Juxtapid

WARNING: RISK OF HEPATOTOXICITY JUXTAPID can cause elevations in transaminases. In the adult clinical trial, 10 (34%) of the 29 patients treated with JUXTAPID had at least one elevation in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3 times the upper limit of normal (ULN). There were no concomitant clinically meaningful elevations of total bilirubin, international normalized ratio (INR), or alkaline phosphatase. In the pediatric clinical trial (5 to 17 years of age), 6 (14%) of the 43 patients experienced elevations in ALT and/or AST ≥ 3 times ULN. No concomitant clinically meaningful elevations in total bilirubin or alkaline phosphatase were observed [see Warnings and Precautions (5.1) ]. JUXTAPID also increases hepatic fat, with or without concomitant increases in transaminases. The median absolute increase in hepatic fat in adult patients was 6% after both 26 and 78 weeks of treatment, from 1% at baseline, measured by magnetic resonance spectroscopy (MRS). The median absolute increase in hepatic fat in pediatric patients aged 5 to 17 years was 4% after 24 weeks and 104 weeks of treatment, from 3% at baseline, measured by nuclear magnetic resonance (NMR). Hepatic steatosis associated with JUXTAPID treatment may be a risk factor for progressive liver disease, including steatohepatitis and cirrhosis [see Warnings and Precautions (5.1) ]. Measure ALT, AST, alkaline phosphatase, and total bilirubin before initiating treatment and then ALT and AST regularly as recommended. During treatment, adjust the dose of JUXTAPID if the ALT or AST are ≥3 times ULN. Discontinue JUXTAPID for clinically significant liver toxicity [ see Dosage and Administration (2.7) and Warnings and Precautions (5.1) ]. Because of the risk of hepatotoxicity, JUXTAPID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the JUXTAPID REMS Program [see Warnings and Precautions (5.2) ]. Prescribe JUXTAPID only to patients with a clinical or laboratory diagnosis consistent with HoFH. The safety and effectiveness of JUXTAPID have not been established in patients with hypercholesterolemia who do not have HoFH [see Indications and Usage (1) ] . WARNING: RISK OF HEPATOTOXICITY See full prescribing information for complete boxed warning. JUXTAPID can cause elevations in transaminases ( 5.1 ). Measure alanine and aspartate aminotransferases (ALT, AST), alkaline phosphatase, and total bilirubin before initiating treatment and then ALT and AST regularly as recommended ( 2.5 , 5.1 ). During treatment, adjust the dose of JUXTAPID if the ALT or AST is ≥3 times the upper limit of normal (ULN) ( 2.5 , 5.1 ). Discontinue JUXTAPID for clinically significant liver toxicity ( 2.5 , 5.1 ). JUXTAPID increases hepatic fat (hepatic steatosis) with or without concomitant increases in transaminases ( 5.1 ). Hepatic steatosis associated with JUXTAPID may be a risk factor for progressive liver disease, including steatohepatitis and cirrhosis ( 5.1 ). Because of the risk of hepatotoxicity, JUXTAPID is available only through a restricted program called the JUXTAPID REMS Program ( 5.2 ). Prescribe JUXTAPID only to patients with a clinical or laboratory diagnosis consistent with homozygous familial hypercholesterolemia (HoFH). The safety and effectiveness of JUXTAPID have not been established in patients with hypercholesterolemia who do not have HoFH ( 1 ).

5 WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity: May cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. Discontinue JUXTAPID if pregnancy detected ( 5.3 ). Gastrointestinal adverse reactions occur in 93% of adult and 72% of pediatric patients and could affect absorption of concomitant oral medications ( 5.5 ). 5.1 Risk of Hepatotoxicity JUXTAPID can cause elevations in transaminases and hepatic steatosis in adults and pediatric patients, as described below [see Warnings and Precautions (5.2) ] . JUXTAPID may induce steatohepatitis, which can progress to cirrhosis over several years. Clinical trials of JUXTAPID for HoFH would have been unlikely to detect this adverse outcome given their size and duration [see Clinical Studies (14) ] . Elevation of Transaminases Elevations in transaminases (ALT and/or AST) are associated with JUXTAPID. In the 78-week adult clinical trial, 10 (34%) of the 29 patients with HoFH had at least one elevation in ALT or AST ≥3 times ULN, and 4 (14%) of the patients had at least one elevation in ALT or AST ≥5 times ULN. There were no concomitant or subsequent clinically meaningful elevations in bilirubin, INR, or alkaline phosphatase [see Adverse Reactions (6.1) ]. No patients discontinued prematurely because of elevated transaminases. Among the 19 patients who subsequently enrolled in the adult HoFH extension trial, one discontinued because of increased transaminases that persisted despite several dose reductions, and one temporarily discontinued because of markedly elevated transaminases (ALT 24 times ULN, AST 13 times ULN) that had several possible causes, including a drug-drug interaction between JUXTAPID and the strong CYP3A4 inhibitor clarithromycin [see Drug Interactions (7.1) ]. In the 104-week open-label trial in pediatric patients aged 5 to 17 years with HoFH exposed to JUXTAPID, 6 (14%) of the 43 patients with HoFH had at least one elevation in ALT and/or AST ≥3 times ULN, including 2 (5%) patients who had at least one elevation in ALT ≥5 times ULN. No patients discontinued treatment because of increased transaminases, although some patients required dose interruptions or reductions for management of liver transaminase elevations. Monitoring of Transaminases Before initiating JUXTAPID and during treatment, monitor transaminases as recommended in Table 7. Table 7: Recommendations for Monitoring Transaminases TIME RECOMMENDATIONS Before initiating treatment Measure ALT, AST, alkaline phosphatase, and total bilirubin. If abnormal, consider initiating JUXTAPID only after an appropriate work-up and the baseline abnormalities have been explained or resolved. JUXTAPID is contraindicated in patients with moderate or severe hepatic impairment, or active liver disease, including unexplained persistent elevations of serum transaminases [see Contraindications (4) ] . During the first year Measure liver-related tests (ALT and AST, at a minimum) prior to each increase in dose or monthly, whichever occurs first. After the first year Measure liver-related tests (ALT and AST, at a minimum) at least every 3 months and before any increase in dose. At any time during treatment If transaminases are >1 and <3 times ULN, no dose modification is required. Continue routine monitoring of liver-related tests (once monthly during the first year of treatment and every 3 months thereafter). If transaminases are ≥3 times ULN, reduce or withhold dosing of JUXTAPID and monitor as recommended [see Dosage and Administration (2.5) ]. Discontinue JUXTAPID for persistent or clinically significant elevations. If transaminase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms), increases in bilirubin ≥2 times ULN, or active liver disease, discontinue treatment with JUXTAPID and identify the probable cause. Hepatic Steatosis JUXTAPID increases hepatic fat, with or without concomitant increases in transaminases. Hepatic steatosis is a risk factor for progressive liver disease, including steatohepatitis and cirrhosis. The long-term consequences of hepatic steatosis associated with JUXTAPID treatment are unknown. During the HoFH clinical trial conducted in adults, the median absolute increase in hepatic fat was 6% after both 26 weeks and 78 weeks of treatment, from 1% at baseline, measured by magnetic resonance spectroscopy (MRS) [see Adverse Reactions (6.1) ]. Clinical data suggest that hepatic fat accumulation is reversible after stopping treatment with JUXTAPID, but whether histological sequelae remain is unknown, especially after long-term use; protocol scheduled liver biopsies were not performed in the adult clinical trial. In a phase 3 trial in pediatric patients, two patients (both aged 5 to 10 years) developed mild hepatic steatosis (as assessed by ultrasound), which resolved without specific medical interventions, other than the protocol specified follow-up ultrasounds and laboratory monitoring. Overall, the median absolute increase in hepatic fat was 4% after 24 weeks and 104 weeks, from 3% at baseline, measured by NMR. As with data from the adult patients, clinical pediatric data suggest that hepatic fat accumulation is reversible after stopping treatment with JUXTAPID, but whether histological sequelae remain is unknown, especially after long term use. Alcohol may increase levels of hepatic fat and induce or exacerbate liver injury. Drinking more than one alcoholic drink per day is not recommended for patients taking JUXTAPID. Exercise caution when using JUXTAPID with other medications known to have potential for hepatotoxicity, such as isotretinoin, amiodarone, acetaminophen (>4 g/day for ≥3 days/week), methotrexate, tetracyclines, and tamoxifen. The effect of concomitant administration of JUXTAPID with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted. JUXTAPID has not been studied concomitantly with other LDL-lowering agents that can also increase hepatic fat. Therefore, the combined use of such agents is not recommended. 5.2 JUXTAPID REMS Program Because of the risk of hepatotoxicity associated with JUXTAPID therapy, JUXTAPID is available through a restricted program under the REMS. Under the JUXTAPID REMS, only certified healthcare providers and pharmacies may prescribe and distribute JUXTAPID. Further information is available at www.JUXTAPIDREMSProgram.com or by telephone at 1-85-JUXTAPID (1-855-898-2743). 5.3 Embryo-Fetal Toxicity Based on findings from animal studies, JUXTAPID use is contraindicated in pregnancy since it may cause fetal harm [see Contraindications (4) , Use in Specific Populations (8.1 , 8.3) ]. In animal reproduction studies in rats and ferrets, embryonic death and fetal malformations were observed at clinically relevant exposures. Females of reproductive potential should have a negative pregnancy test before starting JUXTAPID. Advise females of reproductive potential to use effective contraception during therapy with JUXTAPID and for two weeks after the final dose. If pregnancy is detected, discontinue JUXTAPID. 5.4 Reduced Absorption of Fat-Soluble Vitamins and Serum Fatty Acids Given its mechanism of action in the small intestine, JUXTAPID may reduce the absorption of fat-soluble nutrients. In clinical trials of adult and pediatric patients with HoFH, patients were provided daily dietary supplements of vitamin E, linoleic acid, ALA, EPA, and DHA. In the adult clinical trial, the median levels of serum vitamin E, ALA, linoleic acid, EPA, DHA, and arachidonic acid (AA) decreased from baseline to Week 26 but remained above the lower limit of the reference range. Adverse clinical consequences of these reductions were not observed with JUXTAPID treatment of up to 78 weeks. In the pediatric clinical trial, overall, mean serum vitamin E levels decreased from baseline to Week 104 as expected but were still within or above the upper limit of the reference range. Mean values of linoleic acid, ALA, EPA, AA, and DHA all remained within the normal range or above the upper limit of the reference range during the 104-week trial. Eicosatrienoic acid was below lower limit of normal throughout the trial and increased to a mean normal value by Week 104. Patients treated with JUXTAPID should take daily nutritional supplements that contain the dosages of vitamin E and essential fatty acids recommended in Dosage and Administration (2.2) . Patients with chronic bowel or pancreatic diseases that predispose to malabsorption may be at increased risk for deficiencies in these nutrients with use of JUXTAPID. 5.5 Gastrointestinal Adverse Reactions Gastrointestinal adverse reactions were reported by 27 (93%) of 29 patients in the adult clinical trial. Diarrhea occurred in 79% of patients, nausea in 65%, dyspepsia in 38%, and vomiting in 34%. Other reactions reported by at least 20% of patients include abdominal pain, abdominal discomfort, abdominal distension, constipation, and flatulence [see Adverse Reactions (6) ] . Gastrointestinal adverse reactions of severe intensity were reported by 6 (21%) of 29 patients in the adult clinical trial, with the most common being diarrhea (4 patients, 14%); vomiting (3 patients, 10%); and abdominal pain, distension, and/or discomfort (2 patients, 7%). Gastrointestinal reactions contributed to the reasons for early discontinuation from this trial for 4 (14%) patients. Gastrointestinal adverse reactions were reported by 31 (72%) of the 43 patients in the pediatric clinical trial. Diarrhea occurred in 22 (51%) patients and was more frequently reported by patients 11 to 17 years of age compared to patients 5 to 10 years of age (57% and 45%, respectively). Abdominal pain occurred in 19 (44%) patients and was reported with similar incidences in patients 5 to 10 years of age and 11 to 17 years of age. Vomiting occurred in 12 (28%) patients and was more frequently reported by patients 5 to 10 years of age compared to patients 11 to 17 years of age (50% and 9% of patients, respectively). Gastrointestinal reactions contributed to the reasons for early discontinuation from the trial for 2 (5%) patients. There have been post-marketing reports of severe diarrhea in adults treated with JUXTAPID, including patients being hospitalized because of diarrhea-related complications such as volume depletion. Monitor patients who are more susceptible to complications from diarrhea, such as older patients and patients taking drugs that can lead to volume depletion or hypotension. Instruct patients to stop JUXTAPID and contact their healthcare provider if severe diarrhea occurs or if they experience symptoms of volume depletion, such as lightheadedness, decreased urine output, or tiredness. In such cases, consider reducing the dose or suspending use of JUXTAPID. Absorption of concomitant oral medications may be affected in patients who develop diarrhea or vomiting. To reduce the risk of gastrointestinal adverse reactions, instruct patients or their caregiver(s) to adhere to a low-fat diet supplying <20% of energy from fat or less than 30 grams of fat, whichever is less. Increase the dosage of JUXTAPID gradually. Individualize the maximum daily fat goal based on caloric needs due to age, growth, activity level, and tolerability. Monitor growth and weight loss in pediatric patients who are below the 10th percentile for height, weight, or BMI [see Dosage and Administration (2.1) and (2.2) ] . 5.6 Concomitant Use of CYP3A4 Inhibitors CYP3A4 inhibitors increase the exposure of lomitapide, with strong inhibitors increasing exposure approximately 27-fold. Concomitant use of moderate or strong CYP3A4 inhibitors with JUXTAPID is contraindicated [see Drug Interactions (7.1) ]. In the JUXTAPID clinical trials, one adult patient with HoFH developed markedly elevated transaminases (ALT 24 times ULN, AST 13 times ULN) within days of initiating the strong CYP3A4 inhibitor clarithromycin. If treatment with moderate or strong CYP3A4 inhibitors is unavoidable, JUXTAPID should be stopped during the course of treatment. Avoid food or drinks containing grapefruit during JUXTAPID treatment. Weak CYP3A4 inhibitors can increase the exposure of lomitapide approximately 2-fold; therefore, when JUXTAPID is administered with weak CYP3A4 inhibitors, the dose of JUXTAPID should be decreased by half. Careful titration may then be considered based on LDL-C response and safety/tolerability to half the maximum recommended dosage except when co-administered with oral contraceptives only, in which case the maximum recommended JUXTAPID dose is approximately two thirds the maximum recommended dose (Table 3) [see Dosage and Administration (2.4) and Drug Interactions (7.2) ]. 5.7 Risk of Myopathy with Concomitant Use of Simvastatin or Lovastatin The risk of myopathy, including rhabdomyolysis, with simvastatin and lovastatin monotherapy is dose related. Lomitapide approximately doubles the exposure to simvastatin; therefore, it is recommended to reduce the dose of simvastatin by 50% when initiating JUXTAPID [see Clinical Pharmacology (12.3) ] . While taking JUXTAPID, limit simvastatin dosage to 20 mg daily (or 40 mg daily for patients who have previously tolerated simvastatin 80 mg daily for at least one year without evidence of muscle toxicity). Refer to the simvastatin prescribing information for additional dosing recommendations. Interaction between lovastatin and lomitapide has not been studied. However, the metabolizing enzymes and transporters responsible for the disposition of lovastatin and simvastatin are similar, suggesting that JUXTAPID may increase the exposure of lovastatin; therefore, reducing the dose of lovastatin should be considered when initiating JUXTAPID. 5.8 Risk of Supratherapeutic or Subtherapeutic Anticoagulation with Warfarin JUXTAPID increases the plasma concentrations of warfarin. Increases in the dose of JUXTAPID may lead to supratherapeutic anticoagulation and decreases in the dose of JUXTAPID may lead to subtherapeutic anticoagulation. Difficulty controlling INR contributed to early discontinuation from the adult clinical trial for one of five patients taking concomitant warfarin. Patients taking warfarin should undergo regular monitoring of the INR, especially after any changes in JUXTAPID dosage. The dose of warfarin should be adjusted as clinically indicated [see Drug Interactions (7.3) ] . 5.9 Risk of Malabsorption with Rare Hereditary Disorders of Galactose Intolerance Patients with rare, hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should avoid JUXTAPID as this may result in diarrhea and malabsorption.

<table width="90%"><caption>Table 7: Recommendations for Monitoring Transaminases</caption><col width="30%" align="left" valign="top"/><col width="70%" align="left" valign="top"/><thead><tr><th styleCode="Lrule Rrule">TIME</th><th styleCode="Rrule">RECOMMENDATIONS</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Before initiating treatment</td><td styleCode="Rrule"><list listType="unordered" styleCode="disc"><item>Measure ALT, AST, alkaline phosphatase, and total bilirubin.</item><item>If abnormal, consider initiating JUXTAPID only after an appropriate work-up and the baseline abnormalities have been explained or resolved.</item><item>JUXTAPID is contraindicated in patients with moderate or severe hepatic impairment, or active liver disease, including unexplained persistent elevations of serum transaminases <content styleCode="italics">[see <linkHtml href="#S4">Contraindications (4)</linkHtml>]</content>.</item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">During the first year</td><td styleCode="Rrule"><list listType="unordered" styleCode="disc"><item>Measure liver-related tests (ALT and AST, at a minimum) prior to each increase in dose or monthly, whichever occurs first.</item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">After the first year</td><td styleCode="Rrule"><list listType="unordered" styleCode="disc"><item>Measure liver-related tests (ALT and AST, at a minimum) at least every 3 months and before any increase in dose.</item></list></td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="xmChange">At any time during treatment</content></td><td styleCode="Rrule"><list listType="unordered" styleCode="disc"><item>If transaminases are &gt;1 and &lt;3 times ULN, no dose modification is required. Continue routine monitoring of liver-related tests (once monthly during the first year of treatment and every 3 months thereafter).</item><item>If transaminases are &#x2265;3 times ULN, reduce or withhold dosing of JUXTAPID and monitor as recommended <content styleCode="italics">[see <linkHtml href="#S2.5">Dosage and Administration (2.5)</linkHtml>].</content></item><item>Discontinue JUXTAPID for persistent or clinically significant elevations.</item><item>If transaminase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms), increases in bilirubin &#x2265;2 times ULN, or active liver disease, discontinue treatment with JUXTAPID and identify the probable cause.</item></list></td></tr></tbody></table>

6 ADVERSE REACTIONS The following important adverse reactions have been observed and are discussed in detail in other sections of the label: Risk of hepatotoxicity [see Warnings and Precautions (5.1) ] Reduced absorption of fat-soluble vitamins, and serum fatty acids [see Warnings and Precautions (5.4) ] Gastrointestinal adverse reactions [see Warnings and Precautions (5.5) ] Most common adverse reactions in adult patients (incidence ≥10%) are diarrhea, nausea, dyspepsia, vomiting, and abdominal pain (6.1). Most common adverse reactions in pediatric patients aged 5 to 17 years old (incidence ≥15%) are abdominal pain, alanine aminotransferase increased, aspartate aminotransferase increased, diarrhea, and vomiting ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Chiesi Farmaceutici S.p.A. at 1-888-661-9260 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. Adults with HoFH One single-arm, open-label, 78-week trial has been conducted in 29 adult patients with HoFH, 23 of whom completed at least one year of treatment. The initial dosage of JUXTAPID was 5 mg daily, with titration up to 60 mg daily during an 18-week period based on safety and tolerability. In this trial, the mean age was 31 years (range, 18 to 55 years), 16 (55%) patients were male, 25 (86%) patients were White, 2 (7%) were Asian, 1 (3%) was Black or African American, and 1 (3%) was multi-racial [see Clinical Studies (14) ] . Five (17%) of the 29 patients discontinued treatment due to an adverse reaction. The adverse reactions that contributed to treatment discontinuations included diarrhea (2 patients; 7%) and abdominal pain, nausea, gastroenteritis, weight loss, headache, and difficulty controlling INR on warfarin (1 patient each; 3%). The most common adverse reactions were gastrointestinal, reported by 27 (93%) of 29 patients. Adverse reactions reported by ≥8 (28%) patients in the clinical trial included diarrhea, nausea, vomiting, dyspepsia, and abdominal pain. Other common adverse reactions, reported by 5 to 7 (17 to 24%) patients, included weight loss, abdominal discomfort, abdominal distension, constipation, flatulence, increased ALT, chest pain, influenza, nasopharyngitis, and fatigue. The adverse reactions reported in at least 10% of adult patients are presented in Table 8. Table 8: Adverse Reactions Reported in ≥10% of Patients in the Adult Clinical Trial ADVERSE REACTION N (%) Diarrhea 23 (79) Nausea 19 (65) Dyspepsia 11 (38) Abdominal pain 10 (34) Vomiting 10 (34) Chest pain 7 (24) Decreased weight 7 (24) Abdominal discomfort 6 (21) Abdominal distension 6 (21) Constipation 6 (21) Flatulence 6 (21) Influenza 6 (21) Fatigue 5 (17) Increased ALT 5 (17) Nasopharyngitis 5 (17) Back pain 4 (14) Gastroenteritis 4 (14) Pharyngolaryngeal pain 4 (14) Angina pectoris 3 (10) Defecation urgency 3 (10) Dizziness 3 (10) Fever 3 (10) Gastroesophageal reflux disease 3 (10) Headache 3 (10) Nasal congestion 3 (10) Palpitations 3 (10) Rectal tenesmus 3 (10) Adverse reactions of severe intensity were reported by 8 (28%) of 29 patients, with the most common being diarrhea (4 patients, 14%), vomiting (3 patients, 10%), increased ALT or hepatotoxicity (3 patients, 10%), and abdominal pain, distension, and/or discomfort (2 patients, 7%). Pediatric Patients with HoFH Aged 5 to 17 years A single-arm, open label, multinational, 104-week trial was conducted in 43 pediatric patients with HoFH aged 5 to 17 years. Thirty-nine of the patients completed the trial. The dose of JUXTAPID was escalated from an age-dependent starting dose to a maximum tolerated dose (MTD) as applicable to the pediatric age group and based on acceptable safety and tolerability criteria, in addition to LDL-C goals [see Dosage and Administration (2) and Clinical Studies (14) ] . Table 9: Adverse Reactions Reported in ≥10% of Pediatric Patients Aged 5 to 17 Years ADVERSE REACTION N (%) Elevated transaminases Grouped terms composed of several similar terms 23 (53) Abdominal pain 23 (53) Diarrhea 22 (51) Vomiting 12 (28) Decreased appetite 6 (14) Nausea 5 (12) Transaminase Elevations During the adult clinical trial, 10 (34%) of 29 patients had at least one elevation in ALT and/or AST ≥3 times ULN (see Table 10 ). No clinically meaningful elevations in total bilirubin or alkaline phosphatase were observed. Transaminases typically fell within one to four weeks of reducing the dose or withholding JUXTAPID. Among the 19 adult patients who enrolled in an extension trial following the adult clinical trial, one discontinued because of increased transaminases that persisted despite several dose reductions, and one temporarily discontinued because of markedly elevated transaminases (ALT 24 times ULN, AST 13 times ULN) that had several possible causes, including a drug-drug interaction between JUXTAPID and the strong CYP3A4 inhibitor clarithromycin [see Drug Interactions (7.1) ]. In the pediatric trial, 6 patients experienced elevations in ALT and/or AST ≥3 times ULN (see Table 10 ). No discontinuations occurred due to increased transaminases in the trial, although some patients required interrupting JUXTAPID or reducing the dose. Table 10: Patient Incidence of Transaminase Elevations During the Clinical Trials ADULTS Upper limits of normal (ULN) ranged from 33 to 41 international units/L for ALT and 36 to 43 international units/L for AST. N (%) PEDIATRIC PATIENTS AGED 5 TO 17 YEARS ULN ranged from 21 to 55 international units/L for ALT and 24 to 60 international units/L for AST, based on age and gender. N (%) Total Patients 29 43 Maximum ALT ≥3 to <5 × ULN 6 (21) 3 (7) ≥5 to <10 × ULN 3 (10) 2 (5) ≥10 to <20 × ULN 1 (3) 0 ≥20 × ULN 0 0 Maximum AST ≥3 to <5 × ULN 5 (17) 3 (7) ≥5 to <10 × ULN 1 (3) 0 ≥10 to <20 × ULN 0 0 ≥20 × ULN 0 0 Hepatic Steatosis Hepatic fat was prospectively measured using magnetic resonance spectroscopy (MRS) in all eligible patients during the adult clinical trial. After 26 weeks, the median absolute increase in hepatic fat from baseline was 6%, and the mean absolute increase was 8% (range, 0% to 30%). After 78 weeks, the median absolute increase in hepatic fat from baseline was 6%, and the mean absolute increase was 7% (range, 0% to 18%). Among the 23 patients with evaluable data on at least one occasion during the trial, 18 (78%) exhibited an increase in hepatic fat >5% and 3 (13%) exhibited an increase >20%. Data from individuals who had repeat measurements after stopping JUXTAPID show that hepatic fat accumulation is reversible, but whether histological sequelae remain is unknown. In the pediatric clinical trial, the median absolute increase in hepatic fat was 4% after 24 weeks and 104 weeks, from 3% at baseline, measured by NMR. Among the 19 patients with hepatic fat measured by NMR on at least one occasion during the trial, 8 (42%) patients exhibited an increase in hepatic fat to >10% including 1 (5%) patient with an increase to >20%. Data from pediatric patients with follow-up measurements after Week 104 suggest that hepatic fat accumulation is reversable after stopping treatment with JUXTAPID, but whether histological sequelae remain is unknown, especially after long term use. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of JUXTAPID. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to JUXTAPID exposure. Musculoskeletal: Myalgia Skin reactions: Alopecia

<table width="55%"><caption>Table 8: Adverse Reactions Reported in &#x2265;10% of Patients in the Adult Clinical Trial</caption><col width="65%" align="left" valign="top"/><col width="35%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule">ADVERSE REACTION</th><th styleCode="Rrule">N (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Diarrhea</td><td styleCode="Rrule">23 (79)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">19 (65)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dyspepsia</td><td styleCode="Rrule">11 (38)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Abdominal pain</td><td styleCode="Rrule">10 (34)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Vomiting</td><td styleCode="Rrule">10 (34)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Chest pain</td><td styleCode="Rrule">7 (24)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Decreased weight</td><td styleCode="Rrule">7 (24)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Abdominal discomfort</td><td styleCode="Rrule">6 (21)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Abdominal distension</td><td styleCode="Rrule">6 (21)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Constipation</td><td styleCode="Rrule">6 (21)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Flatulence</td><td styleCode="Rrule">6 (21)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> </td><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Influenza</td><td styleCode="Rrule">6 (21)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fatigue</td><td styleCode="Rrule">5 (17)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Increased ALT</td><td styleCode="Rrule">5 (17)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nasopharyngitis</td><td styleCode="Rrule">5 (17)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Back pain</td><td styleCode="Rrule">4 (14)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Gastroenteritis</td><td styleCode="Rrule">4 (14)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> </td><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> </td><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> </td><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> </td><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> </td><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pharyngolaryngeal pain</td><td styleCode="Rrule">4 (14)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Angina pectoris</td><td styleCode="Rrule">3 (10)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Defecation urgency</td><td styleCode="Rrule">3 (10)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dizziness</td><td styleCode="Rrule">3 (10)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fever</td><td styleCode="Rrule">3 (10)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Gastroesophageal reflux disease</td><td styleCode="Rrule">3 (10)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Headache</td><td styleCode="Rrule">3 (10)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nasal congestion</td><td styleCode="Rrule">3 (10)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Palpitations</td><td styleCode="Rrule">3 (10)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Rectal tenesmus</td><td styleCode="Rrule">3 (10)</td></tr></tbody></table>

<table width="60%"><caption>Table 9: Adverse Reactions Reported in &#x2265;10% of Pediatric Patients Aged 5 to 17 Years</caption><col width="65%" align="left" valign="top"/><col width="35%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule">ADVERSE REACTION</th><th styleCode="Rrule">N (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Elevated transaminases<footnote ID="t9a">Grouped terms composed of several similar terms</footnote></td><td styleCode="Rrule">23 (53)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Abdominal pain<footnoteRef IDREF="t9a"/></td><td styleCode="Rrule">23 (53)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Diarrhea</td><td styleCode="Rrule">22 (51)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Vomiting</td><td styleCode="Rrule">12 (28)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Decreased appetite</td><td styleCode="Rrule">6 (14)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">5 (12)</td></tr></tbody></table>

<table ID="table10" width="85%"><caption>Table 10: Patient Incidence of Transaminase Elevations During the Clinical Trials</caption><col width="50%" align="left" valign="top"/><col width="20%" align="center" valign="top"/><col width="30%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule"> </th><th styleCode="Rrule">ADULTS<footnote>Upper limits of normal (ULN) ranged from 33 to 41 international units/L for ALT and 36 to 43 international units/L for AST. </footnote> N (%)</th><th styleCode="Rrule">PEDIATRIC PATIENTS AGED 5 TO 17 YEARS<footnote>ULN ranged from 21 to 55 international units/L for ALT and 24 to 60 international units/L for AST, based on age and gender.</footnote> N (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule Bold">Total Patients</td><td styleCode="Rrule">29</td><td styleCode="Rrule">43</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule Bold">Maximum ALT</td><td styleCode="Rrule"> </td><td styleCode="Rrule"> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> &#x2265;3 to &lt;5 &#xD7; ULN</td><td styleCode="Rrule">6 (21)</td><td styleCode="Rrule">3 (7)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> &#x2265;5 to &lt;10 &#xD7; ULN</td><td styleCode="Rrule">3 (10)</td><td styleCode="Rrule">2 (5)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> &#x2265;10 to &lt;20 &#xD7; ULN</td><td styleCode="Rrule">1 (3)</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> &#x2265;20 &#xD7; ULN</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule Bold">Maximum AST</td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> &#x2265;3 to &lt;5 &#xD7; ULN</td><td styleCode="Rrule">5 (17)</td><td styleCode="Rrule">3 (7)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> &#x2265;5 to &lt;10 &#xD7; ULN</td><td styleCode="Rrule">1 (3)</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> &#x2265;10 to &lt;20 &#xD7; ULN</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule"> &#x2265;20 &#xD7; ULN</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr></tbody></table>