Componentes:
Método de ação:
Opção de tratamento:
Medicamente revisado por Militian Inessa Mesropovna, Farmácia Última atualização em 17.03.2022
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20 principais medicamentos com os mesmos componentes:
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A terapia com agentes que alteram os lipídios deve ser apenas um componente da intervenção em múltiplos fatores de risco em indivíduos com risco significativamente aumentado de doença vascular aterosclerótica devido à hipercolesterolemia. A terapia medicamentosa é indicada como um complemento à dieta quando a resposta a uma dieta restrita em gordura saturada e colesterol e outras medidas não farmacológicas por si só foi inadequada.
Hipercolesterolemia (Heterozigótica Familiar e Não Familiar) e Dislipidemia Mista
Lipoxan e Lipoxan XL são indicados
- como um complemento à dieta para reduzir os níveis elevados de colesterol total (Total-C), lipoproteína de baixa densidade (LDL-C), triglicerídeo (TG) e apolipoproteína B (Apo B) e aumentar o colesterol de lipoproteína de alta densidade (HDL-C) em pacientes com hipercolesterolemia primária e dislipidemia mista (Fred).
- como um complemento à dieta para reduzir os níveis de Total C, LDL-C e Apo B em meninos e meninas adolescentes que têm pelo menos um ano de pós-menarca, 10 a 16 anos de idade, com hipercolesterolemia familiar heterozigótica e os seguintes resultados estão presentes:
- LDL-C permanece ≥ 190 mg / dL ou
- LDL-C permanece ≥ 160 mg / dL e :
- existe um histórico familiar positivo de doença cardiovascular prematura ou
- dois ou mais outros fatores de risco para doenças cardiovasculares estão presentes
A classificação NCEP dos níveis de colesterol em pacientes pediátricos com histórico familiar de hipercolesterolemia ou DCV prematura está resumida abaixo.
Categoria | Total-C (mg / dL) | LDL-C (mg / dL) |
Aceitável | <170 | <110 |
Borderline | 170-199 | 110-129 |
Alto | ≥ 200 | ≥ 130 |
As crianças tratadas com fluvastatina na adolescência devem ser reavaliadas na idade adulta e as alterações apropriadas feitas no regime de redução do colesterol para atingir as metas de tratamento para adultos.
Prevenção Secundária de Doenças Cardiovasculares
Em pacientes com DCC clinicamente evidente, o Lipaxan e o Lipaxan XL são indicados para:
- reduzir o risco de sofrer procedimentos de revascularização coronária
- retardar a progressão da aterosclerose coronariana
Limitações de uso
Nem o Lipoxan nem o Lipoxan XL foram estudados em condições em que a principal anormalidade é a elevação de quilomícrons, VLDL ou IDL (ou seja,., hiperlipoproteinemia Tipos I, III, IV ou V).
Informações gerais sobre dosagem
Faixa de dose: 20 mg a 80 mg / dia.
Lipoxan / Lipaxan XL pode ser administrado por via oral em dose única, com ou sem alimentos.
Não quebre, esmague ou mastigue os comprimidos de Lipaxan XL ou abra as cápsulas de Lipaxan antes da administração.
Não tome duas cápsulas de Lipaxan 40 mg ao mesmo tempo.
Como o efeito máximo de uma determinada dose é observado dentro de 4 semanas, determinações lipídicas periódicas devem ser realizadas neste momento e a dose ajustada de acordo com a resposta do paciente à terapia e diretrizes de tratamento estabelecidas.
Para pacientes que necessitam de redução de LDL-C para uma meta de ≥ 25%, a dose inicial recomendada é de 40 mg como uma cápsula à noite, 80 mg como um comprimido de Lipoxan XL administrado em dose única a qualquer hora do dia ou 80 mg em doses divididas da cápsula de 40 mg administrada duas vezes ao dia. Para pacientes que necessitam de redução de LDL-C para uma meta de <25%, pode ser usada uma dose inicial de 20 mg.
Pacientes adultos com hipercolesterolemia (hiponto familiar e não familiar) e dislipidemia mista
Pacientes adultos podem ser iniciados no Lipoxan ou no Lipoxan XL. A dose inicial recomendada para Lipoxan é uma cápsula de 40 mg à noite ou uma cápsula de Lipoxan 40 mg duas vezes ao dia. Não tome duas cápsulas de Lipaxan 40 mg ao mesmo tempo.
A dose inicial recomendada para Lipaxan XL é um comprimido de 80 mg administrado em dose única a qualquer hora do dia.
Pacientes pediátricos (10 a 16 anos) com Hipercolesterolemia Familiar Heterozigótica
A dose inicial recomendada é de uma cápsula de 20 mg de lipaxano. Os ajustes de dose, até uma dose diária máxima administrada como cápsulas de Lipaxan 40 mg duas vezes ao dia ou um comprimido de Lipaxan XL 80 mg uma vez ao dia, devem ser feitos em intervalos de 6 semanas. As doses devem ser individualizadas de acordo com o objetivo da terapia 1.
Use com ciclosporina
Não exceda uma dose de 20 mg b.i.d. Lipaxan em pacientes em uso de ciclosporina.
Use com fluconazol
Não exceda uma dose de 20 mg b.i.d. Lipaxan em pacientes em uso de fluconazol.
Hypersensitivity to any Component of this Medication
Lipaxan and Lipaxan XL are contraindicated in patients with hypersensitivity to any component of this medication.
Active Liver Disease
Lipaxan and Lipaxan XL are contraindicated in patients with active liver disease or unexplained, persistent elevations in serum transaminases.
Pregnancy
Lipaxan and Lipaxan XL are contraindicated in women who are pregnant or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Lipaxan and Lipaxan XL may cause fetal harm when administered to pregnant women. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia.
Lipaxan and Lipaxan XL 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, Lipaxan and Lipaxan XL should be discontinued and the patient should be apprised of the potential hazard to the fetus.
Nursing Mothers
Fluvastatin is secreted into the breast milk of animals and because HMG-CoA reductase inhibitors have the potential to cause serious adverse reactions in nursing infants, women who require treatment with Lipaxan or Lipaxan XL should be advised not to breastfeed their infants.
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Skeletal Muscle
Rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with Lipaxan/Lipaxan XL and other drugs in this class.
Lipaxan/Lipaxan XL should be prescribed with caution in patients with predisposing factors for myopathy. These factors include advanced age ( > 65 years), renal impairment, and inadequately treated hypothyroidism.
The risk of myopathy and/or rhabdomyolysis with statins is increased with concurrent therapy with cyclosporine, erythromycin, fibrates or niacin. Myopathy was not observed in a clinical trial in 74 patients involving patients who were treated with Lipaxan/Lipaxan XL together with niacin. Isolated cases of myopathy have been reported during post-marketing experience with concomitant administration of Lipaxan/Lipaxan XL and colchicine. No information is available on the pharmacokinetic interaction between Lipaxan/Lipaxan XL and colchicine.
Uncomplicated myalgia has also been reported in Lipaxan-treated patients. In clinical trials, uncomplicated myalgia has been observed infrequently in patients treated with Lipaxan at rates indistinguishable from placebo. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in CPK values to greater than 10 times the upper limit of normal, was < 0.1% in fluvastatin clinical trials. 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.
Lipaxan/Lipaxan XL therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Lipaxan/Lipaxan XL therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.
Liver Enzymes
Increases in serum transaminases (aspartate aminotransferase [AST]/serum glutamic-oxaloacetic transaminase, or alanine aminotransferase [ALT]/serum glutamic-pyruvic transaminase) have been reported with HMG-CoA reductase inhibitors, including Lipaxan/Lipaxan XL. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy.
Approximately 1.1% of patients treated with Lipaxan capsules in worldwide trials developed dose-related, persistent elevations of serum transaminase levels to more than 3 times the upper limit of normal. Fourteen of these patients (0.6%) were discontinued from therapy. In all clinical trials, a total of 33/2969 patients (1.1%) had persistent transaminase elevations with an average Lipaxan exposure of approximately 71.2 weeks; 19 of these patients (0.6%) were discontinued. The majority of patients with these abnormal biochemical findings were asymptomatic.
In a pooled analysis of all placebo-controlled studies in which Lipaxan capsules were used, persistent transaminase elevations ( > 3 times the upper limit of normal [ULN] on two consecutive weekly measurements) occurred in 0.2%, 1.5%, and 2.7% of patients treated with daily doses of 20, 40, and 80 mg (titrated to 40 mg twice daily) Lipaxan capsules, respectively. Ninety-one percent of the cases of persistent liver function test abnormalities (20 of 22 patients) occurred within 12 weeks of therapy and in all patients with persistent liver function test abnormalities there was an abnormal liver function test present at baseline or by Week 8.
In the pooled analysis of the 24-week controlled trials, persistent transaminase elevation occurred in 1.9%, 1.8% and 4.9% of patients treated with Lipaxan XL 80 mg, Lipaxan 40 mg and Lipaxan 40 mg twice daily, respectively. In 13 of 16 patients treated with Lipaxan XL the abnormality occurred within 12 weeks of initiation of treatment with Lipaxan XL 80 mg.
It is recommended that liver enzyme tests be performed prior to the initiation of Lipaxan/Lipaxan XL, and if signs or symptoms of liver injury occur.
There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including fluvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with Lipaxan/Lipaxan XL, promptly interrupt therapy. If an alternate etiology is not found do not restart Lipaxan/Lipaxan XL.
In very rare cases, possibly drug-related hepatitis was observed that resolved upon discontinuation of treatment.1 Active liver disease or unexplained serum transaminase elevations are contraindications to the use of Lipaxan and Lipaxan XL. Such patients should be closely monitored.
Endocrine Effects
Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including Lipaxan/Lipaxan XL.
Statins interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production.
Lipaxan/Lipaxan XL exhibited no effect upon non-stimulated cortisol levels and demonstrated no effect upon thyroid metabolism as assessed by measurement of thyroid stimulating hormone (TSH). Small declines in total serum testosterone have been noted in treated groups, but no commensurate elevation in LH occurred, suggesting that the observation was not due to a direct effect upon testosterone production. No effect upon FSH in males was noted. Due to the limited number of premenopausal females studied to date, no conclusions regarding the effect of Lipaxan/Lipaxan XL upon female sex hormones may be made.
Two clinical studies in patients receiving fluvastatin at doses up to 80 mg daily for periods of 24 to 28 weeks demonstrated no effect of treatment upon the adrenal response to ACTH stimulation. A clinical study evaluated the effect of Lipaxan at doses up to 80 mg daily for 28 weeks upon the gonadal response to HCG stimulation. Although the mean total testosterone response was significantly reduced (p < 0.05) relative to baseline in the 80 mg group, it was not significant in comparison to the changes noted in groups receiving either 40 mg of Lipaxan or placebo.
Patients treated with Lipaxan/Lipaxan XL who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should be exercised if a statin or other agent used to lower cholesterol levels is administered to patients receiving other drugs (e.g. ketoconazole, spironolactone, cimetidine) that may decrease the levels of endogenous steroid hormones.
CNS Toxicity
CNS effects, as evidenced by decreased activity, ataxia, loss of righting reflex, and ptosis were seen in the following animal studies: the 18-month mouse carcinogenicity study at 50 mg/kg/day, the 6-month dog study at 36 mg/kg/day, the 6-month hamster study at 40 mg/kg/day, and in acute, high-dose studies in rats and hamsters (50 mg/kg), rabbits (300 mg/kg) and mice (1500 mg/kg). CNS toxicity in the acute high-dose studies was characterized (in mice) by conspicuous vacuolation in the ventral white columns of the spinal cord at a dose of 5000 mg/kg and (in rats) by edema with separation of myelinated fibers of the ventral spinal tracts and sciatic nerve at a dose of 1500 mg/kg. CNS toxicity, characterized by periaxonal vacuolation, was observed in the medulla of dogs that died after treatment for 5 weeks with 48 mg/kg/day; this finding was not observed in the remaining dogs when the dose level was lowered to 36 mg/kg/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 drug class. No CNS lesions have been observed after chronic treatment for up to 2 years with fluvastatin in the mouse (at doses up to 350 mg/kg/day), rat (up to 24 mg/kg/day), or dog (up to 16 mg/kg/day).
Prominent bilateral posterior Y suture lines in the ocular lens were seen in dogs after treatment with 1, 8, and 16 mg/kg/day for 2 years.
Patient Counseling Information
Information For Patients
Patients taking Lipaxan/Lipaxan XL should be advised that high cholesterol is a chronic condition and they should adhere to their medication along with their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel to determine goal attainment.
Patients should be advised about substances they should not take concomitantly with Lipaxan/Lipaxan XL. Patients should also be advised to inform other healthcare professionals prescribing a new medication that they are taking Lipaxan/Lipaxan XL.
Muscle Pain
Patients starting therapy with Lipaxan/Lipaxan XL 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.
Liver Enzymes
It is recommended that liver enzyme tests be performed before the initiation of Lipaxan/Lipaxan XL and if signs or symptoms of liver injury occur. All patients treated with Lipaxan/Lipaxan XL 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 Lipaxan/Lipaxan XL. Discuss future pregnancy plans with your patients, and discuss when to stop taking Lipaxan/Lipaxan XL if they are trying to conceive. Patients should be advised that if they become pregnant they should stop taking Lipaxan/Lipaxan XL and call their healthcare professional.
Breastfeeding
Women who are breastfeeding should not use Lipaxan/Lipaxan XL. Patients who have a lipid disorder and are breastfeeding should be advised to discuss the options with their healthcare professional.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
A 2-year study was performed in rats at dose levels of 6, 9, and 18-24 (escalated after 1 year) mg/kg/day. These treatment levels represented plasma drug levels of approximately 9, 13, and 26-35 times the mean human plasma drug concentration after a 40 mg oral dose. A low incidence of forestomach squamous papillomas and 1 carcinoma of the forestomach at the 24 mg/kg/day dose level was considered to reflect the prolonged hyperplasia induced by direct contact exposure to fluvastatin sodium rather than to a systemic effect of the drug. In addition, an increased incidence of thyroid follicular cell adenomas and carcinomas was recorded for males treated with 18-24 mg/kg/day. The increased incidence of thyroid follicular cell neoplasm in male rats with fluvastatin sodium appears to be consistent with findings from other HMG-CoA reductase inhibitors. In contrast to other HMG-CoA reductase inhibitors, no hepatic adenomas or carcinomas were observed.
The carcinogenicity study conducted in mice at dose levels of 0.3, 15 and 30 mg/kg/day revealed, as in rats, a statistically significant increase in forestomach squamous cell papillomas in males and females at 30 mg/kg/day and in females at 15 mg/kg/day. These treatment levels represented plasma drug levels of approximately 0.05, 2, and 7 times the mean human plasma drug concentration after a 40 mg oral dose.
No evidence of mutagenicity was observed in vitro, with or without rat-liver metabolic activation, in the following studies: microbial mutagen tests using mutant strains of Salmonella typhimurium or Escherichia coli; malignant transformation assay in BALB/3T3 cells; unscheduled DNA synthesis in rat primary hepatocytes; chromosomal aberrations in V79 Chinese Hamster cells; HGPRT V79 Chinese Hamster cells. In addition, there was no evidence of mutagenicity in vivo in either a rat or mouse micronucleus test.
In a study in rats at dose levels for females of 0.6, 2 and 6 mg/kg/day and at dose levels for males of 2, 10 and 20 mg/kg/day, fluvastatin sodium had no adverse effects on the fertility or reproductive performance.
Seminal vesicles and testes were small in hamsters treated for 3 months at 20 mg/kg/day (approximately three times the 40 mg human daily dose based on surface area, mg/m²). There was tubular degeneration and aspermatogenesis in testes as well as vesiculitis of seminal vesicles. Vesiculitis of seminal vesicles and edema of the testes were also seen in rats treated for 2 years at 18 mg/kg/day (approximately 4 times the human Cmax achieved with a 40 mg daily dose).
Fluvastatin sodium produced delays in skeletal development in rats at doses of 12 mg/kg/day and in rabbits at doses of 10 mg/kg/day. Malaligned thoracic vertebrae were seen in rats at 36 mg/kg, a dose that produced maternal toxicity. These doses resulted in 2 times (rat at 12 mg/kg) or 5 times (rabbit at 10 mg/kg) the 40 mg human exposure based on mg/m2 surface area. A study in which female rats were dosed during the third trimester at 12 and 24 mg/kg/day resulted in maternal mortality at or near term and postpartum. In addition, fetal and neonatal lethality were apparent. No effects on the dam or fetus occurred at 2 mg/kg/day. A second study at levels of 2, 6, 12 and 24 mg/kg/day confirmed the findings in the first study with neonatal mortality beginning at 6 mg/kg. A modified Segment III study was performed at dose levels of 12 or 24 mg/kg/day with or without the presence of concurrent supplementation with mevalonic acid, a product of HMG-CoA reductase which is essential for cholesterol biosynthesis. The concurrent administration of mevalonic acid completely prevented the maternal and neonatal mortality but did not prevent low body weights in pups at 24 mg/kg on days 0 and 7 postpartum.
Use In Specific Populations
Pregnancy
Pregnancy Category X
Lipaxan/Lipaxan XL is contraindicated in women who are or may become pregnant.
Lipid lowering drugs are contraindicated during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development. Serum cholesterol and triglycerides increase during normal pregnancy. 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 use with Lipaxan/Lipaxan XL during pregnancy. Rare reports of congenital anomalies have been received following intrauterine exposure to other statins. In a review2 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. The number of cases is adequate only to exclude a 3-to 4-fold increase in congenital anomalies over background incidence. In 89% of prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.
Teratology studies with fluvastatin in rats and rabbits showed maternal toxicity at high dose levels, but there was no evidence of embryotoxic or teratogenic potential.
Lipaxan or Lipaxan XL should be administered to women of child-bearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If a woman becomes pregnant while taking Lipaxan or Lipaxan XL, the drug should be discontinued and the patient advised again as to the potential hazards to the fetus.
Nursing Mothers
Based on animal data, fluvastatin is present in breast milk in a 2:1 ratio (milk:plasma). Because of the potential for serious adverse reactions in nursing infants, nursing women should not take Lipaxan or Lipaxan XL.
Pediatric Use
The safety and efficacy of Lipaxan and Lipaxan XL in children and adolescent patients 9-16 years of age with heterozygous familial hypercholesterolemia have been evaluated in open-label, uncontrolled clinical trials for a duration of two years. The most common adverse events observed were influenza and infections. In these limited uncontrolled studies, there was no detectable effect on growth or sexual maturation in the adolescent boys or on menstrual cycle length in girls. Adolescent females should be counseled on appropriate contraceptive methods while on Lipaxan therapy.
Geriatric Use
Fluvastatin exposures were not significantly different between the nonelderly and elderly populations (age ≥ 65 years). Since advanced age ( > 65 years) is a predisposing factor for myopathy, Lipaxan/Lipaxan XL should be prescribed with caution in the elderly.
Hepatic Impairment
Lipaxan and Lipaxan XL are contraindicated in patients with active liver disease or unexplained, persistent elevations in serum transaminases.
Renal Impairment
Dose adjustments for mild to moderate renal impairment are not necessary. Fluvastatin has not been studied at doses greater than 40 mg in patients with severe renal impairment; therefore caution should be exercised when treating such patients at higher doses.
REFERENCES
1. National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics. 89(3):495-501.1992.
2. Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During Pregnancy, Reproductive Toxicology, 10(6): 439-446, 1996.
As seguintes reações adversas graves são discutidas em mais detalhes em outras seções do rótulo :
- Rabdomiólise com mioglobinúria e insuficiência renal aguda e miopatia (incluindo miosite).
- Anormalidades da enzima hepática.
Experiência em estudos clínicos em pacientes adultos
Porque estudos clínicos sobre Lipoxan / Lipaxan XL são realizados em diferentes populações de estudo e desenhos de estudo, a frequência de reações adversas observadas nos estudos clínicos de Lipoxan / Lipaxan XL não pode ser comparada diretamente com a dos estudos clínicos de outras estatinas e pode não refletir a frequência de reações adversas observadas na prática clínica.
No banco de dados de ensaios clínicos controlados por placebo de Lipaxan, de 2326 pacientes tratados com Lipaxan1 (faixa etária de 18 a 75 anos, 44% de mulheres, 94% de caucasianos, 4% de negros, 2% de outras etnias) com duração média do tratamento de 24 semanas, 3,4% dos pacientes em Lipaxan e 2,3% dos pacientes em placebo foram descontinuados devido a reações adversas independentemente da causalidade. As reações adversas mais comuns que levaram à descontinuação do tratamento e ocorreram em uma incidência maior que o placebo foram: transaminase aumentada (0,8%), dor abdominal superior (0,3%), dispepsia (0,3%), fadiga (0,2%) e diarréia (0,2%) .
No banco de dados Lipoxan XL de ensaios clínicos controlados de 912 pacientes tratados com Lipoxan XL (faixa etária de 21 a 87 anos, 52% de mulheres, 91% caucasianos, 4% de negros, 5% de outras etnias) com uma duração média do tratamento de 24 semanas, 3,9% dos pacientes em Lipaxan XL foram descontinuados devido a reações adversas, independentemente da causalidade. As reações adversas mais comuns que levaram à descontinuação do tratamento foram dor abdominal (0,7%), diarréia (0,5%), náusea (0,4%), dispepsia (0,4%) e dor no peito (0,3%).
As experiências adversas clinicamente relevantes que ocorrem nos estudos controlados por Lipaxan e Lipaxan XL com uma frequência> 2%, independentemente da causalidade, incluíram o seguinte :
Tabela 1: Eventos adversos clínicos relatados em> 2% em pacientes tratados com Lipoxan / Lipaxan XL e com uma incidência maior que o placebo em ensaios controlados por placebo, independentemente da causalidade (% dos pacientes) Dosagens agrupadas
Lipaxan1 N = 2326 (%) | Placebo1 N = 960 (%) | Lipoxan XL2 N = 912 (%) | ||
Musculoesquelético | Mialgia | 5.0 | 4.5 | 3.8 |
Artrite | 2.1 | 2.0 | 1.3 | |
Artropatia | NA | NA | 3.2 | |
Respiratório | Sinusite | 2.6 | 1.9 | 3.5 |
Bronquite | 1.8 | 1.0 | 2.6 | |
Gastrointestinal | Dispepsia | 7.9 | 3.2 | 3.5 |
Diarréia | 4.9 | 4.2 | 3.3 | |
Dor abdominal | 4.9 | 3.8 | 3.7 | |
Náusea | 3.2 | 2.0 | 2.5 | |
Flatulência | 2.6 | 2.5 | 1.4 | |
Distúrbio dentário | 2.1 | 1.7 | 1.4 | |
Psiquiátrico | Insônia | 2.7 | 1.4 | 0,8 |
Geniturinário | Infecção do trato urinário | 1.6 | 1.1 | 2.7 |
Diversos | Dor de cabeça | 8.9 | 7.8 | 4.7 |
Sintomas semelhantes à gripe | 5.1 | 5.7 | 7.1 | |
Trauma acidental | 5.1 | 4.8 | 4.2 | |
Fadiga | 2.7 | 2.3 | 1.6 | |
Alergia | 2.3 | 2.2 | 1.0 | |
1Ensaios controlados com cápsulas de lipaxano (20 e 40 mg por dia e 40 mg duas vezes por dia) em comparação com o placebo 2Ensaios controlados com Lipaxan XL 80 mg Comprimidos em comparação com Lipaxan Capsules |
Estudo de prevenção de intervenções em lipoxanos
No Estudo de Prevenção de Intervenção Lipaxana (LIPS), o efeito de Lipaxan 40 mg, administrado duas vezes ao dia sobre o risco de eventos cardíacos recorrentes, foi avaliado em 1677 pacientes com DCC que haviam sido submetidos a um procedimento de intervenção coronária percutânea (ICP). Este foi um estudo multicêntrico, randomizado, duplo-cego e controlado por placebo, os pacientes foram tratados com aconselhamento dietético / estilo de vida e Lipaxan 40 mg (n = 844) ou placebo (n = 833) administrado duas vezes ao dia por uma mediana de 3,9 anos.
Tabela 2: Eventos adversos clínicos relatados em ≥ 2% em pacientes tratados com Lipoxan / Lipaxan XL e com uma incidência maior que o placebo no estudo LIPS, independentemente da causalidade (% dos pacientes)
Lipaxan 40 mg b.i.d N = 822 (%) | Placebo N = 818 (%) | ||
Cardiopatias | Fibrilação atrial | 2.4 | 2.0 |
Distúrbios gastrointestinais | Dor abdominal superior | 6.3 | 4.5 |
Constipação | 3.3 | 2.1 | |
Dispepsia | 4.5 | 4.0 | |
Distúrbio gástrico | 2.7 | 2.1 | |
Náusea | 2.7 | 2.3 | |
Distúrbios gerais | Fadiga | 4.7 | 3.8 |
Edema periférico | 4.4 | 2.9 | |
Infecções e infestações | Bronquite | 2.3 | 2.0 |
Nasofaringite | 2.8 | 2.1 | |
Afecções musculosqueléticas e dos tecidos conjuntivos | Artralgia | 2.1 | 1.8 |
Mialgia | 2.2 | 1.6 | |
Dor na extremidade | 4.1 | 2.7 | |
Distúrbios do sistema nervoso | Tontura | 3.9 | 3.5 |
Síncope | 2.4 | 2.2 | |
Distúrbios respiratórios | Dispnéia de esforço | 2.8 | 2.4 |
Distúrbios vasculares | Hipertensão | 5.8 | 4.2 |
Claudicação intermitente | 2.3 | 2.1 |
Experiência em estudos clínicos em pacientes pediátricos
Em pacientes com idade <18 anos, eficácia e segurança não foram estudadas por períodos de tratamento superiores a dois anos.
Em dois rótulos abertos, estudos não controlados, 66 meninos e 48 meninas com hipercolesterolemia familiar heterozigótica ( 9-16 anos de idade, 80% caucasiano, 19% Outros [ etnia mista] 1% de asiáticos) foram tratados com fluvastatina sódica administrada em cápsulas de Lipaxan 20 mg -40 mg duas vezes ao dia, ou Lipaxan XL 80 mg comprimido de libertação prolongada.
Experiência pós-comercialização
Como as reações adversas de relatórios espontâneos são relatadas voluntariamente de uma população de tamanho incerto, geralmente não é possível estimar com segurança sua frequência ou estabelecer uma relação causal com a exposição a medicamentos. Os seguintes efeitos foram relatados com medicamentos nesta classe. Nem todos os efeitos listados abaixo foram necessariamente associados à terapia com fluvastatina sódica.
Músculo-esquelético: cãibras musculares, mialgia, miopatia, rabdomiólise, artralgias, espasmos musculares, fraqueza muscular, miosite.
Neurológico: disfunção de certos nervos cranianos (incluindo alteração do paladar, comprometimento do movimento extra-ocular, paresis facial), tremor, tontura, vertigem, parestesia, hipoestesia, disestesia, neuropatia periférica, paralisia do nervo periférico.
Houve raros relatórios pós-comercialização de comprometimento cognitivo (por exemplo,., perda de memória, esquecimento, amnésia, comprometimento da memória, confusão) associada ao uso de estatina. Esses problemas cognitivos foram relatados para todas as estatinas. Os relatórios são geralmente não-sérios e reversíveis após a descontinuação da estatina, com tempos variáveis para o início dos sintomas (1 dia a anos) e resolução dos sintomas (mediana de 3 semanas).
Psiquiátrico: ansiedade, insônia, depressão, distúrbios psíquicos
Reações de hipersensibilidade : Uma síndrome de hipersensibilidade aparente foi relatada raramente, incluindo uma ou mais das seguintes características: anafilaxia, angioedema, síndrome do tipo lúpus eritematoso, polimialgia reumática, vasculite, púrpura, trombocitopenia, leucopenia, anemia hemolítica, ANA positivo, ESR (taxa de sedimentação de eritrócitos) aumentar, eosinofilia, artrite, artralgia, urticária, astenia, reação de fotosensibilidade, febre, calafrios, rubor, mal-estar, dispnéia, necrólise epidérmica tóxica, eritema multiforme, incluindo a síndrome de Stevens-Johnson.
Gastrointestinal: pancreatite, hepatite, incluindo hepatite ativa crônica, icterícia colestática, alteração gordurosa no fígado, cirrose, necrose hepática fulminante, hepatoma, anorexia, vômito, insuficiência hepática fatal e não fatal.
Pele: erupção cutânea, dermatite, incluindo dermatite bolhosa, eczema, alopecia, prurido, uma variedade de alterações cutâneas (por exemplo,. nódulos, descoloração, secura da pele / mucosas, alterações nos cabelos / unhas).
Reprodutivo: ginecomastia, perda de libido, disfunção erétil.
Olho: progressão da catarata (opacidades da lente), oftalmoplégia.
Anormalidades laboratoriais : transaminases elevadas, fosfatase alcalina, gama-glutamil transpeptidase e bilirrubina; anormalidades da função tireoidiana.
Até o momento, houve uma experiência limitada com sobredosagem de fluvastatina. Se ocorrer uma overdose, ela deve ser tratada de maneira sintomática com monitoramento laboratorial e medidas de suporte devem ser instituídas conforme necessário. A dializabilidade da fluvastatina sódica e de seus metabólitos em humanos não é conhecida atualmente.
Na população pediátrica, houve relatos de superdosagem com fluvastatina sódica em crianças, incluindo uma criança de 2 anos e os outros 3 anos de idade, qualquer uma das quais pode ter ingerido fluvastatina sódica. A quantidade máxima de fluvastatina sódica que poderia ter sido ingerida foi de 80 mg (cápsulas de 4 x 20 mg). O vômito foi induzido pelo ipecac em ambas as crianças e nenhuma cápsula foi observada em sua emese. Nenhuma criança apresentou sintomas adversos e ambas se recuperaram do incidente sem problemas.
Na experiência pós-comercialização, houve relatos de ingestão acidental de comprimidos de Lipaxan em bebês até 3 anos de idade. Em um caso, foram observados valores séricos aumentados de CPK. Houve relatos de sobredosagem intencional em adolescentes com o desenvolvimento de elevações das enzimas hepáticas, convulsões e gastroenterite / vômito / diarréia. Um caso de overdose intencional como tentativa de suicídio em uma mulher de 15 anos relatou ingestão de 2.800 mg de Lipoxan XL com elevação da enzima hepática.
Absorption
Following oral administration of the capsule, fluvastatin reaches peak concentrations in less than 1 hour. The absolute bioavailability is 24% (range 9%-50%) after administration of a 10 mg dose.
At steady state, administration of fluvastatin with the evening meal results in a 50% decrease in Cmax, a 11% decrease in AUC, and a more than two-fold increase in tmax as compared to administration 4 hours after the evening meal. No significant differences in the lipid-lowering effects were observed between the two administrations. After single or multiple doses above 20 mg, fluvastatin exhibits saturable first-pass metabolism resulting in more than dose proportional plasma fluvastatin concentrations.
Fluvastatin administered as Lipaxan XL 80 mg tablets reaches peak concentration in approximately 3 hours under fasting conditions, after a low-fat meal, or 2.5 hours after a low-fat meal. The mean relative bioavailability of the XL tablet is approximately 29% (range: 9%-66%) compared to that of the Lipaxan immediate-release capsule administered under fasting conditions. Administration of a high-fat meal delayed the absorption (Tmax: 6h) and increased the bioavailability of the XL tablet by approximately 50%. However, the maximum concentration of Lipaxan XL seen after a high-fat meal is less than the peak concentration following a single dose or twice daily dose of the 40 mg Lipaxan capsule.
Distribution
Fluvastatin is 98% bound to plasma proteins. The mean volume of distribution (VDss) is estimated at 0.35 L/kg. At therapeutic concentrations, the protein binding of fluvastatin is not affected by warfarin, salicylic acid and glyburide.
Metabolism
Fluvastatin is metabolized in the liver, primarily via hydroxylation of the indole ring at the 5-and 6-positions. N-dealkylation and beta-oxidation of the side-chain also occurs. The hydroxy metabolites have some pharmacologic activity, but do not circulate in the blood. Fluvastatin has two enantiomers. Both enantiomers of fluvastatin are metabolized in a similar manner.
In vitro data indicate that fluvastatin metabolism involves multiple Cytochrome P450 (CYP) isozymes. CYP2C9 isoenzyme is primarily involved in the metabolism of fluvastatin (approximately 75%), while CYP2C8 and CYP3A4 isoenzymes are involved to a much less extent, i.e. approximately 5% and approximately 20%, respectively.
Excretion
Following oral administration, fluvastatin is primarily (about 90%) excreted in the feces as metabolites, with less than 2% present as unchanged drug. Approximately 5% of a radiolabeled oral dose were recovered in urine. The elimination half-life (t½) of fluvastatin is approximately 3 hours.
However, we will provide data for each active ingredient