Liplat

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.

Prevenção de doenças cardiovasculares

Em pacientes hipercolesterolêmicos sem doença cardíaca coronária clinicamente evidente (DCC), o Liplat (pravastatina sódica) é indicado para:

• reduzir o risco de infarto do miocárdio (IM).
• reduzir o risco de sofrer procedimentos de revascularização do miocárdio.
• reduzir o risco de mortalidade cardiovascular sem aumento da morte por causas não cardiovasculares.

Em pacientes com DCC clinicamente evidente, Liplat é indicado para:

• reduzir o risco de mortalidade total, reduzindo a morte coronariana.
• reduzir o risco de MI .
• reduzir o risco de sofrer procedimentos de revascularização do miocárdio.
• reduzir o risco de acidente vascular cerebral e acidente vascular cerebral / ataque isquêmico transitório (AIT).
• retardar a progressão da aterosclerose coronariana.

Hiperlipidemia

Liplat é indicado:

• como um complemento à dieta para reduzir os níveis elevados de colesterol total (Total-C), lipoproteína de baixa densidade (LDL-C), apolipoproteína B (ApoB) e triglicerídeos (TG) e aumentar o colesterol de lipoproteína de alta densidade (HDL-C) em pacientes com hipercolesterolemia primária e dislipidemia mista (Fredrickson Tipos IIa e IIb).¹
• como adjunto da dieta para o tratamento de pacientes com níveis séricos elevados de TG (Fredrickson Tipo IV). Ã '
• para o tratamento de pacientes com disbetalipoproteinemia primária (Fredrickson Tipo III) que não respondem adequadamente à dieta.
• como um complemento à modificação da dieta e estilo de vida para o tratamento da hipercolesterolemia familiar heterozigótica (HeFH) em crianças e adolescentes com 8 anos ou mais, se após um estudo adequado da dieta, estiverem presentes os seguintes achados :
  1. LDL-C permanece ≥ 190 mg / dL ou
  2. LDL-C permanece ≥ 160 mg / dL e :
• existe um histórico familiar positivo de doença cardiovascular prematura (DCV) ou
• dois ou mais outros fatores de risco de DCV estão presentes no paciente.

Limitações de uso

O Liplat não foi estudado em condições em que a principal anormalidade da lipoproteína é a elevação de quilomícrons (Fredrickson Tipos I e V).

Informações gerais sobre dosagem

O paciente deve ser colocado em uma dieta padrão para baixar o colesterol antes de receber Liplat e deve continuar nessa dieta durante o tratamento com Liplat.

Pacientes adultos

A dose inicial recomendada é de 40 mg uma vez ao dia. Se uma dose diária de 40 mg não atingir os níveis desejados de colesterol, recomenda-se 80 mg uma vez ao dia. O Liplat pode ser administrado por via oral como uma dose única a qualquer hora do dia, com ou sem alimentos. 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 as diretrizes de tratamento estabelecidas.

Pacientes com deficiência renal

Em pacientes com insuficiência renal grave, recomenda-se uma dose inicial de 10 mg de pravastatina diariamente. Embora os comprimidos de Liplat 10 mg não estejam mais disponíveis, estão disponíveis comprimidos de pravastatina 10 mg.

Pacientes pediátricos

Crianças (idades de 8 a 13 anos, inclusivas)

A dose recomendada é de 20 mg uma vez ao dia em crianças de 8 a 13 anos de idade. Doses superiores a 20 mg não foram estudadas nesta população de pacientes.

Adolescentes (14 a 18 anos)

A dose inicial recomendada é de 40 mg uma vez ao dia em adolescentes de 14 a 18 anos de idade. Doses superiores a 40 mg não foram estudadas nesta população de pacientes.

Crianças e adolescentes tratados com pravastatina devem ser reavaliados na idade adulta e alterações apropriadas devem ser feitas no regime de redução do colesterol para atingir as metas adultas de LDL-C

Terapia concomitante de alteração de lipídios

Liplat pode ser usado com resinas de ácido biliar. Ao administrar uma resina de ligação a ácidos biliares (por exemplo,., colestiramina, colestipol) e pravastatina, Liplat deve ser administrado 1 hora ou mais antes ou pelo menos 4 horas após a resina.

Dosagem em pacientes que tomam ciclosporina

Em pacientes que tomam medicamentos imunossupressores, como a ciclosporina, concomitantemente com pravastatina, a terapia deve começar com 10 mg de pravastatina sódica uma vez ao dia na hora de dormir e a titulação para doses mais altas deve ser feita com cautela. A maioria dos pacientes tratados com essa combinação recebeu uma dose máxima de pravastatina sódica de 20 mg / dia. Nos pacientes que tomam ciclosporina, a terapia deve ser limitada a 20 mg de pravastatina sódica uma vez ao dia. Embora os comprimidos de Liplat 10 mg não estejam mais disponíveis, estão disponíveis comprimidos de pravastatina 10 mg.

Dosagem em pacientes que tomam claritromicina

Nos pacientes que tomam claritromicina, a terapia deve ser limitada a 40 mg de pravastatina sódica uma vez ao dia.

Hipersensibilidade

Hipersensibilidade a qualquer componente deste medicamento.

Fígado

Doença hepática ativa ou elevações persistentes inexplicáveis das transaminases séricas.

Gravidez

A aterosclerose é um processo crônico e a descontinuação de medicamentos hipolipemiantes durante a gravidez deve ter pouco impacto no resultado da terapia prolongada da hipercolesterolemia primária. O colesterol e outros produtos da biossíntese do colesterol são componentes essenciais para o desenvolvimento fetal (incluindo a síntese de esteróides e membranas celulares). Como as estatinas diminuem a síntese de colesterol e possivelmente a síntese de outras substâncias biologicamente ativas derivadas do colesterol, elas são contra-indicadas durante a gravidez e nas nutrizes. A PRAVASTATINA DEVE SER ADMINISTRADA A MULHERES DE CRIANÇA APENAS QUANDO ESSES PACIENTES SÃO ALTAMENTE INDIVIDUALMENTE CONCEDENTES E FORAM INFORMADOS DOS PERIGOS POTENCIAIS. Se o paciente engravidar enquanto toma esta classe de medicamento, a terapia deve ser interrompida imediatamente e o paciente informado do risco potencial para o feto.

Aleitamento

A pravastatina está presente no leite humano. Como as estatinas têm potencial para reações adversas graves em lactentes, as mulheres que necessitam de tratamento com Liplat não devem amamentar seus bebês.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Skeletal Muscle

Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with pravastatin and 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.

Uncomplicated myalgia has also been reported in pravastatin-treated patients. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values to greater than 10 times the ULN, was rare ( < 0.1%) in pravastatin clinical trials. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Predisposing factors include advanced age ( ≥ 65), uncontrolled hypothyroidism, and renal impairment.

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 CPK, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation and improvement with immunosuppressive agents.

All patients should be advised to promptly report to their physician unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing Liplat.

Pravastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Pravastatin 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.

The risk of myopathy during treatment with statins is increased with concurrent therapy with either erythromycin, cyclosporine, niacin, or fibrates. However, neither myopathy nor significant increases in CPK levels have been observed in 3 reports involving a total of 100 post-transplant patients (24 renal and 76 cardiac) treated for up to 2 years concurrently with pravastatin 10 to 40 mg and cyclosporine. Some of these patients also received other concomitant immunosuppressive therapies. Further, in clinical trials involving small numbers of patients who were treated concurrently with pravastatin and niacin, there were no reports of myopathy. Also, myopathy was not reported in a trial of combination pravastatin (40 mg/day) and gemfibrozil (1200 mg/day), although 4 of 75 patients on the combination showed marked CPK elevations versus 1 of 73 patients receiving placebo. There was a trend toward more frequent CPK elevations and patient withdrawals due to musculoskeletal symptoms in the group receiving combined treatment as compared with the groups receiving placebo, gemfibrozil, or pravastatin monotherapy. The use of fibrates alone may occasionally be associated with myopathy. The benefit of further alterations in lipid levels by the combined use of Liplat with fibrates should be carefully weighed against the potential risks of this combination.

Cases of myopathy, including rhabdomyolysis, have been reported with pravastatin coadministered with colchicine, and caution should be exercised when prescribing pravastatin with colchicine.

Liver

Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. In 3 long-term (4.8-5.9 years), placebo-controlled clinical trials (WOS, LIPID, CARE), 19,592 subjects (19,768 randomized) were exposed to pravastatin or placebo. In an analysis of serum transaminase values (ALT, AST), incidences of marked abnormalities were compared between the pravastatin and placebo treatment groups; a marked abnormality was defined as a post-treatment test value greater than 3 times the ULN for subjects with pretreatment values less than or equal to the ULN, or 4 times the pretreatment value for subjects with pretreatment values greater than the ULN but less than 1.5 times the ULN. Marked abnormalities of ALT or AST occurred with similar low frequency ( ≤ 1.2%) in both treatment groups. Overall, clinical trial experience showed that liver function test abnormalities observed during pravastatin therapy were usually asymptomatic, not associated with cholestasis, and did not appear to be related to treatment duration. In a 320-patient placebo-controlled clinical trial, subjects with chronic ( > 6 months) stable liver disease, due primarily to hepatitis C or non-alcoholic fatty liver disease, were treated with 80 mg pravastatin or placebo for up to 9 months. The primary safety endpoint was the proportion of subjects with at least one ALT ≥ 2 times the ULN for those with normal ALT ( ≤ ULN) at baseline or a doubling of the baseline ALT for those with elevated ALT ( > ULN) at baseline. By Week 36, 12 out of 160 (7.5%) subjects treated with pravastatin met the prespecified safety ALT endpoint compared to 20 out of 160 (12.5%) subjects receiving placebo. Conclusions regarding liver safety are limited since the study was not large enough to establish similarity between groups (with 95% confidence) in the rates of ALT elevation.

It is recommended that liver function tests be performed prior to the initiation of therapy and when clinically indicated.

Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of pravastatin. Caution should be exercised when pravastatin is administered to patients who have a recent ( < 6 months) history of liver disease, have signs that may suggest liver disease (e.g., unexplained aminotransferase elevations, jaundice), or are heavy users of alcohol.

There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including pravastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with Liplat, promptly interrupt therapy. If an alternate etiology is not found do not restart Liplat.

Endocrine Function

Statins interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. Results of clinical trials with pravastatin in males and post-menopausal females were inconsistent with regard to possible effects of the drug on basal steroid hormone levels. In a study of 21 males, the mean testosterone response to human chorionic gonadotropin was significantly reduced (p < 0.004) after 16 weeks of treatment with 40 mg of pravastatin. However, the percentage of patients showing a ≥ 50% rise in plasma testosterone after human chorionic gonadotropin stimulation did not change significantly after therapy in these patients. The effects of statins on spermatogenesis and fertility have not been studied in adequate numbers of patients. The effects, if any, of pravastatin on the pituitary-gonadal axis in pre-menopausal females are unknown. Patients treated with pravastatin who display clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should also be exercised if a statin or other agent used to lower cholesterol levels is administered to patients also receiving other drugs (e.g., ketoconazole, spironolactone, cimetidine) that may diminish the levels or activity of steroid hormones.

In a placebo-controlled study of 214 pediatric patients with HeFH, of which 106 were treated with pravastatin (20 mg in the children aged 8-13 years and 40 mg in the adolescents aged 14-18 years) for 2 years, there were no detectable differences seen in any of the endocrine parameters (ACTH, cortisol, DHEAS, FSH, LH, TSH, estradiol [girls] or testosterone [boys]) relative to placebo. There were no detectable differences seen in height and weight changes, testicular volume changes, or Tanner score relative to placebo.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

In a 2-year study in rats fed pravastatin at doses of 10, 30, or 100 mg/kg body weight, there was an increased incidence of hepatocellular carcinomas in males at the highest dose (p < 0.01). These effects in rats were observed at approximately 12 times the human dose (HD) of 80 mg based on body surface area (mg/m²) and at approximately 4 times the HD, based on AUC.

In a 2-year study in mice fed pravastatin at doses of 250 and 500 mg/kg/day, there was an increased incidence of hepatocellular carcinomas in males and females at both 250 and 500 mg/kg/day (p < 0.0001). At these doses, lung adenomas in females were increased (p=0.013). These effects in mice were observed at approximately 15 times (250 mg/kg/day) and 23 times (500 mg/kg/day) the HD of 80 mg, based on AUC. In another 2-year study in mice with doses up to 100 mg/kg/day (producing drug exposures approximately 2 times the HD of 80 mg, based on AUC), there were no drug-induced tumors.

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; a forward mutation assay in L5178Y TK +/- mouse lymphoma cells; a chromosomal aberration test in hamster cells; and a gene conversion assay using Saccharomyces cerevisiae. In addition, there was no evidence of mutagenicity in either a dominant lethal test in mice or a micronucleus test in mice.

In a fertility study in adult rats with daily doses up to 500 mg/kg, pravastatin did not produce any adverse effects on fertility or general reproductive performance.

Use In Specific Populations

Pregnancy

Risk Summary

Liplat is contraindicated for use in pregnant woman because of the potential for fetal harm. As safety in pregnant women has not been established and there is no apparent benefit to therapy with Liplat during pregnancy, Liplat should be immediately discontinued as soon as pregnancy is recognized. Limited published data on the use of Liplat in pregnant women are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies, no evidence of fetal malformations was seen in rabbits or rats exposed to 10 times to 120 times, respectively, the maximum recommended human dose (MRHD) of 80 mg/day. Fetal skeletal abnormalities, offspring mortality, and developmental delays occurred when pregnant rats were administered 10 times to 12 times the MRHD during organogenesis to parturition. Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Human Data

Limited published data on pravastatin have not shown an increased risk of major congenital malformations or miscarriage.

Rare reports of congenital anomalies have been received following intrauterine exposure to other statins. In a review² of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate to exclude a ≥ 3 to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.

Animal Data

Embryofetal and neonatal mortality was observed in rats given pravastatin during the period of organogenesis or during organogenesis continuing through weaning. In pregnant rats given oral gavage doses of 4, 20, 100, 500, and 1000 mg/kg/day from gestation days 7 through 17 (organogenesis) increased mortality of offspring and increased cervical rib skeletal anomalies were observed at ≥ 100 mg/kg/day systemic exposure, 10 times the human exposure at 80 mg/day MRHD based on body surface area (mg/m²).

In other studies, no teratogenic effects were observed when pravastatin was dosed orally during organogenesis in rabbits (gestation days 6 through 18) up to 50 mg/kg/day or in rats (gestation days 7 through 17) up to 1000 mg/kg/day. Exposures were 10 times (rabbit) or 120 times (rat) the human exposure at 80 mg/day MRHD based on body surface area (mg/m²).

In pregnant rats given oral gavage doses of 10, 100, and 1000 mg/kg/day from gestation day 17 through lactation day 21 (weaning), increased mortality of offspring and developmental delays were observed at ≥ 100 mg/kg/day systemic exposure, corresponding to 12 times the human exposure at 80 mg/day MRHD, based on body surface area (mg/m²).

In pregnant rats, pravastatin crosses the placenta and is found in fetal tissue at 30% of the maternal plasma levels following administration of a single dose of 20 mg/day orally on gestation day 18, which corresponds to exposure 2 times the MRHD of 80 mg daily based on body surface area (mg/m²). In lactating rats, up to 7 times higher levels of pravastatin are present in the breast milk than in the maternal plasma, which corresponds to exposure 2 times the MRHD of 80 mg/day based on body surface area (mg/m²).

Lactation

Risk Summary

Pravastatin use is contraindicated during breastfeeding. Based on one lactation study in published literature, pravastatin is present in human milk. There is no available information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. Because of the potential for serious adverse reactions in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with Liplat.

Females And Males of Reproductive Potential

Contraception

Females

Liplat may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Liplat.

Pediatric Use

The safety and effectiveness of Liplat in children and adolescents from 8 to 18 years of age have been evaluated in a placebo-controlled study of 2 years duration. Patients treated with pravastatin had an adverse experience profile generally similar to that of patients treated with placebo with influenza and headache commonly reported in both treatment groups. Doses greater than 40 mg have not been studied in this population. Children and adolescent females of childbearing potential should be counseled on appropriate contraceptive methods while on pravastatin therapy. For dosing information.

Double-blind, placebo-controlled pravastatin studies in children less than 8 years of age have not been conducted.

Geriatric Use

Two secondary prevention trials with pravastatin (CARE and LIPID) included a total of 6593 subjects treated with pravastatin 40 mg for periods ranging up to 6 years. Across these 2 studies, 36.1% of pravastatin subjects were aged 65 and older and 0.8% were aged 75 and older. The beneficial effect of pravastatin in elderly subjects in reducing cardiovascular events and in modifying lipid profiles was similar to that seen in younger subjects. The adverse event profile in the elderly was similar to that in the overall population. Other reported clinical experience has not identified differences in responses to pravastatin between elderly and younger patients.

Mean pravastatin AUCs are slightly (25%-50%) higher in elderly subjects than in healthy young subjects, but mean maximum plasma concentration (Cmax ), time to maximum plasma concentration (T max ), and half-life (t½) values are similar in both age groups and substantial accumulation of pravastatin would not be expected in the elderly.

Since advanced age ( ≥ 65 years) is a predisposing factor for myopathy, Liplat should be prescribed with caution in the elderly.

Homozygous Familial Hypercholesterolemia

Pravastatin has not been evaluated in patients with rare homozygous familial hypercholesterolemia. In this group of patients, it has been reported that statins are less effective because the patients lack functional LDL receptors.

REFERENCES

2.Manson JM, Freyssinges C, Ducrocq MB, Stephenson WP. Postmarketing surveillance of lovastatin and simvastatin exposure during pregnancy. Reprod Toxicol. 1996;10(6):439-446.

Pravastatin is generally well tolerated; adverse reactions have usually been mild and transient. In 4-month-long placebo-controlled trials, 1.7% of pravastatin-treated patients and 1.2% of placebo-treated patients were discontinued from treatment because of adverse experiences attributed to study drug therapy; this difference was not statistically significant.

Adverse Clinical Events

Short-Term Controlled Trials

In the Liplat placebo-controlled clinical trials database of 1313 patients (age range 20-76 years, 32.4% women, 93.5% Caucasians, 5% Blacks, 0.9% Hispanics, 0.4% Asians, 0.2% Others) with a median treatment duration of 14 weeks, 3.3% of patients on Liplat and 1.2% patients on placebo discontinued due to adverse events regardless of causality. The most common adverse reactions that led to treatment discontinuation and occurred at an incidence greater than placebo were: liver function test increased, nausea, anxiety/depression, and dizziness.

All adverse clinical events (regardless of causality) reported in ≥ 2% of pravastatin-treated patients in placebo-controlled trials of up to 8 months duration are identified in Table 1:

Table 1: Adverse Events in ≥ 2% of Patients Treated with Pravastatin 5 to 40 mg and at an Incidence Greater Than Placebo in Short-Term Placebo-Controlled Trials (% of patients)

The safety and tolerability of Liplat at a dose of 80 mg in 2 controlled trials with a mean exposure of 8.6 months was similar to that of Liplat at lower doses except that 4 out of 464 patients taking 80 mg of pravastatin had a single elevation of CK > 10 times ULN compared to 0 out of 115 patients taking 40 mg of pravastatin.

Long-Term Controlled Morbidity And Mortality Trials

In the Liplat placebo-controlled clinical trials database of 21,483 patients (age range 24-75 years, 10.3% women, 52.3% Caucasians, 0.8% Blacks, 0.5% Hispanics, 0.1% Asians, 0.1% Others, 46.1% Not Recorded) with a median treatment duration of 261 weeks, 8.1% of patients on Liplat and 9.3% patients on placebo discontinued due to adverse events regardless of causality.

Adverse event data were pooled from 7 double-blind, placebo-controlled trials (West of Scotland Coronary Prevention Study [WOS]; Cholesterol and Recurrent Events study [CARE]; Long-term Intervention with Pravastatin in Ischemic Disease study [LIPID]; Pravastatin Limitation of Atherosclerosis in the Coronary Arteries study [PLAC I]; Pravastatin, Lipids and Atherosclerosis in the Carotids study [PLAC II]; Regression Growth Evaluation Statin Study [REGRESS]; and Kuopio Atherosclerosis Prevention Study [KAPS]) involving a total of 10,764 patients treated with pravastatin 40 mg and 10,719 patients treated with placebo. The safety and tolerability profile in the pravastatin group was comparable to that of the placebo group. Patients were exposed to pravastatin for a mean of 4.0 to 5.1 years in WOS, CARE, and LIPID and 1.9 to 2.9 years in PLAC I, PLAC II, KAPS, and REGRESS. In these long-term trials, the most common reasons for discontinuation were mild, non-specific gastrointestinal complaints. Collectively, these 7 trials represent 47,613 patient-years of exposure to pravastatin. All clinical adverse events (regardless of causality) occurring in ≥ 2% of patients treated with pravastatin in these studies are identified in Table 2.

Table 2: Adverse Events in ≥ 2% of Patients Treated with Pravastatin 40 mg and at an Incidence Greater Than Placebo in Long-Term Placebo-Controlled Trials

In addition to the events listed above in the long-term trials table, events of probable, possible, or uncertain relationship to study drug that occurred in < 2.0% of pravastatin-treated patients in the long-term trials included the following:

Dermatologic: scalp hair abnormality (including alopecia), urticaria.

Endocrine/Metabolic: sexual dysfunction, libido change.

General: flushing.

Immunologic: allergy, edema head/neck.

Musculoskeletal: muscle weakness.

Nervous System: vertigo, insomnia, memory impairment, neuropathy (including peripheral neuropathy).

Special Senses: taste disturbance.

Postmarketing Experience

In addition to the events reported above, as with other drugs in this class, the following events have been reported during postmarketing experience with Liplat, regardless of causality assessment:

Musculoskeletal: myopathy, rhabdomyolysis, tendon disorder, polymyositis.

There have been rare reports of immune-mediated necrotizing myopathy associated with statin use.

Nervous System: dysfunction of certain cranial nerves (including alteration of taste, impairment of extraocular movement, facial paresis), peripheral nerve palsy.

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).

Hypersensitivity: anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, hemolytic anemia, positive ANA, ESR increase, arthritis, arthralgia, asthenia, photosensitivity, chills, malaise, toxic epidermal necrolysis, erythema multiforme (including Stevens-Johnson syndrome).

Gastrointestinal: abdominal pain, constipation, pancreatitis, hepatitis (including chronic active hepatitis), cholestatic jaundice, fatty change in liver, cirrhosis, fulminant hepatic necrosis, hepatoma, fatal and non-fatal hepatic failure.

Dermatologic: a variety of skin changes (e.g., nodules, discoloration, dryness of mucous membranes, changes to hair/nails).

Renal: urinary abnormality (including dysuria, frequency, nocturia).

Respiratory: dyspnea, interstitial lung disease.

Psychiatric: nightmare.

Reproductive: gynecomastia.

Laboratory Abnormalities: liver function test abnormalities, thyroid function abnormalities.

Laboratory Test Abnormalities

Increases in ALT, AST values and CPK have been observed.

Transient, asymptomatic eosinophilia has been reported. Eosinophil counts usually returned to normal despite continued therapy. Anemia, thrombocytopenia, and leukopenia have been reported with statins.

Pediatric Patients

In a 2-year, double-blind, placebo-controlled study involving 100 boys and 114 girls with HeFH (n=214; age range 8-18.5 years, 53% female, 95% Caucasians, < 1% Blacks, 3% Asians, 1% Other), the safety and tolerability profile of pravastatin was generally similar to that of placebo.

Até o momento, houve uma experiência limitada com sobredosagem de pravastatina. Se ocorrer uma overdose, ela deve ser tratada de maneira sintomática com monitoramento laboratorial e medidas de suporte devem ser instituídas conforme necessário.

Geral

Absorção: Liplat é administrado por via oral na forma ativa. Em estudos no homem, as concentrações plasmáticas máximas de pravastatina ocorreram 1 a 1,5 horas após a administração oral. Com base na recuperação urinária do medicamento radiomarcado total, a absorção oral média de pravastatina é de 34% e a biodisponibilidade absoluta é de 17%. Enquanto a presença de alimentos no trato gastrointestinal reduz a biodisponibilidade sistêmica, os efeitos hipolipemiantes do medicamento são semelhantes, tomados com ou 1 hora antes das refeições.

As concentrações plasmáticas de pravastatina, incluindo a área sob a curva de concentração-tempo (AUC), Cmax e mínimo de estado estacionário (Cmin), são diretamente proporcionais à dose administrada. A biodisponibilidade sistêmica da pravastatina administrada após uma dose de ninar diminuiu 60% em comparação com a seguinte dose de AM. Apesar dessa diminuição da biodisponibilidade sistêmica, a eficácia da pravastatina administrada uma vez ao dia à noite, embora não seja estatisticamente significativa, foi marginalmente mais eficaz do que após uma dose matinal.

O coeficiente de variação (CV), com base na variabilidade entre indivíduos, foi de 50% a 60% para a AUC. As médias geométricas de pravastatina C max e AUC após uma dose de 20 mg no estado de jejum foram de 26,5 ng / mL e 59,8 ng * h / mL, respectivamente.

As concentrações plasmáticas mínimas de AUCs em estado estacionário, C max e C não mostraram evidência de acúmulo de pravastatina após a administração uma ou duas vezes ao dia de comprimidos de Liplat.

Distribuição: Aproximadamente 50% da droga circulante está ligada às proteínas plasmáticas.

Metabolismo: As principais vias de biotransformação da pravastatina são: (a) isomerização para pravastatina 6-epi e o 3α-hidroxiisômero da pravastatina (SQ 31.906) e (b) hidroxilação enzimática do anel para SQ 31.945. O metabolito 3α-hidroxiisomérico (SQ 31.906) possui 1/10 a 1/40 da atividade inibidora da HMG-CoA redutase do composto original. A pravastatina sofre extensa extração de primeira passagem no fígado (taxa de extração 0,66).

Excreção: Aproximadamente 20% de uma dose oral radiomarcada é excretada na urina e 70% nas fezes. Após administração intravenosa de pravastatina radiomarcada a voluntários normais, aproximadamente 47% da depuração corporal total foi por excreção renal e 53% por vias não renais (ou seja,., excreção biliar e biotransformação).

Após administração oral de dose única de ¹⁴C-pravastatina, a eliminação radioativa t½ para a pravastatina é de 1,8 horas em humanos.