Name: Juxtapid Capsules
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- Juxtapid Capsules 60 mg
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Indications and Usage for Juxtapid Capsules
Homozygous Familial Hypercholesterolemia
JUXTAPID 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 (LDL-C), 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 JUXTAPID have not been established in patients with hypercholesterolemia who do not have HoFH, including those with heterozygous familial hypercholesterolemia (HeFH).
- The effect of JUXTAPID on cardiovascular morbidity and mortality has not been determined.
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)]
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 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 30.7 years (range, 18 to 55 years), 16 (55%) patients were men, 25 (86%) patients were Caucasian, 2 (7%) were Asian, 1 (3%) was African American, and 1 (3%) was multi-racial [see Clinical Studies (14)].
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.
|ADVERSE REACTION||N (%)|
|Abdominal pain||10 (34)|
|Abdominal discomfort||6 (21)|
|Abdominal distension||6 (21)|
|Gastroesophageal reflux disease||3 (10)|
|Defecation urgency||3 (10)|
|Rectal tenesmus||3 (10)|
|Decreased weight||7 (24)|
|Increased ALT||5 (17)|
|Chest pain||7 (24)|
|Back pain||4 (14)|
|Nervous System Disorders|
|Pharyngolaryngeal pain||4 (14)|
|Nasal congestion||3 (10)|
|Angina pectoris||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%).
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 JUXTAPID.
|Upper limits of normal (ULN) ranged from 33-41 international units/L for ALT and 36-43 international units/L for AST.|
|≥3 to <5 x ULN||6 (21%)|
|≥5 to <10 x ULN||3 (10%)|
|≥10 to <20 x ULN||1 (3%)|
|≥20 x ULN||0|
|≥3 to <5 x ULN||5 (17%)|
|≥5 to <10 x ULN||1 (3%)|
|≥10 to <20 x ULN||0|
|≥20 x ULN||0|
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 JUXTAPID and the strong CYP3A4 inhibitor clarithromycin [see Drug Interactions (7.1)].
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 JUXTAPID show that hepatic fat accumulation is reversible, but whether histological sequelae remain is unknown.
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 disorders: Myalgia
Skin reactions: Alopecia
Juxtapid Capsules Description
Juxtapid Capsules contain lomitapide mesylate, a synthetic lipid-lowering agent for oral administration.
The chemical name of lomitapide mesylate is N-(2,2,2-trifluoroethyl)-9-[4-[4-[[[4'-(trifluoromethyl)[1,1'-biphenyl]-2-yl]carbonyl]amino]-1-piperidinyl]butyl]-9H-fluorene-9-carboxamide, methanesulfonate salt. Its structural formula is:
The empirical formula for lomitapide mesylate is C39H37F6N3O2 ∙ CH4O3S and its molecular weight is 789.8.
Lomitapide mesylate is a white to off-white powder that is slightly soluble in aqueous solutions of pH 2 to 5. Lomitapide mesylate is freely soluble in acetone, ethanol, and methanol; soluble in 2-butanol, methylene chloride, and acetonitrile; sparingly soluble in 1-octanol and 2-propanol; slightly soluble in ethyl acetate; and insoluble in heptane.
Each JUXTAPID capsule contains lomitapide mesylate equivalent to 5, 10, 20, 30, 40 or 60 mg lomitapide free base and the following inactive ingredients: pregelatinized starch, sodium starch glycolate, microcrystalline cellulose, lactose monohydrate, silicon dioxide and magnesium stearate. The capsule shells of all strengths contain gelatin and titanium dioxide; the 5 mg, 10 mg and 30 mg capsules also contain red iron oxide; and the 30 mg, 40 mg and 60 mg capsules also contain yellow iron oxide. The imprinting ink contains shellac, black iron oxide, and propylene glycol.
Juxtapid Capsules - Clinical Pharmacology
Mechanism of Action
JUXTAPID directly binds and inhibits microsomal triglyceride transfer protein (MTP), which resides in the lumen of the endoplasmic reticulum, thereby preventing the assembly of apo B-containing lipoproteins in enterocytes and hepatocytes. This inhibits the synthesis of chylomicrons and VLDL. The inhibition of the synthesis of VLDL leads to reduced levels of plasma LDL-C.
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.
Upon oral administration of a single 60-mg dose of JUXTAPID, 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 10-100 mg.
The mean lomitapide volume of distribution at steady state is 985-1292 liters. Lomitapide is 99.8% plasma-protein bound.
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.
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.
A single-dose, open-label study was conducted to evaluate the pharmacokinetics of 60 mg lomitapide in healthy volunteers with normal hepatic function compared with patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment. In patients with moderate hepatic impairment, lomitapide AUC and Cmax were 164% and 361% higher, respectively, compared with healthy volunteers. In patients with mild hepatic impairment, lomitapide AUC and Cmax were 47% and 4% higher, respectively, compared with healthy volunteers. Lomitapide has not been studied in patients with severe hepatic impairment (Child-Pugh score 10-15) [see Dosage and Administration (2.6), Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.8)].
A single-dose, open-label study was conducted to evaluate the pharmacokinetics of 60 mg lomitapide in patients with end-stage renal disease receiving hemodialysis compared with healthy volunteers with normal renal function. Healthy volunteers had estimated creatinine clearance >80 mL/min by the Cockcroft-Gault equation. Compared with healthy volunteers, lomitapide AUC0-inf and Cmax were 40% and 50% higher, respectively, in patients with end-stage renal disease receiving hemodialysis. Effects of mild, moderate, and severe renal impairment as well as end-stage renal disease not yet on dialysis on lomitapide exposure have not been studied [see Dosage and Administration (2.5) and Use in Specific Populations (8.7)].
[see Dosage and Administration (2.3), Contraindications (4), Warnings and Precautions (5.6), (5.7), (5.8), and Drug Interactions (7)].
In vitro Assessment of Drug Interactions
Lomitapide does not induce CYPs 1A2, 3A4, or 2B6. Lomitapide inhibits CYP3A4. Lomitapide does not inhibit CYPs 1A2, 2B6, 2C9, 2C19, 2D6, or 2E1. M1 and M3 do not induce CYPs 1A2, 3A4, or 2B6. M1 and M3 do not inhibit CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4. Lomitapide is not a P-gp substrate. Lomitapide inhibits P-gp but does not inhibit breast cancer resistance protein (BCRP).
Effects of other Drugs on Lomitapide
Table 6 summarizes the effect of coadministered drugs on lomitapide AUC and Cmax.
|BID = twice daily; QD = once daily |
↑ = increase
|DOSING OF |
|DOSING OF |
|RATIO OF LOMITAPIDE EXPOSURE |
NO EFFECT = 1
|Contraindicated with lomitapide [see Contraindications (4) and Warnings and Precautions (5.6)]|
|Ketoconazole||200 mg BID for |
|60 mg single dose||↑ 27||↑ 15|
|Adjustment necessary when coadministered with lomitapide [see Dosage and Administration (2.3) and Warnings and Precautions (5.6)]|
|Atorvastatin||80 mg QD||20 mg single dose||↑2||↑2.1|
|Ethinyl Estradiol |
(EE) / norgestimate
|0.035 mg EE/ |
|20 mg single dose||↑1.3||↑1.4|
Effect of Lomitapide on other Drugs
Table 7 summarizes the effects of lomitapide on the AUC and Cmax of coadministered drugs.
|a 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. |
b Patients taking warfarin should undergo regular monitoring of the INR, especially after any changes in lomitapide dosage. QD = once daily; INR = international normalized ratio; ↑ = increase; ↓ = decrease
|COADMINISTERED DRUG||DOSING OF |
|DOSING OF |
|CHANGE OF COADMINISTERED DRUG |
EXPOSURE WITH / WITHOUT
|Dosage adjustment necessary when coadministered with lomitapide|
|Simvastatina||40 mg single dose |
20 mg single dose
|60 mg QD × 7 days |
10 mg QD x 7 days
|↑ 99% |
| ↑ 102% |
|Warfarinb||10 mg single dose||60 mg QD x 12 days||R(+) warfarin |
|↑ 28% |
|↑ 14% |
|No dosing adjustments required for the following:|
|Atorvastatin||20 mg single dose |
20 mg single dose
|60 mg QD × 7 days |
10 mg QD × 7 days
|Atorvastatin acid |
|↑ 52% |
|↑ 63% |
|Rosuvastatin||20 mg single dose |
20 mg single dose
|60 mg QD × 7 days |
10 mg QD × 7 days
|↑ 32% |
|↑ 4% |
|Fenofibrate, micronized||145 mg single dose||10 mg QD × 7 days||Fenofibric acid||↓ 10%||↓ 29%|
|Ezetimibe||10 mg single dose||10 mg QD × 7 days||Total |
|↑ 6%||↑ 3%|
|Extended release niacin||1000 mg single dose||10 mg QD × 7 days||Nicotinic acid |
|↑ 10% |
|↑ 11% |
|Ethinyl estradiol||0.035 mg QD x 28 days||50 mg QD x 8 days||Ethinyl estradiol||↓ 8%||↓ 8%|
|Norgestimate||0.25 mg QD x 28 days||50 mg QD x 8 days||17-Deacetyl norgestimate||↑ 6%||↑ 2%|
The safety and effectiveness of JUXTAPID as an adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available, were evaluated in a multinational, single-arm, open-label, 78-week trial involving 29 adults with HoFH. A diagnosis of HoFH was defined by the presence of at least one of the following clinical criteria: (1) documented functional mutation(s) in both LDL receptor alleles or alleles known to affect LDL receptor functionality, or (2) skin fibroblast LDL receptor activity <20% normal, or (3) untreated TC >500 mg/dL and TG <300 mg/dL and both parents with documented untreated TC >250 mg/dL.
Among the 29 patients enrolled, the mean age was 30.7 years (range, 18 to 55 years), 16 (55%) were men, and the majority (86%) were Caucasian. The mean body mass index (BMI) was 25.8 kg/m2, with four patients meeting BMI criteria for obesity; one patient had type 2 diabetes. Concomitant lipid-lowering treatments at baseline included one or more of the following: statins (93%), ezetimibe (76%), nicotinic acid (10%), bile acid sequestrant (3%), and fibrate (3%); 18 (62%) were receiving apheresis.
After a six-week run-in period to stabilize lipid-lowering treatments, including the establishment of an LDL apheresis schedule if applicable, JUXTAPID was initiated at 5 mg daily and titrated to daily doses of 10 mg, 20 mg, 40 mg, and 60 mg at weeks 2, 6, 10, and 14, respectively, based on tolerability and acceptable levels of transaminases. Patients were instructed to maintain a low-fat diet (<20% calories from fat) and to take dietary supplements that provided approximately 400 international units vitamin E, 210 mg alpha-linolenic acid (ALA), 200 mg linoleic acid, 110 mg eicosapentaenoic acid (EPA), and 80 mg docosahexaenoic acid (DHA) per day. After efficacy was assessed at Week 26, patients remained on JUXTAPID for an additional 52 weeks to assess long-term safety. During this safety phase, the dose of JUXTAPID was not increased above each patient's maximum tolerated dose established during the efficacy phase, but changes to concomitant lipid-lowering treatments were allowed.
Twenty-three (79%) patients completed the efficacy endpoint at Week 26, all of whom went on to complete 78 weeks of treatment. Adverse events contributed to premature discontinuation for five patients [see Adverse Reactions (6.1)]. The maximum tolerated doses during the efficacy period were 5 mg (10%), 10 mg (7%), 20 mg (21%), 40 mg (24%), and 60 mg (34%).
The primary efficacy endpoint was percent change in LDL-C from baseline to Week 26. At Week 26, the mean and median percent changes in LDL-C from baseline were -40% (paired t-test p<0.001) and -50%, respectively, based on the intent-to-treat population with last observation carried forward (LOCF) for patients who discontinued prematurely. The mean percent change in LDL-C from baseline through Week 26 is shown in Figure 1 for the 23 patients who completed the efficacy period.
Figure 1: Mean Percent Change in LDL-C from Baseline (Week 26 Completers)
Error bars represent 95% confidence intervals of the mean.
Changes in lipids and lipoproteins through the efficacy endpoint at Week 26 are presented in Table 8.
|a Median values with interquartile range and median % change presented for TG. |
* Statistically significant compared with baseline based on the pre-specified gatekeeping method for controlling Type I error among the primary and key secondary endpoints.
|PARAMETER||BASELINE||WEEK 26/LOCF (N=29)|
|Mean (SD)||Mean (SD)||Mean % Change|
|LDL-C, direct (mg/dL)||336 (114)||190 (104)||-40 *|
|TC (mg/dL)||430 (135)||258 (118)||-36 *|
|apo B (mg/dL)||259 (80)||148 (74)||-39 *|
|Non-HDL-C (mg/dL)||386 (132)||217 (113)||-40|
|VLDL-C (mg/dL)||21 (10)||13 (9)||-29|
|TG (mg/dL)a||92 [72, 128]||57 [36, 78]||-45 *|
|HDL-C (mg/dL)||44 (11)||41 (13)||-7|
After Week 26, during the safety phase of the study, adjustments to concomitant lipid-lowering treatments were allowed. For the study population overall, average reductions in LDL-C, TC, apo B, and non-HDL-C were sustained during chronic therapy.
For Healthcare Professionals
Applies to lomitapide: oral capsule
Very common (10% or more): Chest pain (24%), angina pectoris (10%), palpitations (10%)[Ref]
Very common (10% or more): Diarrhea (79%), nausea (65%), dyspepsia (38%), vomiting (34%), abdominal pain (34%), abdominal discomfort (21%), abdominal distention (21%), constipation (21%), flatulence (21%), gastroesophageal reflux disease (10%), defecation urgency ((10%), rectal tenesmus (10%), gastroenteritis (14%)[Ref]
Very common (10% or more): Increased ALT (17%), at least one elevation in ALT and/or AST greater than or equal to 3 times ULN (29%), hepatic steatosis: of 23 patients in a study for 78 weeks, 18 (78%) exhibited an increase in hepatic fat greater than 5% and 3 (13%) exhibited an increase greater than 20%[Ref]
Very common (10% or more): Influenza (21%)[Ref]
Very common (10% or more): Weight loss (24%)[Ref]
Very common (10% or more): Fatigue (17%), fever (10%), headache (10%), dizziness (10%)[Ref]
Very common (10% or more): Nasopharyngitis (17%), pharyngolaryngeal pain (14%), nasal congestion (10%)[Ref]
Common (1% to 10%): Ecchymosis, papule, rash erythematous, xanthoma[Ref]
Some side effects of lomitapide may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.