Summary Of Exposure |
A) USES: Lomitapide mesylate is indicated as an adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available, to reduce LDL-C, total cholesterol, apolipoprotein B, and non-HDL-C in patients with homozygous familial hypercholesterolemia.
B) PHARMACOLOGY: Lomitapide mesylate is a synthetic lipid-lowering agent that binds to and inhibits microsomal triglyceride transfer protein (MTP), which prevents the assembly of apo B-containing lipoproteins in hepatocytes and enterocytes. Therefore, the synthesis of chylomicrons and VLDL is inhibited, which leads to reduced levels of LDL-C.
C) EPIDEMIOLOGY: Overdose is rare.
D) WITH THERAPEUTIC USE
1) MOST COMMON (34% or greater): Diarrhea, nausea, vomiting, dyspepsia, and abdominal pain. COMMON (17% to 24%): Weight loss, abdominal discomfort, abdominal distension, constipation, flatulence, increased liver enzymes, chest pain, influenza, nasopharyngitis, and fatigue. OTHER EFFECTS: Palpitations, angina pectoris, gastroesophageal reflux disease, defecation urgency, rectal tenesmus, gastroenteritis, back pain, headache, dizziness, pharyngolaryngeal pain, nasal congestion, and fever.
2) DRUG INTERACTION: Concomitant administration of lomitapide with moderate or strong CYP3A4 inhibitors can increase lomitapide exposure 27 fold.
E) WITH POISONING/EXPOSURE
1) Overdose data are limited. Signs and symptoms of an acute overdose are anticipated to be similar to excessive pharmacologic adverse events.
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Vital Signs |
3.3.3) TEMPERATURE
A) WITH THERAPEUTIC USE 1) FEVER: In a single-arm, open-label clinical trial, in which 29 subjects with homozygous familial hypercholesterolemia (HoFH) received lomitapide mesylate therapy for up to 78 weeks, fever was reported in 10% of patients (3 of 29) (Prod Info JUXTAPID(TM) oral capsules, 2014).
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Cardiovascular |
3.5.2) CLINICAL EFFECTS
A) ANGINA 1) WITH THERAPEUTIC USE a) In a single-arm, open-label clinical trial, in which 29 subjects with homozygous familial hypercholesterolemia (HoFH) received lomitapide mesylate therapy for up to 78 weeks, angina pectoris was reported in 10% of patients (3 of 29). Chest pain was reported in 24% of patients (7 of 29) (Prod Info JUXTAPID(TM) oral capsules, 2014).
B) PALPITATIONS 1) WITH THERAPEUTIC USE a) In a single-arm, open-label clinical trial, in which 29 subjects with homozygous familial hypercholesterolemia (HoFH) received lomitapide mesylate therapy for up to 78 weeks, palpitations were reported in 10% of patients (3 of 29) (Prod Info JUXTAPID(TM) oral capsules, 2014).
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Respiratory |
3.6.2) CLINICAL EFFECTS
A) NASOPHARYNGITIS 1) WITH THERAPEUTIC USE a) In a single-arm, open-label clinical trial, in which 29 subjects with homozygous familial hypercholesterolemia (HoFH) received lomitapide mesylate therapy for up to 78 weeks, nasopharyngitis was reported in 17% of patients (5 of 29) (Prod Info JUXTAPID(TM) oral capsules, 2014).
B) PAIN 1) WITH THERAPEUTIC USE a) In a single-arm, open-label clinical trial, in which 29 subjects with homozygous familial hypercholesterolemia (HoFH) received lomitapide mesylate therapy for up to 78 weeks, pharyngolaryngeal pain was reported in 14% of patients (4 of 29) (Prod Info JUXTAPID(TM) oral capsules, 2014).
C) NASAL CONGESTION 1) WITH THERAPEUTIC USE a) In a single-arm, open-label clinical trial, in which 29 subjects with homozygous familial hypercholesterolemia (HoFH) received lomitapide mesylate therapy for up to 78 weeks, nasal congestion was reported in 10% of patients (3 of 29) (Prod Info JUXTAPID(TM) oral capsules, 2014).
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Neurologic |
3.7.2) CLINICAL EFFECTS
A) HEADACHE 1) WITH THERAPEUTIC USE a) In a single-arm, open-label clinical trial, in which 29 subjects with homozygous familial hypercholesterolemia (HoFH) received lomitapide mesylate therapy for up to 78 weeks, headache was reported in 10% of patients (3 of 29) (Prod Info JUXTAPID(TM) oral capsules, 2014).
B) DIZZINESS 1) WITH THERAPEUTIC USE a) In a single-arm, open-label clinical trial, in which 29 subjects with homozygous familial hypercholesterolemia (HoFH) received lomitapide mesylate therapy for up to 78 weeks, dizziness was reported in 10% of patients (3 of 29) (Prod Info JUXTAPID(TM) oral capsules, 2014).
C) FATIGUE 1) WITH THERAPEUTIC USE a) In a single-arm, open-label clinical trial, in which 29 subjects with homozygous familial hypercholesterolemia (HoFH) received lomitapide mesylate therapy for up to 78 weeks, fatigue was reported in 17% of patients (5 of 29) (Prod Info JUXTAPID(TM) oral capsules, 2014).
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Gastrointestinal |
3.8.2) CLINICAL EFFECTS
A) DIARRHEA 1) WITH THERAPEUTIC USE a) In a single-arm, open-label clinical trial, in which 29 subjects with homozygous familial hypercholesterolemia (HoFH) received lomitapide mesylate therapy for up to 78 weeks, diarrhea was reported in 79% of patients (23 of 29). Diarrhea of severe intensity was reported in 4 patients (14%) and diarrhea accounted in treatment discontinuation in 2 patients (7%) (Prod Info JUXTAPID(TM) oral capsules, 2014).
B) NAUSEA 1) WITH THERAPEUTIC USE a) In a single-arm, open-label clinical trial, in which 29 subjects with homozygous familial hypercholesterolemia (HoFH) received lomitapide mesylate therapy for up to 78 weeks, nausea was reported in 65% of patients (19 of 29). Nausea resulted in treatment discontinuation in 1 patient (3%) (Prod Info JUXTAPID(TM) oral capsules, 2014).
C) INDIGESTION 1) WITH THERAPEUTIC USE a) In a single-arm, open-label clinical trial, in which 29 subjects with homozygous familial hypercholesterolemia (HoFH) received lomitapide mesylate therapy for up to 78 weeks, dyspepsia was reported in 38% of patients (11 of 29) (Prod Info JUXTAPID(TM) oral capsules, 2014).
D) VOMITING 1) WITH THERAPEUTIC USE a) In a single-arm, open-label clinical trial, in which 29 subjects with homozygous familial hypercholesterolemia (HoFH) received lomitapide mesylate therapy for up to 78 weeks, vomiting was reported in 34% of patients (10 of 29). Vomiting of severe intensity was reported in 3 patients (10%) (Prod Info JUXTAPID(TM) oral capsules, 2014).
E) ABDOMINAL PAIN 1) WITH THERAPEUTIC USE a) In a single-arm, open-label clinical trial, in which 29 subjects with homozygous familial hypercholesterolemia (HoFH) received lomitapide mesylate therapy for up to 78 weeks, abdominal pain was reported in 34% of patients (10 of 29). Abdominal pain resulted in treatment discontinuation in 1 patient (3%). Abdominal pain, distension, or discomfort of severe intensity was reported in 2 patients (7%) (Prod Info JUXTAPID(TM) oral capsules, 2014).
F) CONSTIPATION 1) WITH THERAPEUTIC USE a) In a single-arm, open-label clinical trial, in which 29 subjects with homozygous familial hypercholesterolemia (HoFH) received lomitapide mesylate therapy for up to 78 weeks, constipation was reported in 21% of patients (6 of 29) (Prod Info JUXTAPID(TM) oral capsules, 2014).
G) GASTROESOPHAGEAL REFLUX DISEASE 1) WITH THERAPEUTIC USE a) In a single-arm, open-label clinical trial, in which 29 subjects with homozygous familial hypercholesterolemia (HoFH) received lomitapide mesylate therapy for up to 78 weeks, gastroesophageal reflux disease (GERD) was reported in 10% of patients (3 of 29) (Prod Info JUXTAPID(TM) oral capsules, 2014).
H) FLATULENCE/WIND 1) WITH THERAPEUTIC USE a) In a single-arm, open-label clinical trial, in which 29 subjects with homozygous familial hypercholesterolemia (HoFH) received lomitapide mesylate therapy for up to 78 weeks, flatulence was reported in 21% of patients (6 of 29) (Prod Info JUXTAPID(TM) oral capsules, 2014).
I) URGENT DESIRE FOR STOOL 1) WITH THERAPEUTIC USE a) In a single-arm, open-label clinical trial, in which 29 subjects with homozygous familial hypercholesterolemia (HoFH) received lomitapide mesylate therapy for up to 78 weeks, defecation urgency was reported in 10% of patients (3 of 29) (Prod Info JUXTAPID(TM) oral capsules, 2014).
J) RECTAL TENESMUS 1) WITH THERAPEUTIC USE a) In a single-arm, open-label clinical trial, in which 29 subjects with homozygous familial hypercholesterolemia (HoFH) received lomitapide mesylate therapy for up to 78 weeks, rectal tenesmus was reported in 10% of patients (3 of 29) (Prod Info JUXTAPID(TM) oral capsules, 2014).
K) GASTROENTERITIS 1) WITH THERAPEUTIC USE a) In a single-arm, open-label clinical trial, in which 29 subjects with homozygous familial hypercholesterolemia (HoFH) received lomitapide mesylate therapy for up to 78 weeks, gastroenteritis was reported in 14% of patients (4 of 29) and led to treatment discontinuation in 1 patient (Prod Info JUXTAPID(TM) oral capsules, 2014).
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Hepatic |
3.9.2) CLINICAL EFFECTS
A) INCREASED LIVER ENZYMES 1) WITH THERAPEUTIC USE a) In a single-arm, open-label clinical trial, in which 29 subjects with homozygous familial hypercholesterolemia (HoFH) received lomitapide mesylate therapy for up to 78 weeks, 34% of patients (10 of 29) reported at least one increased AST or ALT level of at least 3 times the ULN, and 14% (4 of 29) of patients had 1 or more AST or ALT elevations of at least 5 times the ULN. Clinically relevant increases in bilirubin or alkaline phosphatase were not reported, and no patients discontinued lomitapide therapy due to elevated hepatic transaminases (Prod Info JUXTAPID(TM) oral capsules, 2014).
B) STEATOSIS OF LIVER 1) WITH THERAPEUTIC USE a) In a single-arm, open-label clinical trial, in which 29 subjects with homozygous familial hypercholesterolemia (HoFH) received lomitapide mesylate therapy for up to 78 weeks, median absolute increase in hepatic fat was 6% at 26 weeks and at 78 weeks of treatment from 1% at baseline, with a mean absolute increase of 8% (range, 0% to 30%) at week 26 and 7% (range, 0% to 18%) after week 78. Of the 23 patients with data that could be evaluated, 78% (18 of 23) showed an increase of hepatic fat greater than 5%, and 13% (3 of 23) showed an increase of greater than 20%. Hepatic steatosis is a risk factor for progressive hepatic disease, such as steatohepatitis and cirrhosis, and although hepatic fat accumulation associated with lomitapide therapy was reversible in clinical studies, long-term sequelae are unknown (Prod Info JUXTAPID(TM) oral capsules, 2014).
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Musculoskeletal |
3.15.2) CLINICAL EFFECTS
A) BACKACHE 1) WITH THERAPEUTIC USE a) In a single-arm, open-label clinical trial, in which 29 subjects with homozygous familial hypercholesterolemia (HoFH) received lomitapide mesylate therapy for up to 78 weeks, back pain was reported in 14% of patients (4 of 29) (Prod Info JUXTAPID(TM) oral capsules, 2014).
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Reproductive |
3.20.1) SUMMARY
A) Lomitapide mesylate is classified as pregnancy category X. It is contraindicated during pregnancy due to risk of fetal harm. In animal studies, lomitapide was teratogenic.
3.20.2) TERATOGENICITY
A) ANIMAL STUDIES 1) Teratogenicity was demonstrated in pregnant rats and ferrets when lomitapide was administered during organogenesis at exposures estimated to be less than human therapeutic exposure at 60 mg (AUC: 67 nanograms x hr/mL) (Prod Info JUXTAPID(TM) oral capsules, 2014). a) RATS: In pregnant rats given lomitapide (oral gavage doses 0.04, 0.4, or 4 mg/kg/day) from gestation day 6 through organogenesis, fetal malformations were observed at systemic exposure of 2 or more times human exposure at the maximum recommended human dose (MRHD) of 60 mg based on plasma AUC comparisons, and included umbilical hernia, gastroschisis, imperforate anus, alterations in heart size and shape, limb malrotations, skeletal malformations of the tail, and delayed ossification of cranial, vertebral, and pelvic bones. In another study in pregnant female rats given lomitapide (oral gavage doses 0.1, 0.3, or 1 mg/kg/day) from gestation day 7 through termination of nursing on day 20, malformations were observed at systemic exposures equivalent to the human exposure at MRHD of 60 mg based on AUC and pup mortality was increased at 4-times the MRHD (Prod Info JUXTAPID(TM) oral capsules, 2014).
b) FERRETS: In pregnant ferrets given lomitapide (oral gavage doses 1.6, 4, 10, 10, or 25 mg/kg/day) from gestation day 12 through organogenesis, exposures ranging from less than the human exposure at MRHD to 5-times the human exposure at the MRHD resulted in both maternal toxicity and fetal malformations that 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 (Prod Info JUXTAPID(TM) oral capsules, 2014).
c) RABBITS: Embryo-fetal lethality was observed in rabbits who were given lomitapide at oral gavage doses of 20 mg/kg/day or greater (at least 6 times the maximum recommended human dose (MRHD) based on body surface area) (Prod Info JUXTAPID(TM) oral capsules, 2014).
3.20.3) EFFECTS IN PREGNANCY
A) PREGNANCY CATEGORY 1) Lomitapide mesylate is classified as pregnancy category X (Prod Info JUXTAPID(TM) oral capsules, 2014).
2) Lomitapide mesylate is contraindicated during pregnancy due to risk of fetal harm. Women of reproductive potential should obtain a negative pregnancy test prior to therapy initiation and use effective contraception during therapy. A pregnancy registry has been established to monitor the outcomes of pregnancies following lomitapide exposure. Healthcare professionals are encouraged to enroll patients who become pregnant while receiving lomitapide by calling 1-877-902-4099. Additional information is available at www.JUXTAPID.com. If pregnancy occurs during lomitapide therapy, the drug should be discontinued immediately and the healthcare provider notified (Prod Info JUXTAPID(TM) oral capsules, 2014).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) LACK OF INFORMATION 1) BREAST MILK a) It is not known whether lomitapide is excreted into human breast milk. Due to the risk of tumorigenicity observed in a 2-year mouse study, it is recommended to discontinue nursing or discontinue lomitapide in the nursing mother. Consider the importance of therapy to the mother (Prod Info JUXTAPID(TM) oral capsules, 2014).
3.20.5) FERTILITY
A) ANIMAL STUDIES 1) In animal studies, lomitapide doses up to 5 mg/kg/day (exposures about 4-times [females] and 5-times [males] higher than in humans at 60 mg based on AUC) did not produce any effects on fertility (Prod Info JUXTAPID(TM) oral capsules, 2014).
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Carcinogenicity |
3.21.4) ANIMAL STUDIES
A) LACK OF EFFECT 1) MICE: In animal studies, there were statistically significant increases in the incidences of liver adenomas and carcinomas in male mice administered lomitapide doses 1.5 mg/kg/day or greater (2-times or greater than the maximum recommended human dose (MRHD) at 60 mg based on AUC) and in female mice administered lomitapide doses 7.5 mg/kg/day or greater (10-times or greater than the human exposure at 60 mg based on AUC) (Prod Info JUXTAPID(TM) oral capsules, 2014).
2) RATS: In animal studies, there were no statistically significant drug-related increases in tumor incidences at lomitapide exposures up to 6-times (males; doses of 0.25, 1.7, or 7.5 mg/kg/day) and 8-times (females; doses of 0.03, 0.35, or 2 mg/kg/day) higher than human exposure at the MRHD based on AUC, when rats were administered lomitapide by oral gavage for up to 99 weeks; however, the design of the study was suboptimal (Prod Info JUXTAPID(TM) oral capsules, 2014).
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Genotoxicity |
A) In animal studies, lomitapide did not have genotoxic potential in various 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 (Prod Info JUXTAPID(TM) oral capsules, 2014).
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