Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Liver enzyme abnormalities
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.

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 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).

Dose modification based on elevated hepatic aminotransferases

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         •    Confirm elevation with a repeat measurement within one week.
Limit of Normal
(ULN)                     •    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 approximately 4 weeks refer the patient to a hepatologist for further investigation.
•
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 hepatologist for further investigation.

Reintroduction of treatment may be considered if the benefits are considered to outweigh the risks associated 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 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.

Monitoring for evidence of progressive liver disease.
Regular screening for steatohepatitis/fibrosis should be performed at baseline and on an annual basis using the following imaging and biomarker evaluations:

•   Imaging for tissue elasticity, e.g. Fibroscan, acoustic radiation force impulse (ARFI), or magnetic 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 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.

Dehydration

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.

Concomitant use of CYP3A4 inhibitors

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.

Concomitant use of CYP3A4 inducers

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.

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

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

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 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.

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 limits recommended in the protocol. The use of alcohol during lomitapide treatment is not recommended.

Hepatotoxic agents

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.

Reduced absorption of fat-soluble vitamins and serum fatty acids

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.

Contraception measures in women of child-bearing potential

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).

Excipients with known effect

Lactose
Lojuxta contains lactose. Patients with rare hereditary problems of galactose intolerance, total-lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially ‘sodium-free’.

Effects on Driving

4.7    Effects on ability to drive and use machines

Lojuxta has minor influence on the ability to drive and use machines.