Leaflet LOJUXTA 20mg capsules

Liver enzyme abnormalities

Lomitapide can cause elevations in the liver enzymes alanine aminotransferase [ALT] and aspartateaminotransferase [AST] and hepatic steatosis (see section 5.1). There have been no concomitant orsubsequent clinically meaningful elevations in serum bilirubin, International Normalised Ratio (INR),or alkaline phosphatase. The extent to which lomitapide-associated hepatic steatosis promotes theelevations in aminotransferase is unknown. The liver enzyme changes can occur at any time duringtherapy.

Although cases of hepatic dysfunction (elevated aminotransferase with increase in bilirubin or INR) orhepatic 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 andefficacy of lomitapide in HoFH would have been unlikely to detect this adverse outcome given theirsize and duration.

Monitoring of liver function tests

Measure ALT, AST, alkaline phosphatase, total bilirubin, gamma-glutamyl transferase (gamma-GT)and serum albumin before initiation of treatment with Lojuxta. The medicinal product iscontraindicated in patients with moderate or severe hepatic impairment and those with unexplainedpersistent abnormal liver function tests. If the baseline liver-related tests are abnormal, considerinitiating the medicinal product after appropriate investigation by a hepatologist and the baselineabnormalities are explained or resolved.

During the first year, measure liver-related tests (ALT and AST, at a minimum) prior to each increasein dose or monthly, whichever occurs first. After the first year, do these tests at least every 3 monthsand before any increase in dose. Decrease the dose of lomitapide if elevations of aminotransferase areobserved and discontinue treatment for persistent or clinically significant elevations (see Table 2).

Dose modification based on elevated hepatic aminotransferases

Table 2 summarises recommendations for dose adjustment and monitoring for patients who developelevated aminotransferase during therapy with Lojuxta.

Table 2: Dose adjustment and monitoring for patients with elevated aminotransferases

ALT or AST Treatment and monitoring recommendations*≥ 3 x and < 5 x Upper * Confirm elevation with a repeat measurement within one week.

Limit of Normal(ULN) * If confirmed, reduce the dose and obtain additional liver-related testsif not already measured (such as alkaline phosphatase, total bilirubin,and INR).

* Repeat tests weekly and withhold dosing if there are signs of abnormalliver function (increase in bilirubin or INR), if aminotransferase levelsrise above 5 x ULN, or if aminotransferase levels do not fall below 3 x

ULN within approximately 4 weeks. Refer patients with persistentelevations in aminotransferase > 3 x ULN to a hepatologist for furtherinvestigation.

* If resuming Lojuxta after aminotransferase levels resolve to < 3 x

ULN, consider reducing the dose and monitor liver-related tests morefrequently.

≥5 x ULN * Withhold dosing and obtain additional liver-related tests if not alreadymeasured (such as alkaline phosphatase, total bilirubin, and INR). Ifaminotransferase levels do not fall below 3 x ULN withinapproximately 4 weeks refer the patient to a hepatologist for furtherinvestigation.

* If resuming Lojuxta after aminotransferase levels resolve to < 3 x

ULN, reduce the dose and monitor liver-related tests more frequently.

*Recommendations based on age- and gender-appropriate ULN of approximately 30-40 IU/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 ≥ 2 x

ULN, or active liver disease, discontinue treatment with Lojuxta and refer the patient to a hepatologistfor further investigation.

Reintroduction of treatment may be considered if the benefits are considered to outweigh the risksassociated with potential liver disease.

Hepatic steatosis and risk of progressive liver disease

Consistent with the mechanism of action of lomitapide, most treated patients exhibited increases inhepatic fat content. In an open-label Phase 3 study in adults, 18 of 23 patients with HoFH developedhepatic steatosis (hepatic fat > 5.56%) as measured by nuclear magnetic resonance (NMR)spectroscopy (see section 5.1). The median absolute increase in hepatic fat was 6% after both26 weeks and 78 weeks of treatment, from 1% at baseline, measured by NMR spectroscopy. In anopen-label Phase 3 study in paediatric patients, the median absolute increase in hepatic fat was 4.4%and 3.6% after 24 weeks and 104 weeks respectively, from 3.3% at baseline, measured by NMRimaging/magnetic resonance imaging (MRI). Hepatic steatosis is a risk factor for progressive liverdisease including steatohepatitis and cirrhosis. The long term consequences of hepatic steatosisassociated with lomitapide treatment are unknown. Clinical data suggest that hepatic fat accumulationis reversible after stopping treatment with Lojuxta, but whether histological sequelae remain isunknown, especially after long-term use.

Monitoring for evidence of progressive liver disease.

Regular screening for steatohepatitis/fibrosis should be performed at baseline and on an annual basisusing the following imaging and biomarker evaluations:

* For paediatric patients:

* Imaging for hepatic fat content by ultrasound or NMR imaging/MRI

* GammaGT and serum albumin to detect possible liver injury

* For adult patients:

* Imaging for tissue elasticity, e.g. Fibroscan, acoustic radiation force impulse (ARFI), ormagnetic resonance (MR) elastography

* GammaGT and serum albumin to detect possible liver injury

* At least one marker from each of the following categories:

* High sensitivity C-reactive protein (hs-CRP), erythrocyte sedimentation rate(ESR), CK-18 Fragment, NashTest (liver inflammation)

* Enhanced Liver Fibrosis (ELF) panel, Fibrometer, AST/ALT ratio, Fibrosis-4(Fib-4) score, Fibrotest (liver fibrosis)

The performance of these tests and their interpretation should involve collaboration between thetreating physician and the hepatologist. Patients with results suggesting the presence of steatohepatitisor fibrosis should be considered for liver biopsy.

If a patient has biopsy-proven steatohepatitis or fibrosis, the benefit-risk should be reassessed andtreatment stopped if necessary.

Post-marketing reports of dehydration and hospitalisation in patients treated with lomitapide have beenreported. Patients treated with lomitapide should be advised of the potential risk of dehydration inrelation to gastrointestinal adverse reactions and take precautions to avoid fluid depletion.

Concomitant use of CYP3A4 inhibitors

Lomitapide appears to be a sensitive substrate for CYP3A4 metabolism. CYP3A4 inhibitors increasethe exposure of lomitapide, with strong inhibitors increasing exposure approximately 27-fold.

Concomitant use of moderate or strong CYP3A4 inhibitors with Lojuxta is contraindicated (seesection 4.3). In the lomitapide clinical studies, one adult patient with HoFH developed markedlyelevated aminotransferase (ALT 24 x ULN, AST 13 x ULN) within days of initiating the strong

CYP3A4 inhibitor clarithromycin. If treatment with moderate or strong CYP3A4 inhibitors isunavoidable, Lojuxta should be stopped during the course of treatment.

Weak CYP3A4 inhibitors are expected to increase the exposure of lomitapide when takensimultaneously. When administered with atorvastatin, the dose of Lojuxta should either be taken12 hours apart or be decreased by half (see section 4.2). The dose of Lojuxta should be administered12 hours apart from any other weak CYP3A4 inhibitor.

Concomitant use of CYP3A4 inducers

Medicinal products that induce CYP3A4 would be expected to increase the rate and extent ofmetabolism of lomitapide. CYP3A4 inducers exert their effect in a time-dependent manner, and maytake 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 onefficacy 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-druginteraction 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 andconsider increasing the dose of lomitapide 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 ofincreased exposure should be considered and a reduction in the dose of lomitapide may be necessary.

Concomitant use of HMG-CoA reductase inhibitors (‘statins’)

Lomitapide increases plasma concentrations of statins. Patients receiving it as adjunctive therapy to astatin 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 rhabdomyolysiswith or without acute renal failure secondary to myoglobinuria, and can lead to fatality. All patientsreceiving lomitapide in addition to a statin should be advised of the potential increased risk ofmyopathy and told to report promptly any unexplained muscle pain, tenderness, or weakness. Doses ofsimvastatin > 40 mg should not be used with Lojuxta (see section 4.3).

Grapefruit juice

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

Risk of supratherapeutic or subtherapeutic anticoagulation with coumarin based anticoagulants

Lomitapide increases the plasma concentrations of warfarin. Increases in the dose of lomitapide maylead to supratherapeutic anticoagulation, and decreases in the dose may lead to subtherapeuticanticoagulation. Difficulty controlling INR contributed to early discontinuation from the Phase 3 studyfor one of five adult patients taking concomitant warfarin. Patients taking warfarin should undergoregular monitoring of the INR, especially after any changes in the dose of lomitapide. The dose ofwarfarin should be adjusted as clinically indicated.

Use of alcohol

Alcohol may increase levels of hepatic fat and induce or exacerbate liver injury. In the Phase 3 study,3 of 4 adult patients with ALT elevations > 5 x ULN reported alcohol consumption beyond the limitsrecommended 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 havepotential for hepatotoxicity, such as isotretinoin, amiodarone, acetaminophen (> 4 g/day for≥ 3 days/week), methotrexate, tetracyclines, and tamoxifen. The effect of concomitant administrationof lomitapide with other hepatotoxic medicine is unknown. More frequent monitoring of liver-relatedtests may be warranted.

Reduced absorption of fat-soluble vitamins and serum fatty acids

Given its mechanism of action in the small intestine, lomitapide may reduce the absorption offat-soluble nutrients. In both the adult and paediatric Phase 3 studies, patients were provided dailydietary supplements of vitamin E, linoleic acid, ALA, EPA and DHA. In the adult Phase 3 study, themedian levels of serum vitamin E, ALA, linoleic acid, EPA, DHA, and arachidonic acid decreasedfrom baseline to Week 26 but remained above the lower limit of the reference range. Adverse clinicalconsequences 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 unitsvitamin E for adults and children aged 9 years and older or 200 IU vitamin E for children aged 5 to8 years, and approximately 200 mg linoleic acid, 210 mg ALA, 110 mg EPA, and 80 mg DHA.

Contraception measures in women and adolescents of child-bearing potential

Before initiating treatment in women and adolescents of child-bearing potential, appropriate advice oneffective methods of contraception should be provided, and effective contraception initiated. Patientstaking oestrogen-based oral contraceptives should be advised about possible loss of effectiveness dueto 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 theybecome pregnant (see section 4.6).

Lojuxta contains lactose. Patients with rare hereditary problems of galactose intolerance, total-lactasedeficiency 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 sayessentially ‘sodium-free’.