Approval Date: 07/02/2007
Revision Date: 06/13/2017
Jun 29, 2017
April 2018 Drafted
Atorvastatin Calcium Tablets Instructions
Please read the instructions carefully and use under the guidance of your physician
[Drug Name].
Generic Name: Atorvastatin Calcium Tablets
Trade Name: Ala®
English Name: Atorvastatin Calcium Tablets
Hanyu Pinyin: Atorvastatin Pian
[Ingredients]
The main ingredient of this product is atorvastatin calcium.
Chemically: [R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(anilino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1) trihydrate.
Chemical structure formula.
Molecular formula: (C33H34FN2O5)2Ca-3H2O
Molecular weight: 1209.42
[Properties]This product is a white film-coated tablet, which appears white after removing the film coating.
[Indications
Hypercholesterolemia
Patients with primary hypercholesterolemia, including familial hypercholesterolemia (heterozygous type) or mixed hyperlipidemia (equivalent to Fredrickson’s classification of type IIa and IIb), who have been treated with diet and other non-pharmacological If dietary therapy and other non-pharmacological treatments are unsatisfactory, this product can be applied to treat their elevated total cholesterol (TC), elevated low-density lipoprotein cholesterol (LDL-C), elevated apolipoprotein B (apo B), and elevated triglycerides (TG).
In patients with pure subfamilial hypercholesterolemia, atorvastatin calcium may be used in combination with other lipid-lowering therapies (e.g., LDL plasma dialysis) or alone (when no other treatment is available) to lower TC and LDL-C.
Coronary heart disease
Patients with coronary artery disease or critical conditions such as coronary artery disease (e.g., diabetes mellitus, symptomatic atherosclerotic disease, etc.) combined with hypercholesterolemia or mixed dyslipidemia, this product is indicated to: reduce the risk of nonfatal myocardial infarction, reduce the risk of fatal and non fatal strokes, reduce the risk of revascularization, reduce the risk of hospitalization for congestive heart failure, and reduce the risk of angina pectoris.
[Specifications
(1) 10 mg; (2) 20 mg. as atorvastatin (C33H35FN2O5) Count.
[dosage
Patients should be on a standard low-cholesterol diet control prior to initiating this treatment and should also maintain a reasonable diet throughout the treatment period. Dose adjustments should be individualized based on baseline LDL cholesterol levels, treatment goals, and patient outcomes.
The common starting dose is 10 mg once daily. Dose adjustment intervals should be 4 weeks or longer. The maximum dose of this product is 80 mg once daily. Atorvastatin daily dosage may be taken in a single dose at any time of the day and is not affected by meals.
Treatment of primary hypercholesterolemia and mixed hyperlipidemia
Treatment of heterozygous familial hypercholesterolemia
Patients should be given an initial dose of 10 mg/day. The dose should be gradually adjusted to 40 mg/day at 4-week intervals following the principle of individualization of dose. If satisfactory efficacy is still not achieved, dose adjustment to the maximum dose of 80 mg/day or 40 mg once daily of this product with bile acid chelator may be an option.
Treatment of pure subtype familial hypercholesterolemia
In a charitable dosing study with 64 patients, 46 of them had confirmed low density lipoprotein (LDL) receptor information. These 46 patients had a mean reduction in LDL-C of 21%. The dose of this product can be increased to 80 mg/day.
For patients with pure subtype familial hypercholesterolemia, the recommended dose of this product is 10 to 80 mg/day. Atorvastatin calcium should be used as an adjunct to other lipid-lowering therapies (e.g., LDL plasma dialysis method). Or when these therapeutic conditions are not available, this product may be used alone.
Dosing in patients with renal insufficiency
Renal disease does not affect either the plasma concentration of this product or its lipid-lowering effect, so no dose adjustment is necessary.
[Adverse Reactions
The following serious adverse reactions are otherwise described in detail elsewhere in this instruction.
Rhabdomyolysis and myopathy (see [Precautions])
Liver enzyme abnormalities (see [Precautions])
Clinical adverse reactions (foreign literature)
Subjects’ conditions are complex during the implementation of clinical trials, therefore the incidence of adverse reactions obtained in clinical studies for two different drugs cannot be directly compared, while it may not reflect the incidence of adverse reactions in clinical practice.
Atorvastatin calcium placebo-controlled clinical trial enrolled 16,066 patients (atorvastatin n=8755, placebo n=7311, age 10 to 93 years, 39% female; 91% Caucasian white, 3% black, 2% Asian people, and 4% other ethnicities), with a median treatment period of 53 weeks; without considering causality, 9.7% and 9.5% of patients in the atorvastatin calcium and placebo groups, respectively, discontinued the drug due to adverse effects. The five most common adverse reactions that led to patient discontinuation and occurred more frequently in the atorvastatin calcium group than in the placebo group were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), elevated alanine aminotransferase (ALT) (0.4%), and elevated other liver enzymes (0.4%).
The most common (≥2%) and more frequent adverse reactions than placebo in the placebo-controlled trial of atorvastatin calcium (n=8755), without regard to causality, were, in order of prevalence: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea ( 6.8%), extremity pain (6.0%), and urinary tract infection (5.7%). Table 1 summarizes the adverse reactions that occurred in 8755 patients treated with atorvastatin calcium in 17 placebo-controlled trials at an incidence ≥2% and higher than placebo (without regard to causality)
Table 1 Clinical adverse reactions with an incidence ≥2% in patients treated with atorvastatin calcium at any dose and higher than in the placebo group
(without consideration of causality, %)
Adverse Reactions*All doses
N=8755 10mg
N=3908 20mg
N=188 40mg
N=604 80mg
N =4055Placebo
N=7311Nasopharyngitis8.3 12.9 5.3 7.0 4.2 8.2 Joint pain6.9 8.9 11.7 10.6 4.3 6.5 Diarrhea6.8 7.3 6.4 14.1 5.2 6.3 Quadriplegia6.0 8.5 3.7 9.3 3.1 5.9 Urinary tract infections5.7 6.9 6.4 6.4 8.0 4.1 5.6 Indigestion4.7 5.9 3.2 6.0 3.3 4.3 Nauseating4.0 3.7 3.7 7.1 3.8 3.5 Skeletal muscle pain3.8 5.2 3.2 5.1 2.3 3.6 Muscle spasms3.6 4.6 4.8 5.1 2.4 3.0 Myalgia3.5 3.6 5.9 8.4 2.7 3.1 Insomnia3.0 2.8 1.1 5.3 2.8 2.9 Sore Throat2.3 3.9 1.6 2.8 0.7 2.1 *Any dose incidence ≥2% and higher than placebo group
Other adverse reactions reported in placebo-controlled studies include.
Systemic: malaise, fever.
Digestive: abdominal discomfort, belching, flatulence, hepatitis, cholestasis.
Musculoskeletal system: skeletal muscle pain, muscle fatigue, neck pain, swollen joints.
Nutritional and metabolic system: elevated aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) levels, abnormal liver function tests, elevated blood alkaline phosphatase, elevated creatine phosphokinase, hyperglycemia.
Neurological: nightmares.
Respiratory: epistaxis.
Skin and appendages: urticaria.
Special sensations: blurred vision, tinnitus.
Genitourinary system: positive urine leukocytes.
The ASCOT study included 10,305 participants (age range 40-80 years, 19% female; 94.6% Caucasian white, 2.6% African, 1.5% South Asian, 1.3% mixed race or others), were given either atorvastatin calcium 10 mg daily (N=5168) or placebo (N=5137) treatment. During a median follow-up of 3.3 years, the safety and tolerability of the atorvastatin calcium treatment group was comparable to that of the placebo group.
Atorvastatin Collaborative Diabetes Study (CARDS)
In the CARDS study, a total of 2838 subjects with type 2 diabetes (age range 39-77 years, 32% female; 94.3% Caucasian white, 2.4% South Asian, 2.3% Caribbean Black, 1.0% other ethnicity), all of whom were treated with atorvastatin calcium 10 mg daily (n=1428) or placebo (n=1410), with no difference in the overall frequency of adverse events or serious adverse events between treatment groups and no reports of rhabdomyolysis during a median follow-up of 3.9 years.
Treatment New Target Study (TNT)
The TNT study involved 10,001 patients with clinically evident coronary heart disease (age range 29-78 years, 19% female; 94.1% Caucasian white, 2.9% black, 1.0% Asian, 2.0% others), treated with atorvastatin 10 mg (n=5006) or 80 mg (n=4995) daily, had more serious adverse events and treatment interruptions due to adverse events in the high-dose group compared with the low-dose group during a median follow-up of 4.9 years (92,1.8%; 497, 9.9% in the high-dose group, respectively. (69,1.4%; 404, 8.1%, respectively, in the low-dose group). Persistent elevations of aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) (more than 3 times the upper limit of normal on 2 occasions within 4-10 days) occurred in 62 cases (1.3%) in the atorvastatin calcium 80 mg treatment group compared with 9 cases (0.2%) in the atorvastatin 10 mg group. Creatine kinase elevations (more than 10 times the upper limit of normal) were less frequent overall, but occurred more frequently in the high-dose group compared with the low-dose atorvastatin group, 6,0.1% and 13,0.3%, respectively.
Intensive Lipid Lowering to Further Reduce Clinical Endpoint Events Study (IDEAL)
The IDEAL study, which involved 8888 patients (age range 26-80 years, 19% female; 99.3% Caucasian white, 0.4% Asian, 0.3% black, 0.04% other races) receiving daily ator vincristine 80 mg (n=4439) or simvastatin 20-40 mg (n=4449) daily, there was no difference in the overall incidence of adverse events or serious adverse events between the two treatment groups during a median value of 4.8 years of follow-up.
Stroke Prevention with Intensive Cholesterol-Lowering Therapy Study (SPARCL)
The SPARCL study enrolled 4731 subjects (age 21-92 years, 40% female; 93.3% Caucasian whites, 3.0% blacks, 0.6% Asians, and 3.1% other ethnicities) were treated with atorvastatin 80 mg (n=2365) or placebo (n=2366) with a median follow-up value of 4.9 years. The incidence of persistent elevations of AST and/or ALT (more than 3 times the upper limit of normal on 2 occasions within 4-10 days) was higher in patients in the atorvastatin group (0.9%) than in the placebo group (0.1%). Creatine kinase elevations (more than 10 times the upper limit of normal) were rare but occurred more frequently in the atorvastatin group (0.1%) than in the placebo group (0.0%). Diabetes mellitus as an adverse effect was reported in 144 (6.1%) and 89 (3.8%) cases in the atorvastatin and placebo groups, respectively (see [Precautions]).
Post hoc analysis showed a lower incidence of ischemic stroke (218/2365 [9.2%] vs. 274/2366 [11.6%]) and an increased incidence of hemorrhagic stroke in patients in the atorvastatin 80 mg group compared with the placebo group (55/ 2365 [2.3%] vs. 33/2366 [1.4%]). The incidence of fatal hemorrhagic strokes was similar in the atorvastatin calcium and placebo groups, 17 and 18, respectively. The incidence of nonfatal hemorrhagic stroke was significantly higher in the atorvastatin group than in the placebo group, 38 and 16, respectively. Patients with a pre-study history of hemorrhagic stroke may have contributed to an increased risk of hemorrhagic stroke development over the course of the study (7 [16%] in the atorvastatin calcium group vs. 2 [4%] in the placebo group).
No significant difference in all-cause mortality between the two groups: 216 (9.1%) in the atorvastatin calcium 80 mg daily group and 211 (8.9%) in the placebo group. The proportion of patients with cardiovascular death was numerically lower in the atorvastatin calcium 80 mg group (3.3%) than in the placebo group (4.1%). The proportion of patients with non-cardiovascular death was numerically higher in the atorvastatin calcium 80 mg group (5.0%) than in the placebo group (4.0%).
Postmarketing Report
The following adverse reactions were reported from post-marketing applications of atorvastatin calcium after approval. Because postmarketing adverse reaction reports are patient-initiated and the actual number of people using the drug is uncertain, the exact incidence of these adverse reactions cannot be calculated and the causal relationship between these adverse reactions and the drug cannot be determined.
Post-marketing adverse reactions associated with atorvastatin calcium not listed above without considering causality include: allergic reactions, angioneurotic edema, maculopapular rash (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis release), rhabdomyolysis, myositis, fatigue, tendon rupture, lethal or nonlethal hepatic failure, dizziness, depression, peripheral neuropathy, pancreatitis, and interstitial lung disease.
Immune-mediated necrotizing myopathy has occasionally been reported in association with statin use (see [Precautions]).
Hyperglycemic reactions, abnormal glucose tolerance, elevated glycosylated hemoglobin levels, new-onset diabetes, and worsening glycemic control have been reported in postmarketing surveillance of statins, and hypoglycemic reactions have been reported with some statins. In addition, there are rare reports of cognitive impairment in foreign post-marketing surveillance of statins, manifesting as memory loss, memory loss, and confusion, which are mostly non-serious, reversible reactions that can generally recover after discontinuation of the drug. .
Patients with children (age 10-17 years)
In a 26-week controlled study involving 187 boys and postmenarcheal girls aged 10 to 17 years with heterozygous familial hypercholesterolemia or severe hypercholesterolemia, atorvastatin 10 mg to 20 mg/day (n= 140, 31% girls; 92% Caucasian white, 1.6% black, 1.6% Asian, 4.8% other races) had a safety and tolerability similar to placebo (see [Pharmacology and Toxicology], [Precautions], and [Pediatric Dosage]).
[Contraindication
1. Active liver disease, which may include persistent elevation of hepatic AST and/or ALT of unknown cause.
2. Known hypersensitivity to any of the ingredients in this product.
3, Pregnancy
This product is contraindicated in pregnant women or women of childbearing age who may become pregnant. It may cause damage to the fetus when administered to a pregnant woman. The normal state of pregnancy is characterized by elevated levels of serum cholesterol and triglycerides, and cholesterol or cholesterol derivatives are essential for fetal development. Since atherosclerosis is a chronic process, discontinuation of lipid-lowering drug therapy during pregnancy in patients with primary hypercholesterolemia has little effect on the long-term regression of atherosclerotic disease. There is a lack of adequate controlled studies of atorvastatin in pregnant women; however, occasional reports have observed possible fetal congenital anomalies with intrauterine exposure to statins. No evidence of teratogenicity of atorvastatin has been observed in rat and rabbit reproduction studies. For women of childbearing age, only those who are highly unlikely to conceive and have been informed of the potential harms may be prescribed atorvastatin calcium. Patients who conceive while on the drug need to discontinue immediately and consider the potential harm to the fetus (see [Medications for Pregnant and Lactating Women]).
4. Lactating women
It is not known whether atorvastatin can be secreted from human breast milk; however, other drugs in this class can be secreted into breast milk in small amounts. Because statins may have potentially serious adverse effects on newborns who are breastfeeding, breastfeeding is contraindicated in women taking this product (see [Use in Pregnant and Lactating Women]).
[Precautions].
1. skeletal muscle
Atorvastatin calcium and other statins have occasionally been reported in a few cases of acute renal failure secondary to rhabdomyolysis-induced myoglobinuria. A history of renal impairment may be a risk factor for the development of rhabdomyolysis, and the effect of the drug on skeletal muscle needs to be monitored closely in such patients.
As with other statins, atorvastatin can occasionally cause myopathy (defined as muscle pain or muscle weakness with creatine phosphokinase CPK more than 10 times the upper limit of normal). High doses of atorvastatin with specific drugs such as cyclosporine or cytochrome P450 3A4( CYP3A4) strong inhibitors (e.g., clarithromycin, itraconazole, and human immunodeficiency virus HIV (protease inhibitor) co-administration increases the risk of myopathy or rhabdomyolysis.
Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has occasionally been reported in association with statin use. IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase (symptoms persist after discontinuation of statin); muscle biopsies show no significant necrotizing myopathy without significant inflammation; improvement with immunosuppression.
Myopathy should be considered in any patient with diffuse myalgia, muscle pressure or weakness, and/or significant creatine phosphokinase elevation. Patients should be advised to report unexplained muscle pain, muscle tenderness or muscle weakness immediately, especially if accompanied by discomfort or fever or if muscle signs and symptoms persist after discontinuation of atorvastatin calcium. Atorvastatin calcium therapy should be discontinued in the presence of significantly elevated creatine phosphokinase levels or confirmed/suspected myopathy.
If the combination of cyclosporine A, fibrate derivatives (betablockers), erythromycin, clarithromycin, colchicine, hepatitis C protease inhibitor telaprevir, HIV protease inhibitor is applied concurrently during treatment with statins (including atorvastatin calcium) (including saquinavir + ritonavir, lopinavir + ritonavir, tipranavir + ritonavir, dirinavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir), niacin, or imidazole antifungals increases the risk of myopathy. Physicians should carefully weigh the potential benefits and risks when considering combination therapy with atorvastatin and fibrate derivatives (betablockers), erythromycin, clarithromycin, saquinavir + ritonavir, lopinavir + ritonavir, direnavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, imidazole antifungals, or lipid-modifying doses of niacin, and should carefully monitor patients for any muscle signs and symptoms of muscle pain, muscle pressure, or muscle weakness, especially during the months of treatment initiation and during dose up-titration of any of the drugs. When atorvastatin is used concomitantly with the previously mentioned drugs (see [Drug Interactions]), a lower starting and maintenance dose of atorvastatin should be considered. In the context of the above combination, periodic creatine phosphokinase measurements should be considered, but such monitoring does not ensure that the development of severe myopathy can be prevented.
Recommended prescription dosages and drug interactions are summarized in Table 2 (see [Dosage], [Drug Interactions], [Pharmacology and Toxicology] for details).
Table 2 Interacting drugs causing increased risk of atorvastatin myopathy/rhabdomyolysis
Interacting drugsRecommended Prescribed DosageCyclosporine, HIV protease inhibitor (tipranavir + ritonavir), hepatitis C protease inhibitor (telaprevir)Avoid atorvastatinHIV protease inhibitors (lopinavir + ritonavir) Viraprevir + ritonavir)Use caution and use the lowest necessary doseclarithromycin, itraconazole, HIV protease inhibitors (saquinavir + ritonavir*, dirinavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir)Atorvastatin Statin at no more than 20 mg dailyHIV protease inhibitor (nelfinavir) hepatitis C protease inhibitor (boceprevir)Atorvastatin at a daily dose of no more than 40 mg*Use caution and use the minimum necessary dose ([pharmacokinetics])Combined administration of atorvastatin and fosfomycin dilate is not recommended, and therefore it is recommended that fosfomycin be administered in combination with fosfomycin >cidioic acid therapy be suspended for the duration of atorvastatin therapy.
Cases of myopathy including rhabdomyolysis have been reported when atorvastatin is co-administered with colchicine, and caution should be exercised when co-administering atorvastatin and colchicine (see [Drug Interactions]).
Any patient with acute, severe conditions predictive of myopathy or with risk factors (eg, severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine, and electrolyte disturbances, uncontrolled seizures) predisposing to rhabdomyolysis secondary to Renal failure with rhabdomyolysis should be suspended or interrupted with atorvastatin calcium therapy.
2. Abnormal liver function
Like other lipid-lowering therapies, statins can cause abnormalities in biochemical markers of liver function. Clinical trials have shown that 0.7% of patients treated with atorvastatin calcium had persistent elevations (two or more times more than 3 times the upper limit of normal) in serum AST and/or ALT. The incidence of abnormalities in AST and/or ALT was 0.2%, 0.2%, 0.6%, and 2.3% in patients on doses of 10, 20, 40, and 80 mg, respectively.
The following results were observed in patients taking atorvastatin calcium in clinical trials. 1 patient developed jaundice and the other patients had elevated liver function tests (LFT) indices unrelated to jaundice and other clinical signs or symptoms. After dose reduction, drug interruption, or discontinuation, AST and/or ALT levels returned to or approached pretreatment levels without sequelae. 18 of 30 patients with persistently elevated liver function tests continued treatment with reduced atorvastatin calcium dosing.
Liver enzyme testing is recommended prior to initiation of atorvastatin calcium therapy and repeated thereafter according to clinical indications. Fatal or nonfatal liver failure has occurred rarely in postmarketing reports of patients receiving statin therapy, including atorvastatin. Discontinue treatment immediately if severe liver injury with clinical signs and/or hyperbilirubinemia or jaundice occurs during the course of treatment with atorvastatin calcium. Do not restart atorvastatin calcium therapy if no other possible etiology is identified.
Atorvastatin calcium should be used with caution in patients with excessive alcohol consumption and/or a history of liver disease. This product is contraindicated in active liver disease or persistent elevation of AST and/or ALT of unknown cause (see [Contraindications] for details).
3. Endocrine function
Reports have shown that 3- hydroxy -3- methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (including atorvastatin calcium) were associated with glycated hemoglobin(HbA1c) and elevated fasting serum glucose levels.
Statin drugs interfere with cholesterol synthesis and theoretically inhibit the synthesis of adrenal and/or gonadal steroid substances. Clinical studies have shown that atorvastatin calcium does not reduce basal plasma cortisol concentrations or impair adrenal reserve. The effects of statins on male fertility have not been adequately studied in case studies, and the effects on the pituitary-gonadal axis in premenopausal women are currently unknown. Caution should be exercised when statins are combined with drugs that can reduce endogenous steroid hormone levels or activity such as ketoconazole, ambrisentin, and cimetidine.
4. Central nervous system toxicity
Cerebral hemorrhage occurred in a female dog given atorvastatin 120 mg/kg/day for 3 months. Cerebral hemorrhage and optic nerve vacuole formation were also found in another female dog given atorvastatin 280 mg/kg/day at an increased dose for 11 weeks and executed in a near-death state. A dose of 120 mg/kg body weight at a maximum human dose of 80 mg/day would result in a systemic exposure approximately 16 times the human plasma area under the curve (AUC, 0 to 24 hours). In a 2-year study, one tonic convulsion was observed in each of 2 male dogs (one dosed at 10 mg/kg/day and the other at 120 mg/kg/day). No CNS damage was observed in mice at doses up to 400 mg/kg/day and in rats at doses up to 100 mg/kg/day administered for 2 years. These doses were 6 to 11 times (mice) and 8 to 16 times (rats) the human area under the curve (0 to 24) at the recommended maximum human dose of 80 mg per day.
Vascular damage to the central nervous system, characterized by perivascular hemorrhage, edema, and perivascular infiltration of monocytes, was observed in dogs given other statins. In clinically normal dogs, plasma drug levels of another drug of similar chemical structure approximately 30 times higher than the recommended maximum human dose produced optic nerve degeneration (retinal-knee fiber Wallerian degeneration) in a dose-dependent manner.
5. In patients with recent stroke or transient ischemic attack
The SPARCL study (Study of Intensive Cholesterol-Lowering Therapy for Stroke Prevention) enrolled 4731 patients who had a stroke or transient ischemic attack within the last 6 months but did not have coronary artery disease and were treated with atorvastatin calcium 80 mg or placebo. Post hoc analysis of the study showed that the incidence of hemorrhagic stroke was higher in patients in the atorvastatin calcium 80 mg group than in the placebo group (55 [2.3%] and 33 [1.4%], respectively; HR=1.68; 95% CI: 1.09-2.59; p=0.0168), and the incidence of fatal hemorrhagic stroke was similar in both groups (17 and 18 for atorvastatin and placebo, respectively). The incidence of non-fatal hemorrhagic stroke was higher in the atorvastatin group (38, 1.6%) than in the placebo group (16, 0.7%). The higher incidence of hemorrhagic stroke in the atorvastatin group was associated with certain baseline characteristics of patients at study entry, including hemorrhagic stroke and lacunar stroke (see [Adverse Reactions]). .
[Use in Pregnant and Lactating Women
Pregnancy
Pregnancy Category X
Atorvastatin calcium is contraindicated in pregnant women or women of childbearing potential who are at risk of conception. The normal pregnancy state has elevated levels of serum cholesterol and TG, and cholesterol or cholesterol derivatives are essential for fetal development. Atherosclerosis is a chronic process, so discontinuation of lipid-lowering drug therapy during pregnancy in patients with primary hypercholesterolemia has little impact on the long-term regression of atherosclerotic disease.
There is a lack of adequate controlled studies of atorvastatin calcium use during pregnancy. There are rare reports of congenital anomalies due to intrauterine exposure to statins. A follow-up study including approximately 100 pregnant women exposed to other statins found that the incidence of congenital anomalies, spontaneous abortion, and fetal death/stillbirth did not exceed what would be expected in the general population, but this study was only able to exclude a risk of 3 to 4 times the base incidence of congenital anomalies, while 89% of patients started the drug before pregnancy but discontinued it within 3 months of being informed of the pregnancy.
Atorvastatin reached the same drug levels as maternal plasma in the fetal rat liver via the rat placenta. Atorvastatin did not produce teratogenic effects at doses up to 300 mg/kg/day in rats and 100 mg/kg/day in rabbits. Based on body surface area (mg/m2), these doses are approximately 30 times (rats) or 20 times (rabbits) the human exposure (see [Contraindications], Pregnancy).
In a study in rats administered at doses of 20, 100, or 225 mg/kg/day from day 7 of gestation to day 21 of lactation (weaning), the mother’s dose of 225 mg/kg/day at birth, neonatal, weaning, and maturity in young animals Survival rates were reduced. Body weight loss was observed on days 4 and 21 for the mother’s dose of 100 mg/kg/day, and on days 4, 21, and 91 for the mother’s dose of 225 mg/kg/day at birth; delayed development of the young animals (Rotella syndrome at 100 mg/kg/day and auditory startle response at 225 mg/kg/day; aural startle response at 225 mg/kg/day). mg/kg/day for auricular separation and eye fissures). These doses correspond to 6 times the area under the curve (100 mg/kg/day) and 22 times the area under the curve (225 mg/kg/day) for a person taking a daily dose of 80 mg.
Statins may be harmful to the fetus when given to a pregnant woman. Women of childbearing potential should only take this product if pregnancy is unlikely and they have been informed of the potential risks of the drug to the pregnant woman. Women taking this drug should be discontinued and informed of the potential risk to the fetus as soon as they become pregnant, and there is no known clinical benefit to continuing the drug during pregnancy.
It is not known whether atorvastatin is secreted via human milk, but another comparable drug is able to be secreted into milk in small amounts. The plasma and liver drug concentrations of atorvastatin in lactated pups were 50% and 40% of the drug concentration in breast milk, respectively. Animal milk drug concentration levels may not accurately reflect human milk drug concentration levels because another comparable drug can be secreted through human milk and because statins may cause serious adverse reactions in newborns receiving breast milk, so mothers taking this product should not breastfeed (see [Contraindications]).
[Pediatric Use
This product should only be used by a specialist in children/adolescents. Experience with this product in children/adolescents has been limited to a small number (10 to 17 years) of heterozygous familial hyperlipidemia. The recommended starting dose of atorvastatin calcium in the pediatric/adolescent population is 10 mg/day. The safety and efficacy of doses above 20 mg/day have not been studied in controlled pediatric studies, and the long-term effectiveness of atorvastatin calcium for treatment in childhood/adolescence to reduce morbidity and mortality in adulthood has not been demonstrated. No information is available on the safety of this product on growth and development in this population. Controlled clinical trials of atorvastatin calcium in prepubertal or less than 10-year-old patient populations have not been conducted.
Of the 39,828 patients taking atorvastatin calcium in the clinical study, 15,813 (40%) were ≥65 years of age and 2,800 (7%) were ≥75 years of age. There were no differences in overall safety and efficacy between these two populations and younger subjects. Other reports of clinical use experience also showed no differences between the older and younger populations. However, it cannot be excluded that some elderly patients are more sensitive to the drug and that advanced age (≥65 years) is a predisposing factor for myopathy, so atorvastatin calcium should be used with caution in the elderly population.
[Medication for patients with hepatic impairment
Atorvastatin calcium is contraindicated in patients with active liver disease, including unexplained persistent elevated levels of hepatic AST and/or ALT [see [Contraindications] and [Pharmacokinetics]].
[Drug Interactions
Drugs that may interact with statins include: HIV protease inhibitors (e.g., lopinavir, darunavir, ritonavir), azole antifungals (e.g., itraconazole, ketoconazole), macrolide anti-infectives (e.g., erythromycin, clarithromycin, telithromycin), fibrate lipid-regulating agents (e.g., gefibrate, benzofibrate), niacin, nefazodone, cyclosporine, amiodarone, diltiazem, fusidic acid, etc.
The risk of myopathy may be increased during the administration of statin therapy in combination with drugs such as: fibrate derivatives, lipid-modifying doses of niacin, cyclosporine, or strong inhibitors of CYP3A4 (e.g., clarithromycin, HIV protease inhibitors, and itraconazole) (see Skeletal Muscle” and [Pharmacologic Toxicology] in [Precautions]).
Strong inhibitors of CYP3A4: Atorvastatin calcium is metabolized by cytochrome P450 3A4. Co-administration of atorvastatin calcium with strong inhibitors of CYP 3A4 can cause increased plasma concentrations of atorvastatin. The extent of drug interactions and the enhancement of effects depend on the extent to which different products affect CYP3A4.
Clarithromycin: Atorvastatin AUC was significantly increased when atorvastatin calcium 80 mg was coadministered with clarithromycin (500 mg twice daily) compared to atorvastatin calcium alone (see [Pharmacology Toxicology]). Therefore, in patients on clarithromycin, it is recommended that the daily dose of atorvastatin not exceed 20 mg and that atorvastatin calcium be used with caution at a dosage of >20 mg (see “Skeletal Muscle” and [Dosage] in [Precautions]).
Protease inhibitors: Atorvastatin calcium in combination with several HIV protease inhibitors and in combination with a hepatitis C protease inhibitor (telaprevir) compared to atorvastatin calcium alone. Atorvastatin AUC was significantly increased (see [Pharmacology and Toxicology]). Therefore, the combination of atorvastatin calcium should be avoided in patients using the HIV protease inhibitor tipranavir + ritonavir, or the hepatitis C protease inhibitor telaprevir. For patients treated with the HIV protease inhibitor lopinavir + ritonavir, atorvastatin calcium should be used with caution and the lowest necessary dose should be used. For patients treated with the HIV protease inhibitors saquinavir + ritonavir, dirinavir + ritonavir, fosamprenavir, or fosamprenavir + ritonavir, atorvastatin calcium should not be administered at doses greater than 20 mg and should be used with caution. (See “Skeletal Muscle” and [Dosage] under [Precautions]). For patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, the dose of atorvastatin calcium should not exceed 40 mg, and close clinical monitoring is recommended.
Itraconazole: Atorvastatin calcium 40 mg was associated with a significant increase in atorvastatin AUC when co-administered with itraconazole 200 mg (see [Pharmacology and Toxicology]). Therefore, in patients taking itraconazole, it is recommended that the daily dose of atorvastatin not exceed 20 mg and that atorvastatin calcium be used with caution at doses >20 mg (see “Skeletal Muscle” in [Precautions] and [Dosage]).
2. Grapefruit juice: Contains one or more components that inhibit cytochrome P450 3A4 and can increase plasma concentrations of atorvastatin, especially when large amounts of grapefruit juice are consumed (more than 1.2 liters per day).
3. Cyclosporine: Atorvastatin and its metabolites are organic anion-transporting polypeptide(OATP1B1) carrier substrate. oATP1B1 inhibitors (e.g., cyclosporine) increase the bioavailability of atorvastatin. The combination of atorvastatin calcium 10 mg with cyclosporine 5.2 mg/kg/day resulted in a significant increase in the AUC of atorvastatin compared to atorvastatin alone (see [Pharmacology and Toxicology]). The combination of atorvastatin calcium and cyclosporine should be avoided (see [Precautions], “Skeletal Muscle”).
4. Gemfibrozil: Atorvastatin calcium should be avoided in combination with gemfibrozil because of the increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are combined with gemfibrozil (See [Precautions], “Skeletal Muscle”).
5. Other Betablockers: Combination of HMG-CoA reductase inhibitors with other betablockers is known to cause an increased risk of myopathy, and atorvastatin calcium should be taken with caution when combined with a betablocker (see [Precautions], “Skeletal Muscle”). should be taken with caution (see [Precautions], “Skeletal Muscle”).
6. Niacin: The risk of effects on skeletal muscle may be increased when atorvastatin calcium is co-administered with niacin; in this case, consider reducing the dose of atorvastatin calcium (see [Precautions], “Skeletal Muscle”). “Skeletal Muscle”).
7. Rifampin and Other Cytochrome P450 3A4 Inducers: The combination of atorvastatin calcium with cytochrome P450 3A4 inducers (e.g., efavirenz, rifampin) can cause atorvastatin plasma concentrations to produce different levels of reduction. Because of the dual interaction mechanism of rifampin, delayed administration of atorvastatin calcium after rifampin administration is associated with a significant reduction in atorvastatin plasma concentrations, and therefore concomitant administration of atorvastatin calcium with rifampin is recommended.
8. Digoxin: Steady-state plasma concentrations of digoxin increase by approximately 20% when multiple doses of atorvastatin calcium are combined with digoxin, and patients should be monitored appropriately when taking digoxin.
9. Oral contraceptives: Atorvastatin calcium, when combined with oral contraceptives, increases the area under the drug-time curve AUC for norethindrone and ethinyl estradiol (see [Pharmacology and Toxicology]) by approximately 30% and 20%, respectively. This increase in AUC should be taken into account when choosing oral contraceptives for women taking this product.
10. Warfarin: Atorvastatin calcium has no clinically significant effect on prothrombin time when patients are receiving long-term treatment with warfarin.
11. Colchicine: Although studies on the interaction of atorvastatin and colchicine have not been performed, the occurrence of myopathy, including rhabdomyolysis, has been reported with the combination of atorvastatin and colchicine. Caution should be exercised when prescribing atorvastatin in combination with colchicine.
[Drug overdose]
There is no specific treatment for overdose of this product. In the event of an overdose, patients should take symptomatic and supportive treatment measures as needed. Because atorvastatin calcium is extensively bound to plasma proteins, hemodialysis does not significantly increase the clearance of atorvastatin calcium.
[Pharmacology and Toxicology
Clinical Pharmacology
Mechanism of action
Atorvastatin calcium is a selective, competitive inhibitor of HMG-CoA reductase, which acts to convert hydroxymethylglutarate monoacyl coenzyme A to mevalonate, a sterol precursor that includes cholesterol. Clinical studies, pathological studies, and epidemiological studies have shown that elevated plasma levels of TC, LDL-C, and apo B promote atherosclerosis in humans and are risk factors for cardiovascular disease, whereas elevated HDL-C levels are associated with a reduced risk of cardiovascular disease.
In animal models, atorvastatin calcium reduces plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver, and enhances LDL uptake and catabolism by increasing the number of LDL receptors on the surface of liver cells; atorvastatin calcium also reduces LDL production. Atorvastatin calcium also decreases LDL production and LDL particle number. It may reduce LDL-C levels in some patients with pure subtype familial hypercholesterolemia (FH), for whom other lipid-lowering drugs are usually rarely clinically effective.
Atorvastatin calcium lowers TC, LDL-C, and apo B levels in patients with pure and heterozygous familial hypercholesterolemia, nonfamilial hypercholesterolemia, and mixed dyslipidemia. It also lowers very low density lipoprotein cholesterol and TG levels, and may increase HDL-C and apoA-1 levels. Atorvastatin calcium reduces TC, LDL-C, very low-density lipoprotein cholesterol, apo B, TG, and non-HDL-C, and increases HDL-C levels in patients with pure hyper-TGemia. Atorvastatin calcium reduces intermediate density lipoprotein cholesterol in patients with β-lipoprotein abnormalities.
Pharmacodynamics
Atorvastatin calcium and some of its metabolites are pharmacologically active in the human body. The liver is the essential site of action and the primary site of cholesterol synthesis and LDL clearance. The dose administered rather than the systemic drug concentration is more associated with LDL-C reduction. Individualized dosing should be based on the efficacy of the treatment (see [DOSAGE]).
Non-clinical Toxicology
Carcinogenic, teratogenic, reproductive damage
In a 2-year study in rats given dose levels of 10, 30 and 100 mg/kg/day, two rare tumors were found in the muscle of female rats at high doses: a rhabdomyosarcoma and a fibrosarcoma . This dose showed plasma area under the curve (0 to 24) values approximately 16 times the average human plasma drug exposure after the maximum oral dose of 80 mg.
In a 2-year carcinogenicity study in mice, administration of doses of 100, 200, or 400 mg/kg/day resulted in a significant increase in liver adenomas in high-dose male mice and liver cancer in high-dose female mice. These findings occurred at plasma area under the curve (0 to 24) values approximately 6 times the mean plasma drug concentration in humans after exposure to an oral dose of 80 mg.
In in vitro studies, atorvastatin was not mutagenic or teratogenic in the following assays with or without metabolic activity: Ames assay with Salmonella typhimurium and Escherichia coli, HGPRT pro-mutagenic assay analysis in Chinese hamster lung cells, and in chromosomal aberration assay analysis in Chinese hamster lung cells. Atorvastatin was negative in the in vivo micronucleus assay in mice.
Atorvastatin did not have any effect on fertility in rats at doses up to 175 mg/kg/day (15 times the human exposure). In 10 rats given atorvastatin 100 mg/kg/day (16 times the area under the curve when given at 80 mg in humans) for 3 months, 2 rats had hypoplastic and azoospermic epididymis; testicular weights were significantly decreased in the 30 and 100 mg/kg/day dose groups and epididymis weights were decreased in the 100 mg dose group. In male rats given atorvastatin 100 mg/kg/day for 11 weeks prior to mating, sperm motility and sperm cell head concentration decreased, while malformed sperm increased. Administration of 10, 40, or 120 mg/kg/day atorvastatin to dogs for two years did not produce adverse effects on semen parameters or histopathology of reproductive organs.
[Pharmacokinetics
Pharmacokinetics and drug metabolism
Absorption: Atorvastatin calcium is rapidly absorbed after oral administration; plasma concentration peaks within 1-2 hours (Cmax). The degree of absorption increases proportionally with the dose of atorvastatin calcium. The absolute bioavailability of atorvastatin calcium (the parent drug) is approximately 14% while the systemic bioavailability of HMG-CoA reductase inhibitory activity is approximately 30%. The lower systemic bioavailability was attributed to gastrointestinal mucosal clearance and/or hepatic first-pass effects prior to entry into the body circulation. Compared to morning dosing, plasma concentrations were slightly lower for evening dosing (Cmax and AUC of approximately 30%). However, the reduction in LDL-C was the same regardless of time of day dosing (see [DOSAGE]).
Distribution: The mean volume of distribution of atorvastatin calcium is approximately 381 liters. Plasma protein binding was ≥98%. The blood/plasma ratio was approximately 0.25 suggesting that only a small amount of drug penetrated into the red blood cells. Atorvastatin calcium may be secreted into human milk based on observations in rats ([Contraindication], [Use in Pregnant and Lactating Women], and [Caution], “Lactating Women”).
Metabolism: Atorvastatin calcium is extensively metabolized to o- and para-hydroxy derivatives and a variety of beta-oxidation products. In in vitro experiments, the o- and para-hydroxylated metabolites showed comparable inhibition of HMG-CoA reductase to atorvastatin calcium. Approximately 70% of the circulating inhibitory activity against HMG-CoA reductase was produced by the active metabolites. In vitro studies have demonstrated the importance of cytochrome P450 3A4 in atorvastatin calcium metabolism, while administration of erythromycin, a known isoenzyme inhibitor, is consistent with increased plasma concentrations of atorvastatin calcium in humans (see [Precautions], [Drug Interactions]). In animals, the o-hydroxy metabolite undergoes further glucuronidation.
Excretion: Atorvastatin calcium and its metabolites are primarily cleared by bile after hepatic and/or extrahepatic metabolism; however, there appears to be no significant hepatic-intestinal recirculation of atorvastatin calcium. The mean human plasma elimination half-life of atorvastatin calcium is approximately 14 hours, but the half-life of the HMG-CoA reductase inhibitory activity of atorvastatin calcium is approximately 20 to 30 hours due to its active metabolites. After oral administration of atorvastatin calcium, urinary recovery was less than 2% of the administered dose.
Special Populations
Elderly patients: In the healthy elderly population (age ≥65 years), blood concentrations of atorvastatin calcium are higher (Cmax of approximately 40% and AUC of approximately 30%) than in young adults. Clinical data show that atorvastatin calcium, given at any dose, reduces LDL-C significantly more in the elderly population than in young adults (see [Precautions], “Geriatric Dosing”).
Children: There are insufficient data on the pharmacokinetics in the pediatric population.
Gender: There are gender differences in blood levels of atorvastatin calcium (approximately 20% higher in women than in men for Cmax and 10% lower in women than in men for AUC). However, there were no clinically significant gender differences in the LDL-C-lowering effects of atorvastatin calcium in clinical use.
Patients with renal insufficiency: Renal disease has no effect on the blood levels and LDL-C-lowering effect of atorvastatin calcium; therefore, no dose adjustment is required in patients with renal insufficiency (see [DOSAGE]).
Patients on hemodialysis: Although still not studied in patients with end-stage renal disease, hemodialysis does not significantly improve the clearance of atorvastatin calcium because of the extensive binding of this product to plasma proteins.
Patients with hepatic insufficiency: In patients with chronic alcoholic liver disease, blood concentrations of atorvastatin calcium were significantly increased; in patients with Childs-Pugh A, both Cmax and AUC were increased 4-fold, whereas in Childs-Pugh B patients Cmax and AUC were increased 16-fold and 11-fold, respectively (see [Contraindications]). .
Table 3 Effect of combination on atorvastatin pharmacokinetics
Name and dosage of co-medicationAtorvastatinDose (mg)AUC change&Cmax change&# Cyclosporine 5.2mg/kg/day 10mg QD for 28 days↑8.7x↑10.7x# Tilaprevir 500mg BID/Ritonavir 200mg BID for 7 days10mg, SD↑9.4x↑8.6x# Trapivir 750mg q8h for 10 days20mg, SD20mg, SD↑7.88x↑10.6x# #,‡Saquinavir 400mg BID/ritonavir 400mg BID for 15 days40mg QD for 4 days↑3.9x↑4.3x# Clarithromycin 500mg BID, 9 days80mg QD, 8 days↑4.4x↑5.4x# Dirinavir 300mg BID/ritonavir 100mg BID for 9 days10mg QD, 4 days↑3.4x↑ 2.25x# Itraconazole 200mg QD, 4 days40mg, single dose↑3.3x↑20%# Fosamprenavir 700mg BID/ritonavir 100mg BID for 14 days10mg QD for 4 days↑2.53x↑2.84x# Fosamprenavir 1400mg BID, 14 days10mg QD, 4 days ↑2.3x↑4.04x# Nelfinavir 1250mg BID, 14 days10mg QD, 28 days↑74%↑2.2x# Grapefruit Juice 240mL QD*40mg, single dose40mg, single dose↑37%↑16%Diltiazem 240mg QD for 28 days40mg, single dose↑51%No changeErythromycin 500mg QID, 7 days10mg, single dose↑33%↑38%Amlodipine 10mg. Single dose80mg, single dose↑15%↓12%Cimetidine 300mg QID, 2 weeks10mg QD, 2 weeks↓<1%↓11% Colestipol 10mg BID at 28 weeks40mg QD, 28 weeksNot measured↓26%**Maalox Oral Suspension®30mL QD , 17 days↓33%↓34%Efavirenz 600mg QD for 14 days10mg for 3 days↓41%↓1%# Rifampicin 600mg QD, 7 days (co-administered)†40mg, single dose↑30%↑2.7x# Rifampicin 600mg QD, 5 days (given alone)†40mg, single dose↓80%↓40%# Gefiberzi 600mg BID, 7 days40mg, single dose↑35%↓<1%# Fenofibrate 160mg QD, 7 days40mg, single dose↑3%↑2%↑2%Boceprevir 800mg TID, 7 days40mg, single dose↑2.30x↑2.66-fold& X-fold in the table represents the ratio of the co-drug value to the value of atorvastatin alone (i.e., 1-fold = no dosing) (i.e., 1x = no change); percentages (%) in the table represent (coadministered value – administered value alone)/administered value alone (i.e., 0% = no change)
#See [Precautions] and [Drug Interactions] for clinical significance.
* Excessive grapefruit juice dosage (more than 750 mL-1.2 L per day) has been reported to increase AUC (up to 2.5-fold) and/or Cmax (up to 71%) more significantly.
**Samples were taken for testing 8-16 hours after dosing.
†Rifampin has a dual drug interaction mechanism and concomitant administration of atorvastatin in combination with rifampin is recommended; if rifampin is administered followed by atorvastatin the latter plasma drug concentration can be significantly reduced.
‡The applied dose of saquinavir + ritonavir used in this study was not a clinical dose. When clinical doses are used, the incremental value of the exposed dose of atorvastatin is likely to be higher than the incremental value observed in this study. Therefore, caution should be exercised when applying and using the lowest necessary dose.
Table 4 Pharmacokinetic effects of atorvastatin on co-applied drugs
AtorvastatinName and dosage of co-medicationDrug/Dose (mg)AUC changeCmax changes80 mg QD in 15 daysAminotriptyline 600 mg SD ↑3%↓11% 80 mg QD for 14 days# Digoxin 0.25 mg QD for 20 days ↑15%↑20%40 mg QD in 22 daysOral contraceptive QD, 2 months
– Ethisterone 1 mg
– Ethinylestradiol 35µg
↑19%
↑30%10mg QD Tilaprevir 500mg BID/ritonavir 200mg BID for 7 daysNo changeNo change10mg QD, 4 daysFosamprenavir 1400mg BID, 14 daysFosamprenavir 1400mg BID, 14 days↓27%↓18%10mg QD, 4 daysFosamprenavir 700mg BID/ritonavir 100mg BID for 14 daysNo changeNo change# See [Precautions] and [Drug Interactions] for clinical significance
[Storage]Store under shade and seal.
[Package]1. 7 tablets/plate/bag/box, 10 tablets/plate/bag/box in aluminum-plastic blister compound film bag.
2. Double aluminum blister packaging, 7 tablets/plate x 1 plate/box, 7 tablets/plate x 2 plates/box; 10 tablets/plate x 1 plate/box.
[Expiration date] 36 months.
[Execution Standard
[Approval No.]State Drug Administration H19990258, 10 mg; State Drug Administration H20093819, 20 mg.
[Manufacturer
Company Name: Beijing Jialin Pharmaceutical Co.
Manufacturing Address: Shuangqiao East Road, Chaoyang District, Beijing
Postal Code: 100121
Contact: 010-85391864
Quality Complaints: 010-85390101
Company Website: www.jarlin.com.cn