PEGVALIASE Drug Interactions: What You Need to Know

INTERACTIONS Effect of Palynziq on Other PEGylated Products : Monitor for hypersensitivity reactions, including anaphylaxis, with concomitant treatment. ( 7.1 )

7.1 Effect of Palynziq on Other PEGylated Products In a single dose study of Palynziq in adult patients with PKU, two patients receiving concomitant injections of medroxyprogesterone acetate suspension (a formulation containing PEG 3350) experienced a hypersensitivity reaction. One of the two patients experienced a hypersensitivity reaction on day 15 after a single Palynziq dosage of 0.67 mg within 15 minutes following medroxyprogesterone acetate injectable suspension, and subsequently experienced anaphylaxis on day 89 within 30 minutes after the next dose of medroxyprogesterone acetate injectable suspension. The other patient experienced a hypersensitivity reaction on day 40 after a single Palynziq dosage of 0.08 mg within 10 minutes following medroxyprogesterone acetate injectable suspension. Both patients had high anti‑PEG IgG antibody titers at or around the time of the hypersensitivity reactions.

In

Palynziq clinical trials, the majority of patients developed anti‑PEG IgM and IgG antibodies after treatment with Palynziq [see Adverse Reactions ( 6.2 )] . The clinical effects of concomitant treatment with different PEGylated products is unknown. Monitor patients treated with Palynziq and concomitantly with other PEGylated products for hypersensitivity reactions including anaphylaxis.

7.1 Effect of Palynziq on Other PEGylated Products In a single dose study of Palynziq in adult patients with PKU, two patients receiving concomitant injections of medroxyprogesterone acetate suspension (a formulation containing PEG 3350) experienced a hypersensitivity reaction. One of the two patients experienced a hypersensitivity reaction on day 15 after a single Palynziq dosage of 0.67 mg within 15 minutes following medroxyprogesterone acetate injectable suspension, and subsequently experienced anaphylaxis on day 89 within 30 minutes after the next dose of medroxyprogesterone acetate injectable suspension. The other patient experienced a hypersensitivity reaction on day 40 after a single Palynziq dosage of 0.08 mg within 10 minutes following medroxyprogesterone acetate injectable suspension. Both patients had high anti‑PEG IgG antibody titers at or around the time of the hypersensitivity reactions.

In

Palynziq clinical trials, the majority of patients developed anti‑PEG IgM and IgG antibodies after treatment with Palynziq [see Adverse Reactions ( 6.2 )] . The clinical effects of concomitant treatment with different PEGylated products is unknown. Monitor patients treated with Palynziq and concomitantly with other PEGylated products for hypersensitivity reactions including anaphylaxis.

None. None. ( 4 )

AND PRECAUTIONS Hypersensitivity Reactions, Other than Anaphylaxis: Management should be based on the severity of the reaction, recurrence, and clinical judgement, and may include dosage adjustment, temporary drug interruption, or treatment with antihistamines, antipyretics, and/or corticosteroids. ( 5.3 )

Injection Site

Infections : Serious injection site infections, including abscess, cellulitis, necrosis, and ulcer have been reported. Instruct patients to contact their healthcare provider if signs or symptoms of an infection develop, persist, or worsen. ( 5.4 )

5.1 Anaphylaxis In clinical trials of Palynziq with induction/titration/maintenance dosing, 29 out of 285 (10%) patients experienced a total of 42 anaphylaxis episodes <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 , 6.2 )]</span>. The exposure-adjusted rate of anaphylaxis was highest during the induction and titration phases (0.25 episodes/person‑years; 5% of patients with at least one episode) and decreased in the maintenance phase (0.05 episodes/person‑years; 7% of patients with at least one episode). Signs and symptoms of anaphylaxis reported in clinical trials of Palynziq included syncope, hypotension, hypoxia, dyspnea, wheezing, chest discomfort/chest tightness, tachycardia, angioedema (swelling of face, lips, eyes, tongue), throat tightness, skin flushing, rash, urticaria, pruritus, and gastrointestinal symptoms (vomiting, nausea, diarrhea). In clinical trials of Palynziq, anaphylaxis generally occurred within 1 hour after injection (81%; 34/42 episodes); however, delayed episodes also occurred up to 48 hours after Palynziq administration. Most episodes of anaphylaxis occurred within the first year of dosing (69%, 29/42 episodes), but cases also occurred after one year of dosing and up to 1604 days (4.4 years) into treatment. Management of anaphylaxis in Palynziq clinical trials included: administration of auto-injectable epinephrine (48%; 20/42 episodes), corticosteroids (55%; 23/42 episodes), antihistamines (57%; 24/42 episodes), and/or oxygen (5%; 2/42 episodes). Twenty one out of the 29 (72%) patients who experienced anaphylaxis were rechallenged with Palynziq and 6 out of the 21 patients who were rechallenged (29%) had recurrence of anaphylaxis. All anaphylaxis episodes resolved without sequelae. Consider having an adult observer for patients who may need assistance in recognizing and managing anaphylaxis during Palynziq treatment. If an adult observer is needed, the observer should be present during and for at least 60 minutes after Palynziq administration, should be able to administer auto‑injectable epinephrine, and to call for emergency medical support upon its use. Anaphylaxis requires immediate treatment with auto-injectable epinephrine. Prescribe auto‑injectable epinephrine to all patients receiving Palynziq and instruct patients to carry auto‑injectable epinephrine with them at all times during Palynziq treatment. Prior to the first dose, instruct the patient and observer (if applicable) on how to recognize the signs and symptoms of anaphylaxis, how to properly administer auto‑injectable epinephrine, and to seek immediate medical care upon its use. Consider the risks associated with auto-injectable epinephrine use when prescribing Palynziq. Refer to the auto‑injectable epinephrine prescribing information for complete information. Consider the risks and benefits of readministering Palynziq following an episode of anaphylaxis. If the decision is made to readminister Palynziq, administer the first dose under the supervision of a healthcare provider equipped to manage anaphylaxis and closely observe the patient for at least 60 minutes following the dose.

Subsequent

Palynziq dose titration should be based on patient tolerability and therapeutic response [see Dosage and Administration ( 2.4 )] . Consider premedication with an H 1 -receptor antagonist, H 2 -receptor antagonist, and/or antipyretic prior to Palynziq administration based upon individual patient tolerability [see Dosage and Administration ( 2.3 )] . Palynziq is available only through a restricted program under a REMS [see Warnings and Precautions ( 5.2 )].

5.2 Palynziq REMS Program Palynziq is available only through a restricted program under a REMS called the Palynziq REMS, because of the risk of anaphylaxis <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span>. Notable requirements of the Palynziq REMS include the following: Prescribers must be certified with the program by enrolling in the program and completing training. Prescribers must prescribe auto‑injectable epinephrine with Palynziq. Pharmacies must be certified with the program and must dispense only to patients who are authorized to receive Palynziq. Patients must enroll in the program and be educated about the risk of anaphylaxis by a certified prescriber to ensure they understand the risks and benefits of treatment with Palynziq. Patients must have auto‑injectable epinephrine available at all times while taking Palynziq. Further information, including a list of qualified pharmacies, is available at www.PALYNZIQREMS.com or by telephone 1‑855‑758‑REMS (1‑855‑758‑7367).

5.3 Other Hypersensitivity Reactions Hypersensitivity reactions, other than anaphylaxis <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 ), Adverse Reactions ( 6.1 , 6.2 )]</span>, have been reported in 204 out of 285 (72%) patients treated with Palynziq. The exposure adjusted rate of other hypersensitivity reactions was highest during the induction and titration phases (4.3 episodes/person-year; 50% of patients with at least one adverse reaction) and decreased in the maintenance phase (1.3 episodes/person-year; 61% of patients with at least one adverse reaction). Consider premedication with an H 1 ‑receptor antagonist, H 2 ‑receptor antagonist, and/or antipyretic prior to Palynziq administration based upon individual patient tolerability <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 )]</span> . Management of hypersensitivity reactions should be based on the severity of the reaction, recurrence of the reaction, and the clinical judgement of the healthcare provider, and may include dosage adjustment, temporary drug interruption, or treatment with antihistamines, antipyretics, and/or corticosteroids.

5.4 Injection Site Infections Serious injection-site infections including abscess, cellulitis, necrosis, and ulcer have been reported with Palynziq in clinical trials and in the postmarketing setting. Some cases required hospitalization, surgical debridement, intravenous antibiotics, and discontinuation of Palynziq. Provide proper training to patients and/or caregivers on the use of aseptic injection technique. Advise patients to rotate injection sites with each dose and to check the site for redness, swelling, or tenderness. Instruct patients to contact their healthcare provider if signs or symptoms of an infection develop, persist, or worsen. Advise patients to not administer Palynziq into the affected area until the infection has resolved <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) and Adverse Reactions (6.1 , 6.2) ]</span> .

5.1 Anaphylaxis In clinical trials of Palynziq with induction/titration/maintenance dosing, 29 out of 285 (10%) patients experienced a total of 42 anaphylaxis episodes <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 , 6.2 )]</span>. The exposure-adjusted rate of anaphylaxis was highest during the induction and titration phases (0.25 episodes/person‑years; 5% of patients with at least one episode) and decreased in the maintenance phase (0.05 episodes/person‑years; 7% of patients with at least one episode). Signs and symptoms of anaphylaxis reported in clinical trials of Palynziq included syncope, hypotension, hypoxia, dyspnea, wheezing, chest discomfort/chest tightness, tachycardia, angioedema (swelling of face, lips, eyes, tongue), throat tightness, skin flushing, rash, urticaria, pruritus, and gastrointestinal symptoms (vomiting, nausea, diarrhea). In clinical trials of Palynziq, anaphylaxis generally occurred within 1 hour after injection (81%; 34/42 episodes); however, delayed episodes also occurred up to 48 hours after Palynziq administration. Most episodes of anaphylaxis occurred within the first year of dosing (69%, 29/42 episodes), but cases also occurred after one year of dosing and up to 1604 days (4.4 years) into treatment. Management of anaphylaxis in Palynziq clinical trials included: administration of auto-injectable epinephrine (48%; 20/42 episodes), corticosteroids (55%; 23/42 episodes), antihistamines (57%; 24/42 episodes), and/or oxygen (5%; 2/42 episodes). Twenty one out of the 29 (72%) patients who experienced anaphylaxis were rechallenged with Palynziq and 6 out of the 21 patients who were rechallenged (29%) had recurrence of anaphylaxis. All anaphylaxis episodes resolved without sequelae. Consider having an adult observer for patients who may need assistance in recognizing and managing anaphylaxis during Palynziq treatment. If an adult observer is needed, the observer should be present during and for at least 60 minutes after Palynziq administration, should be able to administer auto‑injectable epinephrine, and to call for emergency medical support upon its use. Anaphylaxis requires immediate treatment with auto-injectable epinephrine. Prescribe auto‑injectable epinephrine to all patients receiving Palynziq and instruct patients to carry auto‑injectable epinephrine with them at all times during Palynziq treatment. Prior to the first dose, instruct the patient and observer (if applicable) on how to recognize the signs and symptoms of anaphylaxis, how to properly administer auto‑injectable epinephrine, and to seek immediate medical care upon its use. Consider the risks associated with auto-injectable epinephrine use when prescribing Palynziq. Refer to the auto‑injectable epinephrine prescribing information for complete information. Consider the risks and benefits of readministering Palynziq following an episode of anaphylaxis. If the decision is made to readminister Palynziq, administer the first dose under the supervision of a healthcare provider equipped to manage anaphylaxis and closely observe the patient for at least 60 minutes following the dose.

Subsequent

Palynziq dose titration should be based on patient tolerability and therapeutic response [see Dosage and Administration ( 2.4 )] . Consider premedication with an H 1 -receptor antagonist, H 2 -receptor antagonist, and/or antipyretic prior to Palynziq administration based upon individual patient tolerability [see Dosage and Administration ( 2.3 )] . Palynziq is available only through a restricted program under a REMS [see Warnings and Precautions ( 5.2 )].

5.2 Palynziq REMS Program Palynziq is available only through a restricted program under a REMS called the Palynziq REMS, because of the risk of anaphylaxis <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span>. Notable requirements of the Palynziq REMS include the following: Prescribers must be certified with the program by enrolling in the program and completing training. Prescribers must prescribe auto‑injectable epinephrine with Palynziq. Pharmacies must be certified with the program and must dispense only to patients who are authorized to receive Palynziq. Patients must enroll in the program and be educated about the risk of anaphylaxis by a certified prescriber to ensure they understand the risks and benefits of treatment with Palynziq. Patients must have auto‑injectable epinephrine available at all times while taking Palynziq. Further information, including a list of qualified pharmacies, is available at www.PALYNZIQREMS.com or by telephone 1‑855‑758‑REMS (1‑855‑758‑7367).

5.3 Other Hypersensitivity Reactions Hypersensitivity reactions, other than anaphylaxis <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 ), Adverse Reactions ( 6.1 , 6.2 )]</span>, have been reported in 204 out of 285 (72%) patients treated with Palynziq. The exposure adjusted rate of other hypersensitivity reactions was highest during the induction and titration phases (4.3 episodes/person-year; 50% of patients with at least one adverse reaction) and decreased in the maintenance phase (1.3 episodes/person-year; 61% of patients with at least one adverse reaction). Consider premedication with an H 1 ‑receptor antagonist, H 2 ‑receptor antagonist, and/or antipyretic prior to Palynziq administration based upon individual patient tolerability <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 )]</span> . Management of hypersensitivity reactions should be based on the severity of the reaction, recurrence of the reaction, and the clinical judgement of the healthcare provider, and may include dosage adjustment, temporary drug interruption, or treatment with antihistamines, antipyretics, and/or corticosteroids.