Lonafarnib

1 INDICATIONS AND USAGE ZOKINVY is indicated in patients 12 months of age and older with a body surface area (BSA) of 0.39 m 2 and above: To reduce the risk of mortality in Hutchinson-Gilford Progeria Syndrome (HGPS) For the treatment of processing-deficient Progeroid Laminopathies with either: Heterozygous LMNA mutation with progerin-like protein accumulation Homozygous or compound heterozygous ZMPSTE24 mutations ZOKINVY is a farnesyltransferase inhibitor indicated in patients 12 months of age and older with a body surface area of 0.39 m 2 and above: ( 1 ) To reduce risk of mortality in Hutchinson-Gilford Progeria Syndrome. For treatment of processing-deficient Progeroid Laminopathies with either: Heterozygous LMNA mutation with progerin-like protein accumulation. Homozygous or compound heterozygous ZMPSTE24 mutations. Limitations of Use Not indicated for other Progeroid Syndromes or processing-proficient Progeroid Laminopathies. Based upon its mechanism of action, ZOKINVY would not be expected to be effective in these populations. ( 1 ) Limitations of Use ZOKINVY is not indicated for other Progeroid Syndromes or processing-proficient Progeroid Laminopathies. Based upon its mechanism of action, ZOKINVY would not be expected to be effective in these populations.

12.1 Mechanism of Action Lonafarnib inhibits farnesyltransferase to prevent farnesylation and subsequent accumulation of progerin and progerin-like proteins in the inner nuclear membrane.

2 DOSAGE AND ADMINISTRATION Start at 115 mg/m 2 twice daily with morning and evening meals. ( 2.1 ) After 4 months, increase to 150 mg/m 2 twice daily. ( 2.1 ) Round all total daily doses to nearest 25 mg increment. ( 2.1 ) See full prescribing information for dosage modifications due to adverse reactions. ( 2.2 ) See full prescribing information for preparation and administration instructions. ( 2.4 ) 2.1 Recommended Dosage The starting dosage of ZOKINVY for patients with a BSA of 0.39 m 2 and above is 115 mg/m 2 twice daily with morning and evening meals (see Table 1 ) to reduce the risk of gastrointestinal adverse reactions [see Adverse Reactions ( 6.1 )] . An appropriate dosage strength of ZOKINVY is not available for patients with a BSA of less than 0.39 m 2 [see Indications and Usage ( 1 )] . After 4 months of treatment, increase the dosage to 150 mg/m 2 twice daily with morning and evening meals (see Table 2 ). Round all total daily dosages to the nearest 25 mg increment (see Table 1 and Table 2 ). If a dose is missed, take the dose as soon as possible with food, up to 8 hours prior to the next scheduled dose. If less than 8 hours remain before the next scheduled dose, skip the missed dose, and resume taking ZOKINVY at the next scheduled dose. Table 1 provides the BSA-based dosage recommendations for the starting dosage of 115 mg/m 2 twice daily. Table 1: Recommended Dosage and Administration for 115 mg/m 2 Body Surface Area-Based Dosing BSA (m 2 ) Total Daily Dosage Rounded to Nearest 25 mg Morning Dosing Number of Capsule(s) Evening Dosing Number of Capsule(s) ZOKINVY 50 mg ZOKINVY 75 mg ZOKINVY 50 mg ZOKINVY 75 mg 0.39 - 0.48 100 1 1 0.49 - 0.59 125 1 1 0.6 - 0.7 150 1 1 0.71 - 0.81 175 2 1 0.82 - 0.92 200 2 2 0.93 – 1 225 1 1 2 Table 2 provides the BSA-based dosage recommendations for the dosage of 150 mg/m 2 twice daily. Table 2: Recommended Dosage and Administration for 150 mg/m 2 Body Surface Area-Based Dosing BSA (m 2 ) Total Daily Dosage Rounded to Nearest 25 mg Morning Dosing Number of Capsule(s) Evening Dosing Number of Capsule(s) ZOKINVY 50 mg ZOKINVY 75 mg ZOKINVY 50 mg ZOKINVY 75 mg 0.39 - 0.45 125 1 1 0.46 - 0.54 150 1 1 0.55 - 0.62 175 2 1 0.63 - 0.7 200 2 2 0.71 - 0.79 225 1 1 2 0.8 - 0.87 250 1 1 1 1 0.88 - 0.95 275 2 1 1 0.96 – 1 300 2 2 2.2 Dosage Modifications Due to Adverse Reactions and Drug Interactions Table 3: Recommended ZOKINVY Dosage Modifications Adverse Reaction Severity Monitoring and Dose Modifications for ZOKINVY QTc Interval Prolongation [see Warnings and Precautions ( 5.1 ), Drug Interactions ( 7.1 )] If the QTc interval is greater than or equal to 500 msec Withhold ZOKINVY until QTc interval is less than 470 msec, then resume ZOKINVY at same dosage. Monitor electrocardiograms (ECGs) prior to initiating ZOKINVY, during treatment, and as clinically indicated. Gastrointestinal Adverse Reactions [see Adverse Reactions ( 6.1 )] For patients who have increased their dose of ZOKINVY to 150 mg/m 2 twice daily and are experiencing repeated episodes of vomiting and/or diarrhea resulting in dehydration or weight loss The dose of ZOKINVY can be reduced to the starting dose of 115 mg/m 2 twice daily (see Table 1 ). Ensure ZOKINVY is taken with the morning and evening meals and with an adequate amount of water. CYP3A Drug Interactions [see Warnings and Precautions ( 5.2 ), Adverse Reactions ( 6.1 ), Drug Interactions ( 7.1 )] When moderate CYP3A inhibitors are added for a patient already on steady state ZOKINVY No dosage adjustment for ZOKINVY is recommended. When initiating ZOKINVY in a patient who is concurrently on a moderate CYP3A inhibitor The patient may be at increased risk of adverse reactions. Monitor the patient closely for adverse reactions for at least the first 7 days after initiating ZOKINVY. If the patient experiences an adverse reaction during the first 7 days of the starting dose or thereafter, consider an alternative therapy that is not a moderate CYP3A inhibitor. 2.3 Temporary D

6 ADVERSE REACTIONS The most common adverse reactions (incidence ≥25%) are vomiting, diarrhea, infection, nausea, decreased appetite, fatigue, upper respiratory tract infection, abdominal pain, musculoskeletal pain, electrolyte abnormalities, decreased weight, headache, myelosuppression, increased aspartate aminotransferase, decreased blood bicarbonate, cough, hypertension, and increased alanine aminotransferase. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sentynl Therapeutics, Inc. at 1-888-507-5206 or [email protected] or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial 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. A total of 84 subjects were treated with at least one dose of ZOKINVY with or without additional therapy, of which 8 were treated at a dosage of at least 115 mg/m 2 twice daily for greater than or equal to 10 years. The safety profile of ZOKINVY is based on 128 patient-years of treatment exposure (62 patients with HGPS and 1 patient with processing-deficient Progeroid Laminopathy with LMNA heterozygous mutation) and pooled results from two Phase 2 open-label, single-arm trials (n=63: 28 patients from Study 1 and 35 treatment naïve patients from Study 2). In Study 1, ZOKINVY treatment was initiated at 115 mg/m 2 twice daily and increased to 150 mg/m 2 twice daily after approximately 4 months for a total treatment duration of 24 to 30 months. Treatment naïve patients in Study 2 received ZOKINVY 150 mg/m 2 twice daily for up to 36 months. In both studies, ZOKINVY was administered orally via capsules or the capsule contents were mixed with Ora Blend SF or Ora-Plus and administered orally as a suspension. In these two studies, a total of 63 patients received ZOKINVY for a median duration of 2.2 years, with approximately 1.9 years at the recommended dose of 150 mg/m 2 twice daily. The population was 2 to 17 years old, with a similar proportion of males (33 [52%] patients) and females (30 [48%] patients). Most patients had classic HGPS (60 [95%] patients) compared to non-classic HGPS (2 [3%] patients) and 1 (2%) patient had Progeroid Laminopathy with LMNA heterozygous mutation. Table 4 summarizes adverse reactions reported in the clinical trials. The most common adverse reactions (≥25%) in the clinical trials were vomiting, diarrhea, infection, nausea, decreased appetite, fatigue, upper respiratory tract infection, abdominal pain, musculoskeletal pain, electrolyte abnormalities, decreased weight, headache, myelosuppression, increased aspartate aminotransferase, decreased blood bicarbonate, cough, hypertension, and increased alanine aminotransferase. Table 4: Adverse Reactions in ≥5% of Patients in Study 1 and Treatment-Naïve Patients in Study 2 Receiving ZOKINVY Adverse Reactions ZOKINVY n=63 n (%) 1 Abdominal pain includes stomach pain and abdominal pain. 2 Infection includes abdominal infection, candidiasis, chicken pox, Clostridium difficile colitis, colitis, croup, dengue fever, flu syndrome, flu-like symptoms, fungal infection, gastroenteritis, gastrointestinal infection, Helicobacter pylori infection, infection, infection viral, influenza, nail infection, otitis media, parotitis, perirectal abscess, pneumonia, small intestine infection, submandibular lymphadenitis, tonsillitis, viral infection. 3 Upper respiratory infection includes bronchial infection, bronchitis, sinus infection, and upper respiratory infection. 4 Electrolyte abnormalities include hypermagnesemia, hypokalemia, hyperkalemia, hyponatremia, hypercalcemia, hyperphosphatemia, hypocalcemia, and hypernatremia. 5 Myelosuppression includes absolute neutrophil count decreased, low total white blood cells, lymphopenia, decreased hemoglobin, and hematocrit low. 6 Musculoskeletal pain includes arth

5 WARNINGS AND PRECAUTIONS QTc Interval Prolongation : Increases the QTc interval. Avoid use in patients with symptomatic bradycardia, hypokalemia, or hypomagnesemia, and in combination with other drugs known to prolong the QTc interval. ( 5.1 ) Risk of Reduced Efficacy or Adverse Reactions Due to Drug Interactions : Prior to and during treatment, consider potential for drug interactions and review concomitant medications; monitor for adverse reactions. ( 5.2 , 7 ) Laboratory Abnormalities: Monitor for changes in electrolytes, complete blood counts, and liver enzymes. ( 5.3 ) Nephrotoxicity: Caused nephrotoxicity in rats. Monitor renal function at regular intervals. ( 5.4 , 13.2 ) Retinal Toxicity: Caused rod-dependent, low-light vision decline in monkeys. Perform ophthalmological evaluation at regular intervals and at the onset of any new visual changes. ( 5.5 , 13.2 ) Impaired Fertility: Caused impaired fertility in female rats, impaired fertility and testicular toxicity in male rats, and toxicity in the male reproductive tract in monkeys. Advise females and males of reproductive potential of the animal fertility findings. ( 5.6 , 13.1 , 13.2 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the risk to a fetus and to use effective contraception. ( 5.7 , 8.1 , 8.3 ) 5.1 QTc Interval Prolongation ZOKINVY prolongs the QTc interval. Prolongation of the QTc interval increases the risk of Torsade de pointes, other serious arrhythmias, and sudden death. Avoid use of ZOKINVY in patients with a history of cardiac arrhythmias, as well as in other circumstances that may increase the risk of the occurrence of Torsade de pointes or sudden death, including symptomatic bradycardia, hypokalemia, or hypomagnesemia. Avoid use of ZOKINVY in combination with other drugs known or suspected to prolong the QTc interval [see Drug Interactions ( 7.1 )] . Monitor ECGs prior to initiating ZOKINVY, during treatment, and as clinically indicated. If QTc interval is greater than 500 msec, withhold ZOKINVY until QTc interval is less than 470 msec, then resume ZOKINVY at same dosage. Obtain serum electrolytes prior to initiating ZOKIVNY and during treatment as clinically indicated. Correct serum electrolyte abnormalities. 5.2 Risk of Reduced Efficacy or Adverse Reactions Due to Drug Interactions Coadministration of ZOKINVY with other drugs may result in clinically significant drug interactions [see Dosage and Administration ( 2.2 , 2.3 ), Contraindications ( 4 ), Drug Interactions ( 7.1 , 7.2 )] . These drug interactions can lead to: Reduced efficacy of ZOKINVY Increased risk of adverse reactions from ZOKINVY or co-administered drugs See Table 5 and Table 6 for steps to prevent or manage these clinically significant drug interactions, including dosage recommendations [see Drug Interactions (7.1, 7.2 ) ] . Consider the potential for drug interactions prior to and during ZOKINVY therapy; review concomitant medications during ZOKINVY therapy; and monitor for adverse reactions. 5.3 Laboratory Abnormalities Some patients treated with ZOKINVY developed laboratory abnormalities [see Adverse Reactions ( 6.1 )] . These included: Electrolyte abnormalities (43%), such as hyperkalemia, hypokalemia, hyponatremia, or hypercalcemia Myelosuppression (35%), such as reductions in absolute neutrophil count, white blood cell counts, lymphocytes, hemoglobin, or hematocrit Increased liver enzymes, such as aspartate aminotransferase (35%), or alanine aminotransferase (27%) These laboratory abnormalities often improved while continuing ZOKINVY, but it is not possible to exclude ZOKINVY as a cause of the abnormalities. Periodically monitor electrolytes, complete blood counts, and liver enzymes, and manage abnormalities accordingly. 5.4 Nephrotoxicity Lonafarnib caused nephrotoxicity in rats at plasma drug exposures approximately equal to that achieved with the human dose [ see Nonclinical Toxicology ( 13.2 )] . Monitor renal function at reg

4 CONTRAINDICATIONS ZOKINVY is contraindicated in patients taking: Strong CYP3A inhibitors [see Drug Interactions ( 7.1 )] Strong or moderate CYP3A inducers [see Drug Interactions ( 7.1 )] Midazolam [see Drug Interactions ( 7.2 )] Lovastatin, simvastatin, or atorvastatin [see Drug Interactions ( 7.2 )] Strong CYP3A inhibitors. ( 4 ) Strong or moderate CYP3A inducers. ( 4 ) Midazolam. ( 2.3 , 4 ) Lovastatin, simvastatin, or atorvastatin. ( 4 )