LOJUXTA 10mg capsules medication leaflet

Lojuxta 5 mg hard capsules

Lojuxta 10 mg hard capsules

Lojuxta 20 mg hard capsules

Lojuxta 30 mg hard capsules

Lojuxta 40 mg hard capsules

Lojuxta 60 mg hard capsules

Lojuxta 5 mg hard capsules

Each hard capsule contains lomitapide mesylate equivalent to 5 mg lomitapide.

Each hard capsule contains 70.12 mg of lactose (as monohydrate) (see section 4.4).

Lojuxta 10 mg hard capsules

Each hard capsule contains lomitapide mesylate equivalent to 10 mg lomitapide.

Each hard capsule contains 140.23 mg of lactose (as monohydrate) (see section 4.4).

Lojuxta 20 mg hard capsules

Each hard capsule contains lomitapide mesylate equivalent to 20 mg lomitapide.

Each hard capsule contains 129.89 mg of lactose (as monohydrate) (see section 4.4).

Lojuxta 30 mg hard capsules

Each hard capsule contains lomitapide mesylate equivalent to 30 mg lomitapide.

Each hard capsule contains 194.84 mg of lactose (as monohydrate) (see section 4.4).

Lojuxta 40 mg hard capsules

Each hard capsule contains lomitapide mesylate equivalent to 40 mg lomitapide.

Each hard capsule contains 259.79 mg of lactose (as monohydrate) (see section 4.4).

Lojuxta 60 mg hard capsules

Each hard capsule contains lomitapide mesylate equivalent to 60 mg lomitapide.

Each hard capsule contains 389.68 mg of lactose (as monohydrate) (see section 4.4).

For the full list of excipients, see section 6.1.

Hard capsule.

Lojuxta 5 mg hard capsules

The capsule is an orange cap/orange body hard capsule of 19.4 mm, printed with black ink imprintedwith “5 mg” on body and “A733” on cap.

Lojuxta 10 mg hard capsules

The capsule is an orange cap/white body hard capsule of 19.4 mm, printed with black ink imprintedwith “10 mg” on body and “A733” on cap.

Lojuxta 20 mg hard capsules

The capsule is a white cap/white body hard capsule of 19.4 mm, printed with black ink imprinted with“20 mg” on body and “A733” on cap.

Lojuxta 30 mg hard capsules

The capsule is an orange cap/yellow body hard capsule of 21.6 mm, printed with black ink imprintedwith “30 mg” on body and “A733” on cap.

Lojuxta 40 mg hard capsules

The capsule is a yellow cap/white body hard capsule of 23.4 mm, printed with black ink imprintedwith “40 mg” on body and “A733” on cap.

Lojuxta 60 mg hard capsules

The capsule is a yellow cap/yellow body hard capsule of 23.4 mm, printed with black ink imprintedwith “60 mg” on body and “A733” on cap.

Lojuxta is indicated as an adjunct to a low-fat diet and other lipid-lowering medicinal products with orwithout low density lipoprotein (LDL) apheresis in adult patients with homozygous familialhypercholesterolaemia (HoFH).

Genetic confirmation of HoFH should be obtained whenever possible. Other forms of primaryhyperlipoproteinemia and secondary causes of hypercholesterolaemia (e.g., nephrotic syndrome,hypothyroidism) must be excluded.

Treatment with Lojuxta should be initiated and monitored by a physician experienced in the treatmentof lipid disorders.

The recommended starting dose is 5 mg once daily. After 2 weeks the dose may be increased,according to LDL-C response and based on acceptable safety and tolerability, to 10 mg and then, at aminimum of 4-week intervals, to 20 mg, 40 mg, and to the maximum recommended dose of 60 mg(see section 4.4).

The dose should be escalated gradually to minimise the incidence and severity of gastrointestinaladverse reactions and aminotransferase elevations.

The occurrence and severity of gastrointestinal adverse reactions associated with the use of Lojuxtadecreases in the presence of a low fat diet. Patients should follow a diet supplying less than 20% ofenergy from fat prior to initiating treatment, and should continue this diet during treatment. Dietarycounselling should be provided.

Patients should avoid consumption of grapefruit juice and alcohol (see sections 4.4 and 4.5).

For patients on a stable maintenance dose of Lojuxta who receive atorvastatin either:

* Separate the dose of the medicinal products by 12 hours

OR

* Decrease the dose of Lojuxta by half. Patients on 5 mg should remain on 5 mg.

Careful titration may then be considered according to LDL-C response and safety/tolerability. Upondiscontinuation of atorvastatin the dose of Lojuxta should be up-titrated according to LDL-C responseand safety/tolerability.

For patients on a stable maintenance dose of Lojuxta who receive any other weak cytochrome P450(CYP) 3A4 inhibitor, separate the dose of the medicinal products (Lojuxta and the weak CYP3A4inhibitor) by 12 hours. Exercise additional caution if administering more than 1 weak CYP3A4inhibitor with Lojuxta. Consider limiting the maximum dose of Lojuxta according to desired LDL-Cresponse.

Based on observations of decreased essential fatty acid and vitamin E levels in clinical studies,patients should take daily dietary supplements that provide 400 IU vitamin E and approximately200 mg linoleic acid, 110 mg eicosapentaenoic acid (EPA), 210 mg alpha linolenic acid (ALA) and80 mg docosahexaenoic acid (DHA) per day, throughout treatment with Lojuxta (see section 4.4).

There is limited experience with lomitapide in patients aged 65 years or older. Therefore, particularcaution should be exercised in these patients.

Since the recommended dose regimen involves starting at the low end of the dosing range andescalating cautiously according to individual patient tolerability, no adjustment to the dosing regimenis recommended for the elderly.

Lomitapide is contraindicated in patients with moderate or severe hepatic impairment includingpatients with unexplained persistent abnormal liver function tests (see sections 4.3 and 5.2).

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

Patients with end-stage renal disease receiving dialysis should not exceed 40 mg daily (seesection 5.2).

The safety and efficacy of lomitapide in children < 18 years have not been established and the use ofthis medicinal product in children is therefore not recommended. No data are available.

Oral use.

Administration with food may increase exposure to lomitapide. It should be taken on an emptystomach, at least 2 hours after the evening meal because the fat content of a recent meal may adverselyimpact gastrointestinal tolerability (see section 4.4).

* Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

* Patients with moderate or severe hepatic impairment and those with unexplained persistentabnormal liver function tests (see section 4.2).

* Patients with a known significant or chronic bowel disease such as inflammatory bowel diseaseor malabsorption.

* Concomitant administration of > 40 mg simvastatin (see section 4.5).

* Concomitant use of Lojuxta with strong or moderate CYP3A4 inhibitors (e.g., antifungal azolessuch as itraconazole, fluconazole,ketoconazole, voriconazole, posaconazole; macrolideantibiotics such as erythromycin or clarithromycin; ketolide antibiotics such as telithromycin;

HIV protease inhibitors; the calcium channel blockers diltiazem and verapamil, and theanti-arrhythmic dronedarone [see section 4.5]).

* Pregnancy (see section 4.6).

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, but occur most often during dose escalation.

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 Lojuxta if elevations of aminotransferase areobserved and discontinue treatment for persistent or clinically significant elevations (see Table 1).

Dose modification based on elevated hepatic aminotransferases

Table 1 summarises recommendations for dose adjustment and monitoring for patients who developelevated 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 * 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 3x

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

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

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

≥5x 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 3x ULN withinapproximately 4 weeks refer the patient to a hepatologist for furtherinvestigation.

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

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

*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 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, 18 of 23 patients with HoFH developed hepaticsteatosis (hepatic fat > 5.56%) as measured by nuclear magnetic resonance spectroscopy (MRS) (seesection 5.1). The median absolute increase in hepatic fat was 6% after both 26 weeks and 78 weeks oftreatment, from 1% at baseline, measured by MRS. Hepatic steatosis is a risk factor for progressiveliver disease 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:

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

* Gamma-GT 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, 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 patient with HoFH developed markedly elevatedaminotransferase (ALT 24x ULN, AST 13x ULN) within days of initiating the strong CYP3A4inhibitor 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 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 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 ofincreased exposure should be considered and a reduction in the dose of Lojuxta may be necessary.

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

Lomitapide increases plasma concentrations of statins. Patients receiving Lojuxta as adjunctivetherapy to a statin should be monitored for adverse events that are associated with the use of highdoses of statins. Statins occasionally cause myopathy. In rare cases, myopathy may take the form ofrhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and can lead tofatality. All patients receiving lomitapide in addition to a statin should be advised of the potentialincreased risk of myopathy and told to report promptly any unexplained muscle pain, tenderness, orweakness. Doses of simvastatin > 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 Lojuxta may leadto 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 patients taking concomitant warfarin. Patients taking warfarin should undergo regularmonitoring of the INR, especially after any changes in the dose of Lojuxta. The dose of warfarinshould 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 patients with ALT elevations > 5x 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 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 remainedabove the lower limit of the reference range. Adverse clinical consequences of these reductions werenot observed with lomitapide treatment of up to 78 weeks. Patients treated with Lojuxta should takedaily supplements that contain 400 international units vitamin E and approximately 200 mg linoleicacid, 210 mg ALA, 110 mg EPA, and 80 mg DHA.

Contraception measures in women of child-bearing potential

Before initiating treatment in women of child-bearing potential, appropriate advice on effectivemethods of contraception should be provided, and effective contraception initiated. Patients takingoestrogen-based oral contraceptives should be advised about possible loss of effectiveness due todiarrhoea 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’.

Effects of other medicinal products on lomitapide and other forms of interaction

Table 2: Interactions between Lojuxta and other medicinal products and other forms ofinteraction

Medicinal products Effects on lomitapide levels Recommendation concerningco-administration with Lojuxta

Inhibitors of CYP3A4 Strong and moderate inhibitors Strong and moderate inhibitors

When lomitapide 60 mg was Use of strong or moderate inhibitors ofco-administered with CYP3A4 is contraindicated with Lojuxta. Ifketoconazole 200 mg twice daily, treatment with antifungal azoles (e.g.,a strong inhibitor of CYP3A4, itraconazole, ketoconazole, fluconazole,lomitapide AUC increased voriconazole, posaconazole); theapproximately 27-fold and Cmax antiarrhythmic dronedarone; macrolideincreased approximately 15-fold. antibiotics (e.g., erythromycin,

Interactions between moderate clarithromycin); ketolide antibiotics (e.g.,

CYP3A4 inhibitors and telithromycin); HIV protease inhibitors; thelomitapide have not been studied. calcium channel blockers diltiazem andverapamil is unavoidable, therapy with

Moderate CYP3A4 inhibitors are Lojuxta should be suspended during thepredicted to have a substantial course of treatment (see sections 4.3 andimpact on lomitapide’s 4.4).pharmacokinetics. Concomitantuse of moderate CYP3A4 Grapefruit juice is a moderate inhibitor ofinhibitors are expected to CYP3A4 and is expected to substantiallyincrease lomitapide exposure by increase exposure to lomitapide. Patients4-10 fold based on the results of taking Lojuxta should avoid consumption ofthe study with the strong grapefruit juice.

CYP3A4 inhibitor ketoconazoleand on historical data for themodel CYP3A4 probemidazolam.

Medicinal products Effects on lomitapide levels Recommendation concerningco-administration with Lojuxta

Weak inhibitors Weak inhibitors

Weak CYP3A4 inhibitors are When administered with atorvastatin, theexpected to increase the exposure dose of Lojuxta should either be takenof lomitapide when taken 12 hours apart or be decreased by half (seesimultaneously. section 4.2). The dose of Lojuxta should be

When lomitapide 20 mg was taken 12 hours apart from any otherco-administered simultaneously concomitant weak CYP3A4 inhibitors.

with atorvastatin, a weak Examples of weak CYP3A4 inhibitors

CYP3A4 inhibitor, lomitapide include: alprazolam, amiodarone,

AUC and C increased amlodipine, atorvastatin, azithromycin,maxapproximately 2-fold. When the bicalutamide, cilostazol, cimetidine,dose of lomitapide was taken ciclosporin, clotrimazole, fluoxetine,12 hours apart from atorvastatin, fluvoxamine, fosaprepitant, ginkgo,no clinically meaningful increase goldenseal, isoniazid, ivacaftor, lacidipine,in lomitapide exposure was lapatinib, linagliptin, nilotinib,observed. oestrogen-containing oral contraceptives,pazopanib, peppermint oil, propiverine,

When lomitapide 20 mg was co- ranitidine, ranolazine, roxithromycin, Sevilleadministered simultaneously or oranges, tacrolimus, ticagrelor and tolvaptan.12 hours apart with ethinyl This list is not intended to be comprehensiveestradiol/norgestimate, a weak and prescribers should check the prescribing

CYP3A4 inhibitor, no clinically information of medicinal products to be co-meaningful increase in lomitapide administered with Lojuxta for potentialexposure was observed. CYP3A4 mediated interactions.

The effect of administration of more thanone weak CYP3A4 inhibitor has not beentested, but the effect on the exposure oflomitapide is expected to be greater than forco-administration of the individual inhibitorswith lomitapide.

Exercise additional caution if administeringmore than 1 weak CYP3A4 inhibitor with

Lojuxta.

Inducers of CYP3A4 Medicines that induce CYP3A4 When co-administering CYP3A4 inducerswould be expected to increase the (i.e., aminoglutethimide, nafcillin,rate and extent of metabolism of non-nucleoside reverse transcriptaselomitapide. Consequently, this inhibitors, phenobarbital, rifampicin,would reduce the effect of carbamazepine, pioglitazone, St John’slomitapide. Any impact on Wort, glucocorticoids, modafinil andefficacy is likely to be variable. phenytoin) with Lojuxta, the possibility of adrug-drug interaction affecting efficacyshould be considered. It is recommended toincrease the frequency of LDL-C assessmentduring such concomitant use and considerincreasing the dose of Lojuxta to ensuremaintenance of the desired level of efficacyif the CYP3A4 inducer is intended forchronic use.

Medicinal products Effects on lomitapide levels Recommendation concerningco-administration with Lojuxta

Bile acid sequestrants Lomitapide has not been tested Because bile acid sequestrants can interferefor interaction with bile acid with the absorption of oral medicines, bilesequestrants (resins such as acid sequestrants should be taken at leastcolesevelam and cholestyramine). 4 hours before or at least 4 hours after

Lojuxta.

Effects of lomitapide on other medicinal products

HMG-CoA reductase inhibitors (“statins”)

Lomitapide increases plasma concentrations of statins. When lomitapide 60 mg was administered tosteady 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 wasadministered 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 doserelated. Use of Lojuxta is contraindicated in patients treated with high doses of simvastatin (> 40 mg)(see sections 4.3 and 4.4).

Coumarin anticoagulants

When lomitapide 60 mg was administered to steady state and 6 days following warfarin 10 mg, INRincreased 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 takingcoumarins (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 section4.4).

Fenofibrate, niacin and ezetimibe

When lomitapide was administered to steady state prior to micronised fenofibrate 145 mg, extendedrelease niacin 1 000 mg, or ezetimibe 10 mg, no clinically significant effects on the exposure of any ofthese 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 oralcontraceptive, no clinically meaningful or statistically significant impact on the pharmacokinetics ofthe components of the oral contraceptive (ethinyl estradiol and 17-deacetyl norgestimate, themetabolite of norgestimate) was observed. Lomitapide is not expected to directly influence theefficacy of oestrogen based oral contraceptives; however diarrhoea and/or vomiting may reducehormone absorption. In cases of protracted or severe diarrhoea and/or vomiting lasting more than 2days, 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) mayincrease the absorption of P gp substrates. Dose reduction of the P gp substrate should be consideredwhen used concomitantly with Lojuxta.

In vitro assessment of drug interactions

Lomitapide inhibits CYP3A4. Lomitapide does not induce CYPs 1A2, 3A4, or 2B6, and does notinhibit 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).

Use in women of child-bearing potential

Before initiating treatment in women of child-bearing potential, the absence of pregnancy should beconfirmed, appropriate advice on effective methods of contraception provided, and effectivecontraception initiated. Patients taking oestrogen-based oral contraceptives should be advised aboutpossible loss of effectiveness due to diarrhoea and/or vomiting. Additional contraceptive measuresshould 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 adverseeffects based on findings in animal studies with lomitapide (see section 5.3), a decision should bemade whether to discontinue breast-feeding or discontinue the medicinal product, taking into accountthe importance of the medicinal product to the mother.

No adverse effects on fertility were observed in male and female rats administered lomitapide atsystemic exposures (AUC) estimated to be 4 to 5 times higher than in humans at the maximumrecommended 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 (seesection 4.4).

The most common adverse reactions were gastrointestinal effects. Gastrointestinal adverse reactionswere reported by 27 (93%) of 29 patients in the Phase 3 clinical study. Diarrhoea occurred in 79% ofpatients, nausea in 65%, dyspepsia in 38%, and vomiting in 34%. Other reactions reported by at least20% of patients include abdominal pain, abdominal discomfort, abdominal distension, constipation,and flatulence. Gastrointestinal adverse reactions occurred more frequently during the dose escalationphase 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 reactionscontributed 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%).

The adverse reactions are listed below by SOC (System Organ Class) and by frequency, most frequentreactions first. 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 UP1001and 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 Very common Decreased appetitedisorders Not known Dehydration

Nervous system disorders Common Dizziness

Migraine

Gastrointestinal disorders Very common Diarrhoea

Nausea

Abdominal discomfort

Dyspepsia

Abdominal pain

Abdominal pain upper

Flatulence

Abdominal distension

Common Gastritis

Rectal tenesmus

Aerophagia

Defaecation urgency

Eructation

Frequent bowel movements

Gastric dilatation

Gastric disorder

Gastro-oesophageal reflux disease

Haemorrhoidal haemorrhage

Regurgitation

Hepatobiliary disorders Common Hepatic steatosis

Hepatomegaly

Skin and subcutaneous tissue Common Ecchymosisdisorders Papule

Rash erythematous

Xanthoma

Not known Alopecia

Musculoskeletal and connective Not known Myalgiatissue disorders

General disorders and Common Fatigueadministration site conditions

System Organ Class Frequency Adverse reaction

Investigations Very common Alanine aminotransferase increased

Aspartate aminotransferase increased

Weight decreased

Common International normalised ratioincreased

Blood alkaline phosphatase increased

Blood potassium decreased

Carotene decreased

International normalised ratioabnormal

Liver function test abnormal

Transaminases increased

Vitamin E decreased

Vitamin K decreased

Table 4 lists all adverse reactions for subjects who received lomitapide monotherapy (N = 291) treatedin 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 Uncommon Anaemiadisorders

Metabolism and nutrition Common Decreased appetitedisorders Uncommon Dehydration

Increased appetite

Nervous system disorders Uncommon Paraesthesia

Somnolence

Eye disorders Uncommon Eye swelling

Ear and labyrinth disorders Uncommon Vertigo

Respiratory, thoracic and Uncommon Pharyngeal lesionmediastinal disorders Upper-airway cough syndrome

System Organ Class Frequency Adverse reaction

Gastrointestinal disorders Very common Diarrhoea

Nausea

Flatulence

Common Abdominal pain upper

Abdominal distension

Abdominal pain

Abdominal discomfort

Dyspepsia

Eructation

Abdominal pain lower

Frequent bowel movements

Uncommon Dry mouth

Faeces hard

Gastro-oeosophageal reflux disease

Abdominal tenderness

Epigastric discomfort

Gastric dilatation

Haematemesis

Lower gastrointestinal haemorrhage

Reflux oesophagitis

Hepatobiliary disorders Uncommon Hepatomegaly

Skin and subcutaneous tissue Uncommon Blisterdisorders Dry skin

Hyperhidrosis

Musculoskeletal and connective Common Muscle spasmstissue disorders Uncommon Arthralgia

Myalgia

Pain in extremity

Joint swelling

Muscle twitching

Renal and urinary disorders Uncommon Haematuria

General disorders and Common Fatigueadministrative site conditions Asthenia

Uncommon Chest pain

Chills

Early satiety

Gait disturbance

Malaise

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

Pulmonary function test abnormal

White blood cell count increased

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

In rodents, single oral doses of lomitapide ≥ 600 times higher than the maximum recommended humandose (1 mg/kg) were well tolerated. The maximum dose administered to human subjects in clinicalstudies was 200 mg as a single dose; there were no adverse reactions.

Pharmacotherapeutic group: Lipid modifying agents, other lipid modifying agents, ATC code:

C10AX12

Lomitapide is a selective inhibitor of microsomal transfer protein (MTP), an intracellular lipid-transferprotein that is found in the lumen of the endoplasmic reticulum and is responsible for binding andshuttling individual lipid molecules between membranes. MTP plays a key role in the assembly ofapo B containing lipoproteins in the liver and intestines. Inhibition of MTP reduces lipoproteinsecretion and circulating concentrations of lipoprotein-borne lipids including cholesterol andtriglycerides.

A single arm, open-label study (UP1002/AEGR-733-005) evaluated the efficacy and safety oflomitapide when co-administered with a low-fat diet and other lipid-lowering therapies in adultpatients with HoFH. Patients were instructed to maintain a low-fat diet (< 20% calories from fat) andtheir lipid-lowering therapies at study entry, including apheresis if applicable, from 6 weeks prior tobaseline through at least Week 26. The dose of lomitapide was escalated from 5 mg to an individuallydetermined maximum tolerated dose up to 60 mg. After Week 26, patients remained on lomitapide todetermine the effects of longer-term treatment and were allowed to change background lipid-loweringtherapies. The study provided for a total of 78 weeks of treatment.

Twenty-nine patients were enrolled, of whom 23 completed through Week 78. Sixteen males (55%)and 13 females (45%) were included with a mean age of 30.7 years, ranging from 18 to 55 years. Themean dose of lomitapide was 45 mg at Week 26 and 40 mg at Week 78. At Week 26, the mean percentchange in LDL-C from baseline of LDL-C was -40% (p< 0.001) in the Intent to Treat (ITT)population. Mean percent change from baseline through Week 26 using last observation carriedforward (LOCF) to each assessment is shown in Figure 1.

Figure 1: Mean percent changes from baseline in LDL-C in the major effectiveness study

UP1002/AEGR-733-005 through Week 26 (the Primary Endpoint) using LOCFto each assessment (N = 29)

- 10 -8

- 40 -38

- 39 -40

- 45 -43

Week 0 Week 2 Week 6 Week 10 Week 14 Week 18 Week 22 Week 26

Study Week

Changes in lipids and lipoproteins through Week 26 and Week 78 of lomitapide treatment arepresented in Table 5.

Mean Percent Change from Baseline in LDL-C

Table 5: Absolute values and percent changes from baseline to Weeks 26 and 78 in lipidsand lipoproteins (major effectiveness study UP1002/AEGR-733-005)

Parameter (units) Baseline Week 26/LOCF (N = 29) Week 78 (N = 23)

Mean Mean % p-value Mean %(SD) (SD) Change b (SD) Change p-valueb

LDL-C, direct 336 190 210(mg/dL) (114) (104) -40 < 0.001 (132) -38 < 0.001

Total Cholesterol (TC) 430 258 281(mg/dL) (135) (118) -36 < 0.001 (149) -35 < 0.001

Apolipoprotein B 259 148 151(apo B) (mg/dL) (80) (74) -39 < 0.001 (89) -43 < 0.001

Triglycerides (TG)(mg/dL)a 92 57 -45 0.009 59 -42 0.012

Non high-densitylipoprotein cholesterol 386 217 239(Non-HDL-C) (mg/dL) (132) (113) -40 < 0.001 (146) -39 < 0.001

Very-low-densitylipoprotein cholesterol 21 13 16(VLDL-C) (mg/dL) (10) (9) -29 0.012 (15) -31 0.013

Lipoprotein (a) (Lp(a))(nmol/L)a 66 61 -13 0.094 72 -4 < 0.842

High-densitylipoprotein cholesterol 44 41 43(HDL-C) (mg/dL) (11) (13) -7 0.072 (12) -4.6 0.246a Median presented for TG and Lp(a). p-value is based on the mean percent changeb p-value on the mean percent change from baseline based on paired t-test

At both Week 26 and Week 78, there were significant reductions in LDL-C, TC, apo B, TG,non-HDL-C, VLDL-C and changes in HDL-C trended lower at Week 26 and returned to baselinelevels by Week 78.

The effect of Lojuxta on cardiovascular morbidity and mortality has not been determined.

At baseline, 93% were on a statin, 76% were on ezetimibe, 10% on niacin, 3% on a bile acidsequestrant and 62% were receiving apheresis. Fifteen of 23 (65%) patients had their lipid-loweringtreatment reduced by Week 78, including planned and unplanned reductions/interruptions. Apheresiswas discontinued in 3 out of 13 patients who were on it at Week 26, and frequency was reduced in3 patients while maintaining low LDL-C levels through Week 78. The clinical benefit of reductions inbackground lipid-lowering therapy, including apheresis, is not certain.

Of the 23 patients who completed through Week 78, 19 (83%) had LDL-C reductions ≥ 25% with8 (35%) having LDL-C < 100 mg/dL and 1 having LDL-C < 70 mg/dL at that time point.

In this study, 10 patients experienced elevations in AST and/or ALT > 3 x ULN (see Table 6).

Table 6: Highest liver function test results post first dose (major effectiveness study

UP1002/AEGR-733-005)

Parameter/Abnormality N (%)

ALT

Number of Patients with Assessments 29> 3 to ≤ 5 x ULN 6 (20.7)> 5 to ≤ 10 x ULN 3 (10.3)> 10 to ≤ 20 x ULN 1 (3.4)> 20 x ULN 0

AST

Number of Patients with Assessments 29> 3 to ≤ 5 x ULN 5 (17.2)> 5 to ≤ 10 x ULN 1 (3.4)> 10 to ≤ 20 x ULN 0> 20 x ULN 0

Elevations in ALT and/or AST > 5 x ULN were managed with a dose reduction or temporarysuspension of lomitapide dosing, and all patients were able to continue with study drug treatment. Noclinically meaningful elevations in total bilirubin or alkaline phosphatase were observed. Hepatic fatwas prospectively measured using MRS in all eligible patients during the clinical study (Table 7). Datafrom individuals who had repeat measurements after stopping lomitapide show that hepatic fataccumulation is reversible, but whether histological sequelae remain is unknown.

Table 7: Maximum categorical changes in % hepatic fat (major effectiveness study

UP1002/AEGR-733-005)

Maximum absolute increase Efficacy phase Safety phase Entire trialin % hepatic fat weeks 0-26 weeks 26-78 weeks 0-78

N (%) N (%) N (%)

Number of evaluable patients 22 22 23≤ 5% 9 (41) 6 (27) 5 (22)> 5% to ≤ 10% 6 (27) 8 (36) 8 (35)> 10% to ≤ 15% 4 (18) 3 (14) 4 (17)>15% to ≤ 20% 1 (5) 4 (18) 3 (13)> 20% to ≤ 25% 1 (5) 0 1 (4)> 25% 1 (5) 1 (5) 2 (9)

The European Medicines Agency has deferred the obligation to submit the results of studies with

Lojuxta in one or more subsets of the paediatric population in HoFH (see section 4.2 for informationon paediatric use).

This medicinal product has been authorised under ‘exceptional circumstances’. This means that due tothe rarity of the disease it has not been possible to obtain complete information on this medicinalproduct.

The European Medicines Agency will review any new information which may become available everyyear and this SmPC will be updated as necessary.

The absolute oral bioavailability of lomitapide is 7%. Absorption is not limited by penetration of theactive substance across the intestinal barrier but is predominantly influenced by an extensive first passeffect. Peak plasma concentrations of lomitapide were reached 4-8 hours following oral dosing.

Lomitapide pharmacokinetics is approximately dose-proportional for oral single doses in thetherapeutic range. Doses higher than 60 mg suggest a trend toward nonlinearity and are notrecommended.

Upon multiple dosing Cmax and AUC increased in approximate proportion to lomitapide dose. Cmax and

AUC were increased following either a high-fat meal (77% and 58%, respectively) or low fat meal(70% and 28%, respectively). Accumulation of lomitapide in plasma was consistent with thatpredicted after a single dose following once daily oral dosing above 25 mg for up to 4 weeks.

Inter-individual variability in lomitapide AUC was approximately 50%.

At steady state the accumulation of lomitapide was 2.7 at 25 mg and 3.9 at 50 mg.

Following intravenous administration, the volume of distribution of lomitapide was high(mean = 1 200 litres) despite a high degree (> 99.8%) of binding to plasma protein. In animal studieslomitapide was highly concentrated (200-fold) in the liver.

Lomitapide is extensively metabolised, predominantly by CYP3A4. CYP isoforms 2E1, 1A2, 2B6,2C8, and 2C19 are involved to a lesser extent and isoforms 2D6 and 2C9 are not involved in themetabolism of lomitapide.

Following administration of a radiolabeled oral solution dose to healthy subjects, 93% of theadministered dose was recovered in urine and faeces. Approximately 33% of the radioactivity wasexcreted in urine as metabolites. The remainder was excreted in faeces, primarily as oxidisedmetabolites. The elimination half-life of lomitapide was approximately 29 hours.

Data in the pivotal clinical study were analysed with respect to the impact of potential covariates onlomitapide exposure. Of the parameters examined (race, body mass index (BMI), gender, weight, age),only BMI could be classified as a potential covariate.

Age and gender

There was no clinically relevant effect of age (18-64 years) or gender on the pharmacokinetics oflomitapide. Lomitapide has not been investigated in patients aged 65 years or older.

No dose adjustment is required for Caucasian or Latino patients. There is insufficient information todetermine if Lojuxta requires dose adjustment in other races. However, since the medicinal product isdosed in an escalating fashion according to individual patient safety and tolerability, no adjustment tothe dosing regimen is recommended based on race.

In the renal impairment population, lomitapide was only studied in patients with end-stage renaldisease (ESRD). A pharmacokinetic study in patients with ESRD undergoing hemodialysisdemonstrated a 36% increase in mean lomitapide plasma concentration compared to matched healthycontrols. The terminal half-life of lomitapide was not affected.

A single-dose, open-label study was conducted to evaluate the pharmacokinetics of 60 mg lomitapidein 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 healthyvolunteers. In patients with mild hepatic impairment, lomitapide AUC and Cmax were 47% and 4%higher, respectively, compared with healthy volunteers. Lojuxta has not been studied in patients withsevere hepatic impairment (Child-Pugh score 10-15).

Lomitapide has not been investigated in children less than 18 years of age.

In repeat-dose oral toxicology studies in rodents and dogs, the principal drug-related findings werelipid accumulation in the small intestine and/or liver associated with decreases in serum cholesteroland/or triglyceride levels. These changes are secondary to the mechanism of action of lomitapide.

Other liver-related changes in repeat-dose toxicity studies in rats and dogs included increased serumaminotransferases, subacute inflammation (rats only), and single-cell necrosis. In a 1 year repeat-dosestudy in dogs there were no microscopic changes in the liver although serum AST was minimallyincreased in females.

Pulmonary histiocytosis was observed in rodents. Decreased red blood cell parameters as well aspoikilocytosis and/or anisocytosis were observed in dogs. Testicular toxicity was observed in dogs at205 times the human exposure (AUC) at 60 mg in a 6-month study. No adverse effects on the testeswere observed in a 1-year study in dogs at 64 times the human exposure at 60 mg.

In a dietary carcinogenicity study in mice, lomitapide was administered up to 104 weeks at dosesranging from 0.3 to 45 mg/kg/day. There were statistically significant increases in the incidences ofliver adenoma and carcinoma at doses ≥ 1.5 mg/kg/day in males (≥ 2 times the human exposure at60 mg daily based on AUC) and ≥ 7.5 mg/kg/day in females (≥ 9 times the human exposure at 60 mgbased on AUC). Incidences of small intestinal carcinoma and/or combined adenoma and carcinoma(rare tumours in mice) were significantly increased at doses ≥ 15 mg/kg/day in males (≥ 26 times thehuman exposure at 60 mg based on AUC) and at 15 mg/kg/day in females (22 times the humanexposure at 60 mg based on AUC).

In an oral carcinogenicity study in rats, lomitapide was administered up to 99 weeks at doses up to7.5 mg/kg/day in males and 2.0 mg/kg/day in females. Focal hepatic fibrosis was observed in malesand females and hepatic cystic degeneration was observed in males only. In high-dose males, anincreased incidence of pancreatic acinar cell adenoma was observed at an exposure 6 times that inhumans at 60 mg based on AUC.

Lomitapide was not mutagenic or genotoxic in a battery of in vitro and in vivo studies.

Lomitapide had no effect on reproductive function in female rats at doses up to 1 mg/kg or in male ratsat doses up to 5 mg/kg. Systemic exposures to lomitapide at these doses were estimated to be 4 times(females) and 5 times (males) higher than the human exposure at 60 mg based on AUC.

Lomitapide was teratogenic in rats in the absence of maternal toxicity at an exposure (AUC) estimatedto be twice that in humans at 60 mg. There was no evidence of embryofoetal toxicity in rabbits at3 times the maximum recommended human dose (MRHD) of 60 mg based on body surface area.

Embryofoetal toxicity was observed in rabbits in the absence of maternal toxicity at ≥ 6.5 times the

MRHD. In ferrets, lomitapide was both maternally toxic and teratogenic at < 1 times the MRHD.

Pregelatinised starch (maize)

Sodium starch glycolate (Type A)

Microcrystalline cellulose

Lactose monohydrate

Silica, colloidal anhydrous

Magnesium stearate

Lojuxta 5 mg, 10 mg hard capsules

Gelatin

Titanium dioxide (E171)

Red iron oxide (E172)

Lojuxta 20 mg hard capsules

Gelatin

Titanium dioxide (E171)

Lojuxta 30 mg hard capsules

Gelatin

Titanium dioxide (E171)

Red iron oxide (E172)

Yellow iron oxide (E172)

Lojuxta 40 mg, 60 mg hard capsules

Gelatin

Titanium dioxide (E171)

Yellow iron oxide (E172)

Shellac

Black iron oxide (E172)

Not applicable.

3 years.

Store below 30 °C.

Keep the bottle tightly closed in order to protect from moisture.

High density polyethylene (HDPE) bottle fitted with a polyester/aluminium foil/cardboard inductionseal and polypropylene screw cap.

Package sizes are:28 capsules

No special requirements.

Chiesi Farmaceutici S.p.A.

Via Palermo 26/A43122 Parma

Italy

EU/1/13/851/001 - Lojuxta 5 mg hard capsules

EU/1/13/851/002 - Lojuxta 10 mg hard capsules

EU/1/13/851/003 - Lojuxta 20 mg hard capsules

EU/1/13/851/004 - Lojuxta 30 mg hard capsules

EU/1/13/851/005 - Lojuxta 40 mg hard capsules

EU/1/13/851/006 - Lojuxta 60 mg hard capsules

Date of first authorisation: 31 July 2013

Date of latest renewal: 26 May 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.