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Examiné médicalement par Militian Inessa Mesropovna, Pharmacie Dernière mise à jour le 21.03.2022
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Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate.
Primary Hyperlipidemia
Lipibec Plus® is indicated for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary (heterozygous familial and non-familial) hyperlipidemia or mixed hyperlipidemia.
Homozygous Familial Hypercholesterolemia (HoFH)
Lipibec Plus is indicated for the reduction of elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.
Limitations Of Use
No incremental benefit of Lipibec Plus on cardiovascular morbidity and mortality over and above that demonstrated for atorvastatin has been established. Lipibec Plus has not been studied in Fredrickson type I, III, IV, and V dyslipidemias.
Recommended Dosing
The dosage range of Lipibec Plus is 10/10 mg/day to 10/80 mg/day. The recommended starting dose of Lipibec Plus is 10/10 mg/day or 10/20 mg/day. Lipibec Plus can be administered as a single dose at any time of the day, with or without food. The recommended starting dose for patients who require a larger reduction in LDL-C (greater than 55%) is 10/40 mg/day. After initiation and/or upon titration of Lipibec Plus, lipid levels should be analyzed within 2 or more weeks and dosage adjusted accordingly.
Patients should swallow Lipibec Plus tablets whole. Tablets should not be crushed, dissolved, or chewed.
Patients With Homozygous Familial Hypercholesterolemia
The dosage of Lipibec Plus in patients with homozygous familial hypercholesterolemia is 10/40 mg/day or 10/80 mg/day. Lipibec Plus should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.
Coadministration With Other Drugs
Bile Acid Sequestrants
Dosing of Lipibec Plus should occur either greater than or equal to 2 hours before or greater than or equal to 4 hours after administration of a bile acid sequestrant.
Cyclosporine, Clarithromycin, Itraconazole, Or Certain HIV/HCV Antiviral Agents
In patients taking cyclosporine or the HIV protease inhibitors (tipranavir plus ritonavir) or the hepatitis C protease inhibitor (telaprevir), therapy with Lipibec Plus should be avoided. In patients with HIV taking lopinavir plus ritonavir, caution should be used when prescribing Lipibec Plus and the lowest dose necessary employed. In patients taking clarithromycin, itraconazole, or in patients with HIV taking a combination of saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, therapy with Lipibec Plus should be limited to 10/20 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of Lipibec Plus is employed. In patients taking hepatitis C antiviral agents containing elbasvir and grazoprevir, therapy with Lipibec Plus should not exceed 10/20 mg. In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, therapy with Lipibec Plus should be limited to 10/40 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of Lipibec Plus is employed.
Other Concomitant Lipid-Lowering Therapy
The combination of Lipibec Plus and gemfibrozil is not recommended.
Active liver disease or unexplained persistent elevations of hepatic transaminase levels.
Hypersensitivity to any component of Lipibec Plus.
Women who are pregnant or may become pregnant. Lipibec Plus may cause fetal harm when administered to a pregnant woman. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. There are no adequate and well-controlled studies of Lipibec Plus use during pregnancy; however in rare reports, congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, atorvastatin revealed no evidence of teratogenicity. Lipibec Plus should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the patient becomes pregnant while taking this drug, Lipibec Plus should be discontinued immediately, and the patient should be apprised of the potential hazard to the fetus.
Nursing mothers. It is not known whether atorvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require Lipibec Plus treatment should not breast-feed their infants.
WARNINGS
Included as part of the "PRECAUTIONS" Section
PRECAUTIONS
Myopathy/Rhabdomyolysis
Atorvastatin
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin and with other drugs in this class. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects.
Atorvastatin, like other statins, occasionally causes myopathy, defined as muscle aches or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values >10 times upper limit of normal (ULN). The concomitant use of higher doses of atorvastatin with certain drugs such as cyclosporine and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, and HIV protease inhibitors) increases the risk of myopathy/rhabdomyolysis.
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.
Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing Lipibec Plus. Lipibec Plus therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.
The risk of myopathy during treatment with statins is increased with concurrent administration of cyclosporine, fibric acid derivatives, erythromycin, clarithromycin, the hepatitis C antiviral agents telaprevir, a combination of elbasvir plus grazoprevir, combinations of HIV protease inhibitors, including saquinavir plus ritonavir, lopinavir plus ritonavir, tipranavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, and fosamprenavir plus ritonavir, niacin, or azole antifungals. Physicians considering combined therapy with Lipibec Plus and fibric acid derivatives, erythromycin, clarithromycin, a combination of elbasvir plus grazoprevir, a combination of saquinavir plus ritonavir, lopinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, azole antifungals, or lipid-modifying doses of niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Lower starting and maintenance doses of Lipibec Plus should be considered when taken concomitantly with the aforementioned drugs. Periodic CPK determinations may be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy.
Prescribing recommendations for interacting agents are summarized in Table 1.
Table 1: Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis with Atorvastatin
Interacting Agents | Prescribing Recommendations for Lipibec Plus |
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir), gemfibrozil | Avoid Lipibec Plus. |
HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary. |
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir*, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir), hepatitis C antiviral agents (elbasvir and grazoprevir) | Do not exceed 10/20 mg Lipibec Plus daily. |
HIV protease inhibitor (nelfinavir), hepatitis C protease inhibitor (boceprevir) | Do not exceed 10/40 mg Lipibec Plus daily. |
*Use with caution and with the lowest dose necessary |
Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin coadministered with colchicine, and caution should be exercised when prescribing Lipibec Plus with colchicine.
Lipibec Plus therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).
Ezetimibe
In clinical trials, there was no excess of myopathy or rhabdomyolysis associated with ezetimibe compared with the relevant control arm (placebo or statin alone). However, myopathy and rhabdomyolysis are known adverse reactions to statins and other lipid-lowering drugs. In clinical trials, the incidence of creatine phosphokinase (CPK) >10 times ULN was 0.2% for ezetimibe vs. 0.1% for placebo, and 0.1% for ezetimibe coadministered with a statin vs. 0.4% for statins alone. Risk for skeletal muscle toxicity increases with higher doses of statin, advanced age (>65), hypothyroidism, renal impairment, and depending on the statin used, concomitant use of other drugs.
In postmarketing experience with ezetimibe, cases of myopathy and rhabdomyolysis have been reported. Most patients who developed rhabdomyolysis were taking a statin prior to initiating ezetimibe. However, rhabdomyolysis has been reported with ezetimibe monotherapy and with the addition of ezetimibe to agents known to be associated with increased risk of rhabdomyolysis, such as fibric acid derivatives. Lipibec Plus and a fenofibrate, if taking concomitantly, should both be immediately discontinued if myopathy is diagnosed or suspected. The presence of muscle symptoms and a CPK level >10 times the ULN indicates myopathy.
Liver Enzymes
Atorvastatin
Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Persistent elevations (>3 times ULN occurring on 2 or more occasions) in serum transaminases occurred in 0.7% of patients who received atorvastatin in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg atorvastatin, respectively.
One patient in clinical trials of atorvastatin developed jaundice. Increases in liver function tests (LFT) in other patients were not associated with jaundice or other clinical signs or symptoms. Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent LFT elevations continued treatment with a reduced dose of atorvastatin.
Ezetimibe
In controlled clinical studies, the incidence of consecutive elevations (≥3 times ULN) in hepatic transaminase levels was similar between ezetimibe (0.5%) and placebo (0.3%).
In controlled clinical combination studies of ezetimibe coadministered with atorvastatin, the incidence of consecutive elevations (≥3 times ULN) in hepatic transaminase levels was 0.6% for patients treated with ezetimibe administered with atorvastatin. These elevations in transaminases were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment.
Lipibec Plus
It is recommended that liver enzyme tests be obtained prior to initiating therapy with Lipibec Plus and repeated as clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with Lipibec Plus, promptly interrupt therapy. If an alternate etiology is not found, do not restart Lipibec Plus.
Lipibec Plus should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of Lipibec Plus.
Endocrine Function
Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin.
Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production. Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve and that ezetimibe did not impair adrenocortical steroid hormone production. The effects of statins on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Caution should be exercised if Lipibec Plus is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.
Use In Patients With Recent Stroke Or TIA
In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study where atorvastatin 80 mg vs. placebo was administered in 4,731 subjects without CHD who had a stroke or TIA within the preceding 6 months, a higher incidence of hemorrhagic stroke was seen in the atorvastatin 80 mg group compared to placebo (55, 2.3% atorvastatin vs. 33, 1.4% placebo; HR: 1.68, 95% CI: 1.09, 2.59; p=0.0168). The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 vs. 18 for the atorvastatin and placebo groups, respectively). The incidence of nonfatal hemorrhagic stroke was significantly higher in the atorvastatin (38, 1.6%) group as compared to the placebo group (16, 0.7%). Some baseline characteristics, including hemorrhagic and lacunar stroke on study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group.
CNS Toxicity
Atorvastatin
Brain hemorrhage was seen in a female dog treated for 3 months at 120 mg/kg/day. Brain hemorrhage and optic nerve vacuolation were seen in another female dog that was sacrificed in moribund condition after 11 weeks of escalating doses up to 280 mg/kg/day. The 120 mg/kg dose resulted in a systemic exposure approximately 16 times the human plasma area-under-the-curve (AUC, 0-24 hours) based on the maximum human dose of 80 mg/day. A single tonic convulsion was seen in each of 2 male dogs (one treated at 10 mg/kg/day and one at 120 mg/kg/day) in a 2-year study. No CNS lesions have been observed in mice after chronic treatment for up to 2 years at doses up to 400 mg/kg/day or in rats at doses up to 100 mg/kg/day. These doses were 6 to 11 times (mouse) and 8 to 16 times (rat) the human AUC(0-24) based on the maximum recommended human dose of 80 mg/day.
CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other members of this class. A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose.
Patient Counseling Information
Advise the patient to read the FDA-Approved Patient Labeling (PATIENT INFORMATION).
Patients should be advised to adhere to their National Cholesterol Education Program (NCEP)recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel.
Muscle Pain
All patients starting therapy with Lipibec Plus should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing Lipibec Plus. The risk of this occurring is increased when taking certain types of medication or consuming larger quantities (>1 liter) of grapefruit juice. Patients should discuss all medication, both prescription and over-the-counter, with their physician.
Liver Enzymes
It is recommended that liver enzyme tests be performed before the initiation of Lipibec Plus and if signs or symptoms of liver injury occur. All patients treated with Lipibec Plus should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.
Pregnancy
Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using Lipibec Plus. Discuss future pregnancy plans with your patients, and discuss when to stop taking Lipibec Plus if they are trying to conceive. Patients should be advised that if they become pregnant they should stop taking Lipibec Plus and call their healthcare professional.
Breast-Feeding
Women who are breast-feeding should be advised to not use Lipibec Plus. Patients who have a lipid disorder and are breast-feeding should be advised to discuss the options with their healthcare professionals.
Important Storage And Administration Instructions
Patients should be advised to see the FDA-Approved Patient Labeling (PATIENT INFORMATION).
Tablets should be swallowed whole. Do not crush, dissolve, or chew tablets.
If a dose is missed, the patient should not take an extra dose. Just resume the usual schedule.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
No animal carcinogenicity or fertility studies have been conducted with the combination of ezetimibe and atorvastatin. The combination of ezetimibe with atorvastatin did not show evidence of mutagenicity in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with ezetimibe and atorvastatin with or without metabolic activation. There was no evidence of genotoxicity at doses up to 250 mg/kg with the combination of ezetimibe and atorvastatin (1:1) in the in vivo mouse micronucleus test.
Ezetimibe
A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice.
No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test.
In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe).
Atorvastatin
In a 2-year carcinogenicity study in rats at dose levels of 10, 30, and 100 mg/kg/day, 2 rare tumors were found in muscle in high-dose females: in one, there was a rhabdomyosarcoma and, in another, there was a fibrosarcoma. This dose represents a plasma AUC0-24hr value of approximately 16 times the mean human plasma drug exposure after an 80-mg oral dose.
A 2-year carcinogenicity study in mice given 100, 200, or 400 mg/kg/day resulted in a significant increase in liver adenomas in high-dose males and liver carcinomas in high-dose females. These findings occurred at plasma AUC0-24hr values of approximately 6 times the mean human plasma drug exposure after an 80-mg oral dose.
In vitro, atorvastatin was not mutagenic or clastogenic in the following tests with and without metabolic activation: the Ames test with Salmonella typhimurium and Escherichia coli, the HGPRT forward mutation assay in Chinese hamster lung cells, and the chromosomal aberration assay in Chinese hamster lung cells. Atorvastatin was negative in the in vivo mouse micronucleus test.
Studies in rats performed at doses up to 175 mg/kg (15 times the human exposure) produced no changes in fertility. There was aplasia and aspermia in the epididymis of 2 of 10 rats treated with 100 mg/kg/day of atorvastatin for 3 months (16 times the human AUC at the 80-mg dose); testis weights were significantly lower at 30 and 100 mg/kg and epididymal weight was lower at 100 mg/kg. Male rats given 100 mg/kg/day for 11 weeks prior to mating had decreased sperm motility, spermatid head concentration, and increased abnormal sperm. Atorvastatin caused no adverse effects on semen parameters, or reproductive organ histopathology in dogs given doses of 10, 40, or 120 mg/kg for two years.
Use In Specific Populations
Pregnancy
Pregnancy Category X.
Lipibec Plus
Lipibec Plus is contraindicated in women who are or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy. Lipid-lowering drugs offer no benefit during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy.
There are no adequate and well-controlled studies of Lipibec Plus use during pregnancy. There have been rare reports of congenital anomalies following intrauterine exposure to statins. In a review of about 100 prospectively followed pregnancies in women exposed to other statins, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. However, this study was only able to exclude a three-to-four-fold increased risk of congenital anomalies over background incidence. In 89% of these cases, drug treatment started before pregnancy and stopped during the first trimester when pregnancy was identified.
Statins may cause fetal harm when administered to a pregnant woman. Because Lipibec Plus contains atorvastatin, Lipibec Plus should be administered to women of childbearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the woman becomes pregnant while taking Lipibec Plus, it should be discontinued immediately and the patient advised again as to the potential hazards to the fetus and the lack of known clinical benefit with continued use during pregnancy.
Ezetimibe
In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses.
Atorvastatin
Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma. Atorvastatin was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day. These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure based on surface area (mg/m2).
In a study in rats given 20, 100, or 225 mg/kg/day, from gestation Day 7 through to lactation Day 21 (weaning), there was decreased pup survival at birth, neonate, weaning, and maturity in pups of mothers dosed with 225 mg/kg/day. Body weight was decreased on Days 4 and 21 in pups of mothers dosed at 100 mg/kg/day; pup body weight was decreased at birth and at Days 4, 21, and 91 at 225 mg/kg/day. Pup development was delayed (rotorod performance at 100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye opening at 225 mg/kg/day). These doses correspond to 6 times (100 mg/kg) and 22 times (225 mg/kg) the human AUC at 80 mg/day. Rare reports of congenital anomalies have been received following intrauterine exposure to statin reductase inhibitors.
Nursing Mothers
In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk.
It is not known whether atorvastatin is excreted in human milk, but a small amount of another drug in this class does pass into breast milk. Nursing rat pups had plasma and liver atorvastatin levels of 50% and 40%, respectively, of that in their mother’s milk. Because of the potential for adverse reactions in nursing infants, women taking Lipibec Plus should not breast-feed.
Pediatric Use
Lipibec Plus
Safety and effectiveness have not been established in pediatric patients.
Ezetimibe
Based on total ezetimibe (ezetimibe + ezetimibe-glucuronide) there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the pediatric population <10 years of age are not available.
Atorvastatin
Pharmacokinetic data in the pediatric population are not available.
Geriatric Use
Of the patients who received ezetimibe coadministered with atorvastatin in clinical studies, 1166 were 65 and older (this included 291 who were 75 and older). The effectiveness and safety of Lipibec Plus were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. Since advanced age (≥65 years) is a predisposing factor for myopathy, Lipibec Plus should be prescribed with caution in the elderly.
In geriatric patients, no dosage adjustment of Lipibec Plus is necessary.
Hepatic Impairment
Lipibec Plus is contraindicated in patients with active liver disease or unexplained persistent elevations in hepatic transaminase levels.
Renal Impairment
A history of renal impairment may be a risk factor for statin-associated myopathy. These patients merit closer monitoring for skeletal muscle effects.
In patients with renal impairment, no dosage adjustment of Lipibec Plus is necessary.
The following serious adverse reactions are discussed in greater detail in other sections of the label:
- Rhabdomyolysis and myopathy
- Liver enzyme abnormalities
Clinical Trials Experience
Lipibec Plus
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.
In a Lipibec Plus (ezetimibe and atorvastatin) placebo-controlled clinical trial, 628 patients (age range 18-86 years, 59% women, 85% Caucasians, 6% Blacks, 5% Hispanics, 3% Asians) with a median treatment duration of 12 weeks, 6% of patients on Lipibec Plus and 5% of patients on placebo discontinued due to adverse reactions.
The most common adverse reactions in the group treated with Lipibec Plus that led to treatment discontinuation and occurred at a rate greater than placebo were:
- Myalgia (0.8%)
- Abdominal pain (0.8%)
- Increased hepatic enzymes (0.8%)
The most commonly reported adverse reactions (incidence ≥2% and greater than placebo) in this trial were: increased ALT (5%), increased AST (4%), and musculoskeletal pain (4%).
Lipibec Plus has been evaluated for safety in 2403 patients in 7 clinical trials (one placebo-controlled trial and six active-controlled trials).
Table 2 summarizes the frequency of clinical adverse reactions reported in ≥2% of patients treated with Lipibec Plus (n=255) and at an incidence greater than placebo, regardless of causality assessment, from the placebo-controlled trial.
Table 2*: Clinical and Selected Laboratory Adverse Reactions Occurring in ≥2% of Patients Treated with Lipibec Plus and at an Incidence Greater than Placebo, Regardless of Causality
Body System/Organ Class Adverse Reaction | Placebo (%) n=60 | Ezetimibe 10 mg (%) n=65 | Atorvastatin† (%) n=248 | Lipibec Plus† (%) n=255 |
Nervous system disorders | ||||
Dizziness | 0 | 6 | <1 | 2 |
Respiratory, thoracic, and mediastinal disorders | ||||
Coughing | 0 | 3 | <1 | 2 |
Gastrointestinal disorders | ||||
Abdominal pain | 2 | 2 | 4 | 3 |
Nausea | 0 | 2 | 5 | 3 |
Musculoskeletal and connective tissue disorders | ||||
Arthralgia | 0 | 5 | 6 | 3 |
Muscle weakness | 0 | 2 | 0 | 2 |
Musculoskeletal pain | 3 | 8 | 5 | 4 |
Metabolism and nutrition disorders | ||||
Hyperkalemia | 0 | 0 | <1 | 2 |
Infections and infestations | ||||
Bronchitis | 0 | 2 | 2 | 2 |
Sinusitis | 0 | 3 | 2 | 2 |
Vascular disorders | ||||
Hot flushes | 0 | 0 | <1 | 2 |
Investigations | ||||
ALT increased | 0 | 0 | 2 | 5 |
AST increased | 0 | 0 | <1 | 4 |
* Placebo-controlled combination study in which the active ingredients equivalent to Lipibec Plus were coadministered. † All doses. |
After completing the 12-week study, eligible patients were assigned to coadministered ezetimibe and atorvastatin equivalent to Lipibec Plus (10/10-10/80) or atorvastatin (10-80 mg/day) for an additional 48 weeks. The long-term coadministration of ezetimibe plus atorvastatin had an overall safety profile similar to that of atorvastatin alone.
Ezetimibe
In 10 double-blind, placebo-controlled clinical trials, 2396 patients with primary hyperlipidemia (age range 9-86 years, 50% women, 90% Caucasians, 5% Blacks, 3% Hispanics, 2% Asians) and elevated LDL-C were treated with ezetimibe 10 mg/day for a median treatment duration of 12 weeks (range 0 to 39 weeks).
Adverse reactions reported in ≥2% of patients treated with ezetimibe and at an incidence greater than placebo regardless of causality assessment are shown in Table 3.
Table 3: Clinical Adverse Reactions Occurring in ≥2% of Patients Treated with Ezetimibe and at an Incidence Greater than Placebo, Regardless of Causality
Body System/Organ Class Adverse Reaction | Ezetimibe 10 mg (%) n=2396 | Placebo (%) n=1159 |
Gastrointestinal disorders | ||
Diarrhea | 4.1 | 3.7 |
General disorders and administration site conditions | ||
Fatigue | 2.4 | 1.5 |
Infections and infestations | ||
Influenza | 2.0 | 1.5 |
Sinusitis | 2.8 | 2.2 |
Upper respiratory tract infection | 4.3 | 2.5 |
Musculoskeletal and connective tissue disorders | ||
Arthralgia | 3.0 | 2.2 |
Pain in extremity | 2.7 | 2.5 |
Atorvastatin
In an atorvastatin placebo-controlled clinical trial database of 16,066 patients (8755 atorvastatin vs. 7311 placebo; age range 10.93 years, 39% women, 91% Caucasians, 3% Blacks, 2% Asians, 4% other) with a median treatment duration of 53 weeks, 9.7% of patients on atorvastatin and 9.5% of the patients on placebo discontinued due to adverse reactions regardless of causality.
The most commonly reported adverse reactions (incidence ≥2% and greater than placebo) regardless of causality, in patients treated with atorvastatin in placebo controlled trials (n=8755) were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), pain in extremity (6.0%), and urinary tract infection (5.7%).
Table 4 summarizes the frequency of clinical adverse reactions, regardless of causality, reported in ≥2% and at a rate greater than placebo in patients treated with atorvastatin (n=8755), from seventeen placebo-controlled trials.
Table 4: Clinical Adverse Reactions Occurring in >2% in Patients Treated with any dose of Atorvastatin and at an Incidence Greater than Placebo Regardless of Causality (% of patients).
Adverse Reaction* | Any dose n=8755 | Atorvastatin 10 mg n=3908 | Atorvastatin 20 mg n=188 | Atorvastatin 40 mg n=604 | Atorvastatin 80 mg n=4055 | Placebo n=7311 |
Nasopharyngitis | 8.3 | 12.9 | 5.3 | 7.0 | 4.2 | 8.2 |
Arthralgia | 6.9 | 8.9 | 11.7 | 10.6 | 4.3 | 6.5 |
Diarrhea | 6.8 | 7.3 | 6.4 | 14.1 | 5.2 | 6.3 |
Pain in extremity | 6.0 | 8.5 | 3.7 | 9.3 | 3.1 | 5.9 |
Urinary tract infection | 5.7 | 6.9 | 6.4 | 8.0 | 4.1 | 5.6 |
Dyspepsia | 4.7 | 5.9 | 3.2 | 6.0 | 3.3 | 4.3 |
Nausea | 4.0 | 3.7 | 3.7 | 7.1 | 3.8 | 3.5 |
Musculoskeletal pain | 3.8 | 5.2 | 3.2 | 5.1 | 2.3 | 3.6 |
Muscle spasms | 3.6 | 4.6 | 4.8 | 5.1 | 2.4 | 3.0 |
Myalgia | 3.5 | 3.6 | 5.9 | 8.4 | 2.7 | 3.1 |
Insomnia | 3.0 | 2.8 | 1.1 | 5.3 | 2.8 | 2.9 |
Pharyngolaryngeal pain | 2.3 | 3.9 | 1.6 | 2.8 | 0.7 | 2.1 |
*Adverse Reaction >2% in any dose greater than placebo |
Postmarketing Experience
Because the reactions below are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The additional events described below have been identified during post-approval use of ezetimibe and/or atorvastatin.
Blood and lymphatic system disorders: thrombocytopenia
Nervous system disorders: headache; dizziness; paresthesia; peripheral neuropathy
There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
Gastrointestinal disorders: pancreatitis
Skin and subcutaneous tissue disorders: angioedema; bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis); rash; urticaria
Musculoskeletal and connective tissue disorders: myositis; myopathy/rhabdomyolysis
There have been rare reports of immune-mediated necrotizing myopathy associated with statin use.
Injury, poisoning and procedural complications: tendon rupture
Immune system disorders: anaphylaxis; hypersensitivity reactions
Hepatobiliary disorders: hepatitis; cholelithiasis; cholecystitis; fatal and nonfatal hepatic failure
Psychiatric disorders: depression Respiratory: interstitial lung disease
Laboratory abnormalities: elevated creatine phosphokinase
General disorders and administration site conditions: fatigue
Lipibec Plus
Aucun traitement spécifique du surdosage avec Lipibec Plus ne peut être recommandé. En cas de surdosage, le patient doit être traité de manière symptomatique et des mesures de soutien doivent être mises en place au besoin.
Ezetimibe
Dans les études cliniques, administration d'ézétimibe, de 50 mg / jour à 15 sujets sains jusqu'à 14 jours, de 40 mg / jour à 18 patients atteints d'hyperlipidémie primaire jusqu'à 56 jours et de 40 mg / jour à 27 patients atteints d'homozygote sitostérolémie pendant 26 semaines, était généralement bien toléré. Une patiente atteinte de sitostérolémie homozygote a pris une surdose accidentelle d'ezetimibe 120 mg / jour pendant 28 jours sans aucun événement indésirable clinique ou de laboratoire signalé.
Atorvastatine
En raison de la liaison médicamenteuse étendue aux protéines plasmatiques, l'hémodialyse ne devrait pas améliorer considérablement la clairance de l'atorvastatine.
Des études cliniques ont démontré que des niveaux élevés de C total, de LDL-C et d'Apo B, le principal constituant protéique de la LDL, favorisent l'athérosclérose humaine. De plus, des niveaux réduits de HDL-C sont associés au développement de l'athérosclérose. Des études épidémiologiques ont établi que la morbidité et la mortalité cardiovasculaires varient directement avec le niveau de C total et de LDL-C et inversement avec le niveau de HDL-C. Comme le LDL, les lipoprotéines riches en triglycérides enrichies en cholestérol, y compris les lipoprotéines de très faible densité (VLDL), les lipoprotéines de densité intermédiaire (IDL) et les restes. L'effet indépendant de l'augmentation du HDL-C ou de la réduction des TG sur le risque de morbidité et de mortalité coronaires et cardiovasculaires n'a pas été déterminé.
L'atorvastatine ainsi que certains de ses métabolites sont pharmacologiquement actifs chez l'homme. Le foie est le principal site d'action et le principal site de synthèse du cholestérol et de clairance LDL. La posologie du médicament, plutôt que la concentration systémique du médicament, est mieux corrélée avec la réduction de la LDL-C. L'individualisation de la posologie du médicament doit être basée sur la réponse thérapeutique.
Lipibec Plus
Lipibec Plus s'est révélé bioéquivalent à la co-administration des doses correspondantes d'ezetimibe et de comprimés d'atorvastatine.
Absorption
Ezetimibe
Après administration orale, l'ézétimibe est absorbé et largement conjugué à un glucuronide phénolique pharmacologiquement actif (ézétimibe-glucuronide).
Atorvastatine
Les concentrations plasmatiques maximales d'atorvastatine après administration orale se produisent dans les 1 à 2 heures. L'étendue de l'absorption augmente proportionnellement à la dose d'atorvastatine. La biodisponibilité absolue de l'atorvastatine (médicament parent) est d'environ 14% et la disponibilité systémique de l'activité inhibitrice de l'HMG-CoA réductase est d'environ 30%. La faible disponibilité systémique est attribuée à la clairance présystémique de la muqueuse gastro-intestinale et / ou du métabolisme hépatique de premier passage. Les concentrations plasmatiques d'atorvastatine sont plus faibles (environ 30% pour la Cmax et l'ASC) après l'administration du médicament le soir par rapport au matin. Cependant, la réduction du LDL-C est la même quelle que soit l'heure de la journée d'administration du médicament.
Effet des aliments sur l'absorption orale
Lipibec Plus
Lorsque Lipibec Plus 10/80 comprimés a été administré avec un repas riche en graisses, la Cmax de l'atorvastatine a diminué de 7% et aucun effet sur l'ASC de l'atorvastatine n'a été observé. Un repas riche en graisses n'a eu aucun effet sur la pharmacocinétique de l'ézétimibe non conjugué.
Lipibec Plus peut être pris avec ou sans nourriture.
Distribution
Ezetimibe
L'ézétimibe et l'ézétimibe-glucuronide sont fortement liés (> 90%) aux protéines plasmatiques humaines.
Atorvastatine
Le volume moyen de distribution de l'atorvastatine est d'environ 381 litres. L'atorvastatine est liée à ≥98% aux protéines plasmatiques. Un rapport sang / plasma d'environ 0,25 indique une mauvaise pénétration du médicament dans les globules rouges. D'après les observations chez le rat, l'atorvastatine est susceptible d'être sécrétée dans le lait maternel.
Métabolisme et excrétion
Ezetimibe
L'ézétimibe est principalement métabolisé dans l'intestin grêle et le foie par conjugaison des glucuronides avec excrétion biliaire et rénale ultérieure. Un métabolisme oxydatif minimal a été observé chez toutes les espèces évaluées.
Chez l'homme, l'ézétimibe est rapidement métabolisé en l'ézétimibe-glucuronide. L'ézétimibe et l'ézétimibeglucuronide sont les principaux composés dérivés du médicament détectés dans le plasma, constituant respectivement environ 10 à 20% et 80 à 90% du médicament total dans le plasma. L'ezétimibe et l'ezétimibe-glucuronide sont éliminés du plasma avec une demi-vie d'environ 22 heures pour l'ezétimibe et l'ezétimibeglucuronide. Les profils concentration-temps plasmatiques présentent plusieurs pics, ce qui suggère un recyclage entérohépatique.
Après administration orale de 14Le C-ézétimibe (20 mg) chez l'homme, l'ézétimibe total (ézétimibe + ézétimibe-glucuronide) représentait environ 93% de la radioactivité totale dans le plasma. Après 48 heures, il n'y avait aucun niveau détectable de radioactivité dans le plasma.
Environ 78% et 11% de la radioactivité administrée ont été récupérés dans les excréments et l'urine, respectivement, sur une période de collecte de 10 jours. L'ézétimibe était le principal composant des excréments et représentait 69% de la dose administrée, tandis que l'ézétimibe-glucuronide était le principal composant de l'urine et représentait 9% de la dose administrée.
Atorvastatine
L'atorvastatine est largement métabolisée en dérivés ortho et parahydroxylés et en divers produits de bêta-oxydation. In vitro l'inhibition de l'HMG-CoA réductase par les métabolites ortho-et parahydroxylés est équivalente à celle de l'atorvastatine. Environ 70% de l'activité inhibitrice circulante de l'HMG-CoA réductase est attribuée aux métabolites actifs. In vitro des études suggèrent l'importance du métabolisme de l'atorvastatine par le cytochrome P450 3A4, compatible avec l'augmentation des concentrations plasmatiques d'atorvastatine chez l'homme après la co-administration avec l'érythromycine, un inhibiteur connu de cette isozyme. Chez les animaux, le métabolite ortho-hydroxy subit une glucuronidation supplémentaire.
L'atorvastatine et ses métabolites sont éliminés principalement dans la bile après un métabolisme hépatique et / ou extra-hépatique; cependant, le médicament ne semble pas subir de recirculation entérohépatique. La demi-vie d'élimination plasmatique moyenne de l'atorvastatine chez l'homme est d'environ 14 heures, mais la demi-vie de l'activité inhibitrice de l'HMG-CoA réductase est de 20 à 30 heures en raison de la contribution des métabolites actifs. Moins de 2% d'une dose d'atorvastatine est récupérée dans l'urine après administration orale.