What Are the Differences between Atorvastatin and Simvastatin Treatments?

This product is a compound preparation, and its components are amlodipine besylate and atorvastatin calcium.

Chemical name of amlodipine besylate: 3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -1,4-dihydro-6 -Methyl-3,5-pyridine dicarboxylate benzenesulfonate

Chemical Structure:

Amlodipine Atorvastatin Calcium Tablets, with indications up to one® (Amlodipine and Atorvastatin) are suitable for patients who require a combination of Amlodipine and Atorvastatin. Amlodipine 1, hypertension Amlodipine is suitable for the treatment of hypertension. Can be used alone or in combination with other antihypertensive drugs. 2. Coronary heart disease (CAD) Chronic stable angina pectoris Amlodipine is suitable for the symptomatic treatment of chronic stable angina pectoris. Can be used alone or in combination with other anti-angina drugs. Vasospasm angina pectoris (Prinzmetal's or variant angina pectoris) amlodipine is suitable for the treatment of confirmed or suspected vasospasm angina pectoris. Can be used alone or in combination with other anti-angina drugs. Coronary heart disease confirmed by angiography Recently confirmed by angiography as coronary heart disease, but patients with ejection fraction 40% and no heart failure, amlodipine can reduce the risk of hospitalization due to angina pectoris and the risk of coronary artery reconstruction. Atorvastatin 1. Patients with primary hypercholesterolemia, including familial hypercholesterolemia (heterozygous type) or mixed hyperlipidemia (equivalent to type IIa and IIb of the Fredrickson classification) Patients, if the effects of diet and other non-drug treatments are not satisfactory, this product can be used to treat the increase of total cholesterol, low density lipoprotein cholesterol, apolipoprotein B and triglyceride. In patients with homozygous familial hypercholesterolemia, atorvastatin calcium can be used in combination with other lipid-lowering therapies (such as LDL plasma dialysis) or alone (when no other treatment is available) to reduce total cholesterol and low-density lipids. Protein cholesterol. 2. Coronary heart disease: For patients with coronary heart disease or coronary heart disease (such as diabetes, symptomatic atherosclerotic disease, etc.) combined with hypercholesterolemia or mixed dyslipidemia, this product is suitable for: reducing non-lethality Risk of myocardial infarction, reduced risk of fatal and non-fatal strokes, reduced risk of revascularization, reduced risk of hospitalization due to congestive heart failure, reduced risk of angina pectoris.

Drug Name

Amlodipine Atorvastatin Calcium Tablets

Drug type

prescription

Amlodipine atorvastatin calcium tablets ingredients

This product is a compound preparation, and its components are amlodipine besylate and atorvastatin calcium.

Chemical name of amlodipine besylate: 3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -1,4-dihydro-6 -Methyl-3,5-pyridine dicarboxylate benzenesulfonate

Chemical Structure:

Molecular formula: C ₂₀ H ₂₅ ClN ₂ O ₅ · C ₆ H ₆ O ₃ S.

Molecular weight: 567.1

Chemical name of atorvastatin calcium: [R- (R *, R *)]-2- (4-fluorophenyl) -, -dihydroxy-5- (1-methylethyl) -3 -Phenyl-4-[(aniline) carbonyl] -1H-pyrrole-1-heptanoic acid calcium salt (2: 1) trihydrate

Chemical Structure:

Molecular formula: (C ₃₃ H ₃₄ FN ₂ O ₅ ) ₂ Ca · 3H ₂ O

Molecular weight: 1209.42

Amlodipine Atorvastatin Calcium Tablets Traits

This product is a white film-coated tablet.

Amlodipine atorvastatin calcium tablets indications

Daduyi® (amlodipine and atorvastatin) is suitable for patients who require a combination of amlodipine and atorvastatin.

Amlodipine
1. Hypertension <br /> Amlodipine is suitable for the treatment of hypertension. Can be used alone or in combination with other antihypertensive drugs.

2. Coronary heart disease (CAD)
[u] chronic stable angina [/ u]
Amlodipine is suitable for the symptomatic treatment of chronic stable angina pectoris. Can be used alone or in combination with other anti-angina drugs.

[u] Vascular angina pectoris (Prinzmetal's or variant angina pectoris) [/ u]
Amlodipine is suitable for the treatment of diagnosed or suspected vasospasm angina pectoris. Can be used alone or in combination with other anti-angina drugs.

[u] Coronary heart disease confirmed by angiography [/ u]
In patients with coronary heart disease recently confirmed by angiography but with an ejection fraction 40% and no heart failure, amlodipine can reduce the risk of hospitalization for angina pectoris and the risk of coronary artery reconstruction.

Atorvastatin
[u] 1, Hypercholesterolemia [/ u]
Patients with primary hypercholesterolemia, including those with familial hypercholesterolemia (heterozygous type) or mixed hyperlipidemia (equivalent to type IIa and IIb of the Fredrickson classification), if diet and other non-pharmacological treatments The curative effect is unsatisfactory. The application of this product can treat the increase of total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B and triglyceride.

In patients with homozygous familial hypercholesterolemia, atorvastatin calcium can be used in combination with other lipid-lowering therapies (such as LDL plasma dialysis) or alone (when no other treatment is available) to reduce total cholesterol and low-density lipids. Protein cholesterol.

[u] 2, coronary heart disease: [/ u]
Patients with coronary heart disease or coronary heart disease (such as diabetes, symptomatic atherosclerotic disease, etc.) with hypercholesterolemia or mixed dyslipidemia, this product is suitable for: reducing the risk of non-fatal myocardial infarction Reduce the risk of fatal and non-fatal strokes, reduce the risk of revascularization, reduce the risk of hospitalization due to congestive heart failure, and reduce the risk of angina pectoris.

Amlodipine Atorvastatin Calcium Tablets Specifications

(1) 5mg / 10 mg (based on amlodipine / atorvastatin);
(2) 5mg / 20 mg (based on amlodipine / atorvastatin);
(3) 5mg / 40 mg (based on amlodipine / atorvastatin).

Amlodipine atorvastatin calcium tablets dosage

When using this product to treat hypertension or angina pectoris with hyperlipidemia, the individualization of the therapeutic dose must be considered, and the patient should be adjusted accordingly according to the treatment effect and tolerance of each component.

Amlodipine (hypertension or angina)

Adults: Usually the starting dose of this product for hypertension is 5mg once daily, and the maximum dose is 10mg once daily. Patients of small size, frailty, elderly, or with liver dysfunction, the starting dose is 2.5mg once daily; this dose can also be the dose of this product in combination with other antihypertensive drugs.

Dose adjustments should be based on individual patient response. It should generally be after 7-14 days so that the doctor can assess the patient's response to each dose. If it is clinically needed, in the case of closely monitoring the patient, the dose adjustment can also be performed quickly.

The recommended dose for chronic stable or vasospasm angina pectoris is 5-10 mg once daily. The elderly and patients with liver dysfunction are advised to use lower doses. The effective dose for most people is 10 mg once daily. For dosage and side effects, please refer to [Adverse Reactions].

The recommended dose for coronary heart disease is 5-10 mg once daily. In clinical studies, most patients require a daily dose of 10 mg (see [Clinical Trials]).

Children: Children aged 6-17 years, the recommended oral dose for treating hypertension is 2.5 mg to 5 mg once daily. Studies of pediatric patients above 5 mg have not been conducted (see [Clinical Trials]).

Atorvastatin (hyperlipidemia)
A common starting dose is 10 mg once daily. Dosage adjustment intervals should be 4 weeks or longer. The maximum dose of this product is 80mg once daily. Atorvastatin can be taken once daily at any time of the day and is not affected by meals.
For low-risk patients with cardiovascular events, the treatment goals are LDL-C <4.14mmol / L (or <160mg / dL) and total cholesterol <6.22mmol / L (or <240mg / dL). The treatment goals for intermediate-risk patients are LDL- C <3.37mmol / L (or <130mg / dL) and total cholesterol <5.18mmol / L (or <200mg / dL). The treatment target of high-risk patients is LDL-C <2.59mmol / L (or <100mg / dL). And total cholesterol <4.142mmol / L (or <160mg / dL), the treatment target for very high-risk patients is LDL-C <2.07mmol / L (or <80mg / dL) and total cholesterol <3.11mmol / L (or <120mg / dL).
Extracted from the Chinese Journal of Cardiovascular Diseases, Vol. 35, No. 5, 2007, pp. 390-413, "Guidelines for the Prevention and Treatment of Dyslipidemia in Chinese Adults."
Treatment of primary hypercholesterolemia and mixed hyperlipidemia Most patients take atorvastatin calcium 10mg once daily, and their blood lipid levels can be controlled. The obvious effect can be seen within 2 weeks of treatment, and the maximum effect can be seen within 4 weeks of treatment. Long-term treatment can maintain the effect.

Treatment of heterozygous familial hypercholesterolemia

The patient's initial dose was 10 mg / day. The principle of dose individualization should be followed to gradually adjust the dose to 40 mg / day every 4 weeks. If the satisfactory effect is still not achieved, the dose can be adjusted to the maximum dose of 80mg / day or 40mg once daily with bile acid chelator for treatment.

Treatment of homozygous familial hypercholesterolemia In a charity drug study involving 64 patients, 46 patients had confirmed LDL receptor information. These 46 patients had an average 21% decrease in LDL-C. The dose of this product can be increased to 80mg / day.

For patients with homozygous familial hypercholesterolemia, the recommended dose of this product is 10-80mg / day. Atorvastatin should be used as an adjunct to other lipid-lowering treatments (such as LDL plasma dialysis), or when these conditions are not available, this product can be used alone.

Dosage in patients with renal insufficiency

Kidney disease does not affect the plasma concentration of atorvastatin nor its effect on LDL-C reduction. Therefore, in patients with renal insufficiency, no dose adjustment is required.

Up to one®

The use of this product is equivalent to the separate use of its two components, which can be replaced with each other. Patients can be given the same dose of the drug, or to increase antianginal, lower blood pressure or lipid lowering effects, you can also add amlodipine or atorvastatin or both at the same time.

This product can be used for patients who have already used atorvastatin or amlodipine and need to add another drug. Because one indication is the initial treatment and the other is the maintenance treatment, the dosage of this product should be selected according to the maintenance amount of the ingredients being used and the recommended starting amount of the added single drug ingredient.

This product can be used for the initial treatment of patients with hypertension or angina pectoris accompanied by hyperlipidemia. The recommended starting dose should be an appropriate combination based on the recommended dose for each monotherapy. The maximum dose of amlodipine component in this product can reach 10mg once daily, and the maximum dose of atorvastatin component can reach 80mg once daily.

For details on the use and dosage of atorvastatin and amlodipine, refer to the above section.

Amlodipine atorvastatin calcium tablets adverse reactions

Up to one®

The safety of this product (amlodipine atorvastatin besylate calcium) was evaluated in a double-blind, placebo-controlled study of 1092 patients with hypertension and hyperlipidemia. This product is well tolerated in treatment. For most patients, the adverse reactions are mild to moderate. In clinical studies of this product, no special adverse reactions related to the compound preparation were seen. The nature, extent, and frequency of adverse reactions are similar to those reported for amlodipine and atorvastatin.

The following information is derived from clinical use of amlodipine and atorvastatin.

Amlodipine ingredients in this product

The safety of this product has been confirmed in clinical studies in the United States and other foreign countries, involving more than 11,000 patients. Overall, patients were well tolerated by using this product at daily doses of up to 10 mg. The adverse reactions during the treatment of this product are more mild or moderately reported. Clinically controlled studies directly compared 10mg (N = 1730) of this product with placebo (N = 1250). Only 1.5% of patients in this group were required to discontinue due to adverse reactions. There was no significant difference compared with placebo (about 1%). Common side effects are headache and edema. The incidence (%) of dose-related side effects is as follows:

Other adverse reactions were uncertain in relation to dose, but occurred in more than 1% of placebo-controlled studies, including:

In clinically controlled studies, open studies, or after-sales applications, the incidence of the following events in patients [1% but] 0.1%, the relevance of which is uncertain, are listed here to remind doctors to pay attention:

Cardiovascular system: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, hypotension, peripheral ischemia, syncope, tachycardia, orthostatic dizziness, orthostatic hypotension, vasculitis .

Central and peripheral nervous system: dull feeling, peripheral neuropathy, paresthesia, tremor, dizziness.

Gastrointestinal system: loss of appetite, constipation, indigestion **, difficulty swallowing, diarrhea, flatulence, pancreatitis, vomiting, hyperplasia of the gums.

Whole body: Allergies, fatigue **, back pain, hot flushes, general malaise, pain, stiffness, weight gain, weight loss.

Musculoskeletal system: arthralgia, arthropathy, myalgia cramps **, myalgia.

Psychiatry: sexual dysfunction (male ** and female), insomnia, neuroticism, depression, abnormal dreaming, anxiety, disintegration of personality.

Respiratory system: dyspnea **, epistaxis.

Skin and appendages: Angioedema, erythema polymorpha, pruritus **, rash **, erythema erythema, maculopapular rash.

** In placebo-controlled studies, these events occurred less than 1%, but in all high-dose studies, these side effects occurred in 1% to 2%.

Specific sensations: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus.

Urinary system: frequent urination, dysuria, nocturia.

Autonomic nervous system: dry mouth, sweating

Nutritional metabolism: high blood sugar, thirst

Hematopoietic system: leukopenia, purpura, thrombocytopenia

The following events occurred [0.1%: heart failure, arrhythmia, premature beats, skin discoloration, urticaria, dry skin, hair loss, dermatitis, muscle weakness, twitching, ataxia, hypertonicity, migraine, skin hair Coolness, indifferent emotions, excitement, forgetfulness, gastritis, increased appetite, loose stools, cough, rhinitis, dysuria, polyuria, olfactory disorders, taste disorders, abnormal vision regulation, and dry eyes.

Other occasional adverse reactions are difficult to distinguish from the effects of concomitant drugs or concurrent diseases, such as myocardial infarction or angina.

There was no clinically significant change in routine laboratory test data in the treatment of amlodipine. There were no clinically relevant changes in serum potassium, blood glucose, triglycerides, total cholesterol, HDL cholesterol, uric acid, urea nitrogen, or creatinine.

In the CAMELOT and PREVENT studies (see [Clinical Trials]), the adverse reactions were similar to those previously reported (see above). Peripheral edema is the most common adverse event. The following unexplained incidents of after-sales application are rarely reported: male breast enlargement. In post-sale applications, it has been reported that the use of amlodipine caused patients with jaundice and significantly increased transaminase (most likely due to biliary obstruction or hepatitis) and required hospitalization.

Amlodipine is safe to use in patients with chronic obstructive emphysema, well-compensated congestive heart failure, coronary heart disease, peripheral vascular disease, diabetes, and dyslipidemia.

Atorvastatin ingredients in this product:
The following serious adverse reactions are described in more detail elsewhere in this data sheet:
Rhabdomyolysis and myopathy (see [Caution] "skeletal muscle" under Warnings)
Muscle enzyme abnormalities (see "Precautions" under "Precautions" under "Hepatic dysfunction")

Clinical adverse reactions <br /> The clinical conditions of the subjects during the implementation of clinical trials are complicated, so the incidence of adverse reactions obtained in clinical studies of two different drugs cannot be directly compared, and it may not reflect the incidence of adverse reactions in clinical practice. .

Lipitor placebo-controlled clinical trials enrolled a total of 16,066 patients (lipitor n = 8755, placebo n = 7311, aged 10 to 93 years, 39% were women; 91% were Caucasian, 3% were black , 2% are Asians, 4% are other races), the median treatment period is 53 weeks; without considering the cause and effect, the Lipitor group and the placebo group had 9.7% and 9.5% of patients due to adverse effects, respectively. The reaction was discontinued. The five most common adverse reactions that led to discontinuation of the drug and a higher incidence in the Lipitor group than in the placebo group were myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), and increased ALT (0.4 %) And elevated liver enzymes (0.4%).

Regardless of causality, the most common adverse reactions in Lipitor placebo-controlled trials (n = 8755) (2%) with a higher incidence than placebo were: nasopharyngitis (8.3%), joints Pain (6.9%), diarrhea (6.8%), limb pain (6.0%), and urinary tract infections (5.7%).

Table 1 summarizes the incidence of 2% in 1755 placebo-controlled trials of Lipitor in the 17 placebo-controlled trials, which are higher than those in the placebo group (causality is not considered).

Other adverse reactions reported in placebo-controlled studies include:
Whole body: discomfort, fever;
Digestive system: abdominal discomfort, belching, flatulence, hepatitis, cholestasis;
Musculoskeletal system: skeletal muscle pain, muscle fatigue, neck pain, joint swelling;
Nutrition and metabolic systems: elevated transaminase, abnormal liver function tests, elevated blood alkaline phosphatase, elevated creatine phosphokinase, hyperglycemia;
Nervous system: nightmare;
Respiratory system: epistaxis;
Skin and appendages: urticaria;
Special sensations: blurred vision, tinnitus, urogenital system: urinary leukocyte positive

Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)
The ASCOT study (see [Clinical Trials], Atorvastatin's clinical study) included 10305 participants (age range 40-80 years, 19% females; 94.6% Caucasian Caucasians, 2.6% Africans, 1.5% South Asians, 1.3% mixed race or other races) were given atorvastatin 10 mg (N = 5168) or placebo (N = 5137) daily. During a median follow-up of 3.3 years, the safety and tolerability of the atorvastatin-treated group was comparable to that of the placebo group.

Atorvastatin Collaborative Study on Diabetes (CARDS)
In the CARDS study (see [Clinical Trials], Atorvastatin Clinical Studies), a total of 2838 subjects with type 2 diabetes were selected (age range 39-77 years, 32% women; 94.3% Caucasian Caucasian , 2.4% South Asians, 2.3% Black Caribbeans, 1.0% other races), they all received atorvastatin (lipitor) 10 mg (n = 1428) or placebo (n = 1410) per day During the follow-up of 3.9 years, there was no difference in the frequency of adverse events or serious adverse events between treatment groups, and no rhabdomyolysis was reported.

New Target Therapy Study (TNT)
The TNT study (see [Clinical Trials]) involved 1,001 patients with coronary heart disease with clinical evidence (age range 29-78 years, 19% females; 94.1% Caucasian whites, 2.9% blacks, 1.0% Asians, 2.0% others Species), receiving atorvastatin 10 mg (n = 5006) or 80 mg (n = 4995) daily with a median follow-up period of 4.9 years, compared with the low-dose group, the high-dose group was severely poor Incidents and treatment discontinuation due to adverse events were higher (92, 1.8%; 497, 9.9% in the high-dose group and 69, 1.4%; 404, 8.1% in the low-dose group). In the atorvastatin 80 mg treatment group, 62 patients (1.3%) had a sustained increase in transaminase (more than 3 times the upper limit of normal twice in 4-10 days), while in the atorvastatin 10 mg group, 9 patients (0.2%) ). Creatine kinase elevations (more than 10 times above the upper limit of normal) were generally lower, but compared with the low-dose atorvastatin group, the high-dose group had a higher incidence of 6, 0.1% and 13, 0.3%, respectively.

Intensive lipid-lowering study to further reduce clinical endpoint events (IDEAL)
The IDEAL study (see [Clinical Trials]) involved 8,888 patients (age range 26-80 years, 19% females; 99.3% Caucasian whites, 0.4% Asians, 0.3% blacks, 0.04% other races), receiving daily Total occurrence of adverse events or serious adverse events in the two treatment groups during a median follow-up of 4.8 years with atorvastatin 80 mg (n = 4439) or simvastatin 20-40 mg (n = 4449) There is no difference in rates.

Intensive Cholesterol-lowering Therapy Study (SPARCL)
The SPARCL study included 4,731 subjects who had no clinical evidence of coronary heart disease but had a history of stroke or transient ischemic attack (TIA) within the past 6 months (ages 21-92, 40% females; 93.3% Caucasian whites, 3.0% black, 0.6% Asian, 3.1% other races), received Lipitor 80mg (N = 2365) or placebo (N = 2366), and the median follow-up period was 4.9 years.

The incidence of persistently elevated aminotransferases (more than three times the upper limit of normal twice in 4-10 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) are rare, but the incidence of atorvastatin (0.1%) is higher than that of placebo (0.0%). Diabetes was reported as an adverse reaction. Diabetes occurred in 144 (6.1%) and 89 (3.8%) of the atorvastatin group and the placebo group, respectively (see [Precautions]).

Post hoc analysis showed that compared with the placebo group, the incidence of ischemic stroke was lower in the Lipitor 80mg group (218/2365 [9.2%] vs. 274/2366 [11.6%]), and the incidence of hemorrhagic stroke was increased. (55/2365 [2.3%] vs. 33/2366 [1.4%]). The rates of fatal hemorrhagic stroke in the Lipitor and placebo groups were similar, at 17 and 18, respectively. The incidence of non-fatal hemorrhagic stroke was significantly higher in the atorvastatin group than in the placebo group, with 38 and 16 patients, respectively. Patients with a previous history of hemorrhagic stroke may have an increased risk of hemorrhagic stroke during the study (7 in the Lipitor group [16%] vs. 2 in the placebo group [4%]).

There was no significant difference in all-cause mortality between the two groups: Lipitor 80mg daily (216%, 9.1%), and placebo group 211 (8.9%). The proportion of cardiovascular deaths in the Lipitor 80mg group (3.3%) was numerically lower than in the placebo group (4.1%). The proportion of non-cardiovascular deaths (5.0%) in the Lipitor 80mg group was higher than that in the placebo group (4.0%).

Post-marketing reports <br /> The following adverse reactions come from reports of the approval of the atorvastatin ingredients of this product after they are marketed. Post-marketing adverse reaction reports are actively reported by patients and the number of people who actually use the drug is unclear, so the exact incidence of these adverse reactions cannot be calculated, and the causal relationship between these adverse reactions and the drug cannot be determined.

Regardless of causality, related adverse reactions not listed above after atorvastatin listing include: allergic reactions, angioedema, herpes (including erythema polymorphic, Stevens-Johnson syndrome and Toxic epidermal necrolysis), rhabdomyolysis, fatigue, tendon rupture, liver failure, dizziness, memory loss, depression and peripheral neuropathy.

Pediatric Patients (Age 10-17)
In a 26-week controlled study involving boys and girls after menarche, atorvastatin 10 mg-20 mg / day (n = 140, 31% were girls; 92% Caucasian, 1.6% black, 1.6% Asian, 4.8 % Other races) are similar in safety and tolerability to placebo (see [Clinical Trials], [Precautions], and [Children's Medication]).

Amlodipine Atorvastatin Calcium Tablets Taboo

This product contains atorvastatin, so it should be disabled in patients with active liver disease or persistently elevated serum aminotransferases of unknown origin.

Patients known to be allergic to any of the ingredients in this product should be disabled.

Pregnant and lactating women

Atherosclerosis is a chronic process, and the interruption of lipid-lowering drugs during pregnancy has little effect on the long-term outcome of primary hypercholesterolemia. Cholesterol and other products of cholesterol biosynthesis are important components of fetal development, including the synthesis of steroids and cell membranes. Since HMG-CoA reductase inhibitors reduce cholesterol synthesis and may reduce the synthesis of other cholesterol-derived bioactive substances, its application in pregnant women may be harmful to the fetus. Therefore, HMG-CoA reductase inhibitors are contraindicated in pregnant and lactating women.

This product contains atorvastatin, so it is prohibited for pregnant women or women of childbearing age who may become pregnant. Atorvastatin may cause harm to the fetus when pregnant women take this product. In normal pregnancy, serum cholesterol and triglyceride levels rise, and cholesterol or cholesterol derivatives are essential for fetal development. Atherosclerosis is a chronic disease process, so the discontinuation of lipid-lowering medication during pregnancy in patients with primary hypercholesterolemia has little effect on the long-term outcome of atherosclerotic disease.

There are currently insufficient controlled studies on atorvastatin administration in pregnant women; occasionally, fetal congenital abnormalities have been reported with intrauterine exposure to statins. Rat and rabbit reproduction studies have not observed evidence of teratogenicity of atorvastatin. This product contains atorvastatin. For women of childbearing age, only those who are extremely unlikely to become pregnant and have been informed of the potential harm can be prescribed Lipitor. Patients should be discontinued immediately during pregnancy while taking the drug, and consider the potential harm of the drug to the fetus (see "Pregnant women's medication" under [Precautions]).

Whether atorvastatin or amlodipine in this product can be secreted from human milk is unknown; but other drugs of this type can be secreted into milk in small amounts. Because statins may have potentially serious adverse effects on breast-feeding newborns, women who take this product are prohibited from breast-feeding (see "Pregnancy-Use Medications" under [Precautions]).

Precautions for Amlodipine Atorvastatin Calcium Tablets

Hypotension <br /> Symptomatic hypotension may occur, especially in patients with severe aortic stenosis. Because the effect is gradually exerted, acute hypotension is unlikely to occur.

Beta-blocker discontinuation <br /> Amlodipine is not a beta-blocker and therefore cannot protect against the dangers caused by sudden discontinuation of beta-blockers; any beta-blocker Stagnation should be discontinued gradually.

Endocrine functions <br /> Statins, such as atorvastatin in this product, can interfere with cholesterol synthesis and theoretically inhibit the synthesis of adrenal and / or gonadal steroids. Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentrations or impair adrenal reserve. There are no sufficient case studies on the effects of statins on male fertility, and the effect on the pituitary-gonadal axis of premenopausal women is unclear. Statins should be used with caution when used in combination with drugs that reduce the level or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.

Central nervous system toxicity <br /> Atorvastatin study: Cerebral hemorrhage occurred in a female dog given atorvastatin 120 mg / kg / day for 3 months. After increasing the dose to another female dog, atorvastatin at 280 mg / kg / day for 11 weeks, she was sacrificed in the dying state, and cerebral hemorrhage and formation of optic nerve vacuoles were also found. A dose of 120 mg per kilogram of body weight, calculated at the maximum human dose of 80 mg per day, would result in a systemic exposure of approximately 16 times the area under the human plasma curve (AUC, 0-24 hours). In a two-year study, two male dogs (one administered at 10 mg / kg / day and the other at 120 mg / kg / day) were observed with one tonic convulsion. No central nervous system damage was observed in mice dosed up to 400 mg / kg / day and rats dosed up to 100 mg / kg / day for 2 years of long-term administration. Based on the recommended maximum human dosage of 80 mg per day, these dosages are 6-11 times (mouse) and 8-16 times (rat) the area under the human curve (0-24).

In the administration of other statins, canine central nervous system vascular damage was observed, characterized by bleeding around the blood vessels, edema, and infiltration of the monocyte perivascular space. In clinically normal dogs, when the plasma drug level of another class of drugs with similar chemical structure is about 30 times higher than the maximum recommended human dose, optic neurodegeneration (retinal-knee body wallerian degeneration) occurs in a dose-dependent manner.

Application in patients with recent stroke or transient ischemic attack <br /> Atorvastatin study: SPARCL study (strengthening cholesterol-lowering treatment to prevent stroke) study included a total of 4,731 patients with stroke or transient within 6 months Patients with ischemic attack without coronary heart disease receive atorvastatin 80mg or placebo. Post hoc analysis of this study showed that the incidence of hemorrhagic stroke was higher in the atorvastatin 80mg 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), the incidence of fatal hemorrhagic stroke was similar in the two groups (17 and 18 in the atorvastatin and placebo groups, respectively), and the incidence of non-fatal hemorrhagic stroke in the atorvastatin group ( 38 people (1.6%) were higher than the placebo group (16 people, 0.7%). The higher incidence of hemorrhagic stroke in the atorvastatin group was related to certain baseline characteristics of the patient at the beginning of the study, including hemorrhagic stroke and lacunar stroke (see "Atropine in this product" in [Adverse Reactions] Vastatin ingredients ").

Information for patients <br /> Statins may cause myopathy. Atorvastatin is a statin. It is recommended that patients report unexplained muscle pain, muscle tenderness, and muscle weakness to the doctor, especially if accompanied by General discomfort or fever.

caveat
Skeletal muscle <br /> Atorvastatin and other statins of this product have occasionally been reported in a few cases of rheumatoid arterial myoglobinuria secondary to acute renal failure. A history of kidney damage may be a risk factor for rhabdomyolysis, and these patients need to be closely monitored for the effects of the drug on skeletal muscle.

Like other statins, the atorvastatin component of this product can cause myopathy (myopathy is defined as muscle pain or muscle weakness, accompanied by creatine phosphokinase CPK more than 10 times the upper limit of normal value). High-dose atorvastatin in combination with specific drugs such as cyclosporine or strong CYP3A4 inhibitors (such as clarithromycin, itraconazole, and HIV protease inhibitors) can increase the risk of myopathy or rhabdomyolysis.

Any patient with diffuse myalgia, muscle tenderness or weakness, or significant elevation of creatine phosphokinase should be considered myopathy. Patients should be advised to immediately report unexplained muscle pain, muscle tenderness, or muscle weakness, especially if accompanied by discomfort or fever. Atorvastatin treatment should be discontinued if there is a significant increase in creatine phosphokinase levels or if a diagnosis / suspected myopathy is present.

If cyclosporine A, fibric acid derivatives (fibrates), erythromycin, clarithromycin, ritonavir plus saquinavir or lopinavir plus are used during the treatment of such drugs The combination of navir, nicotinic acid, or imidazole antifungals increases the risk of myopathy. Doctors are considering a combination of atorvastatin and fibric acid derivatives (fibrates), erythromycin, clarithromycin, ritonavir plus saquinavir or lopinavir plus ritonavir, Potential benefits and risks should be carefully weighed in the treatment of immunosuppressive drugs, imidazole antifungals or lipid-lowering niacin, and patients should be carefully monitored for any signs and symptoms of muscle pain, muscle tenderness or muscle weakness, especially During the first few months of treatment and during any dose increase. When atorvastatin is used concurrently with the previously mentioned drugs (see [Drug Interactions]), consideration should be given to reducing the initial and maintenance doses of atorvastatin. In this case, periodic measurements of creatine phosphokinase should be considered, but such monitoring does not ensure that severe myopathy can be prevented.

A summary of the recommended dosage of atorvastatin and the interacting drugs in this product is shown in Table 2 (for details, see "Drug Interactions" and "Clinical Pharmacology" under [Usage and Dosage], [Precautions]).

Any patient with acute or severe conditions that indicates myopathy or risk factors (e.g., severe acute infection, hypotension, major surgery, trauma, severe metabolism, endocrine and electrolyte disorders, uncontrolled seizures) is likely to induce secondary For renal failure with rhabdomyolysis, atorvastatin treatment should be suspended or discontinued.

Abnormal liver function <br /> Atorvastatin, like other statins and other lipid-lowering drugs, can cause abnormal liver function biochemical indicators. Clinical trial results showed that 0.7% of patients receiving atorvastatin had persistently elevated serum transaminase levels (two or more times exceeding the upper limit of normal by three times). The incidences of transaminase abnormalities were 0.2%, 0.2%, 0.6%, and 2.3% in patients at 10, 20, 40, and 80 mg.

The following results were observed in patients taking the atorvastatin component in clinical trials. One patient developed jaundice, and the elevation of liver function tests (LFT) in other patients was not associated with jaundice and other clinical signs or symptoms. After reducing the dosage, discontinuing or stopping the medication, the transaminase level returned to or near the pre-treatment level without sequelae. Of the 30 patients whose liver function tests continued to increase, 18 patients continued treatment with reduced doses of Lipitor.

Liver function should be checked before treatment, 12 weeks after the start of treatment, and 12 weeks after the dose is increased, and thereafter (eg every six months) should be checked regularly. Hepatic enzyme abnormalities usually occur within 3 months before the atorvastatin component of this product, and patients with elevated transaminase should be monitored until normal. If ALT or AST continues to rise more than 3 times the upper limit of normal value, it is recommended to reduce the dose of this product or stop using it.

Active liver disease or unexplained transaminase continues to rise, this product is contraindicated (see [taboo] for details).

Exacerbation of angina pectoris and / or myocardial infarction <br /> Exacerbation of angina pectoris and acute myocardial infarction may occur after starting amlodipine or increasing amlodipine dose, especially in patients with severe obstructive coronary artery disease.

Amlodipine atorvastatin calcium tablets for pregnant and lactating women

Pregnancy classification X (see [Contraindications])

This product contains atorvastatin, so it is prohibited for pregnant women or women of childbearing age who may become pregnant. Atorvastatin may cause harm to the fetus when pregnant women take this product. Women of childbearing age should only take this product if they are very unlikely to become pregnant and have been informed of the potential dangers of the drug to pregnant women. As soon as a woman taking this product becomes pregnant, she should discontinue her medication and inform her of the potential danger to her fetus. Continued medication during pregnancy lacks known clinical benefits.

In normal pregnancy, serum cholesterol and triglyceride levels rise, and cholesterol or cholesterol derivatives are essential for fetal development. Atherosclerosis is a chronic disease process, so the discontinuation of lipid-lowering medication during pregnancy in patients with primary hypercholesterolemia has little effect on the long-term outcome of atherosclerotic disease.

Study of Amlodipine:
When pregnant rats and rabbits receive up to 10 mg amlodipine / kg / day orally during their main organ formation period (based on mg / m2 basis conversion, 8 times * and 23 times * the maximum recommended human dose of 10 mg, respectively) Amlodipine maleate was not found to be teratogenic or other embryo / fetal toxicity. However, a significant reduction in litter size (approximately 50%) was observed in rats treated with amlodipine maleate (dose equivalent to 10 mg amlodipine / kg / day) for 14 days before mating, throughout mating and conception. The number of deaths in the womb increased significantly (about 5 times). Studies have shown that amlodipine maleate at this dose can prolong the fertility and delivery periods in rats. Adequate controlled studies in pregnant women are lacking.

* Based on 50kg patients.

Atorvastatin research:
There are currently insufficient controlled studies on the use of atorvastatin during pregnancy. Rare reports of congenital anomalies due to intrauterine exposure to statins. A follow-up study of approximately 100 pregnant women exposed to other statins found that the incidence of congenital abnormalities, spontaneous abortions, and fetal deaths / stillbirths did not exceed the general population's expectations, but this study could only rule out congenital abnormalities The basic incidence is 3-4 times the risk, while 89% of patients start taking the drug before pregnancy, but stop using the drug within 3 months of becoming aware of it.

Atorvastatin reaches the same drug level in the fetal rat liver as the maternal plasma through the rat's placenta. When rat doses were as high as 300 mg / kg / day and rabbit doses were as high as 100 mg / kg / day, atorvastatin did not cause teratogenic effects. Based on body surface area (mg / m2), these doses are approximately 30 times (rat) or 20 times (rabbit) human exposure.

In one study, rats were dosed at 20, 100, or 225 mg / kg / day, from the 7th day of pregnancy to the 21st day of lactation (weaning), and the mother was given a dose of 225 mg / kg Survival rates at birth, newborn, weaning, and maturity are reduced at / day.
The mother administered a dose of 100 mg / kg / day, and the young animals lost weight on days 4 and 21; the mother administered a dose of 225 mg / kg / day at birth, on days 4, 21, and 91 Live weight loss; delayed development of young animals (Routel syndrome at a dose of 100 mg / kg / day, and auditory startle response at 225 mg / kg / day; auricle separation and Eye crack).

These doses are equivalent to 6 times (100 mg / kg / day) and 22 times (225 mg / kg / day) the area under the curve when a person takes a daily dose of 80 mg.

Childbirth <br /> There are no studies on the effects of this product on pregnant women, including studies of amlodipine and atorvastatin on mothers or fetuses during childbirth and the effect on labor. Studies in rats have shown that amlodipine can prolong the labor of rats.

Medication for lactating women:
Study of Amlodipine:
It is unclear whether the amlodipine component of this product is secreted by human milk.

Atorvastatin research:
It is unclear whether atorvastatin is secreted by human milk, but another similar drug can be secreted into milk in small amounts. The atorvastatin drug concentration in plasma and liver of breast-fed pups was 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 drug of the same kind can be secreted through human milk, and statins may cause serious adverse reactions to breast-feeding newborns. Therefore, taking this product (containing A Trovastat ingredients) mothers should not breastfeed (see [Contraindications]).

Amlodipine atorvastatin calcium tablets for children

6


(4 17 ) 10 mg/

65 AUC40-60%

398281581340%6528007%7565

10mg 80mg Cmax 91%90%80-103%AUC18%90%109-127%







Cimetidine: Combination with Cimetidine does not change the pharmacokinetics of amlodipine.

Maalox®Maalox

100mg



10mg

Warfarin: The combination of amlodipine and warfarin does not change the prothrombin reaction time of warfarin.





CYP3A4 HIV
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CYP 3A4 P450 3A4 CYP3A4 CYP3A4

80mg500mgAUC20mg

40mg+400 mg20mg+400 mg+100 mg
AUCHIV20mg

40mg200mgAUC20mg

P4503A4 1.2

OATP1B1 OATP1B1 () 10mg 5.2mg/kg/AUC10mg

P450 3A4 P450 3A4 ()

20%

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/ <br />

40 mg /kg 100 mg /kg 4 mg/kg mg/m[sup]2[/sup] 11

Severe overdose may cause excessive dilation of peripheral blood vessels with significant hypotension and reflex tachycardia.250mg 120mg105mg(90/50 mmHg)19 30mg 2mg/kg180 /3.5

Cardiopulmonary monitoring should be actively performed if there is an excessive amount of medication. Frequent blood pressure measurements are necessary. If these conservative treatments are applied and the hypotension is still not relieved, consider administering a vasoconstrictor (such as phenylephrine), paying attention to the amount of circulating fluid and urine. Intravenous injection of calcium gluconate is also beneficial in reversing the effects of calcium antagonists. Due to the high binding rate of this product to plasma proteins, dialysis treatment is not beneficial.

15 800 538 24 12/6mmHg13/7mmHg24 24 1 3 Drugs have similar effects on diastolic blood pressure in young and elderly patients. It has a greater effect on systolic blood pressure in elderly patients, which may be related to its higher baseline systolic blood pressure. The effect is similar for black and white races.

268 6 17 2.5 5 mg4 4 8 5mg 5mg 5mmHg Adverse events are similar to adults.

Effects on chronic stable angina:

5-10 mg/861038684354 In five of these studies, a 10 mg dose resulted in a significant increase in exercise (bicycle or activity plate) time.10mg5mg12.8% (63)7.9%(38) In some studies, amlodipine 10 mg can also prolong the 1 mm ST segment deviation and reduce the frequency of angina pectoris. The long-lasting efficacy of amlodipine has been proven in long-term studies in patients with angina pectoris. The decrease in blood pressure (4/1 mmHg) and change in heart rate (+0.3 bpm) in patients with angina pectoris have no significant clinical significance.



4504/1/p[0.012/237/27

For proven coronary heart disease:

PREVENT 825 5-10mg3

CAMELOT 1318 40%76%89%93%89%52%PCI 4%PCI 44%89%83%-74%50%40%32%5-10mg/19 The primary end point was the time at which one of the following events occurred for the patient: angina pectoris admission; coronary artery reconstruction; myocardial infarction; cardiovascular death; heartbeat resuscitation; heart failure admission; stroke / TIA; or peripheral vascular disease.11016.6%15123.1%0.691 (95% CI: 0.540-0.884, p= 0.003) A summary of the main endpoints is shown in Figure 1.22

CAMLOT 274

1-

2 /TIA

8-12 NYHA II/III 697 NYHA 6 13.8 /1153 NYHA III (n=931)NYHA IV (n=222) ACEI 5-10 mgNYHA These composite endpoints are all-cause mortality and cardiovascular morbidity (particularly fatal arrhythmias, acute myocardial infarction, or hospital admission with increased heart failure).222/571 (39%)246/583 (42%)25%

(PRAISE-2)NYHA III (80%) IV (20%)ACEI99%99%99%(n=827)(n=827)33 95%8%29% However, more pulmonary edema was reported in the amlodipine group.



-ASCOT10,30540-8063251 mg/dl (6.5 mmol/l)3(81.1%)55 (84.5%)(33.2%)(24.3%)(26%)/6 (14.3%)(5.1%)(14.4%)(9.8%)(14.3%)/(62.4%)(140/90 mm Hg130/80 mmHg )10 mg/(n=5168) (n=5137) 93.310 mg/

[464010860]36% [(1.9% 3.0% ), p=0.0005 (3)]

310 mg/--ASCOT-LLA

42%(p=0.01)26% (1.7%2.3%)(p=0.51)(p=0.17)

CARDS(CVD)2838(94% , 68%)40-75WHO 2160 mg/dl600 mg/dl(23%)(80%)(30%)(9%)(3%)1:110 mg/(n=1,429)(n=1,411)3.9

627.7%120 mg/dL; 207 mg/dL; 151 mg/dL; 52mg/dL

10 mg/

(83 127)37%, 0.63, 95% (0.48,0.83) (p=0.001) (4 )

4. CARDS 10 mg CHD

48%(21vs 39)HR 0.5295% CI(0.31,0.89)(p=0.016)42% (38vs 64)HR0.5895.1% CI (0.39, 0.86)(p=0.007)CHD

6182(HR 0.73p=0.059)

(TNT) 80 mg/10 mg/10,001 (94% , 81% , 38% 65 )8 10 mg/130mg/dL10 mg/80 mg/4.9 (MCVE)12 80 mg/73, 145, 128, 98 47 mg/dL10 mg/99, 177, 152, 129 48 mg/dL

80 mg/(80 mg/434 10 mg/548 )22%, 0.78, 95%(0.69,0.89), p=0.0002 (5 3)([65, 65)

HR=; CHD=; CI=; MI=; CHF=; CV=;

PVD=; CABG=



80 mg/(3)80 mg/8%

(3)80 mg10 mg80 mg10 mg

(IDEAL)88888080 mg/2040mg/(81%), (99%) 61.7, 121.5 mg/dL76% (PROBE), 4.81280 mg/78, 145, 115, 45100 mg/dL20-40mg105, 179, 142, 47 132 mg/dL

()80 mg/411 (9.3%)20-40 mg/463 (10.4%) , 0.89, 95% ( 0.78,1.01), p=0.07

80 mg/366 (8.2%)20-40 mg/374 (8.4%)80 mg/20-40 mg/

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18710-17(14.1)(n=140)(n=47)26261) 190 mg/dL 2) - 160 mg/dL 218.6 mg/dL (: 138.5-385.0 mg/dL)230.0 mg/dL :160.0-324.5 mg/dL) ()410 mg-130 mg/dL20 mg 420 mg80 (57.1%)

26 , , B 8

26 LDL-C 130.7mg/dl70.0~242.0mg/dlLDL-C 228.5mg/dl152.0~385.0mg/dl

20mg



1660 85/1010/105/2010/205/4010/405/80 10/80mg5mg 10mg10mg20mg40mg 80mg15%22%14%8 8 SBPDBPLDL-C 9

AML-Amlodipine
ATO-Atorvastatin
LDL-C

Mechanism

This product is a compound dosage form of amlodipine and atorvastatin. Amlodipine (an antihypertensive and antianginal drug) is a dihydropyridine calcium (ion) antagonist (calcium antagonist or slow channel blocker). Atorvastatin (a cholesterol-lowering drug) is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. The amlodipine component in this product can inhibit calcium ions from transmembrane inward entry into vascular smooth muscle and myocardium, and the atorvastatin component is a selective and competitive inhibitor of HMG-CoA reductase. The role of HMG-CoA is to convert methylolglutarate-CoA to mevalonate, a sterol precursor including cholesterol.

Amlodipine ingredients in this product

Amlodipine is a calcium dihydropyridine antagonist (also known as a calcium ion antagonist or a slow channel blocker). It inhibits the transmembrane of calcium ions into vascular smooth muscle and the heart muscle. Experimental data show that amlodipine can bind to both dihydropyridine and non-dihydropyridine. The contraction of myocardial and vascular smooth muscle relies on extracellular calcium ions entering the cell through ion channels to complete. Amlodipine can selectively inhibit calcium ion transmembrane transport, and its effect on vascular smooth muscle cells is stronger than that of cardiomyocytes. Negative inotropic effect of this drug can be observed in vitro, but this effect has not been observed in clinical animal doses. Amlodipine does not affect serum calcium concentrations. In the range of physiological pH, amlodipine is an ionized complex (pKa = 8.6), which gradually works by slowly binding / decomposing with calcium channel receptors at the binding site.

Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle, thereby reducing peripheral vascular resistance and blood pressure.

The specific mechanism by which amlodipine can relieve angina has not been fully determined, but the considerations are related to the following factors:

Labor-type colic: Amlodipine reduces the heart rate-systolic blood pressure product by reducing peripheral vascular resistance (post-cardiac load), and achieves a decrease in myocardial oxygen demand at different levels of exercise.

Vasospasm angina pectoris: Amlodipine has been proven in animal experiments and in vitro human coronary vascular experiments: it can inhibit vasospasm, restore coronary and arterial blood perfusion, and adapt to calcium, potassium adrenaline, serotonin, and thrombus. Of the A2 isomer. In vasospasm (Prinzmetal's or variant) angina pectoris, the effect of amlodipine mainly comes from its inhibition of coronary spasm.

Atorvastatin ingredients in this product:

Clinical, pathological, and epidemiological studies have shown that elevated levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (apo B) promote human atherosclerosis. Risk factors for cardiovascular disease, and elevated HDL cholesterol levels are associated with a reduced risk of cardiovascular disease.

In animal models, atorvastatin reduces plasma cholesterol and lipoprotein levels by inhibiting the synthesis of HMG-CoA reductase and cholesterol in the liver, and enhances LDL uptake by increasing the number of LDL receptors on the surface of liver cells And catabolism; atorvastatin also reduces LDL production and the number of LDL particles. Atorvastatin can reduce the level of low-density lipoprotein cholesterol in some homozygous familial hypercholesterolemia (FH) patients, and other lipid-lowering drugs usually have little clinical effect on such patients.

Atorvastatin reduces total cholesterol, low density lipoprotein cholesterol, and apolipoprotein B levels in patients with homozygous and heterozygous familial hypercholesterolemia, nonfamilial hypercholesterolemia, and mixed dyslipidemia. Atorvastatin also reduces very low-density lipoprotein cholesterol and triglyceride levels, and can increase high-density lipoprotein cholesterol and apolipoprotein A-1 levels. Atorvastatin lowers total cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, apolipoprotein B, triglycerides, and non-high-density lipoprotein cholesterol in patients with pure hypertriglyceridemia and increases high LDL cholesterol levels. Atorvastatin can reduce intermediate density lipoprotein cholesterol in patients with beta lipoproteinemia.

Pharmacodynamics

Hemodynamics of amlodipine: After taking a therapeutic dose of amlodipine in patients with hypertension, it can cause vasodilation and lower supine and standing blood pressure. With long-term administration, the decrease in blood pressure was not accompanied by significant changes in heart rate or plasma catecholamine concentration. Hemodynamic studies in patients with chronic stable angina pectoris found that rapid intravenous amlodipine can reduce arterial blood pressure and increase heart rate, but in clinical studies of patients with normal blood pressure angina pectoris, long-term oral amlodipine has a positive effect on heart rate or blood pressure. No significant effect.

Long-term oral amlodipine once a day, the effect of blood pressure control for at least 24 hours. The antihypertensive effect of young and elderly patients is related to plasma concentration. The extent of amlodipine blood pressure reduction is also related to the increase in blood pressure before treatment; therefore, the antihypertensive effect of patients with moderate hypertension (diastolic blood pressure 105-114mmHg) is better than mild hypertension (diastolic blood pressure 90-104mmHg). The patient is 50% stronger. There was no significant clinical change in blood pressure in normal blood pressure subjects (+ 1 / 2 mmHg).

For patients with hypertension with normal renal function, the therapeutic dose of amlodipine can lead to a decrease in renal vascular resistance, an increase in glomerular filtration rate, and an increase in effective renal blood flow without affecting the filtration fraction and proteinuria.

Like other calcium channel antagonists, after amlodipine treatment in patients with normal cardiac function, hemodynamic tests of cardiac function show a small increase in cardiac index at rest and during exercise (or stepping), without Accompanied by dP / dt or changes in left ventricular end-diastolic pressure or volume. In the study of hemodynamics, amlodipine in the therapeutic dose range of animals or humans, even in combination with -blockers in humans, did not show negative inotropic effects. Similar findings were found in the use of other drugs with significant negative inotropic effects in normal healthy people and patients with well-compensated heart failure.

Electrophysiological effects of amlodipine: Amlodipine does not affect sinus node or atrioventricular conduction function in live animal experiments and clinical experiments. In patients with chronic stable angina pectoris, 10 mg intravenously, AH, HV conduction, and sinus node recovery time after pacing did not change significantly. Similar results were observed in patients taking a beta-blocker in combination with amlodipine. No adverse effects on ECG parameters have been observed in clinical studies of amlodipine combined with beta blockers in patients with hypertension or angina pectoris. In patients with angina pectoris only, the application of amlodipine did not change the conduction interval of the ECG, nor did it increase AV block.

LDL-C-lowering effect of atorvastatin: Atorvastatin and some of its metabolites have pharmacological activity in the human body. The liver is the basic site and main site of cholesterol synthesis and low-density lipoprotein clearance. The dose administered rather than the systemic drug concentration was more related to the lowering of LDL cholesterol. The individualized dose should be determined according to the efficacy of the treatment (see [Dosage and Administration]).

Carcinogenic, teratogenic, reproductive damage

Amlodipine study: Rats and mice were given amlodipine 0.5, 1.25, and 2.5 mg / kg / day with food for 2 consecutive years without showing carcinogenic effects. The maximum dose for mice is mg / m2 equivalent to the maximum recommended human dose of 10 mg / day. The maximum dose for rats is calculated as mg / m2, which is twice the maximum recommended dose of 10 mg / day for humans.

Teratogenicity studies of amlodipine have shown no drug-related teratogenic effects, both at the gene and chromosome levels.

Rats (from 64 days before mating to male rats, and from 14 days before mating to female rats) were given amlodipine at a dose of 10 mg / kg / day (converted to mg / m2, 8 times the maximum recommended human dose). No effect on fertility.

Atorvastatin study: In a 2-year study in rats, rats were given doses of 10, 30, and 100 mg / kg / day, and two rare Tumors: one is rhabdomyosarcoma and the other is fibrosarcoma. This dose shows an area under the plasma curve (0-24) that is approximately 16 times the average human plasma drug exposure after a maximum oral dose of 80 mg.

In a two-year carcinogenicity study in mice, the doses administered were 100, 200, or 400 mg / kg / day, which resulted in a significant increase in liver adenomas in male mice and liver cancers in females in high doses. These findings occurred when the area under the plasma curve (0-24) was approximately 6 times the average plasma drug concentration after human exposure to an oral dose of 80 mg.

In vitro studies, atorvastatin was not mutagenic or teratogenic in the following experiments with or without metabolic activity: Ames experiments with Salmonella typhimurium and Escherichia coli in Chinese hamster lung cells HGPRT mutagenicity assay and chromosome aberration assay in Chinese hamster lung cells. Atorvastatin was negative in micronucleus experiments in mice.

In studies conducted in rats at doses as high as 175 mg / kg / day (15 times the human exposure), atorvastatin did not have any effect on animal fertility. 10 rats were given atorvastatin 100 mg / kg / day (16 times the area under the curve when 80 mg was administered to humans) for 3 months, of which 2 rats had epididymal hypoplasia and azoospermia; Testicular weight decreased significantly in the 30 and 100 mg / kg / day dose groups, and epididymal weight decreased in the 100 mg dose group. Male rats were given 100 mg / kg / day of this product before mating for a total of 11 weeks. Sperm motility and sperm cell head concentration decreased, while abnormal sperm increased. Administration of atorvastatin to dogs at 10, 40, or 120 mg / kg / day for two years did not adversely affect semen parameters or histopathology of the reproductive organs.

Pharmacokinetics of Amlodipine Atorvastatin Calcium Tablets

absorb

Amlodipine research: After oral administration of amlodipine, the peak drug concentration was reached within 6-12 hours, and the absolute bioavailability was between 64% and 90%. Food had no effect on the bioavailability of amlodipine alone.

Atorvastatin study: Atorvastatin is absorbed quickly after oral administration; plasma concentration reaches its peak (Cmax) within 1 to 2 hours. The degree of absorption increases in proportion to the dose of atorvastatin. Atorvastatin (parent drug) has an absolute bioavailability of about 14% and a system bioavailability of HMG-CoA reductase inhibitory activity of about 30%. The lower system bioavailability is due to gastrointestinal mucosal clearance and / or liver first-pass effects before entering the systemic circulation. Although Cmax and AUC estimated that food reduced the rate and extent of drug absorption by about 25% and 9%, respectively, atorvastatin reduced the same whether or not they were taken with food. Compared with the morning dose, the plasma concentration at night is slightly lower (Cmax and AUC are about 30%). However, no matter what time of day it is administered, the reduction in LDL cholesterol is the same (see [Dosage and Administration]).

Study of this product: After oral administration of this product, the peak concentrations of amlodipine and atorvastatin were 6-12h and 1-2h, respectively. The absorption rate and degree (bioavailability) of the two were different from those given separately. There was no significant difference in drug comparison (see above).

Food does not affect the bioavailability of amlodipine in this product. Although the absorption rate and extent of atorvastatin in this product are reduced by about 32% and 11% due to food effects, respectively. But similar to when taken alone. Food has no effect on the effect of atorvastatin on LDL-C.

distributed

Amlodipine study: In vivo studies have shown that amlodipine has a plasma protein binding rate of about 93% in patients with hypertension. After 7-8 days of continuous administration, amlodipine reached steady-state plasma concentrations.

Atorvastatin study: The average distributed volume of atorvastatin is approximately 381 liters. Plasma protein binding rate is 98%. A blood / plasma ratio of about 0.25 indicates that only a small amount of the drug penetrates into the red blood cells. According to observations in rats, atorvastatin may be secreted into human milk (see "Contraindications" and "Pregnant and lactating women" and "Pregnant and lactating women").

metabolism

Amlodipine research: Amlodipine is extensively metabolized by the liver, and most (about 90%) is converted into inactive metabolites.

Atorvastatin research: Atorvastatin is extensively metabolized into ortho and para hydroxy derivatives and various beta oxidation products. In vitro experiments, the ortho and para hydroxylated metabolites inhibited HMG-CoA reductase similarly to atorvastatin. About 70% of the circulating inhibitory activity on HMG-CoA reductase is produced by active metabolites. In vitro studies have shown the importance of cytochrome P450 3A4 in the metabolism of atorvastatin, while taking erythromycin, a known isoenzyme inhibitor, is consistent with increased plasma concentrations of atorvastatin in humans (see [Precautions ,medicine interactions). In animals, the ortho-hydroxyl metabolites undergo a further uvidation process.

excretion

Amlodipine research: Amlodipine's plasma clearance is biphasic, with a terminal elimination half-life of approximately 35-50 hours. Amlodipine is extensively (about 90%) metabolized by the liver into inactive metabolites, the other 10% is excreted as the original drug, and 60% of the metabolites are excreted in the urine.

Atorvastatin research: Atorvastatin and its metabolites are mainly eliminated by the bile after liver and / or extrahepatic metabolism; however, atorvastatin does not appear to have significant hepatoenteric recirculation. Atorvastatin has a mean human plasma elimination half-life of about 14 hours, but due to its active metabolites, the half-life of atorvastatin on HMG-CoA reductase inhibitory activity is about 20-30 hours. After oral administration of atorvastatin, the urine recovery was less than 2% of the dose.

Special population

Elderly patients

Amlodipine study: Reduced amlodipine clearance in elderly patients can increase AUC by about 40-60%, so lower initial doses may be required.

Atorvastatin study: In healthy older adults (aged 65 years or older), atorvastatin has higher plasma concentrations than young people (Cmax is about 40% and AUC is about 30%). Clinical data show that atorvastatin at any dose reduces LDL-C significantly more in the elderly than in the young (see [Medication for the Elderly]).

Child patient

Amlodipine study: 62 patients with hypertension aged 6-17 years were treated with 1.25mg-20mg amlodipine. Body weight clearance and volume of distribution are similar to adults.

Atorvastatin Study: Pharmacokinetic data in children are insufficient.

gender

Atorvastatin study: There is a gender difference in the plasma concentration of atorvastatin (females are about 20% higher than men in terms of Cmax, and females are 10% lower than men in terms of AUC). However, in clinical applications, there is no clinically significant gender difference in the effect of atorvastatin on LDL-C.

Patients with renal insufficiency

Study of Amlodipine: Kidney damage has no significant effect on the pharmacokinetics of amlodipine. Patients with renal insufficiency can therefore receive a regular initial dose.

Atorvastatin study: Kidney disease has no effect on atorvastatin's plasma concentration and LDL-C lowering effect, so patients with renal insufficiency do not need to adjust the dose (see [Dosage and Administration]).

Patients on hemodialysis

Although patients with end-stage renal disease have not yet been studied, hemodialysis does not significantly improve clearance of amlodipine and / or atorvastatin due to the extensive binding of these two drugs to plasma proteins.

Patients with liver dysfunction

Study of Amlodipine: The elderly and patients with hepatic insufficiency can increase AUC by about 40-60% due to decreased clearance of amlodipine. Therefore a lower initial dose is required.

Atorvastatin study: In patients with chronic alcoholic liver disease, the plasma concentration of atorvastatin increased significantly; in Childs-Pugh A patients, Cmax and AUC increased by 4 times, while in Childs-Pugh B Cmax and AUC of atorvastatin increased 16-fold and 11-fold, respectively, in patients (see [Contraindications]).

Patients with cardiac insufficiency

Amlodipine study: In patients with moderate to severe heart failure, the increase in AUC of amlodipine is similar to that in elderly and patients with liver dysfunction.

Pharmacokinetics study of atorvastatin combination Table 11. Effect of pharmacokinetics of atorvastatin combination on atorvastatin

& X times in the table represents the ratio of the combined drug value to the atorvastatin alone administration value (ie 1 time = no change); the percentage (%) in the table represents (combination value-alone administration value) / alone administration Value (ie 0% = no change)
# For the clinical significance, please refer to [Caution] skeletal muscle under Warning and Drug Interaction under [Caution].
* It has been reported that excessive use of grapefruit juice (over 750 ml-1.2 liters per day) can increase AUC (up to 2.5 times) and / or Cmax (up to 71%) more significantly.
** Sampling test 8-16 hours after administration.
Rifampicin has a dual drug interaction mechanism. Atorvastatin and rifampin are recommended to be taken at the same time. If rifampin is taken first and then atorvastatin is used, the plasma drug concentration of the latter can be significantly reduced.

Table 12. Atorvastatin effects on pharmacokinetics of co-administered drugs

# For clinical significance, see "Drug Interactions" under [Precautions].

Amlodipine Atorvastatin Calcium Tablets Storage

Protected from light and sealed.

Amlodipine Atorvastatin Calcium Tablets Packaging

Bottle; 7 tablets / bottle, 30 tablets / bottle. Aluminum aluminum blister packaging; 7 tablets / box, 30 tablets / box.

Validity of Amlodipine Atorvastatin Calcium Tablets

36 months.

Amlodipine atorvastatin calcium tablet implementation standard

JX20070048