Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Chiesi Farmaceutici S.p.A., Via Palermo 26/A, 43122 Parma, Italy
Lomitapide can cause elevations in the liver enzymes alanine aminotransferase [ALT] and aspartate aminotransferase [AST] and hepatic steatosis (see section 5.1). There have been no concomitant or subsequent clinically meaningful elevations in serum bilirubin, International Normalised Ratio (INR), or alkaline phosphatase. The extent to which lomitapide-associated hepatic steatosis promotes the elevations in aminotransferase is unknown. The liver enzyme changes can occur at any time during therapy, but occur most often during dose escalation.
Although cases of hepatic dysfunction (elevated aminotransferase with increase in bilirubin or INR) or hepatic failure have not been reported, there is concern that lomitapide could induce steatohepatitis, which can progress to cirrhosis over several years. The clinical studies supporting the safety and efficacy of lomitapide in HoFH would have been unlikely to detect this adverse outcome given their size and duration.
Measure ALT, AST, alkaline phosphatase, total bilirubin, gamma-glutamyl transferase (gamma-GT) and serum albumin before initiation of treatment with Lojuxta. The medicinal product is contraindicated in patients with moderate or severe hepatic impairment and those with unexplained persistent abnormal liver function tests. If the baseline liver-related tests are abnormal, consider initiating the medicinal product after appropriate investigation by a hepatologist and the baseline abnormalities are explained or resolved.
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, do these tests at least every 3 months and before any increase in dose. Decrease the dose of Lojuxta if elevations of aminotransferase are observed and discontinue treatment for persistent or clinically significant elevations (see Table 1).
Table 1 summarises recommendations for dose adjustment and monitoring for patients who develop elevated aminotransferase during therapy with Lojuxta.
Table 1. Dose adjustment and monitoring for patients with elevated aminotransferases:
| ALT or AST | Treatment and monitoring recommendations* |
|---|---|
| ≥3x and <5x Upper Limit of Normal (ULN) | • Confirm elevation with a repeat measurement within one week. • If confirmed, reduce the dose and obtain additional liver-related tests if not already measured (such as alkaline phosphatase, total bilirubin, and INR). • Repeat tests weekly and withhold dosing if there are signs of abnormal liver function (increase in bilirubin or INR), if aminotransferase levels rise above 5 x ULN, or if aminotransferase levels do not fall below 3x ULN within approximately 4 weeks. Refer patients with persistent elevations in aminotransferase >3x ULN to a hepatologist for further investigation. • If resuming Lojuxta after aminotransferase levels resolve to <3x ULN, consider reducing the dose and monitor liver-related tests more frequently. |
| ≥5x ULN | • Withhold dosing and obtain additional liver-related tests if not already measured (such as alkaline phosphatase, total bilirubin, and INR). If aminotransferase levels do not fall below 3x ULN within |
* Recommendations based on an ULN of approximately 30-40 international units/L.
If aminotransferase 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 refer the patient to a hepatologist for further investigation.
Reintroduction of treatment may be considered if the benefits are considered to outweigh the risks associated with potential liver disease.
Consistent with the mechanism of action of lomitapide, most treated patients exhibited increases in hepatic fat content. In an open-label Phase 3 study, 18 of 23 patients with HoFH developed hepatic steatosis (hepatic fat >5.56%) as measured by nuclear magnetic resonance spectroscopy (MRS) (see section 5.1). The median absolute increase in hepatic fat was 6% after both 26 weeks and 78 weeks of treatment, from 1% at baseline, measured by MRS. Hepatic steatosis is a risk factor for progressive liver disease including steatohepatitis and cirrhosis. The long term consequences of hepatic steatosis associated with lomitapide treatment are unknown. 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.
Regular screening for steatohepatitis/fibrosis should be performed at baseline and on an annual basis using the following imaging and biomarker evaluations:
The performance of these tests and their interpretation should involve collaboration between the treating physician and the hepatologist. Patients with results suggesting the presence of steatohepatitis or fibrosis should be considered for liver biopsy.
If a patient has biopsy-proven steatohepatitis or fibrosis, the benefit-risk should be reassessed and treatment stopped if necessary.
Post-marketing reports of dehydration and hospitalisation in patients treated with lomitapide have been reported. Patients treated with lomitapide should be advised of the potential risk of dehydration in relation to gastrointestinal adverse reactions and take precautions to avoid fluid depletion.
Lomitapide appears to be a sensitive substrate for CYP3A4 metabolism. 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 (see section 4.3). In the lomitapide clinical studies, one patient with HoFH developed markedly elevated aminotransferase (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.
Weak CYP3A4 inhibitors are expected to increase the exposure of lomitapide when taken simultaneously. When administered with atorvastatin, the dose of Lojuxta should either be taken 12 hours apart or be decreased by half (see section 4.2). The dose of Lojuxta should be administered 12 hours apart from any other weak CYP3A4 inhibitor.
Medicinal products that induce CYP3A4 would be expected to increase the rate and extent of metabolism of lomitapide. CYP3A4 inducers exert their effect in a time-dependent manner, and may take at least 2 weeks to reach maximal effect after introduction. Conversely, on discontinuation, CYP3A4 induction may take at least 2 weeks to decline.
Co-administration of a CYP3A4 inducer is expected to reduce the effect of lomitapide. Any impact on efficacy is likely to be variable. When co-administering CYP3A4 inducers (i.e. aminoglutethimide, nafcillin, non-nucleoside reverse transcriptase inhibitors, phenobarbital, rifampicin, carbamazepine, pioglitazone, glucocorticoids, modafinil and phenytoin) with Lojuxta, the possibility of a drug-drug interaction affecting efficacy should be considered. The use of St. John’s Wort should be avoided with Lojuxta.
It is recommended to increase the frequency of LDL-C assessment during such concomitant use and consider increasing the dose of Lojuxta to ensure maintenance of the desired level of efficacy if the CYP3A4 inducer is intended for chronic use. On withdrawal of a CYP3A4 inducer, the possibility of increased exposure should be considered and a reduction in the dose of Lojuxta may be necessary.
Lomitapide increases plasma concentrations of statins. Patients receiving Lojuxta as adjunctive therapy to a statin should be monitored for adverse events that are associated with the use of high doses of statins. Statins occasionally cause myopathy. In rare cases, myopathy may take the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and can lead to fatality. All patients receiving lomitapide in addition to a statin should be advised of the potential increased risk of myopathy and told to report promptly any unexplained muscle pain, tenderness, or weakness. Doses of simvastatin >40 mg should not be used with Lojuxta (see section 4.3).
Grapefruit juice must be omitted from the diet while patients are treated with Lojuxta.
Lomitapide increases the plasma concentrations of warfarin. Increases in the dose of Lojuxta may lead to supratherapeutic anticoagulation, and decreases in the dose may lead to subtherapeutic anticoagulation. Difficulty controlling INR contributed to early discontinuation from the Phase 3 study for one of five patients taking concomitant warfarin. Patients taking warfarin should undergo regular monitoring of the INR, especially after any changes in the dose of Lojuxta. The dose of warfarin should be adjusted as clinically indicated.
Alcohol may increase levels of hepatic fat and induce or exacerbate liver injury. In the Phase 3 study, 3 of 4 patients with ALT elevations > 5x ULN reported alcohol consumption beyond the limits recommended in the protocol. The use of alcohol during lomitapide treatment is not recommended.
Caution should be exercised when Lojuxta is used with other medicinal products 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 lomitapide with other hepatotoxic medicine is unknown. More frequent monitoring of liver-related tests may be warranted.
Given its mechanism of action in the small intestine, lomitapide may reduce the absorption of fat-soluble nutrients. In the Phase 3 study, patients were provided daily dietary supplements of vitamin E, linoleic acid, ALA, EPA and DHA. In this study, 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 lomitapide treatment of up to 78 weeks. Patients treated with Lojuxta should take daily supplements that contain 400 international units vitamin E and approximately 200 mg linoleic acid, 210 mg ALA, 110 mg EPA, and 80 mg DHA.
Before initiating treatment in women of child-bearing potential, appropriate advice on effective methods of contraception should be provided, and effective contraception initiated. Patients taking oestrogen-based oral contraceptives should be advised about possible loss of effectiveness due to diarrhoea and/or vomiting (see section 4.5). Oestrogen-containing oral contraceptives are weak CYP3A4 inhibitors (see section 4.2).
Patients should be advised to immediately contact their physician and stop taking Lojuxta if they become pregnant (see section 4.6).
Lojuxta contains lactose. Patients with rare hereditary problems of galactose intolerance, total-lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially ‘sodium-free’.
Table 2. Interactions between Lojuxta and other medicinal products and other forms of interaction:
| Medicinal products | Effects on lomitapide levels | Recommendation concerning co-administration with Lojuxta |
|---|---|---|
| Inhibitors of CYP3A4 | Strong and moderate inhibitors When lomitapide 60 mg was co-administered with ketoconazole 200 mg twice daily, a strong inhibitor of CYP3A4, lomitapide AUC increased approximately 27-fold and Cmax increased approximately 15-fold. Interactions between moderate CYP3A4 inhibitors and lomitapide have not been studied. Moderate CYP3A4 inhibitors are predicted to have a substantial impact on lomitapide’s pharmacokinetics. Concomitant use of moderate CYP3A4 inhibitors are expected to increase lomitapide exposure by 4-10 fold based on the results of the study with the strong CYP3A4 inhibitor ketoconazole and on historical data for the model CYP3A4 probe midazolam. | Strong and moderate inhibitors Use of strong or moderate inhibitors of CYP3A4 is contraindicated with Lojuxta. If treatment with antifungal azoles (e.g., itraconazole, ketoconazole, fluconazole, voriconazole, posaconazole); the antiarrhythmic dronedarone; macrolide antibiotics (e.g., erythromycin, clarithromycin); ketolide antibiotics (e.g., telithromycin); HIV protease inhibitors; the calcium channel blockers diltiazem and verapamil is unavoidable, therapy with Lojuxta should be suspended during the course of treatment (see sections 4.3 and 4.4). Grapefruit juice is a moderate inhibitor of CYP3A4 and is expected to substantially increase exposure to lomitapide. Patients taking Lojuxta should avoid consumption of grapefruit juice. |
| Weak inhibitors Weak CYP3A4 inhibitors are expected to increase the exposure of lomitapide when taken simultaneously. When lomitapide 20 mg was co-administered simultaneously with atorvastatin, a weak CYP3A4 inhibitor, lomitapide AUC and Cmax increased approximately 2-fold. When the dose of lomitapide was taken 12 hours apart from atorvastatin, no clinically meaningful increase in lomitapide exposure was observed. When lomitapide 20 mg was co-administered simultaneously or 12 hours apart with ethinyl estradiol/norgestimate, a weak CYP3A4 inhibitor, no clinically meaningful increase in lomitapide exposure was observed. | Weak inhibitors When administered with atorvastatin, the dose of Lojuxta should either be taken 12 hours apart or be decreased by half (see section 4.2). The dose of Lojuxta should be taken 12 hours apart from any other concomitant weak CYP3A4 inhibitors. Examples of weak CYP3A4 inhibitors include: alprazolam, amiodarone, amlodipine, atorvastatin, azithromycin, bicalutamide, cilostazol, cimetidine, ciclosporin, clotrimazole, fluoxetine, fluvoxamine, fosaprepitant, ginkgo, goldenseal, isoniazid, ivacaftor, lacidipine, lapatinib, linagliptin, nilotinib, oestrogen-containing oral contraceptives, pazopanib, peppermint oil, propiverine, ranitidine, ranolazine, roxithromycin, Seville oranges, tacrolimus, ticagrelor and tolvaptan. This list is not intended to be comprehensive and prescribers should check the prescribing information of medicinal products to be co-administered with Lojuxta for potential CYP3A4 mediated interactions. The effect of administration of more than one weak CYP3A4 inhibitor has not been tested, but the effect on the exposure of lomitapide is expected to be greater than for co-administration of the individual inhibitors with lomitapide. Exercise additional caution if administering more than 1 weak CYP3A4 inhibitor with Lojuxta. | |
| Inducers of CYP3A4 | Medicines that induce CYP3A4 would be expected to increase the rate and extent of metabolism of lomitapide. Consequently, this would reduce the effect of lomitapide. Any impact on efficacy is likely to be variable. | When co-administering CYP3A4 inducers (i.e., aminoglutethimide, nafcillin, non-nucleoside reverse transcriptase inhibitors, phenobarbital, rifampicin, carbamazepine, pioglitazone, St John’s Wort, glucocorticoids, modafinil and phenytoin) with Lojuxta, the possibility of a drug-drug interaction affecting efficacy should be considered. It is recommended to increase the frequency of LDL-C assessment during such concomitant use and consider increasing the dose of Lojuxta to ensure maintenance of the desired level of efficacy if the CYP3A4 inducer is intended for chronic use. |
| Bile acid sequestrants | Lomitapide has not been tested for interaction with bile acid sequestrants (resins such as colesevelam and cholestyramine). | Because bile acid sequestrants can interfere with the absorption of oral medicines, bile acid sequestrants should be taken at least 4 hours before or at least 4 hours after Lojuxta. |
Lomitapide increases plasma concentrations of statins. When lomitapide 60 mg was administered to steady state prior to simvastatin 40 mg, simvastatin acid AUC and Cmax increased 68% and 57%, respectively. When lomitapide 60 mg was administered to steady state prior to atorvastatin 20 mg, atorvastatin acid AUC and Cmax increased 52% and 63%, respectively. When lomitapide 60 mg was administered to steady state prior to rosuvastatin 20 mg, rosuvastatin Tmax increased from 1 to 4 hours, AUC was increased 32%, and its Cmax was unchanged. The risk of myopathy with simvastatin is dose related. Use of Lojuxta is contraindicated in patients treated with high doses of simvastatin (>40 mg) (see sections 4.3 and 4.4).
When lomitapide 60 mg was administered to steady state and 6 days following warfarin 10 mg, INR increased 1.26-fold. AUCs for R ( + ) -warfarin and S ( - ) -warfarin increased 25% and 30%, respectively. Cmax for R ( + ) -warfarin and S ( - ) -warfarin increased 14% and 15%, respectively. In patients taking coumarins (such as warfarin) and Lojuxta concomitantly, INR should be determined before starting Lojuxta and monitored regularly with dosage of coumarins adjusted as clinically indicated (see section 4.4).
When lomitapide was administered to steady state prior to micronised fenofibrate 145 mg, extended release niacin 1 000 mg, or ezetimibe 10 mg, no clinically significant effects on the exposure of any of these medicinal products were observed. No dose adjustments are required when co-administered with Lojuxta.
When lomitapide 50 mg was administered to steady state along with an oestrogen-based oral contraceptive, no clinically meaningful or statistically significant impact on the pharmacokinetics of the components of the oral contraceptive (ethinyl estradiol and 17-deacetyl norgestimate, the metabolite of norgestimate) was observed. Lomitapide is not expected to directly influence the efficacy of oestrogen based oral contraceptives; however diarrhoea and/or vomiting may reduce hormone absorption. In cases of protracted or severe diarrhoea and/or vomiting lasting more than 2 days, additional contraceptive measures should be used for 7 days after resolution of symptoms.
Lomitapide inhibits P-gp in vitro, and may increase the absorption of P-gp substrates. Coadministration of Lojuxta with P gp substrates (such as aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, talinolol, tolvaptan, topotecan) may increase the absorption of P gp substrates. Dose reduction of the P gp substrate should be considered when used concomitantly with Lojuxta.
Lomitapide inhibits CYP3A4. Lomitapide does not induce CYPs 1A2, 3A4, or 2B6, and does not inhibit CYPs 1A2, 2B6, 2C9, 2C19, 2D6, or 2E1. Lomitapide is not a P-gp substrate but does inhibit P-gp. Lomitapide does not inhibit breast cancer resistance protein (BCRP).
Before initiating treatment in women of child-bearing potential, the absence of pregnancy should be confirmed, appropriate advice on effective methods of contraception provided, and effective contraception initiated. Patients taking oestrogen-based oral contraceptives should be advised about possible loss of effectiveness due to diarrhoea and/or vomiting. Additional contraceptive measures should be used until resolution of symptoms (see section 4.5).
Lojuxta is contraindicated during pregnancy. There are no reliable data on its use in pregnant women. Animal studies have shown developmental toxicity (teratogenicity, embryotoxicity, see section 5.3). The potential risk for humans is unknown.
It is not known whether lomitapide is excreted into human milk. Because of the potential for adverse effects based on findings in animal studies with lomitapide (see section 5.3), a decision should be made whether to discontinue breast-feeding or discontinue the medicinal product, taking into account the importance of the medicinal product to the mother.
No adverse effects on fertility were observed in male and female rats administered lomitapide at systemic exposures (AUC) estimated to be 4 to 5 times higher than in humans at the maximum recommended human dose (see section 5.3).
Lojuxta has minor influence on the ability to drive and use machines.
The most serious adverse reactions during treatment were liver aminotransferase abnormalities (see section 4.4).
The most common adverse reactions were gastrointestinal effects. Gastrointestinal adverse reactions were reported by 27 (93%) of 29 patients in the Phase 3 clinical study. Diarrhoea 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 occurred more frequently during the dose escalation phase of the study and decreased once patients established the maximum tolerated dose of lomitapide.
Gastrointestinal adverse reactions of severe intensity were reported by 6 (21%) of 29 patients in the Phase 3 clinical study, with the most common being diarrhoea (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 study for 4 (14%) patients.
The most commonly reported adverse reactions of severe intensity were diarrhoea (4 subjects, 14%), vomiting (3 patients, 10%), and abdominal distension and ALT increased (2 subjects each, 7%).
Frequency of the adverse reactions is defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).
Table 3 lists all adverse reactions reported across the 35 patients treated in the Phase 2 Study UP1001 and in the Phase 3 Study UP1002/AEGR-733-005 or its extension study AEGR-733-012.
Table 3. Frequency of adverse reactions in HoFH patients:
| System Organ Class | Frequency | Adverse reaction |
|---|---|---|
| Infections and infestations | Common | Gastroenteritis |
| Metabolism and nutrition disorders | Very common | Decreased appetite |
| Not known | Dehydration | |
| Nervous system disorders | Common | Dizziness Headache Migraine |
| Gastrointestinal disorders | Very common | Diarrhoea Nausea Vomiting Abdominal discomfort Dyspepsia Abdominal pain Abdominal pain upper Flatulence Abdominal distension Constipation |
| Common | Gastritis Rectal tenesmus Aerophagia Defaecation urgency Eructation Frequent bowel movements Gastric dilatation Gastric disorder Gastrooesophageal reflux disease Haemorrhoidal haemorrhage Regurgitation | |
| Hepatobiliary disorders | Common | Hepatic steatosis Hepatotoxicity Hepatomegaly |
| Skin and subcutaneous tissue disorders | Common | Ecchymosis Papule Rash erythematous Xanthoma |
| Not known | Alopecia | |
| Musculoskeletal and connective tissue disorders | Not known | Myalgia |
| General disorders and administration site conditions | Common | Fatigue |
| Investigations | Very common | Alanine aminotransferase increased Aspartate aminotransferase increased Weight decreased |
| Common | International normalised ratio increased Blood alkaline phosphatase increased Blood potassium decreased Carotene decreased International normalised ratio abnormal Liver function test abnormal Prothrombin time prolonged Transaminases increased Vitamin E decreased Vitamin K decreased |
Table 4 lists all adverse reactions for subjects who received lomitapide monotherapy (N=291) treated in Phase 2 studies in subjects with elevated LDL-C (N=462).
Table 4. Frequency of adverse reactions in elevated LDL-C patients:
| System Organ Class | Frequency | Adverse reaction |
|---|---|---|
| Infections and infestations | Uncommon | Gastroenteritis Gastrointestinal infection Influenza Nasopharyngitis Sinusitis |
| Blood and lymphatic system disorders | Uncommon | Anaemia |
| Metabolism and nutrition disorders | Common | Decreased appetite |
| Uncommon | Dehydration Increased appetite | |
| Nervous system disorders | Uncommon | Paraesthesia Somnolence |
| Eye disorders | Uncommon | Eye swelling |
| Ear and labyrinth disorders | Uncommon | Vertigo |
| Respiratory, thoracic and mediastinal disorders | Uncommon | Pharyngeal lesion Upper-airway cough syndrome |
| Gastrointestinal disorders | Very common | Diarrhoea Nausea Flatulence |
| Common | Abdominal pain upper Abdominal distension Abdominal pain Vomiting Abdominal discomfort Dyspepsia Eructation Abdominal pain lower Frequent bowel movements | |
| Uncommon | Dry mouth Faeces hard Gastrooeosophageal reflux disease Abdominal tenderness Epigastric discomfort Gastric dilatation Haematemesis Lower gastrointestinal haemorrhage Reflux oesophagitis | |
| Hepatobiliary disorders | Uncommon | Hepatomegaly |
| Skin and subcutaneous tissue disorders | Uncommon | Blister Dry skin Hyperhidrosis |
| Musculoskeletal and connective tissue disorders | Common | Muscle spasms |
| Uncommon | Arthralgia Myalgia Pain in extremity Joint swelling Muscle twitching | |
| Renal and urinary disorders | Uncommon | Haematuria |
| General disorders and administrative site conditions | Common | Fatigue Asthenia |
| Uncommon | Chest pain Chills Early satiety Gait disturbance Malaise Pyrexia | |
| Investigations | Common | Alanine aminotransferase increased Aspartate aminotransferase increased Hepatic enzyme increased Liver function test abnormal Neutrophil count decreased White blood cell count decreased |
| Uncommon | Weight decreased Blood bilirubin increased Gamma-glutamyltransferase increased Neutrophil percentage increased Protein urine Prothrombin time prolonged Pulmonary function test abnormal White blood cell count increased |
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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