FDA label c395d7f5-cc38-407a-85fd-7dc4b3fd32f3

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 regular intervals during ZOKINVY therapy. 5.5 Retinal Toxicity Lonafarnib caused rod-dependent, low-light vision decline in monkeys at plasma drug exposures similar to that achieved with the human dose [see Nonclinical Toxicology ( 13.2 )] . Perform ophthalmological evaluation at regular intervals and at the onset of any new visual changes during ZOKINVY therapy. 5.6 Impaired Fertility Lonafarnib caused impaired fertility in female rats at 1.2 times the human dose based on plasma drug exposure [see Nonclinical Toxicology ( 13.1 )] . Lonafarnib caused impaired fertility and testicular toxicity in male rats at 1.5 times the human dose based on plasma drug exposure [see Nonclinical Toxicology ( 13.1 )] , and toxicity in the male reproductive tract in monkeys at doses lower than the human dose based on plasma drug exposure [see Nonclinical Toxicology ( 13.2 )] . Advise females and males of reproductive potential of the animal fertility findings, and that the impact on pubertal development and the potential for impaired fertility with ZOKINVY therapy in humans have not been adequately evaluated [see Use in Specific Populations ( 8.3 )] . 5.7 Embryo-Fetal Toxicity Based on findings from animal reproduction studies, ZOKINVY can cause embryo-fetal harm when administered to pregnant women. In animal reproduction studies, oral administration of lonafarnib in pregnant rats during organogenesis produced embryo-fetal toxicity at plasma drug exposures that were approximately equal to the recommended human dose. In pregnant rabbits, oral administration of lonafarnib during organogenesis produced skeletal malformations and variations at exposures lower than the human exposure. Advise pregnant women of the risk to a fetus. Advise females of reproductive potential to avoid becoming pregnant and to use appropriate effective contraception during treatment with ZOKINVY [see Use in Specific Populations ( 8.1 , 8.3 )] .

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 Eiger BioPharmaceuticals, Inc. at 833-267-0545 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 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 arthritis, back pain, bone pain, foot pain, intercostal pain, joint pain, knee pain, leg pain, musculoskeletal pain, pain in ankle/extremity/fingers/hip/leg/limb/lower limbs/left arm, shoulder pain, unilateral leg pain. Excludes musculoskeletal pain for abdomen. 7 Cerebral ischemia includes cerebral ischemia, central nervous system hemorrhage, and ischemia cerebrovascular. 8 Ocular changes include visual acuity change, corneal clouding, conjunctivitis, watering eyes, keratitis. Adverse Reactions ZOKINVY n=63 n (%) Gastrointestinal disorders Vomiting 57 (90%) Diarrhea 51 (81%) Nausea 35 (56%) Abdominal Pain 1 30 (48%) Constipation 14 (22%) Flatulence 4 (6%) General disorders and administration site conditions Fatigue 32 (51%) Pyrexia 9 (14%) Infections and Infestations Infection 2 49 (78%) Upper Respiratory Tract Infection 32 (51%) Rhinitis 12 (19%) Investigations Decreased appetite (anorexia) 33 (53%) Electrolyte abnormalities 4 27 (43%) Weight decreased 23 (37%) Myelosuppression 5 22 (35%) Increased aspartate aminotransferase 22 (35%) Decreased blood bicarbonate 21 (33%) Hypertension 18 (29%) Increased alanine aminotransferase 17 (27%) Dehydration 3 (5%) Musculoskeletal and connective tissue disorders Musculoskeletal pain 6 30 (48%) Nervous system disorders Headache 23 (37%) Cerebral ischemia 7 7 (11%) Ophthalmic Ocular changes 8 15 (24%) Psychiatric disorders Depressed mood 3 (5%) Respiratory, thoracic and mediastinal disorders Cough 21 (33%) Epistaxis 13 (21%) Skin and subcutaneous tissue disorders Rash 7 (11%) Pruritus 5 (8%) Mucositis 5 (8%) Gastrointestinal Adverse Reactions As noted in Table 4 , gastrointestinal adverse reactions were the most frequently reported adverse reactions. Of the 57 patients who experienced vomiting, 30 (53%) patients had mild vomiting (defined as no intervention required), 26 (46%) patients had moderate vomiting (defined as outpatient intravenous hydration; medical intervention required), and 1 (2%) patient had severe vomiting (defined as tube feeding, total parenteral nutrition, or hospitalization indicated). Of the 35 patients who experienced nausea, 34 (97%) patients had mild nausea (defined as loss of appetite without alteration in eating habits) and 1 (3%) patient had moderate nausea (defined as oral intake decreased without significant weight loss, dehydration, or malnutrition). During the first four months of treatment in Study 1, 19 (68%) patients had vomiting and 10 (36%) patients had nausea. By the end of therapy, 4 (14%) patients who were still on ZOKINVY required antiemetics or anti-nauseants. A total of 4 patients discontinued ZOKINVY, mostly due to nausea or vomiting. Of the 51 patients who experienced diarrhea, the majority of patients (approximately 92%) experienced mild or moderate diarrhea; 38 (75%) patients reported mild diarrhea (defined as an increase of less than 4 stools per day over baseline) and 9 (18%) patients reported moderate diarrhea (defined as increase of 4 to 6 stools per day over baseline; limiting instrumental activities of daily living). Four (8%) patients reported severe diarrhea (defined as increase of seven or more stools per day over baseline; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self-care activities of daily living). During the first four months of treatment in Study 1, 23 (82%) patients had diarrhea; by the end of therapy, 3 (11%) patients had diarrhea. Twelve (43%) patients were treated with loperamide. Alanine Aminotransferase and Aspartate Aminotransferase Elevations Increased alanine aminotransferase was commonly reported (17 [27%] patients). Of the 17 patients with increased alanine aminotransferase, 14 (82%) patients had mild increases (defined as greater than upper limit of normal (ULN) to 3.0 times ULN if baseline was normal; 1.5 to 3.0 times ULN if baseline was abnormal), 1 (6%) patient had moderate increases (defined as greater than 3.0 to 5.0 times ULN if baseline was normal or abnormal), and 2 (12%) patients had severe increases (defined as greater than 5.0 to 20.0 times ULN if baseline was normal or abnormal). Increased aspartate aminotransferase was also commonly reported (22 [35%] patients). Of the 22 patients with increased aspartate aminotransferase, 21 (95%) patients had mild increases (defined as greater than ULN to 3.0 times ULN if baseline was normal; 1.5 to 3.0 times ULN if baseline was abnormal) and 1 (5%) patient had a severe increase (defined as greater than 5.0 to 20.0 times ULN if baseline was normal or abnormal). One patient with alanine and aspartate aminotransferase elevations also experienced hypertriglyceridemia and hyperglycemia resulting in discontinuation of ZOKINVY. Hypertension Increases in blood pressure have been documented in patients treated with ZOKINVY. At baseline, 22 (35%) patients had either a systolic blood pressure or a diastolic blood pressure or both above the 95th percentile. Over the course of the trials, 18 (29%) patients had hypertension based on systolic blood pressure or diastolic blood pressure measurements above the 95th percentile on 3 or more occasions. Five (8%) patients who were normotensive at baseline had either systolic blood pressure or diastolic blood pressure above the 95th percentile at the end of treatment.

<table ID="table4" width="775" styleCode="Noautorules"><caption>Table 4: Adverse Reactions in &#x2265;5% of Patients in Study 1 and Treatment-Na&#xEF;ve Patients in Study 2 Receiving ZOKINVY</caption><col width="80%" align="left"/><col width="20%" align="center"/><tfoot><tr><td colspan="2">¹Abdominal pain includes stomach pain and abdominal pain. ²Infection 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. ³Upper respiratory infection includes bronchial infection, bronchitis, sinus infection, and upper respiratory infection. ⁴Electrolyte abnormalities include hypermagnesemia, hypokalemia, hyperkalemia, hyponatremia, hypercalcemia, hyperphosphatemia, hypocalcemia, and hypernatremia. ⁵Myelosuppression includes absolute neutrophil count decreased, low total white blood cells, lymphopenia, decreased hemoglobin, and hematocrit low. ⁶Musculoskeletal pain includes arthritis, back pain, bone pain, foot pain, intercostal pain, joint pain, knee pain, leg pain, musculoskeletal pain, pain in ankle/extremity/fingers/hip/leg/limb/lower limbs/left arm, shoulder pain, unilateral leg pain. Excludes musculoskeletal pain for abdomen. ⁷Cerebral ischemia includes cerebral ischemia, central nervous system hemorrhage, and ischemia cerebrovascular. ⁸Ocular changes include visual acuity change, corneal clouding, conjunctivitis, watering eyes, keratitis.</td></tr></tfoot><tbody><tr><td styleCode="Toprule Botrule Lrule Rrule" valign="bottom"><content styleCode="bold">Adverse Reactions</content></td><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">ZOKINVY n=63 n (%)</content></td></tr><tr><td colspan="2" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Gastrointestinal disorders</content></td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Vomiting</td><td styleCode="Toprule Botrule Lrule Rrule">57 (90%)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Diarrhea</td><td styleCode="Toprule Botrule Lrule Rrule">51 (81%)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Nausea</td><td styleCode="Toprule Botrule Lrule Rrule">35 (56%)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Abdominal Pain¹</td><td styleCode="Toprule Botrule Lrule Rrule">30 (48%)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Constipation</td><td styleCode="Toprule Botrule Lrule Rrule">14 (22%)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Flatulence</td><td styleCode="Toprule Botrule Lrule Rrule">4 (6%)</td></tr><tr><td colspan="2" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">General disorders and administration site conditions</content></td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Fatigue</td><td styleCode="Toprule Botrule Lrule Rrule">32 (51%)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Pyrexia</td><td styleCode="Toprule Botrule Lrule Rrule">9 (14%)</td></tr><tr><td colspan="2" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Infections and Infestations</content></td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Infection²</td><td styleCode="Toprule Botrule Lrule Rrule">49 (78%)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Upper Respiratory Tract Infection</td><td styleCode="Toprule Botrule Lrule Rrule">32 (51%)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Rhinitis</td><td styleCode="Toprule Botrule Lrule Rrule">12 (19%)</td></tr><tr><td colspan="2" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Investigations</content></td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Decreased appetite (anorexia)</td><td styleCode="Toprule Botrule Lrule Rrule">33 (53%)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Electrolyte abnormalities⁴</td><td styleCode="Toprule Botrule Lrule Rrule">27 (43%)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Weight decreased</td><td styleCode="Toprule Botrule Lrule Rrule">23 (37%)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Myelosuppression⁵</td><td styleCode="Toprule Botrule Lrule Rrule">22 (35%)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Increased aspartate aminotransferase</td><td styleCode="Toprule Botrule Lrule Rrule">22 (35%)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Decreased blood bicarbonate</td><td styleCode="Toprule Botrule Lrule Rrule">21 (33%)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Hypertension</td><td styleCode="Toprule Botrule Lrule Rrule">18 (29%)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Increased alanine aminotransferase</td><td styleCode="Toprule Botrule Lrule Rrule">17 (27%)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Dehydration</td><td styleCode="Toprule Botrule Lrule Rrule">3 (5%)</td></tr><tr><td colspan="2" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Musculoskeletal and connective tissue disorders</content></td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Musculoskeletal pain⁶</td><td styleCode="Toprule Botrule Lrule Rrule">30 (48%)</td></tr><tr><td colspan="2" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Nervous system disorders</content></td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Headache</td><td styleCode="Toprule Botrule Lrule Rrule">23 (37%)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Cerebral ischemia⁷</td><td styleCode="Toprule Botrule Lrule Rrule">7 (11%)</td></tr><tr><td colspan="2" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Ophthalmic</content></td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Ocular changes⁸</td><td styleCode="Toprule Botrule Lrule Rrule">15 (24%)</td></tr><tr><td colspan="2" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Psychiatric disorders</content></td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Depressed mood</td><td styleCode="Toprule Botrule Lrule Rrule">3 (5%)</td></tr><tr><td colspan="2" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content></td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Cough</td><td styleCode="Toprule Botrule Lrule Rrule">21 (33%)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Epistaxis</td><td styleCode="Toprule Botrule Lrule Rrule">13 (21%)</td></tr><tr><td colspan="2" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Skin and subcutaneous tissue disorders</content></td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Rash</td><td styleCode="Toprule Botrule Lrule Rrule">7 (11%)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Pruritus</td><td styleCode="Toprule Botrule Lrule Rrule">5 (8%)</td></tr><tr><td styleCode="Toprule Botrule Lrule Rrule"> Mucositis</td><td styleCode="Toprule Botrule Lrule Rrule">5 (8%)</td></tr></tbody></table>