Date of approval.
Date of revision.
Atorvastatin Calcium Dispersible Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Atorvastatin Calcium Dispersible Tablets
English name: Atorvastatin Calcium Dispersible Tablets
Hanyu Pinyin: Attuofatatinggai Fensanpian
Ingredients
The main ingredient of this product is Atorvastatin Calcium.
Chemical name: [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(anilino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1) trihydrate.
The chemical structure formula is
Molecular formula: (C33H34FN2O5)2Ca-3H2O
Molecular weight: 1209.42
【Properties】.
This product is white or off-white tablet.
Indications
Hypercholesterolemia
For patients with primary hypercholesterolemia, including familial hypercholesterolemia (heterozygous) or mixed hyperlipidemia (corresponding to Fredrickson’s classification IIa and IIb), if dietary and other non-pharmacological treatments are unsatisfactory, this product can be used to treat elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), low-density lipoprotein cholesterol (LDL-C), and low-density lipoprotein cholesterol (LDL-C). (LDL-C), Apolipoprotein B (Apo B), and Triglycerides (TG) if dietary and other non-pharmacologic therapy is not effective.
In patients with Homozygous familial hypercholesterolemia (HoFH), 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 total cholesterol (TC) and low-density lipoprotein cholesterol ( LDL-C).
Coronary heart disease
For patients with coronary artery disease or at-risk conditions such as coronary artery disease (e.g., diabetes, symptomatic atherosclerotic disease, etc.) combined with hypercholesterolemia or mixed dyslipidemia, this product is indicated to: reduce the risk of non-fatal myocardial infarction, reduce the risk of fatal and non-fatal stroke, reduce the risk of revascularization, reduce the risk of hospitalization for congestive heart failure, and reduce the risk of angina pectoris.
【Specifications】.
According to C33H35FN2O5 (1) 10 mg (2) 20 mg
Dosage]
This product can be swallowed directly or taken orally, or it can be put into an appropriate amount of warm boiled water and then taken orally after being dispersed evenly.
Patients should be on a standard low-cholesterol diet before starting this treatment and should 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 usual starting dose is 10 mg once daily. Dose adjustments should be made at 4-week intervals or longer. The maximum dose of this product is 80 mg once daily. The daily dose of atorvastatin 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
Lipid levels are controlled in most patients taking atorvastatin calcium 10 mg once daily. Significant efficacy is seen within 2 weeks of treatment, with maximum efficacy seen within 4 weeks of treatment. Long-term treatment maintains efficacy.
Treatment of pure congenic familial hypercholesterolemia
The recommended dose of this product is 10 to 80 mg/day for patients with pure subtype familial hypercholesterolemia. Atorvastatin calcium should be used as an adjunct to other lipid-lowering therapies, such as low-density lipoprotein (LDL) plasma dialysis Or, when these therapeutic conditions are not available, this product may be used alone.
Dosing in patients with renal insufficiency
Renal disease has no effect on either the plasma concentration or the lipid-lowering effect of this product, so no dose adjustment is necessary.
Dosage for patients taking cyclosporine, clarithromycin, itraconazole, or specific protease inhibitors
Avoid treatment with atorvastatin calcium in patients treated with cyclosporine or human immunodeficiency virus (HIV) protease inhibitors (tipranavir + ritonavir) or hepatitis C virus (HCV) protease inhibitors (glatiramerivir + piramisvir). Use the lowest dose of atorvastatin calcium necessary in patients with human immunodeficiency virus treated with lopinavir in combination with ritonavir. In patients treated with clarithromycin, itraconazole, ebacivir + gizoprevir, or saquinavir in combination with ritonavir, dirinavir in combination with ritonavir, fosamprenavir, or fosamprenavir in combination with ritonavir for human immunodeficiency virus, the therapeutic dose of atorvastatin calcium should be limited to 20 mg and an appropriate clinical evaluation is recommended to ensure that the lowest dose of atorvastatin calcium necessary is used . In patients on the human immunodeficiency virus protease inhibitor nelfinavir, the therapeutic dose of atorvastatin calcium is limited to 40 mg. When atorvastatin is used with other protease inhibitors, it is recommended that an appropriate clinical evaluation be performed to ensure that the dose of atorvastatin calcium used is the lowest dose required (see [Precautions] and [Drug Interactions]).
Adverse Reactions]
The following serious adverse reactions are described in detail elsewhere in this instruction.
Rhabdomyolysis and myopathy (see [Precautions]).
Liver enzyme abnormalities (see [Precautions]).
Clinical Trial Experience
The incidence of adverse reactions obtained in clinical trials with two different drugs cannot be directly compared because of the complexity of the subjects’ conditions during the implementation of the clinical trials and may not reflect the incidence of adverse reactions in clinical practice.
The placebo-controlled clinical trial of atorvastatin calcium enrolled 16,066 patients (atorvastatin calcium N=8755, placebo N=7311, age from 10 to 93 years, 39% female; 91% Caucasian white, 3% black, 2% Asian, 4% other races) with a median treatment period of 53 weeks; without considering causality, the atorvastatin calcium group and placebo groups, 9.7% and 9.5% of patients discontinued due to adverse effects, respectively. The five most common adverse reactions that led to discontinuation and were more frequent 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%).
Without considering causality, the most common (≥2%) and more frequent adverse reactions than placebo in the placebo-controlled trial of atorvastatin calcium (N=8755) were, in order, 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 in the placebo group (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=875510 mg
N=390820 mg
N=18840 mg
N=60480 mg
N=4055 placebo
N=7311 Nasopharyngitis8.312.95.37.04.28.2 Arthralgia6.98.911.710.64.36.5 Diarrhea6.87.36.414.15.26.3 Extremity pain6.08.53.79.33.15.9 Urinary tract infection5.76.96.48.04.15.6 Indigestion4.75.93.26 .03.34.3 nausea4.03.73.77.13.83.5 skeletal muscle pain3.85.23.25.12.33.6 muscle spasm3.64.64.85.12.43.0 myalgia3.53.65.98.42.73.1 insomnia3.02.81.15.32.82.9 sore throat2.33.91.62. 80.72.1* Incidence of any dose ≥ 2% and higher than placebo group
Other adverse reactions reported in placebo-controlled studies include
Systemic: malaise, fever.
Digestive system: abdominal discomfort, belching, gastrointestinal distention, 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), 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.
Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)
The Anglo-Scandinavian Cardiac Outcomes Study (ASCOT) included 10,305 participants (age range 40 to 80 years, 19% female; 94.6% Caucasian white, 2.6% African, 1.5% South Asian, 1.3% mixed or other ethnicity) given atorvastatin calcium 10 mg daily (N=5168) or placebo (N= 5137) treatment. The safety and tolerability of the atorvastatin calcium treatment group was comparable to the placebo group during a median follow-up of 3.3 years.
The Collaborative Atorvastatin Diabetes Study,
(CARDS)
In the Collaborative Atorvastatin Diabetes Study (CARDS), a total of 2838 subjects (age range 39-77 years, 32% female; 94.3% Caucasian white, 2.4% South Asian, 2.3% Black Caribbean, 1.0% other ethnicity) with type 2 diabetes were enrolled and received either atorvastatin calcium 10 mg daily (N=1428) or placebo (N =1410), there were no differences in the overall frequency of adverse events or serious adverse events between treatment groups and no reports of rhabdomyolysis during a median value of 3.9 years of follow-up.
Treating to New Targets Study (TNT)
The Treating to New Targets Study (TNT) involved 10,001 patients (age range 29 to 78 years, 19% female; 94.1% Caucasian white, 2.9% black, 1.0% Asian, and 2.0% other races) with clinically evidenced coronary artery disease treated with atorvastatin calcium 10 mg (N=5006) or 80 mg (N=4995) daily at a median follow-up value of years during 4.9 years, there were more serious adverse events and treatment interruptions due to adverse events in the high-dose group compared to the low-dose group (92, 1.8%; 497, 9.9% in the high-dose group and 69, 1.4%; 404, 8.1% in the low-dose group, respectively). 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 to 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.
Incremental Decrease in Endpoints Through Aggressive Lipid Lowering Study (IDEAL)
The Intensive Endpoint Event Reduction Through Aggressive Lipid Lowering Study (IDEAL) 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 atorvastatin calcium 80 mg (N=4439) or simvastatin 20-40 mg (N=4449) daily ) treatment, 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 by Aggressive Reduction in Cholesterol Levels (SPARCL) Study
The Intensive Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study enrolled 4731 subjects (age 21-92 years, 40% female; 93.3% Caucasian white, 3.0% black, 0.6% Asian, 3.1% other ethnicity) who had no clinical evidence of coronary heart disease but had a history of stroke or transient ischemic attack (TIA) within the last 6 months. Asian, 3.1% other ethnicities), received atorvastatin calcium 80 mg (N=2365) or placebo (N=2366) with a median follow-up of 4.9 years. The incidence of 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 to 10 days) was higher 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 was reported as an adverse effect in 144 (6.1%) and 89 (3.8%) cases each in the atorvastatin and placebo groups (see [caution]).
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 (55/2365 [2.3%] vs. 33/2366 [1.4%]) in patients in the atorvastatin calcium 80 mg group compared with the placebo group. 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 been at increased risk of developing hemorrhagic stroke over the course of the study (7 [16%] in the atorvastatin calcium group vs. 2 [4%] in the placebo group).
There was no significant difference in all-cause mortality between the two groups: 216 (9.1%) in the atorvastatin calcium 80 mg daily group vs. 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 deaths was numerically higher in the atorvastatin calcium 80 mg group (5.0%) than in the placebo group (4.0%).
Adverse Reactions in Clinical Studies of Atorvastatin Calcium in Pediatric Patients
In a 26-week controlled study of boys and postmenarcheal girls (aged 10 to 17 years) with heterozygous familial hypercholesterolemia (N=140, 31% girls; 92% Caucasian, 1.6% black, 1.6% Asian, 4.8% other), atorvastatin calcium 10 mg to 20 mg/day (as an adjunct to dietary therapy that to lower total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B levels) had a safety and tolerability similar to placebo (see [Pharmacokinetics], [Precautions], and [Pediatric Dosage]).
Postmarketing Reports
The following adverse reactions were reported after the approval of atorvastatin calcium for marketing use. Because post-marketing adverse reactions were reported on a patient-initiated basis and the actual number of people using the drug was not determined, the exact incidence of these adverse reactions could not be calculated and the causal relationship between these adverse reactions and the drug could not be determined.
Without considering causality, post-marketing adverse reactions associated with atorvastatin calcium not listed above include: allergic reactions, angioneurotic edema, maculopapular rash (including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis release), rhabdomyolysis, myositis, fatigue, tendon rupture, fatal or non-fatal 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]).
Postmarketing surveillance of statins has reported hyperglycemic reactions, abnormal glucose tolerance, elevated glycosylated hemoglobin levels, new-onset diabetes, and worsening glycemic control, and some statins have reported hypoglycemic reactions.
Rarely, cognitive impairment has been reported in post-marketing surveillance of statins abroad, manifesting as memory loss, memory decline, and confusion. The time to onset of cognitive impairment is uncertain (one day to several years), and the time to remission is uncertain (median time of three weeks).
[Contraindications
1. Active liver disease, which may include persistent elevation of hepatic aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) of unknown cause.
2. Known hypersensitivity to any of the ingredients in this product.
3. Pregnancy (see [Use in Pregnant and Lactating Women]).
4. Lactating women (see [Use in Pregnant and Lactating Women]).
Precautions]
1. Skeletal muscle
A few cases of acute renal failure secondary to rhabdomyolysis-induced myoglobinuria have occasionally been reported with atorvastatin calcium and other statins. A history of renal impairment may be a risk factor for the development of rhabdomyolysis, and the effects of the drug on skeletal muscle need to be monitored closely in these 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 strong inhibitors of cytochrome P450 3A4 (CYP 3A4) (e.g., clarithromycin, itraconazole, and human immunodeficiency virus (HIV) and hepatitis C virus (HCV)) virus (HCV) protease inhibitors) may increase the risk of myopathy or rhabdomyolysis.
Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has occasionally been reported in association with statin use. Immune-mediated necrotizing myopathy (IMNM) is characterized by proximal muscle weakness and elevated serum creatine kinase (symptoms persist after discontinuation of statin); muscle biopsy shows necrotizing myopathy without significant inflammation; and improvement with immunosuppressive agents.
Myopathy should be considered in any patient with diffuse myalgia, muscle induration 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.
Concomitant use of the drugs listed in Table 2 during treatment with statins, including atorvastatin calcium, increases the risk of myopathy. Physicians should carefully weigh the potential benefits and risks when considering combined treatment with atorvastatin calcium and any of the above drugs and should carefully monitor patients for any signs and symptoms of muscle pain, muscle pressure, or muscle weakness, especially during the months of treatment initiation and during dose escalation of either drug. When atorvastatin is administered concomitantly with the previously mentioned drugs (see [Drug Interactions]), a lower starting and maintenance dose of atorvastatin should be considered. Regular creatine phosphokinase measurements are to be considered in the case of the above mentioned combinations, but such monitoring does not ensure that severe myopathy can be prevented.
Recommended prescription dosages and drug interactions are summarized in Table 2 (see [Dosage], [Drug Interactions], [Pharmacology and Toxicology]).
Table 2. Interactions causing increased risk of atorvastatin myopathy/rhabdomyolysis Drug Interactions Recommended Prescription Dosage Cyclosporine, tipranavir + ritonavir, griseofulvin + pirenzavir, telaprevir Avoid atorvastatin Clarithromycin, Itraconazole, saquinavir + ritonavir*, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, epamivir +gelzopravir atorvastatin daily dose not to exceed 20 mg nelfinavir, boceprevir atorvastatin daily dose not to exceed 40 mg lopinavir + ritonavir, cimetapivir, fibrate derivatives, erythromycin, azole antifungals, lipid-regulated doses of niacin, colchicine use with caution and use the minimum necessary dose* use the minimum necessary dose ([pharmacokinetics])
Combined administration of atorvastatin and fidicic acid is not recommended, therefore it is recommended that atorvastatin therapy be suspended during fidic acid therapy.
Atorvastatin calcium therapy should be suspended or interrupted in any patient with acute, severe conditions predictive of myopathy or with risk factors (e.g., severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disturbances, uncontrolled seizures) predisposing to renal failure secondary to rhabdomyolysis.
2. abnormal liver function
As with other lipid-lowering therapies, statins can cause abnormalities in hepatic function and biochemical parameters. Clinical trials have shown that 0.7% of patients treated with atorvastatin calcium had persistent elevations (two or more times more than three times the upper limit of normal) of serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT). The incidence of abnormal aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) was 0.2%, 0.2%, 0.6%, and 2.3% for 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, while the other patients had elevated liver function tests (LFTs) independent of jaundice and other clinical signs or symptoms. After dose reduction, drug interruption, or discontinuation, aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) levels returned to or approached pretreatment levels without sequelae. 18 of the 30 patients with persistently elevated liver function tests continued treatment at a reduced dose of atorvastatin calcium.
Liver enzyme testing was recommended prior to initiation of atorvastatin calcium therapy and repeated thereafter according to clinical indications. Fatal or nonfatal hepatic failure has occurred rarely in postmarketing reports of patients treated with statins, 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 who have consumed excessive alcohol and/or have a history of liver disease. This product is contraindicated in active liver disease or persistent elevations of aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) of unknown cause (see [Contraindications] for details).
3. Endocrine function
The use of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors (including atorvastatin calcium) has been reported to be associated with elevated glycated hemoglobin A1C (HbA1c) and fasting serum glucose levels.
Statins interfere with cholesterol synthesis and theoretically inhibit the synthesis of adrenal and/or gonadal steroids. 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 combining statins with drugs that can reduce the levels or activity of endogenous steroid hormones 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 noted in another female dog given at an increased dose of atorvastatin 280 mg/kg/day for 11 weeks and executed in a near-death condition. A dose of 120 mg/kg body weight at the 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 area under the human curve (0 to 24 hours) based on the recommended maximum human dose of 80 mg per day.
Canine CNS vascular damage, characterized by perivascular hemorrhage, edema, and perivascular infiltration of mononuclear cells, was observed when other statins were administered. 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 Study of Prevention of Stroke with Intensive Cholesterol-Lowering Therapy (SPARCL) enrolled 4731 patients with a recent stroke or transient ischemic attack within the last 6 months but without coronary artery disease 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 in the atorvastatin and placebo groups, respectively, and 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 the patients at study entry, including hemorrhagic stroke and lacunar stroke (see [Adverse Reactions]).
For pregnant and lactating women]
Pregnancy
Risk Summary
The safety of atorvastatin calcium in women during pregnancy has not been established and there is no clear benefit of lipid-lowering agents during pregnancy; therefore, atorvastatin calcium is contraindicated in pregnant women. Because 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors reduce cholesterol synthesis and potentially the synthesis of other biologically active cholesterol derivatives, administration of atorvastatin calcium to pregnant women may be harmful to the fetus. Atorvastatin calcium should be discontinued as soon as pregnancy is confirmed (see [Contraindications]). Because of the limited published data on atorvastatin use, there are insufficient data to establish a drug-related risk of serious congenital malformations or miscarriage. In rat and rabbit reproduction studies, no evidence of embryo-fetal toxicity or congenital malformations was seen when the highest dose was 30 and 20 times the human exposure (i.e., the maximum recommended human dose (MRHD, 80 mg)), respectively (based on body surface area (mg/m2)). In rats using atorvastatin during pregnancy and lactation, decreased postnatal pup growth and development was observed at doses greater than or equal to 6 times the maximum recommended human dose (see data).
The expected background risk of significant birth defects and miscarriage is unknown for the population eligible for the indication. In the general U.S. population, the predicted background risks of major birth defects and miscarriage in clinically confirmed pregnancies are 2-4% and 15-20%, respectively.
Data
Human data
Published observational studies, meta-analyses, and case report data on atorvastatin calcium are limited, and the available data do not demonstrate an increased risk of serious congenital malformations or miscarriage. In rare reports, fetal congenital anomalies have been observed following in utero exposure to other 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. One review reported prospective follow-up of approximately 100 pregnant women taking simvastatin or lovastatin and showed that the incidence of congenital anomalies, spontaneous abortion, and fetal death/stillbirth did not exceed the expected incidence in the general population. The number of cases was sufficient to exclude the possibility that the increase in the rate of congenital anomalies exceeded more than 3-fold to 4-fold the background incidence. In 89% of prospectively followed pregnancies, the drug was initiated before pregnancy and discontinued at some point during the first trimester when pregnancy was detected.
Lactation
Risk Summary
Atorvastatin calcium should be contraindicated during lactation (see [Contraindications]). There is a lack of available information on the effects of this product on breastfed infants or on lactation. It is not known if atorvastatin is present in human milk, but studies have shown that another comparable drug can enter human milk and that atorvastatin is present in rat milk. Because of the potential for serious adverse reactions in breastfed infants, women should be advised not to breastfeed during treatment with atorvastatin calcium.
Female and Male Fertility
Contraception
Atorvastatin calcium may be harmful to the fetus when administered to pregnant women. Females of childbearing potential should be advised to use effective contraception during treatment with atorvastatin calcium (see [Medication for Pregnant and Lactating Women]).
Pediatric Dosage]
Heterozygous familial hypercholesterolemia
The recommended starting dose of atorvastatin calcium is 10 mg/day and the usual dose is 10 mg/day to 20 mg/day.
The safety and efficacy of atorvastatin calcium have been confirmed in a number of pediatric patients aged 10 to 17 years with heterozygous familial hypercholesterolemia. After an adequate trial of dietary therapy to reduce total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B levels with adjuvant therapy and the presence of one of the following.
LDL-C ≥ 190 mg/dL, or
LDL-C ≥ 160 mg/dL and
A positive family history of familial hypercholesterolemia or the presence of premature cardiovascular disease (CVD) in a first or second degree relative, or
The presence of two or more other risk factors for CVD.
Evidence supporting the use of atorvastatin calcium for this indication comes from the following studies (see [DOSAGE], [ADVERSE REACTIONS], and [PHARMACOLOGY]).
A 6-month placebo-controlled clinical trial in 187 boys and postmenarcheal girls (10 to 17 years of age). Patients treated with atorvastatin calcium 10 mg or 20 mg/day had a substantially similar profile of adverse reactions to those treated with placebo. Atorvastatin had no significant effect on growth and sexual maturation in boys or on the menstrual cycle in girls in this controlled study with limited conditions.
A three-year open, uncontrolled trial enrolling 163 pediatric patients (10 to 15 years of age) with heterozygous familial hypercholesterolemia in which patients were given progressively increasing doses to achieve an LDL-C < 130 mg/dL target. The starting dose of atorvastatin calcium was 10 mg/day, with a maximum dose of 80 mg/day. Despite the limitations of the uncontrolled study design, the safety and efficacy of atorvastatin calcium in reducing LDL-C were generally consistent with those observed in adult patients.
Contraceptive advice should be provided to post-primary girl patients if appropriate (see [Pregnant and Lactating Women’s Dosage]).
The safety and efficacy of atorvastatin doses above 20 mg have not been studied in pediatric controlled studies, and the long-term effectiveness of atorvastatin for treatment in childhood to reduce morbidity and mortality in adulthood has not been demonstrated.
The safety and efficacy of atorvastatin calcium in pediatric patients under 10 years of age with pure subtype familial hypercholesterolemia have not been demonstrated.
[Geriatric Use].
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 susceptibility factor for myopathy, so atorvastatin calcium should be used with caution in the elderly population.
Use in patients with hepatic impairment
Atorvastatin calcium is contraindicated in patients with active liver disease, including unexplained persistent elevations in hepatic aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) levels (see [Contraindications] and [Pharmacokinetics]).
Drug Interactions]
Drugs that may interact with statins include: human immunodeficiency virus (HIV) protease inhibitors (e.g., lopinavir, darunavir, ritonavir), azole antifungals (e.g., itraconazole, ketoconazole), macrolide anti-infectives (e.g., erythromycin, clarithromycin, telithromycin), fibrate lipid regulators (e.g., gefibrate, benzofibrate), niacin, nefazodone, cyclosporine, aminoglutethimide, diltiazem. amiodarone, diltiazem, fondesic acid, etc.
The risk of myopathy may be increased during statin therapy in combination with drugs such as: fibrate derivatives, lipid-regulating doses of niacin, cyclosporine, or strong inhibitors of cytochrome P450 3A4 (CYP 3A4) (e.g., clarithromycin, human immunodeficiency virus (HIV) and hepatitis C virus (HCV) protease inhibitors, and itraconazole) (see [Precautions] and [ Pharmacology and Toxicology]).
1. Strong inhibitor of cytochrome P450 3A4 (CYP 3A4): Atorvastatin calcium is metabolized by cytochrome P450 3A4 (CYP 3A4). Co-administration of atorvastatin calcium with strong inhibitors of cytochrome P450 3A4 (CYP 3A4) can cause an increase in atorvastatin plasma concentrations. The extent of the drug interaction and the enhancement of the effect depends on the degree of effect of the different products on cytochrome P450 3A4 (CYP 3A4).
Clarithromycin: Atorvastatin AUC was significantly increased when atorvastatin calcium 80 mg was co-administered with clarithromycin (500 mg twice daily) compared to atorvastatin calcium alone (see [Pharmacology and Toxicology]). Therefore, for patients applying clarithromycin, it is recommended that the daily dose of atorvastatin not exceed 20 mg and that atorvastatin calcium dosage> 20 mg be used with caution (see [Dosage] and [Precautions]).
Protease inhibitors: Atorvastatin AUC is significantly increased when atorvastatin calcium is co-administered with several protease inhibitor combinations and when co-administered with telaprevir (see [Pharmacokinetics]). The combination of atorvastatin calcium should be avoided in patients using tipranavir + ritonavir or glepiravir + piramisvir, or telaprevir. For patients treated with lopinavir + ritonavir or simeprevir, the lowest necessary dose of atorvastatin calcium should be used. The dose of atorvastatin calcium should not exceed 20 mg for patients treated with saquinavir + ritonavir, dirinavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, or ebacivir + gemcitabine. for patients taking nelfinavir or boceprevir, the dose of atorvastatin calcium should not exceed 40 mg and close clinical monitoring is recommended (see [DOSAGE Dosage] and [Precautions]).
Itraconazole: Atorvastatin AUC is significantly increased with the combination of atorvastatin calcium 40 mg and itraconazole 200 mg (see [Pharmacology and Toxicology]). Therefore patients applying itraconazole are advised to use atorvastatin at a daily dose of no more than 20 mg and atorvastatin calcium at a dosage > 20 mg with caution (see [Dosage] and [Precautions]).
2. Grapefruit juice: contains one or more components that inhibit cytochrome P450 3A4 (CYP 3A4) and can increase the plasma concentration of atorvastatin, especially when large amounts of grapefruit juice are consumed (more than 1.2 liters per day).
3. Cyclosporine: Atorvastatin is a substrate of hepatic transport proteins, and its metabolites are substrates of the organic anion transporting polypeptide 1B1 (OATP1B1) carrier. Organic anion transporting polypeptide 1B1 (OATP1B1) inhibitors, such as 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]).
4. Gleevec + piramisvir; ibrasvir + gizoprevir.
Concomitant administration of glegravir + pirunciclovir or ibrasvir + gemcitabine may increase plasma concentrations of atorvastatin and increase the risk of myopathy.
Concomitant administration of glegravir + pirunciclovir and atorvastatin increased plasma concentrations of atorvastatin by 8.3-fold, in part because of BCRP, OATP1B1/1B3, and CYP3A inhibition; therefore, concomitant administration of atorvastatin calcium is not recommended for patients on concomitant medications containing glegravir + pirunciclovir.
Concomitant administration of ibrasvir + gemcitabine and atorvastatin can increase the plasma concentration of atorvastatin by 1.9-fold, in part due to BCRP, OATP1B1/1B3, and CYP3A inhibition; therefore, the daily dose of atorvastatin calcium should not exceed 20 mg in patients taking concomitant medications containing ibrasvir + gemcitabine (see [Dosage], [Precautions], and [Pharmacology and Toxicology]).
5. Gemfibrozil: Combination of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors with gemfibrozil is associated with an increased risk of myopathy/rhabdomyolysis and should therefore be avoided (see [Precautions]).
6. Other beta drugs: Combination of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors with other beta drugs is known to increase the risk of myopathy and atorvastatin calcium should be administered with caution when combined with beta drugs (see [Precautions]).
7. niacin: The risk of skeletal muscle effects may be increased when atorvastatin calcium is combined with niacin; in this case, a reduction in the dose of atorvastatin calcium should be considered (see [Precautions]).
8. Rifampin and other cytochrome P450 3A4 (CYP 3A4) inducers: The combination of atorvastatin calcium and cytochrome P450 3A4 (CYP 3A4) inducers (e.g., efavirenz, rifampin) can produce different levels of reductions in atorvastatin plasma concentrations. Due to 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.
9. Digoxin: Steady-state plasma concentrations of digoxin are increased when multiple doses of atorvastatin calcium are combined with digoxin (see [Pharmacology and Toxicology]). Patients should be monitored appropriately when taking digoxin.
10. 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. The increase in AUC should be taken into account when choosing oral contraceptives for women taking this product.
11. Warfarin: Atorvastatin calcium has no clinically significant effect on prothrombin time when the patient is receiving long-term treatment with warfarin.
12. Colchicine: Although studies on the interaction of atorvastatin and colchicine have not been conducted, the occurrence of myopathy (including rhabdomyolysis) when atorvastatin is combined with colchicine has been reported, and caution should be exercised when prescribing atorvastatin in combination with colchicine.
Overdose]
There are no special treatment measures for overdose. In case of overdose, patients should take symptomatic and supportive treatment measures as needed. Hemodialysis does not significantly increase the clearance of atorvastatin calcium due to the extensive binding of atorvastatin calcium to plasma proteins.
Pharmacology and Toxicology
Pharmacological effects
Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, a rate-limiting enzyme that converts 3-hydroxy-3-methyl-glutaryl coenzyme A to mevalonate (a precursor to sterols including cholesterol). Very low density lipoproteins (VLDL) are produced in the liver and carry triglycerides and cholesterol, which are released into the plasma for further transport to surrounding tissues. Low-density lipoproteins (LDL) are converted from low-density lipoproteins (VLDL), most of which are catabolized and metabolized by intra- and extrahepatic receptors in the liver cells.
Atorvastatin reduces plasma cholesterol and serum lipoprotein concentrations by inhibiting HMG-CoA reductase and cholesterol biosynthesis in the liver, and enhances LDL uptake and metabolism by increasing LDL receptors on the hepatic cell surface.
Atorvastatin decreases LDL production and LDL particle number. Atorvastatin leads to a significant and persistent increase in LDL receptor activity and consequently beneficial changes in circulating LDL particle mass. Atorvastatin was effective in reducing LDL cholesterol levels in patients with purex familial hypercholesterolemia, for whom lipid-lowering drugs are usually ineffective.
Toxicological studies
Genotoxicity.
Atorvastatin was negative in the Salmonella typhimurium and Escherichia coli Ames tests, the HGPRT mutation test in Chinese hamster lung cells, the chromosomal aberration test in Chinese hamster lung cells, and the in vivo micronucleus test in mice.
Reproductive toxicity.
No significant effects on fertility were observed in male rats given atorvastatin up to 175 mg/kg/day (15 times the human exposure) and in female rats given atorvastatin up to 225 mg/kg (56 times the human exposure). 10 rats were given atorvastatin 100 mg/kg/day (16 times the AUC at 80 mg human dose) orally for 3 months and 2 rats had hypoplastic and azoospermic epididymis; testicular weight was significantly decreased in the 30 and 100 mg/kg/day groups, and epididymis weight was decreased in the 100 mg/kg/day group. Male rats given atorvastatin 100 mg/kg/day orally for 11 weeks before mating showed decreased sperm motility and sperm cell head concentration and increased malformed sperm. No significant effects on semen parameters or histomorphology of reproductive organs were observed in dogs given atorvastatin 10, 40, or 120 mg/kg/day orally for 2 years.
No fetal malformations were observed in pregnant rats given atorvastatin up to 300 mg/kg/day orally during the organogenesis phase (30 times the MRHD, converted to body surface area); increased maternal loss after implantation and decreased fetal weight were seen at 300 mg/kg/day.
In pregnant rabbits given orally up to 100 mg/kg/day (20 times the MRHD in terms of body surface area) during the organogenesis period, no fetal malformations were observed; increased maternal post-arrival loss was seen at 50 and 100 mg/kg/day, and decreased fetal weight was seen at 100 mg/kg/day.
In pregnant rats given atorvastatin 20, 100 and 225 mg/kg/day from day 7 of gestation to day 20 of lactation (lactation), 100 mg/kg/day (6 times MRHD by AUC) decreased pup weight until 21 days postpartum with delayed development and Rotella syndrome; 225 mg/kg/day (22 times MRHD by AUC) decreased pup weight until 91 days postpartum. Weight loss to 91 days postnatal, delayed development, auditory startle response, auricular separation and ocular fissures were seen.
Carcinogenicity.
In a 2-year study in rats administered orally at doses of 10, 30, and 100 mg/kg/day, 2 rare tumors were found in the muscle of high-dose females: one a rhabdomyosarcoma and the other a fibrosarcoma. The high-dose AUC values were approximately 16 times the mean AUC of the maximum human oral dose of 80 mg. In a 2-year carcinogenicity study in mice, administration of 100, 200, or 400 mg/kg/day resulted in a significant increase in hepatic adenomas in male mice and hepatocellular carcinomas in female mice in the high-dose group, with an AUC approximately 6 times the average AUC of the human oral dose of 80 mg.
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 in proportion to the dose of atorvastatin calcium. The absolute bioavailability of atorvastatin calcium (the parent drug) is approximately 14% while the systemic bioavailability of 3-hydroxy-3-methylglutaryl coenzyme A (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 ~30%). However, the reduction in low-density lipoprotein cholesterol (LDL-C) is the same regardless of time of day dosing (see [DOSAGE AND ADMINISTRATION]).
Distribution: The mean volume of distribution of atorvastatin calcium is approximately 381 liters. Plasma protein binding ≥ 98%. A blood/plasma ratio of approximately 0.25 suggests that only a small amount of drug penetrates into the red blood cells. Based on observations in rats, atorvastatin calcium may be secreted into human milk ([contraindication] and [use in pregnant and lactating women]).
Metabolism: Atorvastatin calcium is extensively metabolized to ortho- and para-hydroxy derivatives and various b-oxidation products. In in vitro experiments, the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase by ortho- and para-hydroxylated metabolites was comparable to that of atorvastatin calcium. Approximately 70% of the circulating inhibitory activity against 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase was produced by the active metabolites. In vitro studies have demonstrated the importance of cytochrome P450 3A4 (CYP 3A4) in the metabolism of atorvastatin calcium, while administration of erythromycin, a known isoenzyme inhibitor, is consistent with increased plasma concentrations of atorvastatin calcium in humans (see [Precautions] and [Drug Interactions]). In animals, the o-hydroxy metabolite undergoes a further glucuronidation process.
Excretion: Atorvastatin calcium and its metabolites are primarily cleared by bile after hepatic and/or extrahepatic metabolism; however, atorvastatin calcium does not appear to undergo significant hepatic-intestinal recirculation. The mean plasma elimination half-life of atorvastatin calcium in humans is approximately 14 hours, but the half-life of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitory activity of atorvastatin calcium is approximately 20 to 30 hours due to its active metabolites. The urinary recovery of atorvastatin calcium after oral administration is 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 low-density lipoprotein cholesterol (LDL-C) to a significantly greater extent in the elderly population than in young adults (see [Precautions]).
Children: Because body weight was the only significant covariate in the population pharmacokinetic model for atorvastatin (data used in an 8-week open study including pediatric patients with heterozygous familial hypercholesterolemia [10 to 17 years of age, N=29]), when adjusted for anisotropic scaling by body weight, the apparent oral clearance of atorvastatin in pediatric subjects performed similarly to adult subjects were similar.
Gender: There were gender differences in blood concentrations of atorvastatin calcium (approximately 20% higher for Cmax and 10% lower for AUC in females than in males). However, there were no clinically significant gender differences in the low-density lipoprotein cholesterol (LDL-C) lowering effect 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 the product to plasma proteins.
Patients with hepatic insufficiency: Blood concentrations of atorvastatin calcium were significantly increased in patients with chronic alcoholic liver disease; both Cmax and AUC were increased 4-fold in patients with Childs-Pugh A, whereas Cmax and AUC were increased 16-fold and 11-fold, respectively, in patients with Childs-Pugh B (see [Contraindications]).
Drug Interaction Studies
Atorvastatin is a substrate for the hepatic transporters (OATP1B1 and OATP1B3). The metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also a substrate for the efflux transporter BCRP, which may limit intestinal absorption and biliary clearance of atorvastatin.
Table 3. effect of co-administration on atorvastatin pharmacokinetics Name and dosage of co-administration atorvastatin Dose (mg) AUC ratio&Cmax ratio&# cyclosporine 5.2 mg/kg/day, stable dose 10 mg once daily for 28 days 8.6910.66# tipranavir 500 mg twice a day/ritonavir 200 mg once a day twice a day for 7 days 10 mg single dose 9.368.58#Gletarevir 400 mg once a day/pramivir 120 mg once a day for 7 days 10 mg once a day for 7 days 8.2822.00#Telaprevir 750 mg every 8 hours for 10 days 20 mg single dose 7.8810.60#,‡ saquinavir 400 mg twice a day/ritonavir 400 mg twice a day for 15 days 40 mg once a day for 4 days 3.934.31# Ebatesvir 50 mg once a day/ Gepamivir 200 mg once a day for 13 days 10 mg single dose 1.944.34# Cimetapivir 150 mg once a day for 10 days 40 mg single dose 2.121.70# Clarithromycin 500 mg twice a day for 9 days 80 mg once a day for 8 days 4.545.38#dirinavir 300 mg twice a day/ritonavir 100 mg twice a day for 9 days 10 mg once a day for 4 days 3.452.25#itraconazole 200 mg once a day for 4 days
40 mg single dose 3.321.20#Fosamprenavir 700 mg twice a day/ritonavir 100 mg twice a day, 14 days 10 mg once a day, 4 days 2.532.84#Fosamprenavir 1400 mg twice a day, 14 days 10 mg once a day, 4 days 2.304.04#Nelfinavir 1250 mg twice a day, 14 days 10 mg once a day once a day for 28 days 1.742.22# grapefruit juice 240 ml once a day * 40 mg single dose 1.371.16 diltiazem 240 mg once a day for 28 days 40 mg single dose 1.511.00 erythromycin 500 mg four times a day for 7 days 10 mg single dose 1.331.38 amlodipine 10 mg single dose 80 mg single dose 1.180.91 Cimetidine 300 mg four times a day for 2 weeks 10 mg once a day for 2 weeks 1.000.89 Colestipol 10 g twice a day for 24 weeks 40 mg once a day for 8 weeks NA0.74** Maalox® (aluminum hydroxide/magnesium hydroxide) oral suspension 30 ml once a day for 17 days 10 mg once a day for 15 days 0.660. 67 Efavirenz 600 mg once daily for 14 days 10 mg once daily for 3 days 0.591.01# Rifampicin 600 mg once daily for 7 days (coadministered)† 40 mg single dose 1.122.90# Rifampicin 600 mg once daily for 5 days (coadministered alone)† 40 mg single dose 0.200.60# Gemfibezil 600 mg twice daily for 7 days 40 mg single dose 1.351.00# fenofibrate 160 mg once a day for 7 days 40 mg single dose 1.031.02 boceprevir 800 mg three times a day for 7 days 40 mg single dose 2.322.66& Representative treatment ratio (coadministered with atorvastatin/administered with atorvastatin alone).
#
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 (AUC ratio up to 2.5) and/or Cmax (Cmax ratio up to 1.71) more significantly.
**Rates sampled for testing 8 to 16 hours after dosing.
† Rifampicin has a dual drug interaction mechanism and concurrent administration of atorvastatin in combination with rifampicin is recommended; if rifampicin is administered first followed by atorvastatin it may result in a significant decrease in plasma drug concentrations in the latter.
‡ The applied doses of saquinavir + ritonavir used in this study were not clinical doses. 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 Name and dosage of atorvastatin combination Drug/dose (mg) AUC ratio Cmax ratio 80 mg once daily for 15 days Amantabiline 600 mg single dose 1.030.8980 mg once daily for 10 days # Digoxin 0.25 mg once daily for 20 days 1.151.2040 mg once daily for 22 days Oral contraceptives once daily for 2 months
Ethinylestradiol 1 mg
Ethinyl estradiol 35 μg1.28
1.19
1.23
1.3010 mg once daily tipranavir 500 mg twice a day/ritonavir 200 mg twice a day for 7 days 1.080.9610 mg once a day for 4 days fosamprenavir 1400 mg twice a day for 14 days 0.730.8210 mg once a day for 4 days fosamprenavir 700 mg twice a day/ritonavir 100 mg twice a day for 14 days 0.990.94#
See [Drug Interactions] for clinical significance.
[Storage].
Store under shade and seal.
Packaging
(1) 10 mg (C33H35FN2O5) pharmaceutical aluminum foil + polyamide/aluminium/polyvinyl chloride cold press molding solid pharmaceutical composite hard tablets: 3 tablets/plate x 1 plate/box; 4 tablets/plate x 1 plate/box; 6 tablets/plate x 1 plate/box, 6 tablets/plate x 2 plates/box; 7 tablets/plate x 1 plate/box, 7 tablets/plate x 2 plates/box, 7 tablets/plate x 4 plates/box, 7 tablets/plate x 8 plates/box (1) 8 tablets/plate x 1 plate/box; 9 tablets/plate x 1 plate/box; 10 tablets/plate x 1 plate/box; 12 tablets/plate x 1 plate/box; 10 tablets/plate x 20 plates/box; 14 tablets/plate x 1 plate/box, 14 tablets/plate x 2 plates/box.
(2) 20 mg (C33H35FN2O5) pharmaceutical aluminum foil + polyamide / aluminum / PVC cold press molding solid pharmaceutical composite hard tablets: 6 tablets / plate × 1 plate / box, 6 tablets / plate × 2 plates / box; 7 tablets / plate × 1 plate / box, 7 tablets / plate × 2 plates / box, 7 tablets / plate × 4 plates / box, 7 tablets / plate × 8 plates / box; 8 tablets / plate × 1 plate / box, 8 tablets / plate × 2 plates / box 9 tablets/plate×1 plate/box, 9 tablets/plate×2 plate/box; 10 tablets/plate×1 plate/box, 10 tablets/plate×2 plate/box; 12 tablets/plate×1 plate/box, 12 tablets/plate×2 plate/box; 14 tablets/plate×1 plate/box, 14 tablets/plate×2 plate/box.
[Expiration date
24 months
【Execution standard】
【Approval number】
10 mg: State Drug Quantifier H20120021
20 mg: State Drug Certificate H20163163
Marketing Authorization Holder
Name of the marketing license holder: Shenzhen Jiurui Health Technology Development Co.
Address of the holder of the marketing authorization: Room 201, Building A, No. 1, Qianwan Road 1, Qianhai Hong Kong-Shenzhen Cooperation Zone, Shenzhen (located in Shenzhen Qianhai Business Secretary Co., Ltd.)
Postal code: 518000
Telephone number: 0755-25111805
【Manufacturer
Company name: Guangdong Encyclopedia Pharmaceutical Co.
Production address: Yangjiang City, Guangdong Province, west of the city Ma Yan
Postal code: 529500
Telephone number: 0662-3172387
Fax number: 0662-3175878
Web
Address: www.yjphar.com