Amlodipine and atorvastatin tablets are indicated in patients for whom treatment with both amlodipine and atorvastatin is appropriate. Amlodipine Hypertension Amlodipine is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including amlodipine.
Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. Amlodipine may be used alone or in combination with other antihypertensive agents. Coronary Artery Disease (CAD) Chronic Stable Angina Amlodipine is indicated for the symptomatic treatment of chronic stable angina.
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Amlodipine may be used alone or in combination with other antianginal agents. Vasospastic Angina (Prinzmetal’s or Variant Angina) Amlodipine is indicated for the treatment of confirmed or suspected vasospastic angina. Amlodipine may be used as monotherapy or in combination with other antianginal agents. Angiographically Documented CAD In patients with recently documented CAD by angiography and without heart failure or an ejection fraction < 40%, amlodipine is indicated to reduce the risk of hospitalization for angina and to reduce the risk of a coronary revascularization procedure.
Atorvastatin Atorvastatin is indicated: To reduce the risk of: Myocardial infarction (MI), stroke, revascularization procedures, and angina in adults with multiple risk factors for coronary heart disease (CHD) but without clinically evident CHD MI and stroke in adults with type 2 diabetes mellitus with multiple risk factors for CHD but without clinically evident CHD Non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for congestive heart failure, and angina in adults with clinically evident CHD As an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C) in: Adults with primary hyperlipidemia.
Adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). As an adjunct to other LDL-C-lowering therapies, or alone if such treatments are unavailable, to reduce LDL-C in adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia (HoFH). As an adjunct to diet for the treatment of adults with: Primary dysbetalipoproteinemia Hypertriglyceridemia Amlodipine and atorvastatin tablets are a combination of amlodipine besylate, a calcium channel blocker, and atorvastatin calcium, a HMG CoA-reductase inhibitor (statin), indicated in patients for whom treatment with both amlodipine and atorvastatin is appropriate ( 1 ).
Amlodipine is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. Amlodipine is indicated for the treatment of Coronary Artery Disease ( 1 ). Atorvastatin is indicated ( 1 ): To reduce the risk of: Myocardial infarction (MI), stroke, revascularization procedures, and angina in adults with multiple risk factors for coronary heart disease (CHD) but without clinically evident CHD.
MI and stroke in adults with type 2 diabetes mellitus with multiple risk factors for CHD but without clinically evident CHD. Non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for congestive heart failure, and angina in adults with clinically evident CHD. As an adjunct to diet to reduce low-density lipoprotein (LDL-C) in: Adults with primary hyperlipidemia. Adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH).
As an adjunct to other LDL-C-lowering therapies to reduce LDL-C in adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia. As an adjunct to diet for the treatment of adults with: Primary dysbetalipoproteinemia. Hypertriglyceridemia.
Contraindications
Acute liver failure or decompensated cirrhosis [see Warnings and Precautions ( 5.3 )]. Hypersensitivity to amlodipine, atorvastatin or any excipients in amlodipine and atorvastatin tablets. Hypersensitivity reactions, including anaphylaxis, angioneurotic edema, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported [see Adverse Reactions ( 6.2 )]. Acute liver failure or decompensated cirrhosis (4).
Hypersensitivity to amlodipine, atorvastatin or any excipient in amlodipine and atorvastatin tablets (4).
Warnings and precautions
Myopathy and Rhabdomyolysis: Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher Amlodipine and atorvastatin tablets dosage. Discontinue amlodipine and atorvastatin tablets if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue amlodipine and atorvastatin tablets in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis.
Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing amlodipine and atorvastatin tablets dosage. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever (2, 5.1, 7.3, 8.5, 8.6). Immune-Mediated Necrotizing Myopathy (IMNM): Rare reports of IMNM, an autoimmune myopathy, have been reported with statin use. Discontinue amlodipine and atorvastatin tablets in IMNM is suspected ( 5.2 ).
Hepatic Dysfunction: Increases in serum transaminases have occurred, some persistent. Rare reports of fatal and non-fatal hepatic failure have occurred. Consider testing liver enzymes before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue amlodipine and atorvastatin tablets ( 5.3 ). Angina or myocardial infarction may occur with initiation or dose increase (5.4) Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis.
However, acute hypotension is unlikely ( 5.5 ).
5.1Myopathy and Rhabdomyolysis Amlodipine
and atorvastatin tablets may cause myopathy (muscle pain, tenderness, or weakness associated with elevated creatine kinase [CK]) and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including Amlodipine and atorvastatin tablets. Risk Factors for Myopathy Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs (including other lipid-lowering therapies), and higher amlodipine and atorvastatin dosage [see Drug Interactions ( 7.3 ) and Use in Specific Populations (8.5, 8.6)].
Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis Amlodipine and atorvastatin exposure may be increased by drug interactions due to inhibition of cytochrome P450 enzyme 3A4 (CYP3A4) and/or transporters (e.g., breast cancer resistant protein [BCRP], organic anion-transporting polypeptide [OATP1B1/OATP1B3] and P-glycoprotein [P-gp]), resulting in an increased risk of myopathy and rhabdomyolysis. Concomitant use of cyclosporine, gemfibrozil, tipranavir plus ritonavir or glecaprevir plus pibrentasvir with amlodipine and atorvastatin is not recommended.
Amlodipine and atorvastatin dosage modifications are recommended for patients taking certain anti-viral, azole antifungals, or macrolide antibiotic medications [see Dosage and Administration ( 2 )] . Cases of myopathy/rhabdomyolysis have been reported with atorvastatin co-administered with lipid modifying doses (>1 gram/day) of niacin, fibrates, colchicine, and ledipasvir plus sofosbuvir [see Adverse Reactions ( 6.1 )] .
Consider if the benefit of use of these products outweighs the increased risk of myopathy and rhabdomyolysis [See Drug Interaction ( 7.3 )] Concomitant intake of large quantities, more than 1.2 liters daily, of grapefruit juice is not recommended in patients taking amlodipine and atorvastatin tablets [see Drug Interactions ( 7.3 )]. Discontinue amlodipine and atorvastatin tablets if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected.
Muscle symptoms and CK elevations may resolve if amlodipine and atorvastatin tablets are discontinued. Temporarily discontinue amlodipine and atorvastatin tablets in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy).
Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the Amlodipine and atorvastatin dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.
5.2Immune-Mediated Necrotizing Myopathy
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin ws administered. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase that persists despite discontinuation of statin treatment; positive anti-HMG-CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents.
Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Discontinue amlodipine and atorvastatin tablets if IMNM is suspected.
5.3Hepatic Dysfunction Increases
in serum transaminases have been reported with use of atorvastatin [see Adverse Reactions ( 6.1 )]. In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. Persistent increases to more than three times the ULN in serum transaminases have occurred in approximately 0.7% of patients receiving atorvastatin in clinical trials.
There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury [see Use in Specific Populations ( 8.7 )]. Consider liver enzyme testing before atorvastatin initiation and when clinically indicated thereafter. Atorvastatin is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications ( 4 )].
If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue atorvastatin.
5.4Increased Angina and Myocardial Infarction
Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of amlodipine, particularly in patients with severe obstructive coronary artery disease.
5.5Hypotension
Symptomatic hypotension is possible with use of amlodipine, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension is unlikely.
5.6Increases in HbA1c and Fasting Serum Glucose Levels Increases in HbA1c
and fasting serum glucose levels have been reported with statins, including atorvastatin. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.
5.7Increased Risk of Hemorrhagic Stroke on Atorvastatin
80 mg with Recent Hemorrhagic Stroke In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial where 2365 adult patients, without CHD who had a stroke or Transient Ischemic Attack (TIA) within the preceding 6 months, were treated with atorvastatin 80 mg, a higher incidence of hemorrhagic stroke was seen in the atorvastatin 80 mg group compared to placebo (55, 2.3% atorvastatin vs. 33, 1.4% placebo; HR: 1.68, 95% CI: 1.09, 2.59; p=0.0168).
The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 vs. 18 for the atorvastatin and placebo groups, respectively). The incidence of non-fatal hemorrhagic stroke was significantly higher in the atorvastatin group (38, 1.6%
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Interactions
Data from a drug-drug interaction study involving 10 mg of amlodipine and 80 mg of atorvastatin in healthy subjects indicate that the pharmacokinetics of amlodipine are not altered when the drugs are co-administered. The effect of amlodipine on the pharmacokinetics of atorvastatin showed no effect on the C max : 91% (90% confidence interval: 80 to 103%), but the AUC of atorvastatin increased by 18% (90% confidence interval: 109 to 127%) in the presence of amlodipine, which is not clinically meaningful.
No drug interaction studies have been conducted with amlodipine and atorvastatin and other drugs, although studies have been conducted in the individual amlodipine and atorvastatin components, as described below: Amlodipine See full prescribing information for details regarding concomitant use of amlodipine and atorvastatin tablets with other drugs or grapefruit juice that increase the risk of myopathy and rhabdomyolysis (2.5, 7.3 ).
Rifampin: May reduce atorvastatin plasma concentrations. Administer simultaneously with atorvastatin ( 7.4 ) Oral Contraceptives: May increase plasma levels of norethindrone and ethinyl estradiol; consider this effect when selecting an oral contraceptive ( 7.5 ). Digoxin: May increase digoxin plasma levels; monitor patients appropriately ( 7.5 ).
7.1 Impact of Other Drugs on Amlodipine CYP3A Inhibitors Co-administration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A inhibitors to determine the need for dose adjustment [see Clinical Pharmacology ( 12.3 )] . CYP3A Inducers No information is available on the quantitative effects of CYP3A inducers on amlodipine.
Blood pressure should be closely monitored when amlodipine is co-administered with CYP3A inducers. Sildenafil Monitor for hypotension when sildenafil is co-administered with amlodipine [see Clinical Pharmacology ( 12.2 )] .
7.2Impact of Amlodipine on Other Drugs Immunosuppressants
Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered. Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate [see Clinical Pharmacology ( 12.3 )] . Atorvastatin
7.3Drug
Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with Atorvastatin Atorvastatin is a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-gp, or BCRP). Atorvastatin plasma levels can be significantly increased with concomitant administration of inhibitors of CYP3A4 and transporters. Table 3 includes a list of drugs that may increase exposure to atorvastatin and may increase the risk of myopathy and rhabdomyolysis when used concomitantly and instructions for preventing or managing them [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 )] .
Table 3. Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with Atorvastatin Cyclosporine or Gemfibrozil Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin and cyclosporine, an inhibitor of CYP3A4 and OATP1B1 [see Clinical Pharmacology ( 12.3 )] . Gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine or gemfibrozil with atorvastatin .
Intervention: Concomitant use of cyclosporine or gemfibrozil with atorvastatin is not recommended. Anti-Viral Medications Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin with many anti-viral medications, which are inhibitors of CYP3A4 and/or transporters (e.g., BCRP, OATP1B1/1B3, P-gp, MRP2, and/or OAT2) [see Clinical Pharmacology ( 12.3 )] . Cases of myopathy and rhabdomyolysis have been reported with concomitant use of ledipasvir plus sofosbuvir with atorvastatin.
Intervention: Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with atorvastatin is not recommended. In patients taking lopinavir plus ritonavir, or simeprevir, consider the risk/benefit of concomitant use with atorvastatin. In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir do not exceed atorvastatin 20 mg.
In patients taking nelfinavir, do not exceed atorvastatin 40 mg [see Dosage and Administration ( 2 )] . Consider the risk/benefit of concomitant use of ledipasvir plus sofosbuvir with atorvastatin. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Examples: Tipranavir plus ritonavir, glecaprevir plus pibrentasvir, lopinavir plus ritonavir, simeprevir, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovir, nelfinavir, and ledipasvir plus sofosbuvir .
Select Azole Antifungals or Macrolide Antibiotics Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin with select azole antifungals or macrolide antibiotics, due to inhibition of CYP3A4 and/or transporters [see Clinical Pharmacology ( 12.3 )] . Intervention: In patients taking clarithromycin or itraconazole, do not exceed atorvastatin 20 mg [see Dosage and Administration ( 2 )] .
Consider the risk/benefit of concomitant use of other azole antifungals or macrolide antibiotics with atorvastatin. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Examples: Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole. Niacin Clinical Impact: Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid modifying dosages of niacin (≥1 gram/day niacin) with atorvastatin.
Intervention: Consider if the benefit of using lipid modifying dosages of niacin concomitantly with atorvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Fibrates (other than Gemfibrozil) Clinical Impact: Fibrates may cause myopathy when given alone.
The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with atorvastatin. Intervention: Consider if the benefit of using fibrates concomitantly with atorvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
Colchicine Clinical Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with atorvastatin. Intervention: Consider the risk/benefit of concomitant use of colchicine with atorvastatin. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Grapefruit Juice Clinical Impact: Grapefruit juice consumption, especially excessive consumption, more than 1.2 liters/daily can raise the plasma levels of atorvastatin and may increase the risk of myopathy and rhabdomyolysis.
Intervention: Avoid intake of large quantities of grapefruit juice, more than 1.2 liters daily, when taking atorvastatin.
7.4Drug
Interactions that may Decrease Exposure to Atorvastatin Table 4 presents drug interactions that may decrease exposure to atorvastatin and instructions for preventing or managing them. Table 4. Drug Interactions that may Decrease Exposure to Atorvastatin Rifampin
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Pregnancy and breastfeeding
8.1Pregnancy Risk Summary Atorvastatin
Discontinue atorvastatin when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Atorvastatin decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, atorvastatin may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology ( 12.1 )]. In addition, treatment of hyperlipidemia is not generally necessary during pregnancy.
Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients. Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations.
Published data from prospective and retrospective observational cohort studies with atorvastatin use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data). In animal reproduction studies, no adverse developmental effects were observed in pregnant rats or rabbits orally administered atorvastatin at doses that resulted in up to 30 and 20 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 80 mg, based on body surface area (mg/m 2 ).
In rats administered atorvastatin during gestation and lactation, decreased postnatal growth and development delay were observed at doses ≥ 6 times the MRHD (see Data). Amlodipine The limited available data based on post marketing reports with amlodipine use in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with porrly controlled hypertension in pregnancy (see Clinical Considerations).
In anomal reproduction studies, there was no evidence of adverse developmental effects when pregnant rats and rabbits were treated orally with amlodipine maleate during organorgenesis at doses approximately 10 and 20-times MRHD, rspectively. However for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold). Amlodipine has been shown to prolong the gestation perid and the duration of labor in rats at this dose (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need fir cesarean section and post-partum hemorrhage).
Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Data Human Data Atorvastatin A Medicaid cohort linkage study of 1,152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders – including maternal age, diabetics mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods.
The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.
Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births. Animal Data Atorvastatin Was administered to pregnant rats and rabbits during organogenesis at oral doses up to 300 mg/kg/day and 100 mg/kg/day, respectively.
Atorvastatin was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day. These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure at the MRHD based on surface area (mg/m 2 ). In rats, the maternally toxic dose of 300 mg/kg resulted in incrased post-implantation loss and decreased fetal body weight. At the maternally toxic doses of 50 and 100 mg/kg/day in rabbits, there was increased post-implantation loss, and at 100 mg/kg/day fetal body weights were decreased.
In a study in pregnant rats administered 20, 100, or 225 mg/kg/day, from gestation day 7 through to lactation day 20 (weaning), there was decreased survival at birth, postnatal day 4, weaning, and post-weaning in pups of mothers dosed with 225 mg/kg/day, a dose at which maternal toxicity was observed. Pup body weight was decreased through postnatal day 21 at 100 mg/kg/day, and through postnatal day 91 at 225 mg/kg/day.
Pup development was delayed (rotorod performance at 100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye-opening at 225 mg/kg/day). These doses of atorvastatin correspond to 6 times (100 mg/kg) and 22 times (225 mg/kg) the human exposure at the MRHD, based on AUC. Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma. Amlodipine No evidence of teratogenicity or other embyo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses up to 10 mg amlodipine/kg/day (approximately 10 and 20 times the MRHD based on body surface area, respectively) during their respective period of major organogenesis.
However, for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) in rats rceiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose.
Adverse reactions
The following important adverse reactions are described below and elsewhere in the labeling: Myopathy and Rhabdomyolysis [see Warnings and Precautions ( 5.1 )] Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions ( 5.2 )] Hepatic Dysfunction [see Warnings and Precautions ( 5.3 )] Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions ( 5.6 )] Most common adverse reaction to amlodipine is edema which occurred in a dose related manner ( 6.1 ).
Most common adverse reactions (incidence ≥5%) are nasopharyngitis, arthralgia, diarrhea, pain in extremity, and urinary tract infection to atorvastatin ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800- 706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Amlodipine and Atorvastatin Amlodipine and atorvastatin has been evaluated for safety in 1,092 patients in double-blind placebo-controlled studies treated for co-morbid hypertension and dyslipidemia.
In general, treatment with amlodipine and atorvastatin was well tolerated. For the most part, adverse reactions have been mild or moderate in severity. In clinical trials with amlodipine and atorvastatin, no adverse reactions peculiar to this combination have been observed. Adverse reactions are similar in terms of nature, severity, and frequency to those reported previously with amlodipine and atorvastatin. The following information is based on the clinical experience with amlodipine and atorvastatin.
Amlodipine Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. In general, treatment with amlodipine was well tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with amlodipine were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine (N=1,730) at doses up to 10 mg to placebo (N=1,250), discontinuation of amlodipine because of adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%).
The most commonly reported side effects more frequent than placebo are dizziness and edema. The incidence (%) of side effects that occurred in a doserelated manner are as follows: Amlodpine 2.5 mg N=275 5 mg N=296 10 mg N=268 Placebo N=520 Edema 1.8 3 10.8
0.6 Other adverse reactions that were not clearly dose related but were reported at an incidence greater than 1.0% in placebo-controlled clinical trials include the following: Amlodipine (%) (N=1,730) Placebo (%) (N=1,250) Fatigue 4.5
2.8 Nausea 2.9
1.9 Abdominal Pain 1.6
0.3 Somnolece 1.4
0.6 Edema, flushing, palpitations, and somnolence appear to be more common in women than in men. The following events occurred in < 1% but > 0.1% of patients treated with amlodipine in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship: Cardiovascular : arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, peripheral ischemia, syncope, tachycardia, vasculitis.
Central and Peripheral Nervous System : hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo. Gastrointestinal : anorexia, constipation, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia. General : allergic reaction, asthenia, 2 back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease. Musculoskeletal System : arthralgia, arthrosis, muscle cramps, 2 myalgia.
Psychiatric : sexual dysfunction (male 2 and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization. Respiratory System : dyspnea, 2 epistaxis. Skin and Appendages : angioedema, erythema multiforme, pruritus, 2 rash, 2 rash erythematous, rash maculopapular. Special Senses : abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus. Urinary System : micturition frequency, micturition disorder, nocturia.
Autonomic Nervous System : dry mouth, sweating increased. Metabolic and Nutritional : hyperglycemia, thirst. Hemopoietic : leukopenia, purpura, thrombocytopenia. 2 These events occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies. Amlodipine therapy has not been associated with clinically significant changes in routine laboratory tests.
No clinically relevant changes were noted in serum potassium, serum glucose, total TG, TC, HDL-C, uric acid, blood urea nitrogen, or creatinine. Atorvastatin In the atorvastatin placebo-controlled clinical trial database of 16,066 patients (8,755 atorvastatin vs. 7,311 placebo; age range 10 to 93 years, 39% female, 91% White, 3% Black or African American, 2% Asian, 4% other) with a median treatment duration of 53 weeks, the most common adverse reactions in patients treated with atorvastatin that led to treatment discontinuation and occurred at a rate greater than placebo were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), alanine aminotransferase increase (0.4%), and hepatic enzyme increase (0.4%).
Table 2 summarizes adverse reactions, reported in ≥ 2% and at a rate greater than placebo in patients treated with atorvastatin (n=8,755), from seventeen placebo-controlled trials. Table 2. Adverse Reactions Occurring in ≥ 2% in Patients Atorvastatin-Treated with any Dose and Greater than Placebo Adverse Reaction % Placebo N=7,311 % 10 mg N=3,908 % 20 mg N=188 % 40 mg N=604 % 80 mg N=4,055 % Any dose N=8,755 Nasopharyngitis 8.2 12.9 5.3 7 4.2
2.3 Other adverse reactions reported in placebo-controlled trials include: Body as a Whole : malaise, pyrexia Digestive System : abdominal discomfort, eructation, flatulence, hepatitis, cholestasis Musculoskeletal System : musculoskeletal pain, muscle fatigue, neck pain, joint swelling Metabolic and Nutritional System : transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, creatine phosphokinase increase, hyperglycemia Nervous System : nightmare Respiratory System : epistaxis Skin and Appendages : urticaria Special Senses : vision blurred, tinnitus Urogenital System : white blood cells urine positive.
Elevations in Liver Enzyme Tests Persistent elevations in serum transaminases, defined as more than 3 times the ULN and occurring on 2 or more occasions, occurred in 0.7% of patients who received atorvastatin in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively. One patient in clinical trials developed jaundice. Increases in liver enzyme tests in other patients were not associated with jaundice or other clinical signs or symptoms.
Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent liver enzyme elevations continued treatment with a reduced dose of atorvastatin. Treating to New Targets Study (TNT) In TNT [see Clinical Studies ( 14.6 )] 10,001 subjects (age range 29 to 78 years, 19% female; 94% White, 3% Black or African Americ
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Composition
Active ingredients
AMLODIPINE BESYLATE EQ 10MG BASE; ATORVASTATIN CALCIUM EQ 40MG BASE
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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