Sephience

1 INDICATIONS AND USAGE SEPHIENCE is indicated for the treatment of hyperphenylalaninemia (HPA) in adult and pediatric patients 1 month of age and older with sepiapterin-responsive phenylketonuria (PKU). SEPHIENCE is to be used in conjunction with a phenylalanine (Phe)-restricted diet. SEPHIENCE is a phenylalanine hydroxylase (PAH) activator indicated for the treatment of hyperphenylalaninemia (HPA) in adult and pediatric patients 1 month of age and older with sepiapterin-responsive phenylketonuria (PKU). SEPHIENCE is to be used in conjunction with a phenylalanine (Phe)- restricted diet. ( 1 )

2 DOSAGE AND ADMINISTRATION Patients treated with SEPHIENCE should be on a dietary protein and a Phe-restricted diet. ( 2.1 ) Administer SEPHIENCE orally once daily with food. ( 2.2 ) The recommended starting dosage of SEPHIENCE is: ( 2.2 ) Age SEPHIENCE (mg/kg) per day Less than 6 months 7.5 mg/kg 6 months to less than 1 year 15 mg/kg 1 year to less than 2 years 30 mg/kg 2 years and older 60 mg/kg Important Administration Information: prepare SEPHIENCE calculated daily doses of < 1,000 mg as a liquid mixture (25 mg/mL), and administer exact prescribed dose volume (mL). ( 2.2 , 2.3 ) See full prescribing information for complete preparation and administration instructions. ( 2.3 ) 2.1 Important Recommendation Prior to SEPHIENCE Treatment Treatment with SEPHIENCE should be directed by physicians knowledgeable in the management of PKU. Biochemical response to SEPHIENCE treatment cannot generally be pre-determined by laboratory testing (e.g., molecular testing), and should be determined through a therapeutic evaluation of SEPHIENCE [see Dosage and Administration ( 2.2 ) and Clinical Studies ( 14.1 )]. Obtain baseline blood Phe concentration before initiating treatment. All patients with PKU who are treated with SEPHIENCE should be on a dietary protein and Phe-restricted diet that is based on blood Phe levels. Patients should undergo regular dietary assessments, including protein and Phe intake, by their healthcare provider [see Dosage and Administration ( 2.2 )]. 2.2 Recommended Dosage and Administration The recommended starting dosage of SEPHIENCE is based on the patient’s age and is administered orally once daily (see Table 1 ). Administer SEPHIENCE with food [see Clinical Pharmacology ( 12.3 )] . Table 1: Recommended Starting Dosage of SEPHIENCE * in Pediatric and Adult Patients * For calculated daily doses less than 1,000 mg, the final concentration of prepared SEPHIENCE liquid mixture is 25 mg/mL [see Dosage and Administration ( 2.3 )] . ** 60 mg/kg is the maximum daily dose for all patients. Age SEPHIENCE (mg/kg) per day ** Less than 6 months 7.5 mg/kg 6 months to less than 1 year 15 mg/kg 1 year to less than 2 years 30 mg/kg 2 years and older 60 mg/kg Evaluation Period Dosage Titration in Patients Less than 2 Years of Age After initiating treatment at the starting dosage by age ( Table 1 ), check blood Phe levels to determine response to treatment within 2 weeks. If blood Phe does not decrease, SEPHIENCE dosage may be titrated incrementally based on blood Phe levels to a maximum daily dosage of 60 mg/kg. Existing dietary protein and Phe intake should not be modified during the evaluation period. Discontinuation for Lack of Biochemical Response Discontinue SEPHIENCE in patients whose blood Phe does not decrease after 2 weeks of treatment at the maximum daily dosage of 60 mg/kg. Dosage Modification and Monitoring Monitor blood Phe levels during treatment, and if needed, modify the daily dosage of SEPHIENCE within the range of 7.5 mg/kg to 60 mg/kg and/or dietary protein and Phe intake to ensure adequate blood Phe level control. Frequent blood Phe monitoring is recommended in the pediatric population [see Warnings and Precautions ( 5.2 )] . Missed Dose A missed dose should be taken as soon as possible but 2 doses should not be administered on the same day. Resume the normal dosing schedule the following day. 2.3 Preparation and Administration Instructions Doses Less Than 1,000 mg ( administration based on 25 mg/mL concentration ) Determine the required number of SEPHIENCE packets and the required volume of water or apple juice to achieve a concentration of 25 mg/mL mixture (see Table 2 ). Table 2: Number of SEPHIENCE Packets and Volume to Prepare a SEPHIENCE Mixture of 25 mg/mL for Doses Less than 1,000 mg Abbreviations: mg, milligrams; mL, milliliters a For calculated daily doses less than 1,000 mg, round the dose up to the nearest 250 mg to determine the number of SEPHIENCE packets and prepare each 250 mg packet with 9 mL of water or apple juice. Daily Dose (mg) Number of 1,000 mg packets a Number of 250 mg packets a Volume of water or apple juice (mL) 250 mg or less 0 1 9 mL 251 mg to 500 mg 0 2 18 mL 501 mg to 750 mg 0 3 27 mL 751 mg to 999 mg 1 0 36 mL Calculate the prescribed dose volume to the nearest 0.2 mL. Divide the calculated daily dose (mg) by the final concentration (25 mg/mL) of SEPHIENCE liquid mixture for doses less than 1,000 mg. Prescribed dose volume (mL) = SEPHIENCE calculated dose (mg)) 25 mg/mL Prepare a liquid mixture. Open and empty the entire content of each SEPHIENCE packet into an appropriate-size container and mix with the required volume of water or apple juice per Table 2 . Stir the contents for 30 seconds or more until the mixture is uniformly mixed. Using a graduated oral dosing syringe, draw up the prescribed dose volume to the nearest 0.2 mL. Administer the prescribed dose volume (mL). Administer immediately. If particles are remaining in the syringe, draw up additional water or apple juice and administer the contents immediately. Repeat if particles still remain. Discard unused portion of SEPHIENCE mixture remaining in the container. Consume additional food after administration of the prescribed dose volume. Doses 1,000 mg or Greater ( whole packet administration ) Determine the required number of SEPHIENCE packets and the required volume of water, apple juice, strawberry jam, or applesauce (see Table 3 ). Table 3: Number of SEPHIENCE Packets and Volume to Prepare a SEPHIENCE Mixture for Doses of 1,000 mg or Greater Abbreviations: mg, milligrams; mL, milliliters; Tbsp, tablespoons a For calculated daily doses 1,000 mg or greater, round the dose to the nearest 250 mg to determine the number of SEPHIENCE packets required. b For each 1,000 mg packet, add 2 Tbsp (30 mL) of water, apple juice, strawberry jam, or applesauce, and then add an additional quantity of 2 Tbsp (30 mL) for up to three 250 mg packet(s) and then mix. Daily Dose (mg) Number of 1,000 mg packets a Number of 250 mg packets a Volume of water, apple juice, strawberry jam, or applesauce b 1,000 mg to 1,124 mg 1 0 2 Tbsp or 30 mL 1,125 mg to 1,374 mg 1 1 4 Tbsp or 60 mL 1,375 mg to 1,624 mg 1 2 1,625 mg to 1,874 mg 1 3 1,875 mg to 2,124 mg 2 0 2,125 mg to 2,374 mg 2 1 6 Tbsp or 90 mL 2,375 mg to 2,624 mg 2 2 2,625 mg to 2,874 mg 2 3 2,875 mg to 3,124 mg 3 0 3,125 mg to 3,374 mg 3 1 8 Tbsp or 120 mL 3,375 mg to 3,624 mg 3 2 3,625 mg to 3,874 mg 3 3 3,875 mg to 4,124 mg 4 0 4,125 mg to 4,374 mg 4 1 10 Tbsp or 150 mL 4,375 mg to 4,624 mg 4 2 4,625 mg to 4,874 mg 4 3 4,875 mg to 5,124 mg 5 0 5,125 mg to 5,374 mg 5 1 12 Tbsp or 180 mL 5,375 mg to 5,624 mg 5 2 5,625 mg to 5,874 mg 5 3 5,875 mg to 6,124 mg 6 0 Prepare a liquid or soft food mixture. Open and empty the entire content of each SEPHIENCE packet into a container. Mix with the required amount of water, apple juice, strawberry jam, or applesauce per Table 3 . Stir the contents for 30 seconds or more when mixing SEPHIENCE with water or apple juice or 60 seconds or more when mixing SEPHIENCE with strawberry jam or applesauce until the mixture is uniform. Administer the dose. Consume the entire mixture immediately. If particles are remaining in the container, add additional water or juice to the container and administer the contents immediately. Repeat if particles still remain. Consume additional food after administration of the entire mixture. 2.4 Storage Instructions for the Liquid and Soft Food Mixtures If the SEPHIENCE liquid or soft food mixture is not administered immediately, cover and store the mixture at controlled room temperature between 20°C to 25°C (68°F to 77°F) for up to 6 hours or refrigerate between 2°C to 8°C (36°F to 46°F) for up to 24 hours. If the liquid or soft food mixture is stored, stir for at least 30 or 60 seconds, respectively, prior to administration of the prescribed dose. Discard unused SEPHIENCE mixture after 6 hours at controlled room temperature or after 24 hours if refrigerated.

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS Increased Bleeding : SEPHIENCE may increase the risk of bleeding. Consider treatment interruption in patients with active bleeding. ( 5.1 ) Hypophenylalaninemia : Some pediatric PKU patients experienced hypophenylalaninemia; monitor patients blood Phe levels during treatment. ( 5.2 ) Interaction with Levodopa : Seizures, over-stimulation or irritability may occur; monitor patients for a change in neurologic status. ( 5.3 ) 5.1 Increased Bleeding SEPHIENCE may increase the risk of bleeding. Bleeding events, including superficial hematomas, prolonged bleeding, and heavy menstrual bleeding have occurred in patients treated with SEPHIENCE [see Adverse Reactions ( 6.1 )] . One patient with non-traumatic superficial hematomas and prolonged bleeding was re-challenged at a lower dose of SEPHIENCE with recurrence of symptoms, which led to treatment discontinuation. The patient experienced symptoms 15 days after initial exposure and two days after rechallenge. The patient had normal blood counts and coagulation studies at the time of the bleeding. Inform the patient about the increased risk of bleeding associated with SEPHIENCE and to follow up with his/her healthcare provider if he/she experiences any signs of increased bleeding. Consider treatment interruption with SEPHIENCE in patients with active bleeding. 5.2 Hypophenylalaninemia In clinical trials of SEPHIENCE, some pediatric PKU patients experienced hypophenylalaninemia (low blood Phe), including some patients with multiple low blood Phe levels, during treatment with SEPHIENCE [see Adverse Reactions ( 6.1 )] . Prolonged levels of blood Phe that are too low have been associated with catabolism and endogenous protein breakdown, which has been associated with adverse developmental outcomes. Monitor blood Phe levels during treatment and if needed, modify the dosage of SEPHIENCE and/or dietary protein and Phe intake to ensure adequate blood Phe level control. Frequent blood Phe monitoring is recommended in the pediatric population [see Dosage and Administration ( 2.2 )] . 5.3 Interaction with Levodopa In a 10-year post-marketing safety surveillance program for a non-PKU indication using another drug that is a phenylalanine hydroxylase (PAH) activator, 3 patients with underlying neurological disorders experienced seizures, exacerbation of seizures, over-stimulation, and irritability during co-administration with levodopa. Monitor patients who are receiving levodopa for changes in neurological status during treatment with SEPHIENCE [see Drug Interactions ( 7.2 )] .

7 DRUG INTERACTIONS Dihydrofolate Reductase (DHFR) Inhibitors : Avoid concomitant use (e.g., trimethoprim, methotrexate, trimetrexate, pemetrexed, pralatrexate, raltitrexed, or piritrexim). ( 7.1 ) Sepiapterin Reductase (SR) Inhibitors : Avoid concomitant use (e.g. sulfasalazine or sulfamethoxazole). ( 7.1 ) Interaction with Levodopa : Monitor patients for a change in neurologic status. ( 7.2 ) Drugs Affecting Nitric Oxide-Mediated Vasorelaxation : Potential for vasorelaxation; monitor blood pressure (e.g., PDE-5 inhibitors). ( 7.2 ) 7.1 Effects of Other Drugs on SEPHIENCE Avoid concomitant use of drugs known to inhibit folate synthesis dihydrofolate reductase (DHFR) (e.g., trimethoprim, methotrexate, trimetrexate, pemetrexed, pralatrexate, raltitrexed, and piritrexim) while taking SEPHIENCE. Concomitant administration of such drugs may reduce sepiapterin metabolism to tetrahydrobiopterin (BH 4 ). If concomitant use is not avoidable, monitor blood Phe levels. Avoid concomitant use of sepiapterin reductase (SR) inhibitors with SEPHIENCE. Concomitant administration of such drugs may reduce sepiapterin metabolism to BH 4 . If concomitant use is not avoidable, monitor blood Phe levels. 7.2 Effects of SEPHIENCE on Other Drugs SEPHIENCE may increase the availability of tyrosine, a precursor of levodopa. Neurologic events were reported postmarketing in patients receiving another PAH activator and levodopa concomitantly for a non-PKU indication. Monitor patients for a change in neurologic status when levodopa is administered with SEPHIENCE [see Warnings and Precautions ( 5.3 )] . 7.3 Drugs Affecting Nitric Oxide-Mediated Vasorelaxation SEPHIENCE and PDE-5 inhibitors induce vasorelaxation, thus concomitant use of SEPHIENCE with PDE-5 inhibitors may reduce blood pressure even further. Monitor for signs and symptoms of hypotension with concomitant use of SEPHIENCE with drugs that affect nitric oxide-mediated vasorelaxation (e.g., PDE-5 inhibitors such as sildenafil, vardenafil, or tadalafil).

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Increased Bleeding [see Warnings and Precautions ( 5.1 )] . Hypophenylalaninemia [see Warnings and Precautions ( 5.2 )] . Most common adverse reactions with SEPHIENCE (≥2% and greater than placebo) were diarrhea, headache, abdominal pain, hypophenylalaninemia, feces discoloration, and oropharyngeal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact PTC Therapeutics, Inc. at 1-866-562-4620 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 safety of SEPHIENCE was evaluated in Trial 1 [Part 1 (open label); Part 2, (placebo-controlled)]; and Trial 2 (open-label). The two trials included a total of 215 SEPHIENCE-treated patients with PKU: 10 (5%) were <2 years old, 118 (55%) were ≥2 and <17 years old, and 87 (40%) were ≥17 years old. All patients received SEPHIENCE from 7.5 mg/kg/day up to 60 mg/kg/day and the median duration of treatment (in weeks) was 25.5 [see Clinical Studies ( 14.1 )] . Trial 1 Trial 1 included a total of 157 patients (85 male and 72 female, aged 1 year to 61 years old) with PKU across both parts of the trial. The patients received dosages from 20 mg/kg up to 60 mg/kg daily and the median duration of treatment was 8 weeks. Table 4 lists the most common adverse reactions that were reported in ≥2% of patients treated with SEPHIENCE and greater than that of the placebo group in Part 2 of Trial 1. Table 4: Adverse Reactions for SEPHIENCE in Adult and Pediatric Patients with PKU that Occurred in ≥2% of Sepiapterin-Treated Patients and Greater than Placebo (Trial 1 Part 2) a Includes Abdominal pain; Abdominal pain upper, Abdominal discomfort. Adverse Reaction SEPHIENCE N=56 N (%) Placebo N=54 N (%) Diarrhea 4 (7) 1 (2) Headache 4 (7) 1 (2) Abdominal pain a 3 (5) 1 (2) Hypophenylalaninemia 2 (4) 0 Feces discoloration 2 (4) 0 Oropharyngeal pain 2 (4) 1 (2) Adverse reactions were similar across both adult and pediatric populations except for hypophenylalaninemia ( see Description of Selected Adverse Reactions ). Description of Selected Adverse Reactions Increased Bleeding In Trial 1 Part 2, a case of heavy menstrual bleeding was reported in a SEPHIENCE-treated patient. Less than 2% of patients in Trial 2 experienced increased bleeding, which included heavy menstrual bleeding, non-traumatic superficial hematomas, and prolonged bleeding. Hypophenylalaninemia In Trial 1 Part 2, hypophenylalaninemia was seen in 5% (2/37) of sepiapterin-treated pediatric patients and in no adult patients. Some pediatric patients in Trial 2 had multiple low blood Phe levels.

8.1 Pregnancy Risk Summary Available data on the use of SEPHIENCE during pregnancy are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Uncontrolled blood Phe concentrations before and during pregnancy are associated with an increased risk of adverse pregnancy outcomes and fetal adverse effects ( see Clinical Considerations ) . In animal reproduction studies, oral administration of sepiapterin to pregnant rats and rabbits during organogenesis at dose exposures up to 9- and 6- times the human exposure at the maximum recommended human dose (MRHD) of 60 mg/kg, respectively, resulted in no adverse developmental effects ( see Data ). All pregnancies have a background risk of birth defects, loss, or other adverse 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. The background risk of major birth defects and miscarriage in pregnant women with PKU who maintain blood Phe concentrations greater than 600 micromol/L during pregnancy is greater than the corresponding background risk for pregnant women without PKU. Clinical Considerations Disease-Associated Maternal and/or Embryofetal Risk Uncontrolled blood Phe concentrations before and during pregnancy are associated with an increased risk of adverse outcomes and fetal adverse effects ( see Data ). To reduce the risk of hyperphenylalaninemia-induced fetal adverse effects, blood Phe concentrations should be maintained between 120 and 360 micromol/L during pregnancy and during the 3 months before conception [see Dosage and Administration ( 2.2 )] . Data Human Data Available data from the Maternal Phenylketonuria Collaborative Study on 468 pregnancies and 331 live births in pregnant women with PKU demonstrated that uncontrolled Phe concentrations above 600 micromol/L are associated with an increased risk for major birth defects (including microcephaly, major cardiac malformations), intrauterine fetal growth retardation, and future intellectual disability with low IQ. Animal Data In an embryo-fetal development study in rats, SEPHIENCE was administered at dose levels of 100, 300, or 1,000 mg/kg/day via oral gavage to pregnant rats during the period of organogenesis from gestation day (GD) 7 to GD 17. There were no maternal or embryo-fetal developmental toxicities noted at doses up to 1,000 mg/kg/day (9-fold the human AUC 0-24 at the MRHD). In an embryo-fetal development study in pregnant rabbits, SEPHIENCE was administered at dose levels of 100, 300, or 1,000 mg/kg/day via oral gavage to pregnant rabbits during the period of organogenesis from gestation day (GD) 7 to GD 19. There were no maternal or embryo-fetal developmental toxicities at doses up to 1,000 mg/kg/day (6-fold the human AUC 0-24 at the MRHD). In the pre- and post-natal development study in rats, SEPHIENCE was administered at dose levels of 30, 100, and 300 mg/kg/day via oral gavage once daily to pregnant rats from GD 6 to lactation day 20. SEPHIENCE did not induce effects on maternal reproductive function or on developmental and reproductive parameters of male and female offspring up to 300 mg/kg (7-fold the human AUC 0-24 at the MRHD).