (not limited to the injection site) lasting at least 14 days. Mean duration of these reactions was 58 days (median: 34 days; range: 14 to 638 days). Generalized skin reactions were more frequent during the induction/titration phase (0.7 episodes/patient-years), and decreased over time (0.3 episodes/patientyears in the maintenance phase).

The mean time from first dose of Palynziq to onset of skin reactions was 319 days (median: 169 days; range: 2 to 1237 days). 5% of these reactions persisted at least 180 days, and 85% of these reactions were reported as resolved at the time of last observation (up to 59 months of follow-up).

Angioedema

In clinical trials, 22 out of 285 (8%) patients experienced 45 episodes of angioedema (symptoms included: pharyngeal edema, swollen tongue, lip swelling, mouth swelling, eyelid edema and face edema) occurring independent of anaphylaxis. Angioedema (included under Hypersensitivity in Table 2) was more frequent during the induction/titration phase (0.15 episodes/patient-year) and decreased over time (0.06 episodes/patient-year in the maintenance phase). Three patients discontinued treatment. All episodes resolved. Angioedema can present as a symptom of anaphylaxis [see WARNINGS AND PRECAUTIONS].

Serum Sickness

In clinical trials, serum sickness was reported in 7 out of 285 (2%) patients. Serum sickness episodes were more frequent during the induction/titration phase (0.04 episodes/patient-year) and decreased over time (less than 0.01 episodes/patient-year during the maintenance phase). All serum sickness reactions resolved without sequelae (duration of serum sickness ranged from 1 to 8 days). Out of the 7 patients who experienced serum sickness, 5 patients continued treatment without a recurrence, and managed serum sickness with drug interruption, dosage reduction and/or concomitant medication. Two patients discontinued treatment.

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to

Palynziq in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

All patients treated with Palynziq developed a sustained total anti-drug antibody (TAb) response with a majority of patients (91%; N = 235/258) developing that response by Week 4 of treatment. Mean TAb titers peaked 2 weeks after Palynziq initiation and remained elevated throughout treatment (greater than 1 year after treatment initiation). Anti-phenylalanine ammonia lyase (PAL) IgM antibodies were detected in all patients with a majority of patients (98%; N = 265/270) becoming positive for anti-PAL IgM by 2 months after treatment initiation. Anti-PAL IgG antibodies were detected in almost all patients (N = 226/227) by 4 months after treatment initiation. Mean anti-PAL IgM and IgG titers peaked at approximately 3 and 6 months, respectively, after treatment initiation and remained elevated throughout treatment (greater than 1 year after treatment initiation). Drug-induced anti-PEG IgM and IgG antibodies were detected in the majority of patients (98%; N = 277/284 for IgM; and 278/284 for IgG) with mean titers for both peaking at 1 to 3 months after treatment initiation [see DRUG INTERACTIONS]. Neutralizing antibodies (NAb) capable of inhibiting PAL enzyme activity were detected on at least one measurement in the majority of patients (88%; N = 249/284) over time. Mean NAb titers peaked and reached a plateau at 16 to 20 weeks of treatment and then remained present throughout treatment (greater than 1 year after treatment initiation).

Twenty-five of 26 patients who had anaphylaxis were tested for anti-pegvaliase-pqpz IgE antibodies, which recognize the PEGylated protein product. Of the 25 patients tested for anti-pegvaliase-pqpz IgE antibodies, 24 patients tested negative. The one patient who tested positive for anti-pegvaliase-pqpz IgE antibodies on the screening test did not have sufficient sample to confirm IgE positivity. This patient tested negative for anti-pegvaliase-pqpz IgE at routine visits prior to and after the anaphylaxis episode (not at times of anaphylaxis). Sixty-eight of 285 patients in clinical trials were tested for both anti-PAL IgE antibodies, which recognize the recombinant PAL protein, and for anti-pegvaliase-pqpz IgE antibodies during routine study visits (not at times of anaphylaxis episodes) or during additional visits for hypersensitivity reactions. Of those 68 patients, 5 (7%) tested positive at least once for anti-PAL IgE antibodies but negative for anti-pegvaliase-pqpz IgE antibodies.

The highest frequency of hypersensitivity reactions (consistent with a Type III immune complex-mediated hypersensitivity mechanism) occurred within the first 6 months of Palynziq treatment when the mean circulating immune complex (CIC) concentrations were at their highest and mean complement C3 and C4 concentrations were at their lowest. Mean CIC concentrations decreased and complement levels increased over time as the exposure-adjusted rate of hypersensitivity reactions decreased. IgG and IgM CIC concentrations were above the upper limit of normal in 63% (N = 164/259) and 41% of patients (N = 106/259), respectively, at 12 weeks of Palynziq treatment. The incidence of CIC positivity decreased over time. 61% of patients (N = 110/180) had complement C3 concentrations less than lower limit of normal (LLN) at 6 months after treatment initiation and 38% of patients (N = 94/248) had complement C4 concentrations less than LLN at 3 months after treatment initiation. The incidence of low complement C3 and C4 concentrations decreased over time, but approximately 39% (N = 19/49) and 12% (N = 6/49) of patients had low C3 and C4 concentrations, respectively, at 36 months after treatment initiation.

Higher antibody responses for all antibody analytes, including NAb, were associated with lower mean trough pegvaliase-pqpz concentrations and with higher blood phenylalanine concentrations. Hypersensitivity reactions occurred more frequently in patients with higher antibody titers for some but not all antibody analytes. Patients with higher mean change in IgG CIC concentrations from pre-treatment baseline tended to have higher discontinuation rates than patients with lower mean change in IgG CIC concentrations. Mean antibody titers for anti-PAL IgG and IgM, TAb, and NAb remained relatively stable with long-term treatment.

Included as part of the PRECAUTIONS section.

No Information provided

Palynziq™
(Pal-lin-zeek)
(pegvaliase-pqpz) injection

What is the most important information I should know about Palynziq?

Palynziq can cause a severe allergic reaction (anaphylaxis) that may be life-threatening and can happen any timeduring treatment with Palynziq. Severe allergic reactions are a serious but common side effect of Palynziq.

• You will receive your first injection of Palynziq in a healthcare setting where you will be closely watched for at least 1 hour after your injection for a severe allergic reaction.
• If you have a severe allergic reaction during treatment with Palynziq, you will need to receive an auto-injection of epinephrine immediately and get emergency medical help right away.
• Your healthcare provider will decide if you (or your caregiver) are able to give the Palynziq injections, recognize the signs and symptoms of a severe allergic reaction, give an injection of epinephrine and call for emergency medical help, if needed.
• Your healthcare provider may recommend that an adult observer (or your caregiver) be with you when you give your Palynziq injection, and for at least 1 hour after your injection to watch you for signs and symptoms of a severe allergic reaction and, if needed, give you an injection of epinephrine and call for emergency medical help.

Stop injecting Palynziq and get emergency medical care right away if you have any of the following symptoms of a severe allergic reaction during treatment with Palynziq:

• fainting (passing out)
• dizziness or lightheadedness
• sudden confusion
• trouble breathing or wheezing
• chest discomfort or chest tightness
• fast heart rate
• swelling of your face, lips, eyes, or tongue
• throat tightness
• flushed skin
• skin rash, itching, or raised bumps on skin
• nausea, vomiting, or diarrhea
• losing control of urine or stools
• Your healthcare provider will prescribe an auto-injectable epinephrine for you and will teach you (or your caregiver) and your observer, if needed, when and how to use it if you have a severe allergic reaction. Keep the auto-injectable epinephrine with you at all times during treatment with Palynziq. Read the Patient Information that comes with the auto-injectable epinephrine that your healthcare provider prescribes for you for more information.
• If you have a severe allergic reaction, do not continue to take Palynziq until you talk with your healthcare provider. Tell your healthcare provider that you had a severe allergic reaction. Your healthcare provider will tell you if you can continue treatment with Palynziq.
  • Your healthcare provider may prescribe other medicines to take before your Palynziq injection that may help reduce the symptoms of an allergic reaction.
  • If your healthcare provider decides that you can continue treatment with Palynziq after a severe allergic reaction, you will receive your next injection of Palynziq in a healthcare setting where you will be closely watched for at least 1 hour after your injection for a severe allergic reaction.
• Your healthcare provider will give you a Palynziq Patient Wallet Card that describes symptoms that you (or your caregiver), or your observer, should know that require you to get emergency medical care right away. Carry this card with you at all times during treatment with Palynziq. It is important to show your Palynziq Patient Wallet Card to any other healthcare provider who treats you.

Palynziq is only available through a restricted program called the Palynziq Risk Evaluation and Mitigation Strategy (REMS) Program. Before you can receive Palynziq, you must:

• enroll in this program.
• receive education about the risk of a severe allergic reaction (anaphylaxis) by a healthcare provider certified in the Palynziq REMS to be sure that you understand the risks and benefits of treatment with Palynziq.
• fill the prescription your healthcare provider gives you for the auto-injectable epinephrine and carry it with you at all times during treatment with Palynziq.
• carry the Palynziq Patient Wallet Card with you at all times.

Talk to your healthcare provider for more information about the Palynziq REMS and how to enroll.

What is Palynziq?

Palynziq is a prescription medicine used to lower blood levels of phenylalanine in adults with PKU (phenylketonuria) who have uncontrolled blood phenylalanine levels above 600 micromol/L (10 mg/dL) on their current treatment.

It is not known if Palynziq is safe and effective in children.

Before injecting Palynziq, tell your healthcare provider about all of your medical conditions, including if you:

• cannot or are not willing to use auto-injectable epinephrine to treat a severe allergic reaction.
• are pregnant or plan to become pregnant. Palynziq may harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you might be pregnant while taking Palynziq.
  • If your phenylalanine levels are too high or too low during pregnancy, this may also affect your unborn baby. You and your healthcare provider can decide the best way for you to manage your blood phenylalanine levels and discuss the risks and benefits of taking Palynziq during pregnancy to you and your unborn baby. It is very important to keep your phenylalanine levels at the levels your healthcare provider recommends during pregnancy.
  • Pregnancy Surveillance Program. There is a pregnancy surveillance program for females who take Palynziq during pregnancy, or who become pregnant while receiving Palynziq or within 1 month after their last dose of Palynziq. The purpose of this program is to collect information about the health of you and your baby while taking Palynziq. Talk to your healthcare provider about how you can take part in this program or call BioMarin at 1-866-906-6100.
• are breastfeeding or plan to breastfeed. It is not known if Palynziq passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take Palynziq.

Tell your healthcare provider about all the medicines you take, including prescription or over-the-counter medicines, vitamins, or herbal supplements.

How should I take Palynziq?

• Your healthcare provider will give you the Palynziq injection until they decide that you (or your caregiver) can give it. See “What is the most important information I should know about Palynziq?”
• Your healthcare provider may prescribe medicine for you to take before your Palynziq injection to help reduce the symptoms of an allergic reaction.
• If your healthcare provider decides that you (or your caregiver) can give your Palynziq injections, you (or your caregiver) will be shown how to prepare and give your Palynziq injections. See the “Instructions for Use” for detailed instructions on how to prepare and give an injection of Palynziq.
• Use Palynziq exactly as your healthcare provider tells you to. Your healthcare provider will tell you how much Palynziq to inject and when to inject it.
• Palynziq comes in prefilled syringes with 3 different strengths (2.5 mg, 10 mg, or 20 mg). You may need more than 1 Palynziq prefilled syringe for your prescribed dose.
• Monitor the amount of protein and phenylalanine that you eat or drink. Your healthcare provider may change the amount of protein and phenylalanine you should have in your diet during treatment with Palynziq, depending on the levels of phenylalanine in your blood. Follow your healthcare provider's instructions about the amount of protein and phenylalanine you should have in your diet.
• If you miss a dose, take your next dose at the regular time. Do not take two doses of Palynziq to make up for a missed dose.

What are the possible side effects of Palynziq?

Palynziq may cause serious side effects, including:

• See “What is the most important information I should know about Palynziq?”
• Other allergic reactions to Palynziq can happen during treatment with Palynziq. Contact your healthcare provider right away if you have any of the following symptoms of an allergic reaction including: rash, itching, or swelling or the face, lips, eyes, or tongue. Your healthcare provider may change your dose of Palynziq, stop your treatment with Palynziq for a period of time, or prescribe medicine for you to take before your Palynziq injection to help reduce the symptoms of an allergic reaction.

The most common side effects of Palynziq include:

• injection site reactions, such as redness, itching, pain, bruising, rash, swelling, tenderness
• joint pain
• headache
• skin reactions that spread on your skin and last at least 14 days, such as itching, rash, redness
• itching
• nausea
• stomach pain
• mouth and throat pain
• vomiting
• cough
• diarrhea
• feel very tired
• low levels of phenylalanine in your blood

These are not all the possible side effects of Palynziq. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Palynziq?

• Store Palynziq in the refrigerator at 36°F to 46°F (2°C to 8°C).
• If needed, you may store Palynziq at room temperature between 68°F to 77°F (20°C to 25°C) for up to 30 days.
  • Write the date that you remove Palynziq from the refrigerator on the carton.
  • If stored at room temperature, do not put Palynziq back in the refrigerator.
• Keep Palynziq in the original carton to protect from light.
• Do not freeze or shake Palynziq.
• Throw away Palynziq if it has been kept at room temperature for 30 days and has not been used, or after the expiration date on the carton, whichever comes first.

Keep Palynziq and all medicines out of the reach of children.

General Information about the safe and effective use of Palynziq.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Palynziq for a condition for which it was not prescribed. Do not give Palynziq to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Palynziq that is written for health professionals.

What are the ingredients in Palynziq?

Active ingredients: pegvaliase-pqpz

Inactive ingredients: sodium chloride, trans-cinnamic acid, tromethamine, and tromethamine hydrochloride

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Instructions for Use

Palynziq
(Pal-lin-zeek)
(pegvaliase-pqpz) injection prefilled syringe

Read this Instructions for Use before you start using the Palynziq prefilled syringe and each time you get a new prescription. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

Follow these instructions carefully while you are using Palynziq. If your healthcare provider decides that you (or your caregiver) can give the injections of Palynziq at home, your healthcare provider will show you (or your caregiver) how to inject Palynziq the right way. Your healthcare provider should watch you (or your caregiver) give the first Palynziq injection and monitor you for signs and symptoms of a severe allergic reaction (anaphylaxis). Do not inject Palynziq until your healthcare provider shows you (or your caregiver) how to inject Palynziq the right way and has watched you (or your caregiver) give your injection.

Talk to your healthcare provider if you (or your caregiver) have any questions about how to inject Palynziq the right way.

Do not share your prefilled syringes with anyone else. You may give an infection to them or get an infection from them.

Store your Palynziq prefilled syringe(s) in its original carton in the refrigerator. See “Storage of Palynziq” at the end of this Instructions for Use.

Supplies you will need for each injection of Palynziq (See Figure A):

• Palynziq prefilled syringe(s) in sealed tray(s). Each tray contains 1 prefilled syringe. You may need more than 1 prefilled syringe for your prescribed dose.
• 1 gauze pad or cotton ball
• 1 alcohol pad
• 1 bandage
• 1 puncture resistant or sharps disposal container. See “Dispose of the used prefilled syringes” at the end of this Instructions for Use.

Figure A

Important things to know about using your Palynziq prefilled syringe:

• Inject only 1 time with each Palynziq prefilled syringe. Do not use a Palynziq syringe more than 1 time.
• Do not pull back on the plunger at any time.
• Do not remove the needle cap until you are ready to inject.

Figure B below shows what the prefilled syringe looks like before use.

Figure B

Select the correct Palynziq prefilled syringe(s) for your dose. You may need more than 1 prefilled syringe for your prescribed dose. Your healthcare provider will tell you which syringe(s) to use. Ask your healthcare provider if you have any questions.

When you receive your Palynziq prefilled syringe(s), check that the name “Palynziq” appears on the carton(s).

• Palynziq prefilled syringes come in 3 different strengths (See Figure C).
• Before you inject Palynziq, check each carton and syringe to make sure you have the right prefilled syringe for your prescribed dose.

Figure C

Set up your injection

Step 1: Gather your supplies for the injection(s) (See Figure A) and place them on a clean flat surface.

Figure D

Take out the number of cartons needed for your prescribed dose from the refrigerator.

Check the expiration date on the carton(s) (See Figure D).

• If the expiration date has passed, do not use the prefilled syringe(s) in that carton. Call BioMarin at 1-866-906-6100 or your healthcare provider for help with Palynziq.

Step 2: Open the carton(s) and take out the sealed tray(s) that you need for your prescribed dose (See Figure E). You may need more than 1 prefilled syringe for your prescribed dose.

Figure E

Place the sealed tray(s) on a clean, flat surface out of reach of children and pets.

Put the carton with any remaining trays back in the refrigerator.

Step 3: Let the sealed tray(s) sit at room temperature for at least 30 minutes. Injecting Palynziq when cold can make the injection feel uncomfortable.

• Do not warm up the prefilled syringe in any other way other than letting it sit at room temperature. Do not warm in a microwave and do not place in hot water.

Step 4: Peel off the cover from the tray (See Figure F).

Figure F

Step 5: Hold the middle of the prefilled syringe body and remove the prefilled syringe from the tray (See Figure G).

Figure G

• Throw away the prefilled syringe if it looks damaged or used, and use a new prefilled syringe for your injection. See “Dispose of the used prefilled syringes” at the end of this Instructions for Use. Call BioMarin at 1-866-906-6100 or your healthcare provider for help with Palynziq.
• Do not remove the needle cap from the prefilled syringe until Step 12.
• Do not shake or roll the syringe in your hands.

Step 6: Check the prefilled syringe label to make sure you have the correct strength for your prescribed dose.

Step 7: Look at the liquid through the viewing window (See Figure H).

Figure H

• It is normal to see air bubbles. Do not flick or try to push the bubbles out.

The liquid should look clear and colorless to pale yellow. Throw away the prefilled syringe if the liquid is cloudy, discolored, or has particles in it and use a new prefilled syringe for your injection. See “Dispose of the used prefilled syringes” at the end of this Instructions for Use. Call BioMarin at 1-866-906-6100 or your healthcare provider for help with Palynziq.

Choose and prepare injection site

Step 8: Choose your injection site.

The recommended injection sites are:

• Front middle of the thighs.
• The abdomen except for the 2 inch (5 centimeter) area directly around the belly button (navel).

If a caregiver is giving the injection, the top of the buttocks and the back of the upper arms may also be used (See Figure I).

Figure I

• Do not inject into moles, scars, birthmarks, bruises, rashes, or areas where the skin is hard, tender, red, damaged, burned, inflamed, or tattooed.
• If you need more than 1 injection for your dose, the injection sites should be at least 2 inches away from each other. The second injection site can be on the same part of the body or a different part of the body (See Figures I and J).
• For each injection, change (rotate) your injection sites. Choose an injection site that is at least 2 inches away from the injection site that you used for the last injection. It can be on the same part of the body or a different part of the body (See Figures I and J).

Figure J

Step 9: Wash your hands well with soap and water before injecting Palynziq (See Figure K).

Figure K

Step 10: Clean the chosen site with an alcohol pad. Let the skin air dry for at least 10 seconds before injecting Palynziq (See Figure L).

Figure L

• Do not touch the cleaned injection site.
• Do not remove the needle cap until you are ready to inject Palynziq.

Inject Palynziq

Step 11: Hold the body of the prefilled syringe with one hand with the needle facing away from you (See Figure M).

Figure M

• Do not use the prefilled syringe if it is dropped. Throw away the prefilled syringe if it is dropped and use a new prefilled syringe for your injection. See “Dispose of the used prefilled syringes” at the end of this Instructions for Use. Call BioMarin at 1-866-906-6100 or your healthcare provider for help with Palynziq.

Step 12: Pull the needle cap straight off the needle (See Figure N).

Figure N

• Do not twist the needle cap during removal.
• Do not hold the prefilled syringe by the plunger or plunger head while taking the needle cap off.
• Before injecting Palynziq, check to make sure that the needle is not damaged or bent. Throw away the prefilled syringe if the needle is damaged or bent and use a new prefilled syringe for your injection. See “Dispose of the used prefilled syringes” at the end of this Instructions for Use. Call BioMarin at 1-866-906-6100 or your healthcare provider for help with Palynziq.

You may see a drop of liquid on the tip of the needle. This is normal. Do not wipe it away. Throw the needle cap away in a puncture resistant or sharps disposal container.

Step 13: Hold the body of the prefilled syringe in 1 hand between your thumb and index finger. Use your other hand to pinch up the skin around the injection site. Hold the skin firmly (See Figure O).

Figure O

• Do not touch the plunger head while inserting the needle into the skin.

Step 14: Use a quick motion to fully insert the needle into the pinched skin at a 45 to 90 degree angle (See Figure P).

Figure P

Release the pinch of skin. Use that hand to hold the bottom of the prefilled syringe steady. Place the thumb of your other hand on the plunger head and place your index and middle fingers under the finger grips (See Figure P).

Step 15: Use your thumb to push in the plunger slowly and steadily as far as it will go to inject all the medicine (See Figure Q). More pressure on the plunger may be needed to inject all the medicine for the 10 mg and 20 mg strength prefilled syringes.

Figure Q

Step 16: Slowly move your thumb up to release the plunger. The needle will automatically be covered by the prefilled syringe body (See Figure R).

Figure R

Treat injection site

Step 17: Treat injection site (if needed).

If you see drops of blood at the injection site, press a cotton ball or gauze over the injection site and hold for about 10 seconds. You may cover the injection site with a small adhesive bandage if needed.

If more than 1 prefilled syringe is needed for your prescribed dose:

Step 18: If your healthcare provider tells you to use more than one prefilled syringe for your prescribed dose, repeat Steps 4 to 17 listed above for each prefilled syringe that you use.

• Note: Do not give the injection in the same spot. The injection sites should be at least 2 inches away from each other. See Step 8 for information on choosing an injection site.

Dispose of the used prefilled syringes

Step 19: Put your used prefilled syringes in a puncture resistant container, such as an FDA-cleared sharps disposal container immediately after use (See Figure S).

Figure S

Do not throw away (dispose of) prefilled syringes in your household trash.

If you do not have an FDA-cleared sharps disposal container, you may use a household container that is:

• made of a heavy-duty plastic,
• can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,
• upright and stable during use,
• leak-resistant, and
• properly labeled to warn of hazardous waste inside the container.

When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal

Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.

Note: Keep sharps disposal container out of the reach of children and pets.

Storage of Palynziq

• Store Palynziq in the refrigerator at 36°F to 46°F (2°C to 8°C) (See Figure T).
• If needed, you may store Palynziq at room temperature between 68°F to 77°F (20°C to 25°C) for up to 30 days.
  • Write the date that you remove Palynziq from the refrigerator on the carton.
  • If stored at room temperature, do not put Palynziq back in the refrigerator.

Figure T

• Keep Palynziq in the original carton to protect from light.
• Do not freeze or shake Palynziq.
• Throw away Palynziq if it has been kept at room temperature for 30 days and has not been used, or after the expiration date on the carton, whichever comes first.

Keep Palynziq and all medicines out of the reach of children.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

The following serious adverse reactions are discussed below and in other sections of labeling:

• Anaphylaxis [see WARNINGS AND PRECAUTIONS]
• Other Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

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.

The data described below reflect a total treatment exposure of 580 patient-years in 285 patients who received Palynziq in an induction/titration/maintenance regimen in clinical trials [see Clinical Studies]. Of the 285 patients, 229 patients were exposed to Palynziq for 24 weeks, 209 patients were exposed for 1 year, 137 patients were exposed for 2 years, and 85 patients were exposed for 3 years or longer. The patient population was evenly distributed between male and female patients, the mean age was 29 years (range: 16 to 56 years), and 98% of patients were White.

The most common adverse reactions (at least 20% of patients in either treatment phase) were injection site reactions, arthralgia, hypersensitivity reactions, headache, generalized skin reactions lasting at least 14 days, pruritus, nausea, abdominal pain, oropharyngeal pain, vomiting, cough, diarrhea, and fatigue.

Of the 285 patients exposed to Palynziq in an induction/titration/maintenance regimen in clinical trials, 31 (11%) patients discontinued treatment due to adverse reactions. The most common adverse reactions leading to treatment discontinuation were hypersensitivity reactions (6% of patients) including anaphylaxis (3% of patients) and angioedema (1% of patients), arthralgia (4% of patients), generalized skin reactions lasting at least 14 days (2% of patients), and injection site reactions (1% of patients).

The most common adverse reactions leading to dosage reduction were arthralgia (14% of patients), hypersensitivity reactions (9% of patients), injection site reactions (4% of patients), alopecia (3% of patients), and generalized skin reactions lasting at least 14 days (2% of patients).

The most common adverse reactions leading to temporary drug interruption were arthralgia (13% of patients), hypersensitivity reactions (13% of patients), anaphylaxis (4% of patients), and injection site reactions (4% of patients).

Table 2 lists adverse reactions reported in at least 15% of patients treated with Palynziq in an induction/titration/maintenance dosage regimen in clinical trials, and illustrates the adverse reaction rates over time by treatment phase. Table 3 lists laboratory abnormalities reported in at least 10% of patients treated with Palynziq in an induction/titration/maintenance dosage regimen in clinical trials.

For these analyses, the induction/titration phase was defined as the time prior to reaching a stable dose (completing an 8-week phase at the same dose level). Once a stable dosage was reached, patients were considered to be in the maintenance phase thereafter. Safety data for patients who reached the maintenance phase are included within either the induction/titration or maintenance phases depending on the onset date of the adverse reaction. Safety data for patients who did not reach the maintenance phase are included within the induction/titration phase. The maintenance phase includes data for patients who were previously on Palynziq and transitioned to placebo during the randomized withdrawal period of Study 302 [see Clinical Studies].

Rates of adverse reactions (adjusted for duration of exposure) generally decreased over time and for some stayed relatively stable. In the maintenance phase, the rate of adverse reactions (adjusted for duration of exposure) in patients who reached the maintenance phase was comparable across dosages evaluated. The types and rate of adverse reactions reported during the maintenance phase in patients who received 20 mg once daily and 40 mg once daily were similar.

Rates of laboratory abnormalities (adjusted for duration of exposure) stayed relatively stable over time, except for complement C4 below lower limit of normal (LLN) and hs-CRP above 0.287 mg/dL over a 6 month period (both decreased over time) and hypophenylalaninemia (blood phenylalanine concentration below 30 micromol/L) on a single measurement (increased over time). The types and rates of laboratory abnormalities (adjusted for duration of exposure) reported during the maintenance phase in patients receiving 20 mg once daily and 40 mg once daily were similar with the exception of hs-CRP above 0.287 mg/dL over a 6 month period (exposure-adjusted event rates 0.04 and 0.08 in patients on 20 mg once daily and 40 mg once daily, respectively).

Table 2: Adverse Reactions* Reported in at least 15% of PKU Patients Treated with Palynziq in an Induction/Titration/Maintenance Regimen in Clinical Trials - Incidence and Exposure-Adjusted Rates

Table 3: Laboratory Abnormalities Reported in at least 10% of PKU Patients Treated with Palynziq in an Induction/Titration/Maintenance Regimen in Clinical Trials - Incidence and Exposure-Adjusted Rates

Arthralgia

In clinical trials, 235 out of 285 (83%) patients experienced episodes consistent with arthralgia (includes back pain, musculoskeletal pain, pain in extremity, and neck pain). Arthralgia episodes were more frequent during the induction/titration phase (7.6 episodes/patient-year) and decreased over time (1.5 episodes/patient-year in the maintenance phase). Thirty-nine out of 285 (14%) patients had one episode of arthralgia, 32 (11%) patients had 2 episodes of arthralgia, 18 (6%) had 3 episodes of arthralgia, and 146 (51%) had 4 or more episodes of arthralgia. Arthralgia occurred as early as after the first dose of Palynziq and occurred at any time during treatment. The mean duration of arthralgia was 14 days (median: 3 days, range: 1 to 580 days), and 19% of arthralgia episodes had a duration of at least 14 days. Severe arthralgia (severe pain limiting self-care activities of daily living) was reported by 14 (5%) patients. In addition to arthralgia, other joint-related signs and symptoms reported were: joint swelling (22 patients; 8%), joint stiffness (22 patients; 8%), and musculoskeletal stiffness (19 patients; 7%). Arthralgia episodes were managed with medications (e.g., nonsteroidal anti-inflammatory drugs, glucocorticoids, and acetaminophen), Palynziq dosage reduction (4% of episodes), Palynziq interruption (4% of episodes), or Palynziq withdrawal (0.6% of episodes). 97% of arthralgia episodes were reported as resolved at the time of last observation (up to 59 months of follow-up).

Injection Site Reactions

Injection site reactions were reported as early as after the first dose of Palynziq and occurred at any time during treatment. Injection site reactions were more frequent during the induction/titration phase (21.9 episodes/patient-years) and decreased over time (4 episodes/patient-years in the maintenance phase). The mean duration of injection site reaction was 8 days (median: 2 days, range: 1 to 970 days), and 7% of injection site reactions had a duration of at least 14 days. 99% of injection site reactions were reported as resolved at the time of last observation (up to 59 months of follow-up).

Three injection site reactions consistent with granulomatous skin lesions were reported (each reaction occurring in one patient): granulomatous dermatitis (occurred after 464 days of Palynziq treatment and lasted 16 days), xanthogranuloma (occurred after 378 days of Palynziq treatment and lasted 638 days) was treated with a topical antihistamine, corticosteroid, and Palynziq treatment was discontinued, and necrobiosis lipoidica diabeticorum (occurred after 281 days of Palynziq treatment and lasted 281 days). Necrobiosis lipoidica diabeticorum was treated with steroid injections and complicated by Pseudomonas infection. All three injection site reactions resolved.

One patient reported soft tissue infection (occurred after 196 days of Palynziq treatment and lasted 8 days) associated with mesenteric panniculitis treated with antibiotics, which resulted in treatment discontinuation.

Generalized Skin Reactions (Not Limited To The Injection Site) Lasting At Least 14 Days

In clinical trials, 125 out of 285 (44%) patients treated with Palynziq experienced generalized skin reactions (not limited to the injection site) lasting at least 14 days. Mean duration of these reactions was 58 days (median: 34 days; range: 14 to 638 days). Generalized skin reactions were more frequent during the induction/titration phase (0.7 episodes/patient-years), and decreased over time (0.3 episodes/patientyears in the maintenance phase).

The mean time from first dose of Palynziq to onset of skin reactions was 319 days (median: 169 days; range: 2 to 1237 days). 5% of these reactions persisted at least 180 days, and 85% of these reactions were reported as resolved at the time of last observation (up to 59 months of follow-up).

Angioedema

In clinical trials, 22 out of 285 (8%) patients experienced 45 episodes of angioedema (symptoms included: pharyngeal edema, swollen tongue, lip swelling, mouth swelling, eyelid edema and face edema) occurring independent of anaphylaxis. Angioedema (included under Hypersensitivity in Table 2) was more frequent during the induction/titration phase (0.15 episodes/patient-year) and decreased over time (0.06 episodes/patient-year in the maintenance phase). Three patients discontinued treatment. All episodes resolved. Angioedema can present as a symptom of anaphylaxis [see WARNINGS AND PRECAUTIONS].

Serum Sickness

In clinical trials, serum sickness was reported in 7 out of 285 (2%) patients. Serum sickness episodes were more frequent during the induction/titration phase (0.04 episodes/patient-year) and decreased over time (less than 0.01 episodes/patient-year during the maintenance phase). All serum sickness reactions resolved without sequelae (duration of serum sickness ranged from 1 to 8 days). Out of the 7 patients who experienced serum sickness, 5 patients continued treatment without a recurrence, and managed serum sickness with drug interruption, dosage reduction and/or concomitant medication. Two patients discontinued treatment.

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to

Palynziq in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

All patients treated with Palynziq developed a sustained total anti-drug antibody (TAb) response with a majority of patients (91%; N = 235/258) developing that response by Week 4 of treatment. Mean TAb titers peaked 2 weeks after Palynziq initiation and remained elevated throughout treatment (greater than 1 year after treatment initiation). Anti-phenylalanine ammonia lyase (PAL) IgM antibodies were detected in all patients with a majority of patients (98%; N = 265/270) becoming positive for anti-PAL IgM by 2 months after treatment initiation. Anti-PAL IgG antibodies were detected in almost all patients (N = 226/227) by 4 months after treatment initiation. Mean anti-PAL IgM and IgG titers peaked at approximately 3 and 6 months, respectively, after treatment initiation and remained elevated throughout treatment (greater than 1 year after treatment initiation). Drug-induced anti-PEG IgM and IgG antibodies were detected in the majority of patients (98%; N = 277/284 for IgM; and 278/284 for IgG) with mean titers for both peaking at 1 to 3 months after treatment initiation [see DRUG INTERACTIONS]. Neutralizing antibodies (NAb) capable of inhibiting PAL enzyme activity were detected on at least one measurement in the majority of patients (88%; N = 249/284) over time. Mean NAb titers peaked and reached a plateau at 16 to 20 weeks of treatment and then remained present throughout treatment (greater than 1 year after treatment initiation).

Twenty-five of 26 patients who had anaphylaxis were tested for anti-pegvaliase-pqpz IgE antibodies, which recognize the PEGylated protein product. Of the 25 patients tested for anti-pegvaliase-pqpz IgE antibodies, 24 patients tested negative. The one patient who tested positive for anti-pegvaliase-pqpz IgE antibodies on the screening test did not have sufficient sample to confirm IgE positivity. This patient tested negative for anti-pegvaliase-pqpz IgE at routine visits prior to and after the anaphylaxis episode (not at times of anaphylaxis). Sixty-eight of 285 patients in clinical trials were tested for both anti-PAL IgE antibodies, which recognize the recombinant PAL protein, and for anti-pegvaliase-pqpz IgE antibodies during routine study visits (not at times of anaphylaxis episodes) or during additional visits for hypersensitivity reactions. Of those 68 patients, 5 (7%) tested positive at least once for anti-PAL IgE antibodies but negative for anti-pegvaliase-pqpz IgE antibodies.

The highest frequency of hypersensitivity reactions (consistent with a Type III immune complex-mediated hypersensitivity mechanism) occurred within the first 6 months of Palynziq treatment when the mean circulating immune complex (CIC) concentrations were at their highest and mean complement C3 and C4 concentrations were at their lowest. Mean CIC concentrations decreased and complement levels increased over time as the exposure-adjusted rate of hypersensitivity reactions decreased. IgG and IgM CIC concentrations were above the upper limit of normal in 63% (N = 164/259) and 41% of patients (N = 106/259), respectively, at 12 weeks of Palynziq treatment. The incidence of CIC positivity decreased over time. 61% of patients (N = 110/180) had complement C3 concentrations less than lower limit of normal (LLN) at 6 months after treatment initiation and 38% of patients (N = 94/248) had complement C4 concentrations less than LLN at 3 months after treatment initiation. The incidence of low complement C3 and C4 concentrations decreased over time, but approximately 39% (N = 19/49) and 12% (N = 6/49) of patients had low C3 and C4 concentrations, respectively, at 36 months after treatment initiation.

Higher antibody responses for all antibody analytes, including NAb, were associated with lower mean trough pegvaliase-pqpz concentrations and with higher blood phenylalanine concentrations. Hypersensitivity reactions occurred more frequently in patients with higher antibody titers for some but not all antibody analytes. Patients with higher mean change in IgG CIC concentrations from pre-treatment baseline tended to have higher discontinuation rates than patients with lower mean change in IgG CIC concentrations. Mean antibody titers for anti-PAL IgG and IgM, TAb, and NAb remained relatively stable with long-term treatment.

Read the entire FDA prescribing information for Palynziq (Pegvaliase-pqpz Injection, for Subcutaneous Use)

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Very bad irritation where the shot was given.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about Palynziq (pegvaliase-pqpz), please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Skip the missed dose and use your next dose at the regular time. Do not use two doses at one time.

Stop the Palynziq injection and get emergency medical help if you have signs of an allergic reaction:

• hives, rash, itching;

• confusion, dizziness, feeling like you might pass out;

• nausea, vomiting, diarrhea;

• loss of bladder or bowel control;

• fast heartbeats;

• wheezing, chest tightness, difficult breathing;

• flushing (warmth, redness, or tingly feeling); or

• swelling of your face, lips, tongue, or throat.

Common side effects may include:

• a spreading skin reaction (itching, redness, rash) that could last at least 14 days;

• headache, joint pain;

• nausea, vomiting, stomach pain, diarrhea;

• tiredness; or

• pain, tenderness, bruising, redness, itching, or swelling where the injection was given.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

It is very important that your doctor check your progress at regular visits to make sure that this medicine is working properly and to check for serious unwanted effects.

This medicine may cause serious allergic reactions, including anaphylaxis. This can be life-threatening and requires immediate medical attention. Tell your doctor right away if you have a rash, itching, hoarseness, trouble breathing, trouble swallowing, or any swelling of your hands, face, or mouth after using this medicine. Keep with you an epinephrine autoinjector pen at all times in case of a severe allergic reaction.

Patients will be given a Palynziq™ information card that they should carry with them at all times. This card describes symptoms of an unwanted effect which may occur. Always show this card to any healthcare professional who may treat you.