Lojuxta

Homozygous Familial Hypercholesterolemia

Lojuxta is indicated as an adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available, to reduce low-density lipoprotein cholesterol (LDLC), total cholesterol (TC), apolipoprotein B (apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH).

Limitations Of Use

• The safety and effectiveness of Lojuxta have not been established in patients with hypercholesterolemia who do not have HoFH, including those with heterozygous familial hypercholesterolemia (HeFH).
• The effect of Lojuxta on cardiovascular morbidity and mortality has not been determined.

Initiation And Maintenance Of Therapy

Before beginning treatment with Lojuxta:

• Measure transaminases (ALT, AST), alkaline phosphatase, and total bilirubin ;
• Obtain a negative pregnancy test in females of reproductive potential ; and,
• Initiate a low-fat diet supplying <20% of energy from fat.

The recommended starting dosage of Lojuxta is 5 mg once daily, and the dose should be escalated gradually based on acceptable safety and tolerability. Transaminases should be measured prior to any increase in dose. The maintenance dosage of Lojuxta should be individualized, taking into account patient characteristics such as goal of therapy and response to treatment, to a maximum of 60 mg daily as described in Table 1. Modify dosing for patients taking concomitant weak CYP3A4 inhibitors and for those with renal impairment or baseline hepatic impairment. Monitor transaminases during treatment with Lojuxta as described in WARNINGS AND PRECAUTIONS, and reduce or withhold dosing for patients who develop transaminase values ≥3x the upper limit of normal (ULN).

Table 1: Recommended Regimen for Titrating Dosage

To reduce the risk of developing a fat-soluble nutrient deficiency due to Lojuxta's mechanism of action in the small intestine, patients treated with Lojuxta should take daily supplements that contain 400 international units vitamin E and at least 200 mg linoleic acid, 210 mg alpha-linolenic acid (ALA), 110 mg eicosapentaenoic acid (EPA), and 80 mg docosahexaenoic acid (DHA).

Administration

Lojuxta should be taken once daily with a glass of water, without food, at least 2 hours after the evening meal because administration with food may increase the risk of gastrointestinal adverse reactions. Patients should swallow Lojuxta capsules whole. Capsules should not be opened, crushed, dissolved, or chewed.

Dosing With Cytochrome P450 3A4 Inhibitors

Lojuxta is contraindicated with concomitant use of moderate and strong cytochrome P450 3A4 (CYP3A4) inhibitors.

The recommended maximum dosage of Lojuxta is 30 mg daily with concomitant use of weak CYP3A4 inhibitors (such as alprazolam, amiodarone, amlodipine, atorvastatin, bicalutamide, cilostazol, cimetidine, cyclosporine, fluoxetine, fluvoxamine, ginkgo, goldenseal, isoniazid, lapatinib, nilotinib, pazopanib, ranitidine, ranolazine, ticagrelor, zileuton). However, the recommended maximum dosage of Lojuxta is 40 mg daily with concomitant use of oral contraceptives.

When initiating a weak CYP3A4 inhibitor in a patient already taking Lojuxta 10 mg daily or more, decrease the dose of Lojuxta by half; patients taking Lojuxta 5 mg daily may continue with the same dosage. Careful titration of Lojuxta may then be considered according to LDL-C response and safety/tolerability to a maximum recommended dosage of 30 mg daily except when coadministered with oral contraceptives, in which case the maximum recommended lomitapide dosage is 40 mg daily.

Dose Modification Based On Elevated Transaminases

Table 2 summarizes recommendations for dose adjustment and monitoring for patients who develop elevated transaminases during therapy with Lojuxta.

Table 2: Dose Adjustment and Monitoring for Patients with Elevated Transaminases

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 ≥2x ULN, or active liver disease, discontinue treatment with Lojuxta and investigate to identify the probable cause.

Dosing In Patients With Renal Impairment

Patients with end-stage renal disease receiving dialysis should not exceed 40 mg daily. There are no data available to guide dosing in other patients with renal impairment.

Dosing In Patients With Baseline Hepatic Impairment

Patients with mild hepatic impairment (Child-Pugh A) should not exceed 40 mg daily.

Lojuxta is contraindicated in the following conditions:

• Pregnancy.
• Concomitant administration of Lojuxta with moderate or strong CYP3A4 inhibitors, as this can increase Lojuxta exposure.
• Patients with moderate or severe hepatic impairment (based on Child-Pugh category B or C) and patients with active liver disease, including unexplained persistent elevations of serum transaminases.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Risk Of Hepatotoxicity

Lojuxta can cause elevations in transaminases and hepatic steatosis, as described below. To what extent Lojuxta-associated hepatic steatosis promotes the elevations in transaminases is unknown. Although cases of hepatic dysfunction (elevated transaminases with increase in bilirubin or INR) or hepatic failure have not been reported, there is concern that Lojuxta could induce steatohepatitis, which can progress to cirrhosis over several years. The clinical studies supporting the safety and efficacy of Lojuxta in HoFH would have been unlikely to detect this adverse outcome given their size and duration.

Elevation Of Transaminases

Elevations in transaminases (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]) are associated with Lojuxta. In the clinical trial, 10 (34%) of the 29 patients with HoFH had at least one elevation in ALT or AST ≥3x ULN, and 4 (14%) of the patients had at least one elevation in ALT or AST ≥5x ULN. There were no concomitant or subsequent clinically meaningful elevations in bilirubin, INR, or alkaline phosphatase.

During the 78-week HoFH clinical trial, no patients discontinued prematurely because of elevated transaminases. Among the 19 patients who subsequently enrolled in the HoFH extension study, one discontinued because of increased transaminases that persisted despite several dose reductions, and one temporarily discontinued because of markedly elevated transaminases (ALT 24x ULN, AST 13x ULN) that had several possible causes, including a drug-drug interaction between Lojuxta and the strong CYP3A4 inhibitor clarithromycin.

Monitoring Of Transaminases

Before initiating Lojuxta and during treatment, monitor transaminases as recommended in Table 3.

Table 3: Recommendations for Monitoring Transaminases

Hepatic Steatosis

Lojuxta 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 Lojuxta treatment are unknown. During the HoFH clinical trial, 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). Clinical data suggest that hepatic fat accumulation is reversible after stopping treatment with Lojuxta, but whether histological sequelae remain is unknown, especially after long-term use; protocol liver biopsies were not performed in the HoFH clinical trial.

Alcohol may increase levels of hepatic fat and induce or exacerbate liver injury. It is recommended that patients taking Lojuxta should not consume more than one alcoholic drink per day.

Caution should be exercised when Lojuxta is used 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 Lojuxta with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.

Lojuxta 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.

Lojuxta REMS Program

Because of the risk of hepatotoxicity associated with Lojuxta therapy, Lojuxta is available through a restricted program under the REMS. Under the Lojuxta REMS, only certified healthcare providers and pharmacies may prescribe and distribute Lojuxta. Further information is available at www.LojuxtaREMSProgram.com or by telephone at 1-85Lojuxta (1-855-898-2743).

Embryo-Fetal Toxicity

Lojuxta may cause fetal harm when administered to a pregnant woman based on findings of teratogenicity in rats and ferrets. Females of reproductive potential should have a negative pregnancy test before starting Lojuxta and should use effective contraception during therapy with Lojuxta.

Oral contraceptives are weak CYP3A4 inhibitors.

Reduced Absorption Of Fat-Soluble Vitamins And Serum Fatty Acids

Given its mechanism of action in the small intestine, Lojuxta may reduce the absorption of fat-soluble nutrients. In the HoFH clinical trial, patients were provided daily dietary supplements of vitamin E, linoleic acid, alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). In this trial, the median levels of serum vitamin E, ALA, linoleic acid, EPA, DHA, and arachidonic acid 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 Lojuxta treatment of up to 78 weeks. Patients treated with Lojuxta should take daily supplements that contain 400 international units vitamin E and at least 200 mg linoleic acid, 210 mg ALA, 110 mg EPA, and 80 mg DHA. Patients with chronic bowel or pancreatic diseases that predispose to malabsorption may be at increased risk for deficiencies in these nutrients with use of Lojuxta.

Gastrointestinal Adverse Reactions

Gastrointestinal adverse reactions were reported by 27 (93%) of 29 patients in the HoFH 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.

Gastrointestinal adverse reactions of severe intensity were reported by 6 (21%) of 29 patients in the HoFH 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 the trial for 4 (14%) patients.

There have been postmarketing reports of severe diarrhea with the use of Lojuxta, 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 Lojuxta 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 Lojuxta.

Absorption of concomitant oral medications may be affected in patients who develop diarrhea or vomiting.

To reduce the risk of gastrointestinal adverse events, patients should adhere to a low-fat diet supplying <20% of energy from fat and the dosage of Lojuxta should be increased gradually.

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 Lojuxta is contraindicated. In the Lojuxta clinical trials, one patient with HoFH developed markedly elevated transaminases (ALT 24x ULN, AST 13x ULN) within days of initiating the strong CYP3A4 inhibitor clarithromycin. If treatment with moderate or strong CYP3A4 inhibitors is unavoidable, Lojuxta should be stopped during the course of treatment.

Grapefruit juice must be omitted from the diet while being treated with Lojuxta.

Weak CYP3A4 inhibitors can increase the exposure of lomitapide approximately 2-fold; therefore, when Lojuxta is administered with weak CYP3A4 inhibitors, the dose of Lojuxta should be decreased by half. Careful titration may then be considered based on LDL-C response and safety/tolerability to a maximum recommended dosage of 30 mg daily except when coadministered with oral contraceptives, in which case the maximum recommended lomitapide dosage is 40 mg daily.

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 Lojuxta. While taking Lojuxta, 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 Lojuxta may increase the exposure of lovastatin; therefore, reducing the dose of lovastatin should be considered when initiating Lojuxta.

Risk Of Supratherapeutic Or Subtherapeutic Anticoagulation With Warfarin

Lojuxta increases the plasma concentrations of warfarin. Increases in the dose of Lojuxta may lead to supratherapeutic anticoagulation, and decreases in the dose of Lojuxta may lead to subtherapeutic anticoagulation. Difficulty controlling INR contributed to early discontinuation from the HoFH 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 Lojuxta dosage. The dose of warfarin should be adjusted as clinically indicated.

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 Lojuxta as this may result in diarrhea and malabsorption.

Patient Counseling Information

See FDA-approved labeling (Medication Guide)

Patients should be informed that a registry for patients taking Lojuxta has been established in order to monitor and evaluate the long-term effects of Lojuxta. Patients are encouraged to participate in the registry and should be informed that their participation is voluntary. For information regarding the registry program visit www.Lojuxta.com or call 1-877-902-4099.

Advise patients of the following:

Risk Of Hepatotoxicity

• Lojuxta can cause both elevations in transaminases and hepatic steatosis. Discuss with the patient the importance of monitoring of liver-related tests before taking Lojuxta, prior to each dose escalation, and periodically thereafter.
• Patients should be advised of the potential for increased risk of liver injury if alcohol is consumed while taking Lojuxta. It is recommended that patients taking Lojuxta limit consumption to not more than one alcoholic drink per day.
• Lojuxta is commonly associated with nausea, vomiting, and abdominal pain. Advise patients to promptly report these symptoms if they increase in severity, persist, or change in the character, as they might reflect liver injury. Patients should also report any other symptoms of possible liver injury, including fever, jaundice, lethargy, or flu-like symptoms.

Lojuxta REMS Program

• Lojuxta is only available through a restricted program called Lojuxta REMS Program and therefore, Lojuxta is only available from certified pharmacies that are enrolled in the program.

Females Of Reproductive Potential

• Lojuxta is contraindicated in pregnancy.
• Advise females of reproductive potential that they should have a negative pregnancy test before starting Lojuxta and that they should use effective contraception while taking Lojuxta. If oral contraceptives are initiated while taking Lojuxta, the dose of Lojuxta may require adjustment. Hormone absorption from oral contraceptives may be incomplete if vomiting or diarrhea occurs while taking Lojuxta, warranting the use of additional contraceptive methods.
• Nursing Mothers: A decision should be made whether to discontinue nursing or discontinue Lojuxta.

Dietary Supplements

• Discuss with the patient the importance of taking daily supplements that contain 400 international units vitamin E and at least 200 mg linoleic acid, 210 mg alpha-linolenic acid (ALA), 110 mg eicosapentaenoic acid (EPA), and 80 mg docosahexaenoic acid (DHA).

Gastrointestinal Adverse Reactions

• Inform the patient that gastrointestinal adverse reactions are common with Lojuxta. These include, but are not limited to, diarrhea, nausea/vomiting, abdominal pain/discomfort, flatulence, and constipation. Strict adherence to a low-fat diet (<20% of total calories from fat) may reduce these reactions.
• Instruct the patient to stop Lojuxta 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.
• Tell the patient that taking Lojuxta with food may adversely impact gastrointestinal tolerability; therefore, they should take Lojuxta at least 2 hours after the evening meal, swallowing each capsule whole.
• Absorption of oral medications may be affected in patients who develop diarrhea or vomiting. For example, hormone absorption from oral contraceptives may be incomplete, warranting the use of additional contraceptive methods. Patients who develop these symptoms should seek advice from their healthcare provider.

Drug Interactions

• Tell the patient to omit grapefruit juice from his/her diet while on Lojuxta.
• Because multiple drug-drug interactions have been described with Lojuxta, advise the patient to tell their healthcare provider(s) about all medications, nutritional supplements, and vitamins that they are taking or may be taking while taking Lojuxta.

Missed Doses

• If a dose of Lojuxta is missed, the normal dose should be taken at the usual time the next day. If dosing is interrupted for more than a week, tell the patient to contact their healthcare provider before restarting treatment.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

In a 2-year dietary carcinogenicity study in mice, lomitapide was administered at doses of 0.3, 1.5, 7.5, 15, or 45 mg/kg/day. There were statistically significant increases in the incidences of liver adenomas and carcinomas in males at doses ≥1.5 mg/kg/day (≥2-times the MRHD at 60 mg based on AUC) and in females at ≥7.5 mg/kg/day (≥10-times the human exposure at 60 mg based on AUC). Incidences of small intestinal carcinomas in males and combined adenomas and carcinomas in females were significantly increased at doses ≥15 mg/kg/day (≥23-times the human exposure at 60 mg based on AUC).

In a 2-year carcinogenicity study in rats, lomitapide was administered by oral gavage for up to 99 weeks at doses of 0.25, 1.7, or 7.5 mg/kg/day in males and 0.03, 0.35, or 2.0 mg/kg/day in females. While the design of the study was suboptimal, there were no statistically significant drug-related increases in tumor incidences at exposures up to 6-times (males) and 8-times (females) higher than human exposure at the MRHD based on AUC.

Lomitapide did not exhibit genotoxic potential in a battery of studies, including the in vitro Bacterial Reverse Mutation (Ames) assay, an in vitro cytogenetics assay using primary human lymphocytes, and an oral micronucleus study in rats.

Lomitapide had no effect on fertility in rats at doses up to 5 mg/kg/day at systemic exposures estimated to be 4-times (females) and 5-times (males) higher than in humans at 60 mg based on AUC.

Use In Specific Populations

Pregnancy

Pregnancy Category X.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Lojuxta during pregnancy. For additional information visit www.Lojuxta.com or call the Global Lomitapide Pregnancy Exposure Registry (PER) at 1-877-902-4099. Healthcare professionals are encouraged to call the PER at 1-877-902-4099 to enroll patients who become pregnant during Lojuxta treatment.

Risk Summary

Lojuxta is contraindicated during pregnancy because Lojuxta may cause fetal harm when administered to a pregnant woman. Lomitapide was teratogenic in rats and ferrets at exposures estimated to be less than human therapeutic exposure at 60 mg (AUC = 67 ng*h/mL) when administered during organogenesis. There was no evidence of teratogenicity in rabbits at 3 times the maximum recommended human dose (MRHD) of 60 mg based on body surface area. Embryo-fetal lethality was observed in rabbits at 6-times the MRHD. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Animal Data

Oral gavage doses of 0.04, 0.4, or 4 mg/kg/day lomitapide given to pregnant rats from gestation day 6 through organogenesis were associated with fetal malformations at ≥2-times human exposure at the MRHD (60 mg) based on plasma AUC comparisons. Fetal malformations included umbilical hernia, gastroschisis, imperforate anus, alterations in heart shape and size, limb malrotations, skeletal malformations of the tail, and delayed ossification of cranial, vertebral and pelvic bones.

Oral gavage doses of 1.6, 4, 10, or 25 mg/kg/day lomitapide given to pregnant ferrets from gestation day 12 through organogenesis were associated with both maternal toxicity and fetal malformations at exposures that ranged from less than the human exposure at the MRHD to 5times the human exposure at the MRHD. Fetal malformations included umbilical hernia, medially rotated or short limbs, absent or fused digits on paws, cleft palate, open eye lids, low-set ears, and kinked tail.

Oral gavage doses of 0.1, 1, or 10 mg/kg/day lomitapide given to pregnant rabbits from gestation day 6 through organogenesis were not associated with adverse effects at systemic exposures up to 3-times the MRHD of 60 mg based on body surface area comparison. Treatment at doses of ≥20 mg/kg/day, ≥6-times the MRHD, resulted in embryo-fetal lethality.

Pregnant female rats given oral gavage doses of 0.1, 0.3, or 1 mg/kg/day lomitapide from gestation day 7 through termination of nursing on lactation day 20 were associated with malformations at systemic exposures equivalent to human exposure at the MRHD of 60 mg based on AUC. Increased pup mortality occurred at 4-times the MRHD.

Nursing Mothers

It is not known whether lomitapide is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for lomitapide in a 2-year mouse study, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness have not been established in pediatric patients.

Geriatric Use

Clinical studies of Lojuxta did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dosing for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Females Of Reproductive Potential

Lojuxta may cause fetal harm. Females who become pregnant during Lojuxta therapy should stop Lojuxta immediately and notify their healthcare provider.

Pregnancy Testing

Females of reproductive potential should have a negative pregnancy test before starting Lojuxta.

Contraception

Females of reproductive potential should use effective contraception during Lojuxta therapy. Oral contraceptives are weak CYP3A4 inhibitors. Hormone absorption from oral contraceptives may be incomplete if vomiting or diarrhea occurs while taking Lojuxta, warranting the use of additional contraceptive methods.

Renal Impairment

Patients with end-stage renal disease receiving dialysis should not exceed 40 mg daily since lomitapide exposure in these patients increased approximately 50% compared with healthy volunteers. Effects of mild, moderate, and severe renal impairment, including those with end-stage renal disease not yet receiving dialysis, on lomitapide exposure have not been studied. However, it is possible that patients with renal impairment who are not yet receiving dialysis may experience increases in lomitapide exposure exceeding 50%.

Hepatic Impairment

Patients with mild hepatic impairment (Child-Pugh A) should not exceed 40 mg daily since the lomitapide exposure in these patients increased approximately 50% compared with healthy volunteers. Lojuxta is contraindicated in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment since the lomitapide exposure in patients with moderate hepatic impairment increased 164% compared with healthy volunteers.

The following important adverse reactions have been observed and are discussed in detail in other sections of the label:

• Risk of hepatotoxicity
• Reduced absorption of fat-soluble vitamins, and serum fatty acids
• Gastrointestinal adverse reactions

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.

One single-arm, open-label, 78-week trial has been conducted in 29 patients with HoFH, 23 of whom completed at least one year of treatment. The initial dosage of Lojuxta 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 30.7 years (range, 18 to 55 years), 16 (55%) patients were men, 25 Â (86%) patients were Caucasian, 2 (7%) were Asian, 1 (3%) was African American, and 1 (3%) was multi-racial.

Five (17%) of the 29 patients with HoFH that participated in the clinical trial 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 HoFH clinical trial included diarrhea, nausea, vomiting, dyspepsia, and abdominal pain. Other common adverse reactions, reported by 5 to 7 (17-24%) 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 patients during the HoFH clinical trial are presented in Table 4.

Table 4: Adverse Reactions Reported in ≥10% of Patients in the Clinical Trial in HoFH

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%).

Transaminase Elevations

During the HoFH clinical trial, 10 (34%) of 29 patients had at least one elevation in ALT and/or AST ≥3x ULN (see Table 5). 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 Lojuxta.

Table 5: Patient Incidence of Transaminase Elevations During the HoFH Clinical Trial

Upper limits of normal (ULN) ranged from 33-41 international units/L for ALT and 36-43 international units/L for AST.

Among the 19 patients who enrolled in an extension study following the HoFH clinical trial, one discontinued because of increased transaminases that persisted despite several dose reductions, and one temporarily discontinued because of markedly elevated transaminases (ALT 24x ULN, AST 13x ULN) that had several possible causes, including a drug-drug interaction between Lojuxta and the strong CYP3A4 inhibitor clarithromycin.

Hepatic Steatosis

Hepatic fat was prospectively measured using magnetic resonance spectroscopy (MRS) in all eligible patients during the HoFH 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 Lojuxta show that hepatic fat accumulation is reversible, but whether histological sequelae remain is unknown.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Lojuxta. 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 Lojuxta exposure.

Musculoskeletal disorders: Myalgia

Skin reactions: Alopecia

There is no specific treatment in the event of overdose of Lojuxta. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Liver-related tests should be monitored. Hemodialysis is unlikely to be beneficial given that lomitapide is highly protein bound.

Effects On QT Interval

At a concentration 23 times the Cmax of the maximum recommended dose, lomitapide does not prolong QTc to any clinically relevant extent.

Absorption

Upon oral administration of a single 60-mg dose of Lojuxta, the lomitapide tmax is around 6 hours in healthy volunteers. The absolute bioavailability of lomitapide is approximately 7%. Lomitapide pharmacokinetics is approximately dose-proportional for oral single doses from 10100 mg.

Distribution

The mean lomitapide volume of distribution at steady state is 985-1292 liters. Lomitapide is 99.8% plasma-protein bound.

Metabolism

Lomitapide is metabolized extensively by the liver. The metabolic pathways include oxidation, oxidative N-dealkylation, glucuronide conjugation, and piperidine ring opening. Cytochrome P450 (CYP) 3A4 metabolizes lomitapide to its major metabolites, M1 and M3, as detected in plasma. The oxidative N-dealkylation pathway breaks the lomitapide molecule into M1 and M3. M1 is the moiety that retains the piperidine ring, whereas M3 retains the rest of the lomitapide molecule in vitro. CYPs 1A2, 2B6, 2C8, and 2C19 may metabolize lomitapide to a small extent to M1. M1 and M3 do not inhibit activity of microsomal triglyceride transfer protein in vitro.

Excretion

In a mass-balance study, a mean of 59.5% and 33.4% of the dose was excreted in the urine and feces, respectively. In another mass-balance study, a mean of 52.9% and 35.1% of the dose was excreted in the urine and feces, respectively. Lomitapide was not detectable in urine samples. M1 is the major urinary metabolite. Lomitapide is the major component in the feces. The mean lomitapide terminal half-life is 39.7 hours.