Drug Information

Drug Interaction:

DRUG INTERACTIONS-

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

Indication:

BRIEF SUMMARY

PEGVALIASEPQPZ-(May 2018)

Indn- To treat adults with a rare and serious genetic disease known as phenylketonuria (PKU)

Comp. Injection: 2.5 mg/0.5 mL, 10 mg/0.5 mL, and 20 mg/mL in a single-dose prefilled syringe. The recommended initial dosage is 2.5 mg subcutaneously once weekly for 4 weeks.

ADR- Most common adverse reactions (at least 20% in either treatment phase) are: 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

CI- None.

WARNINGS-

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.

Pat Infm

Anaphylaxis and Other Hypersensitivity Reactions- Advise patients that Palynziq may cause hypersensitivity reactions, including anaphylaxis that can occur at any time.

Instruct patients to recognize the signs and symptoms of anaphylaxis.

Instruct patients to carry auto-injectable epinephrine with them at all times during Palynziq treatmen

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U.S. FDA APPROVED DRUGS DURING 2018

Sr.No- 14

Name of the Drug- PALLYNZIQ

Active Ingredient - Pegavaliasepqpz

Pharmacological Classification-

To treat adults with a rare and serious genetic disease

known as phenylketonuria (PKU)

Date of Approval- 5-24-2018

(Ref- FDA approved List 2018)

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use

PALYNZIQ safely and effectively. See full prescribing information for PALYNZIQ. PALYNZIQ (pegvaliase-pqpz) injection, for subcutaneous use

Initial U.S. Approval: 2018

WARNING:

RISK OF ANAPHYLAXIS See full prescribing information for complete boxed warning.

Anaphylaxis has been reported after administration of Palynziq and may occur at any time during treatment.

Administer the initial dose of Palynziq under the supervision of a healthcare provider equipped to manage anaphylaxis, and closely observe patients for at least 60 minutes following injection.

Prior to self-injection, confirm patient competency with self-administration, and patient’s and observer’s (if applicable) ability to recognize signs and symptoms of anaphylaxis and to administer auto-injectable epinephrine, if needed.

Prescribe auto-injectable epinephrine. Prior to first dose, instruct the patient and observer (if applicable) on its appropriate use.

Instruct the patient to seek immediate medical care upon its use.

Instruct patients to carry auto-injectable epinephrine with them at all times during Palynziq treatment.

Palynziq is available only through a restricted program called the Palynziq REMS.

INDICATIONS AND USAGE

Palynziq is a phenylalanine-metabolizing enzyme indicated to reduce blood phenylalanine concentrations in adult patients with phenylketonuria who have uncontrolled blood phenylalanine concentrations greater than 600 micromol/L on existing management.

Adverse Reaction:

ADVERSE REACTIONS

Most common adverse reactions (at least 20% in either treatment phase) are: 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

Contra-Indications:

CONTRAINDICATIONS-

None.

WARNINGS 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.

Dosages/ Overdosage Etc:

INDICATIONS AND USAGE

Palynziq is a phenylalanine-metabolizing enzyme indicated to reduce blood phenylalanine concentrations in adult patients with phenylketonuria who have uncontrolled blood phenylalanine concentrations greater than 600 micromol/L on existing management.

DOSAGE AND ADMINISTRATION

Dosage

Obtain baseline blood phenylalanine concentration before initiating treatment.

The recommended initial dosage is 2.5 mg subcutaneously once weekly for 4 weeks.

Titrate the dosage in a step-wise manner over at least 5 weeks based on tolerability to achieve a dosage of 20 mg subcutaneously once daily.

See full prescribing information for titration regimen.

Assess patient tolerability, blood phenylalanine concentration, and dietary protein and phenylalanine intake throughout treatment.

Consider increasing the dosage to a maximum of 40 mg subcutaneously once daily in patients who have been on 20 mg once daily continuously for at least 24 weeks and who have not achieved either a 20% reduction in blood phenylalanine concentration from pre-treatment baseline or a blood phenylalanine concentration less than or equal to 600 micromol/L.

Discontinue Palynziq in patients who have not achieved at least a 20% reduction in blood phenylalanine concentration from pre-treatment baseline or a blood phenylalanine concentration less than or equal to 600 micromol/L after 16 weeks of continuous treatment with the maximum dosage of 40 mg once daily

Reduce the dosage and/or modify dietary protein and phenylalanine intake, as needed, to maintain blood phenylalanine concentrations within a clinically acceptable range and above 30 micromol/L.

Blood Phenylalanine Monitoring and Diet

Obtain blood phenylalanine concentrations every 4 weeks until a maintenance dosage is established.

After a maintenance dosage is established, periodically monitor blood phenylalanine concentrations.

Counsel patients to monitor dietary protein and phenylalanine intake, and adjust as directed by their healthcare provider.

Premedication- Consider premedication for hypersensitivity reactions.

Administration Instructions

Rotate injection sites. If more than one injection is needed for a single dose, the injection sites should be at least 2 inches away from each other.

DOSAGE FORMS AND STRENGTHS-

Injection: 2.5 mg/0.5 mL, 10 mg/0.5 mL, and 20 mg/mL in a single-dose prefilled syringe.

Patient Information:

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Anaphylaxis and Other Hypersensitivity Reactions- Advise patients that Palynziq may cause hypersensitivity reactions, including anaphylaxis that can occur at any time.

Instruct patients to recognize the signs and symptoms of anaphylaxis.

Instruct patients to carry auto-injectable epinephrine with them at all times during Palynziq treatment.

Instruct the patient and observer (if applicable) on the appropriate use of auto-injectable epinephrine for anaphylaxis ,

Instruct patients who experience anaphylaxis to seek immediate medical care, discontinue therapy, and resume treatment only at the instruction of a healthcare provider

Inform the patient of the following notable requirements:

Patients must be enrolled in the Palynziq REMS.

Patients must 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 fill a prescription for auto-injectable epinephrine and carry it with them at all times.

Patients will be given a Palynziq Patient Wallet Card that they should carry with them at all times. This card describes symptoms which, if experienced, should prompt the patient and observer (if applicable) to immediately seek medical care.

Advise the patient to show the Palynziq Wallet Card to other treating healthcare providers.

Palynziq is available only from certified pharmacies participating in the program. Therefore, provide patients with the telephone number and website for information on how to obtain the product.

Administration- Advise patients to monitor their dietary protein and phenylalanine intake throughout treatment with Palynziq, and adjust intake as directed by their healthcare provider based on blood phenylalanine concentrations.

Provide appropriate instruction for methods of self-injection, including careful review of the Palynziq Medication Guide and Instructions for Use. Instruct patients in the use of aseptic technique when administering Palynziq

Inform patients that a healthcare provider will show them or their caregiver how to prepare to inject Palynziq before self-administering.

Advise patients not to inject into moles, scars, birthmarks, bruises, rashes, or areas where the skin is hard, tender, red, damaged, burned, inflamed, or tattooed. Advise patients to rotate areas of injection with each dose.

Advise patients to check the injection site for redness, swelling, and tenderness, and to contact their healthcare provider if they have a skin reaction and it does not clear up, or worsens.

Advise patients to follow sharps disposal recommendations [see Instructions for Use for patients on safe disposal procedures. )

Advise patients that the shelf-life expires after storage at room temperature for 30 days or after the expiration date on the product carton, whichever is earlier

Pregnancy- Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy

Advise women who are exposed to Palynziq during pregnancy or who become pregnant within one month following the last dose of Palynziq that there is a pregnancy surveillance program that monitors pregnancy outcomes.

Encourage these patients to report their pregnancy to BioMarin (1-866-906-6100)

Manufactured by: BioMarin Pharmaceutical Inc. Novato, CA 94949 US License No. 1649 Reference ID: 4268502 Medication Guide Palynziq™ (Pal-lin-zeek)

Pharmacology/ Pharmacokinetics:

CLINICAL PHARMACOLOGY-

1.Mechanism of Action- Pegvaliase-pqpz is a PEGylated phenylalanine ammonia lyase (PAL) enzyme that converts phenylalanine to ammonia and trans-cinnamic acid. It substitutes for the deficient phenylalanine hydroxylase (PAH) enzyme activity in patients with PKU and reduces blood phenylalanine concentrations.

2.Pharmacodynamics- Palynziq treatment of adult patients with PKU resulted in the reduction of blood phenylalanine concentrations from pre-treatment baseline. The reduction of blood phenylalanine concentrations diminished with decreased pegvaliase-pqpz plasma concentrations.

3.Pharmacokinetics- The pharmacokinetics of pegvaliase-pqpz exhibit high inter-patient and intra-patient variability due to the heterogeneity of the immune response in adult patients with PKU. Higher antibody titers correlated with higher apparent clearance of pegvaliase-pqpz.

Absorption- The median Tmax was approximately 8 hours. The mean ± SD (range) peak concentration (Cmax) at steady state was: 14.0 ± 16.3 (0.26 to 68.5) mg/L and 16.7 ± 19.5 (0.24 to 63.8) mg/L, respectively.

Distribution- The mean ± SD (range) apparent volume of distribution was 26.4 ± 64.8 (1.8 to 241) L and 22.2 ± 19.7 (3.1 to 49.5) L, respectively.

Elimination- The mean ± SD (range) apparent clearance at steady state was 0.39 ± 0.87 (0.018 to 3.66) L/h and 1.25 ± 2.46 L/h (0.034 to 8.88), respectively. The mean ± SD (range) half-life was 47 ± 42 (14 to 132) hours and 60 ± 45 (14 to 127) hours, respectively.

Metabolism- The metabolism of phenylalanine ammonia lyase is expected to occur via catabolic pathways and be degraded into small peptides and amino acids.

Excretion- The route of elimination of pegvaliase-pqpz has not been studied in humans.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity and genotoxicity studies have not been performed with pegvaliase-pqpz. Based on its mechanism of action, pegvaliase-pqpz is not expected to be tumorigenic. Pegvaliase-pqpz produced impaired fertility in female rats at 20 mg/kg/day subcutaneously (19.4 times the human steady-state AUC at the maximum recommended daily dose), as indicated by decreases in corpora lutea, implantations, and litter size. These effects were associated with toxicity (decreased body weight, ovarian weight, and food consumption). No effects on mating or fertility were observed in female rats with 8 mg/kg/day subcutaneously (4.2 times the human steady-state AUC at the ma

Pregnancy and lactation:

USE IN SPECIFIC POPULATIONS-

1. Pregnancy Risk Summary- Based on findings in studies of pregnant animals without PKU treated with pegvaliase-pqpz, Palynziq may cause fetal harm when administered to a pregnant woman.

Limited available data with pegvaliase-pqpz use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes.

Advise pregnant women of the potential risks to the fetus.

A reproduction study in pregnant rabbits treated with pegvaliase-pqpz demonstrated a high incidence of fetal malformations throughout the skeletal system, and in kidneys, lungs, and eyes.

All pregnancies have a background risk of major birth defects, pregnancy loss, or other adverse pregnancy outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

2.Lactation Risk Summary

There are no data on the presence of pegvaliase-pqpz in human milk, the effects on the breastfed infant, or the effects on milk production.

The developmental and health benefits of breastfeeding should be considered along with the clinical need for Palynziq treatment and any potential adverse effect on the breastfed infant from Palynziq or from the underlying condition.

3.Pediatric Use- The safety and effectiveness of Palynziq in pediatric patients have not been established.

4.Geriatric Use- Clinical studies of Palynziq did not include patients aged 65 years and older.

14/18. Pegvaliasepqpz- (PALLYNZIQ)-@- (May- 2018)- Genetic disorders known as serious phenylketonurial (PKU)

Drug Interaction

Indication

Adverse Reaction

Contra-Indications

Dosages/ Overdosage Etc

Patient Information

Pharmacology/ Pharmacokinetics

Pregnancy and lactation