英文药名:Lojuxta(lomitapide hard capsules) 中文药名:甲磺酸洛美他派硬胶囊 生产厂家:Aegerion制药
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 Lojuxta 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. 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 trials, 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 may substantially increase the exposure of lomitapide. The dose of Lojuxta should be reduced when administered with a weak CYP3A4 inhibitor and patients monitored carefully (see section 4.2). Concomitant use of CYP3A4 inducers Medicines 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 Lojuxta. 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 Lojuxta 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 trial for one of five patients taking concomitant warfarin. Patients taking warfarin should undergo regular monitoring of the INR, especially after any changes in Lojuxta dosage. 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 trial, 3 of 4 patients with ALT elevations >5x ULN reported alcohol consumption beyond the limits recommended in the protocol. The use of alcohol during Lojuxta 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 Lojuxta 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 trial, patients were provided daily dietary supplements of vitamin E, linoleic acid, ALA, EPA and DHA. In this trial, 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 at least 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). Lactose Lojuxta contains lactose and therefore should not be administered to patients with rare hereditary problems of galactose intolerance, the Lapp-lactase deficiency or glucose-galactose malabsorption. 4.5 Interaction with other medicinal products and other forms of interaction Effects of other medicinal products on Lojuxta and other forms of interaction Table 2: Interactions between Lojuxta and other medicinal products and other forms of interaction
HMG-CoA Reductase Inhibitors (“Statins”): 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). Coumarin anticoagulants: 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). Fenofibrate, niacin and ezetimibe: When lomitapide was administered to steady state prior to micronised fenofibrate 145 mg, extended release niacin 1000 mg, or ezetimibe 10 mg, no clinically significant effects on the exposure of any of these medicinal products was observed. No dose adjustments are required when co-administered with Lojuxta. Oral contraceptives: When lomitapide 50 mg was administered to steady state along with an oestrogen-based oral contraceptive, no clinically meaningful nor statistically significant impact on the pharmacokinetics of the components of the oral contraceptive (ethinylestradiol and 17-deacetyl norgestimate, the metabolite of norgestimate) were 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. P-gp substrates: 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. In vitro assessment of drug interactions: 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). 4.6 Fertility, pregnancy and lactation Pregnancy 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. Use in women of child-bearing potential 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). Breast-feeding 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. Fertility 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). 4.7 Effects on ability to drive and use machines Lojuxta may have a minor influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile 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 trial. 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 trial, 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 trial 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%). Tabulated list of adverse reactions 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
Table 4: Frequency of Adverse Reactions in Elevated LDL-C Patients
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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard. 4.9 Overdose There is no specific treatment in the event of overdose. In rodents, single oral doses of lomitapide ≥600 times higher than the maximum recommended human dose (1 mg/kg) were well tolerated. The maximum dose administered to human subjects in clinical studies was 200 mg as a single dose; there were no adverse reactions. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Other lipid modifying agents, plain. ATC code: C10AX12 Mechanism of action Lomitapide is a selective inhibitor of microsomal transfer protein (MTP), an intracellular lipid-transfer protein that is found in the lumen of the endoplasmic reticulum and is responsible for binding and shuttling individual lipid molecules between membranes. MTP plays a key role in the assembly of apo B containing lipoproteins in the liver and intestines. Inhibition of MTP reduces lipoprotein secretion and circulating concentrations of lipoprotein-borne lipids including cholesterol and triglycerides. Clinical efficacy and safety A single arm, open-label study (UP1002/AEGR-733-005) evaluated the efficacy and safety of lomitapide when co-administered with a low-fat diet and other lipid-lowering therapies in adult patients with HoFH. Patients were instructed to maintain a low-fat diet (<20% calories from fat) and their lipid-lowering therapies at study entry, including apheresis if applicable, from 6 weeks prior to baseline through at least Week 26. The dose of lomitapide was escalated from 5 mg to an individually determined maximum tolerated dose up to 60 mg. After Week 26, patients remained on lomitapide to determine the effects of longer-term treatment and were allowed to change background lipid-lowering therapies. 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. The mean dose of lomitapide was 45 mg at Week 26 and 40 mg at Week 78. At Week 26, the mean percent change 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 carried forward (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 LOCF to each assessment (N=29) Changes in lipids and lipoproteins through Week 26 and Week 78 of lomitapide treatment are presented in Table 5.
b 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 baseline levels 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 acid sequestrant and 62% were receiving apheresis. Fifteen of 23 (65%) patients had their lipid-lowering treatment reduced by Week 78, including planned and unplanned reductions/interruptions. Apheresis was discontinued in 3 out of 13 patients who were on it at Week 26, and frequency was reduced in 3 patients while maintaining low LDL-C levels through Week 78. The clinical benefit of reductions in background lipid-lowering therapy, including apheresis, is not certain. Of the 23 patients who completed through Week 26, 19 (83%) had LDL-C reductions ≥25% with 8 (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)
Table 7: Maximum categorical changes in % hepatic fat (major effectiveness study UP1002/AEGR-733-005)
5.2 Pharmacokinetic properties Absorption The absolute oral bioavailability of lomitapide is 7%. Absorption is not limited by penetration of the drug across the intestinal barrier but is predominantly influenced by an extensive first pass effect. Peak plasma concentrations of lomitapide were reached 4-8 hours following oral dosing. Lomitapide pharmacokinetics is approximately dose-proportional for oral single doses in the therapeutic range. Doses higher than 60 mg suggest a trend toward nonlinearity and are not recommended. 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 that predicted 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. Distribution Following intravenous administration, the volume of distribution of lomitapide was high (mean=1200 litres) despite a high degree (>99.8%) of binding to plasma protein. In animal studies lomitapide was highly concentrated (200-fold) in the liver. Biotransformation 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 the metabolism of lomitapide. Elimination Following administration of a radiolabeled oral solution dose to healthy subjects, 93% of the administered dose was recovered in urine and faeces. Approximately 33% of the radioactivity was excreted in urine as metabolites. The remainder was excreted in faeces, primarily as oxidised metabolites. The elimination half-life of lomitapide was approximately 29 hours. Special populations: Data in the pivotal clinical trial were analyzed with respect to the impact of potential covariates on lomitapide 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 of lomitapide. Race No dose adjustment is required for Caucasian or Latino patients. There is insufficient information to determine if Lojuxta requires dose adjustment in other races. However, since the medicinal product is dosed in an escalating fashion according to individual patient safety and tolerability, no adjustment to the dosing regimen is recommended based on race. Renal insufficiency In the renal impairment population, lomitapide was only studied in patients with end-stage renal disease (ESRD). A pharmacokinetic study in patients with ESRD undergoing hemodialysis demonstrated a 36% increase in mean lomitapide plasma concentration compared to matched healthy controls. The terminal half-life of lomitapide was not affected. Hepatic insufficiency A single-dose, open-label study was conducted to evaluate the pharmacokinetics of 60 mg lomitapide in healthy volunteers with normal hepatic function compared with patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment. In patients with moderate hepatic impairment, lomitapide AUC and Cmax were 164% and 361% higher, respectively, compared with healthy volunteers. In patients with mild hepatic impairment, lomitapide AUC and Cmax were 47% and 4% higher, respectively, compared with healthy volunteers. Lojuxta has not been studied in patients with severe hepatic impairment (Child-Pugh score 10-15). Paediatric population Lojuxta has not been investigated in children less than 18 years of age. Elderly population Lojuxta has not been investigated in patients aged 65 years or older. 5.3 Preclinical safety data In repeat-dose oral toxicology studies in rodents and dogs, the principal drug-related findings were lipid accumulation in the small intestine and/or liver associated with decreases in serum cholesterol and/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 serum aminotransferases, subacute inflammation (rats only), and single-cell necrosis. In a 1 year repeat-dose study in dogs there were no microscopic changes in the liver although serum AST was minimally increased in females. Pulmonary histiocytosis was observed in rodents. Decreased red blood cell parameters as well as poikilocytosis and/or anisocytosis were observed in dogs. Testicular toxicity was observed in dogs at 205 times the human exposure (AUC) at 60 mg in a 6-month study. No adverse effects on the testes were observed in a 1-year study in dogs at 64 times the human exposure at 60mg. In a dietary carcinogenicity study in mice, lomitapide was administered up to 104 weeks at doses ranging from 0.3 to 45 mg/kg/day. There were statistically significant increases in the incidences of liver adenoma and carcinoma at doses ≥1.5 mg/kg/day in males (≥ 2 times the human exposure at 60 mg daily based on AUC) and ≥7.5 mg/kg/day in females (≥ 9 times the human exposure at 60 mg based 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 the human exposure at 60 mg based on AUC) and at 15 mg/kg/day in females (22 times the human exposure at 60 mg based on AUC). In an oral carcinogenicity study in rats, lomitapide was administered up to 99 weeks at doses up to 7.5 mg/kg/day in males and 2.0 mg/kg/day in females. Focal hepatic fibrosis was observed in males and females and hepatic cystic degeneration was observed in males only. In high-dose males, an increased incidence of pancreatic acinar cell adenoma was observed at an exposure 6 times that in humans 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 rats at 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) estimated to be twice that in humans at 60 mg. There was no evidence of embryofoetal toxicity in rabbits at 3 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. 6. Pharmaceutical particulars 6.1 List of excipients Capsule content Pregelatinised starch (maize) Sodium starch glycolate Microcrystalline cellulose Lactose monohydrate Silica, colloidal anhydrous Magnesium stearate Capsule shell Gelatin Titanium dioxide (E171) Red iron oxide (E172) Printing ink Shellac Black iron oxide (E172) Propylene glycol 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years. 6.4 Special precautions for storage Store below 30°C. Keep the bottle tightly closed in order to protect from moisture. 6.5 Nature and contents of container High density polyethylene (HDPE) bottle fitted with a polyester/aluminium foil/cardboard induction seal and polypropylene screw cap. Package sizes are: 28 capsules 6.6 Special precautions for disposal and other handling No special requirements. 7. Marketing authorisation holder Aegerion Pharmaceuticals Ltd Lakeside House 1 Furzeground Way Stockley Park East Uxbridge UB11 1BD United Kingdom 8. Marketing authorisation number(s) 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 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 31 July 2013 10. Date of revision of the text 18 December 2013 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. |