CADUET (amlodipine and atorvastatin) is indicated in patients for whom treatment with both amlodipine and atorvastatin is appropriate.

CADUET is 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 non-fatal 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:

• oMyocardial infarction (MI), stroke, revascularization procedures, and angina in adults with multiple risk factors for coronary heart disease (CHD) but without clinically evident CHD.
• oMI and stroke in adults with type 2 diabetes mellitus with multiple risk factors for CHD but without clinically evident CHD.
• oNon-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:

• oAdults with primary hyperlipidemia.
• oAdults 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:

• oPrimary dysbetalipoproteinemia.
• oHypertriglyceridemia.

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. 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:

• oMyocardial infarction (MI), stroke, revascularization procedures, and angina in adults with multiple risk factors for coronary heart disease (CHD) but without clinically evident CHD
• oMI and stroke in adults with type 2 diabetes mellitus with multiple risk factors for CHD but without clinically evident CHD
• oNon-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:

• oAdults with primary hyperlipidemia.
• oAdults 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:

• oPrimary dysbetalipoproteinemia
• oHypertriglyceridemia

CADUET

Dosage of CADUET must be individualized on the basis of both effectiveness and tolerance for each individual component in the treatment of hypertension/angina and hyperlipidemia. Select doses of amlodipine and atorvastatin independently.

CADUET may be substituted for its individually titrated components. Patients may be given the equivalent dose of CADUET or a dose of CADUET with increased amounts of amlodipine, atorvastatin, or both for additional antianginal effects, blood pressure lowering, or lipid-lowering effect.

CADUET may be used to provide additional therapy for patients already on one of its components. CADUET may be used to initiate treatment in patients with hyperlipidemia and either hypertension or angina.

Important Dosage Information

Take CADUET orally once daily at any time of the day, with or without food.

Amlodipine

The usual initial antihypertensive oral dosage of amlodipine is 5 mg once daily, and the maximum dose is 10 mg once daily.

Pediatric (age > 6 years), small adult, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 2.5 mg once daily and this dose may be used when adding amlodipine to other antihypertensive therapy.

Adjust dosage according to blood pressure goals. In general, wait 7 to 14 days between titration steps. Titration may proceed more rapidly, however, if clinically warranted, provided the patient is assessed frequently.

Angina The recommended dosage of amlodipine for chronic stable or vasospastic angina is 5–10 mg, with the lower dose suggested in the elderly and in patients with hepatic insufficiency. Most patients will require 10 mg for adequate effect.

Coronary Artery Disease The recommended dosage range of amlodipine for patients with CAD is 5–10 mg once daily. In clinical studies, the majority of patients required 10 mg [see Clinical Studies (14.4)].

Pediatrics The effective antihypertensive oral dose of amlodipine in pediatric patients ages 6–17 years is 2.5 mg to 5 mg once daily. Doses in excess of 5 mg daily have not been studied in pediatric patients [see Clinical Pharmacology (12.3) and Clinical Studies (14.1)].

Atorvastatin

Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating atorvastatin, and adjust the ‎dosage if ‎‎necessary.‎ ‎

Recommended Dosage in Adult Patients

The recommended starting dosage of atorvastatin is 10 mg to 20 mg once daily. The dosage range is 10 mg to 80 mg once daily. Patients who require reduction in LDL-C greater than 45% may be started at 40 mg once daily.

Recommended Dosage in Pediatric Patients 10 Years of Age and Older with H eFH

The recommended starting dosage of atorvastatin is 10 mg once daily. The dosage range is 10 mg to 20 mg once daily.

Recommended Dosage in Pediatric Patients 10 Years of Age and Older with HoFH

The recommended starting dosage of atorvastatin is 10 mg to 20 mg once daily. The dosage range is 10 mg to 80 mg once daily.

Dosage Modifications Due to Drug Interactions

Concomitant use of atorvastatin with the following drugs requires dosage modification of atorvastatin [see Warnings and Precautions (5.1) and Drug Interactions (7.1)].

Anti-Viral Medications

• In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, do not exceed atorvastatin 20 mg once daily.

• In patients taking nelfinavir, do not exceed atorvastatin 40 mg once daily.

Select Azole Antifungals or Macrolide Antibiotics

• In patients taking clarithromycin or itraconazole, do not exceed atorvastatin 20 mg once daily.

For additional recommendations regarding concomitant use of atorvastatin with other anti-viral medications, azole antifungals or macrolide antibiotics, [see Drug Interactions (7.1)].

• •Acute liver failure or decompensated cirrhosis [see Warnings and Precautions (5.3)].
• •Hypersensitivity to amlodipine, atorvastatin or any excipients in ‎CADUET. 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 CADUET (4).

• Myopathy and Rhabdomyolysis: Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher CADUET dosage. Discontinue CADUET if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue CADUET 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 CADUET 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 CADUET if 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 CADUET (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).

CADUET 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 CADUET.

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 CADUET 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

CADUET 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 CADUET is not recommended. CADUET 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 Interactions (7.3)].

Concomitant intake of large quantities, more than 1.2 liters daily, of grapefruit juice is not recommended in patients taking CADUET [see Drug Interactions (7.3)].

Discontinue CADUET if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK elevations may resolve if CADUET is discontinued. Temporarily discontinue CADUET 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 CADUET dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.

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 was 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 CADUET if IMNM is suspected.

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.

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.

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.

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.

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%) as compared to the placebo group (16, 0.7%). Some baseline characteristics, including hemorrhagic and lacunar stroke on study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group [see Adverse Reactions (6.1)]. Consider the risk/benefit of use of atorvastatin 80 mg in patients with recent hemorrhagic stroke.

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 Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

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.

CADUET

CADUET (amlodipine/atorvastatin) has been evaluated for safety in 1092 patients in double-blind placebo-controlled studies treated for co-morbid hypertension and dyslipidemia. In general, treatment with CADUET was well tolerated. For the most part, adverse reactions have been mild or moderate in severity. In clinical trials with CADUET, 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=1730) at doses up to 10 mg to placebo (N=1250), 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 dose related manner are as follows:

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:

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 (male2 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 16066 patients (8755 atorvastatin vs. 7311 placebo; age range 10‑93 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=8755), from seventeen placebo-controlled trials.

Table 2. Adverse Reactions Occurring in ≥ 2% in Patients Atorvastatin-Treated with any Dose and Greater than Placebo

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 patients (age range 29–78 years, 19% female; 94% White, 3% Black or African American, 1% Asian, 2% other) with clinically evident CHD were treated with atorvastatin 10 mg daily (n=5006) or atorvastatin 80 mg daily (n=4995). In the high-dose atorvastatin group, there were more patients with serious adverse reactions (1.8%) and discontinuations due to adverse reactions (9.9%) as compared to the low-dose group (1.4%; 8.1%, respectively) during a median follow-up of 4.9 years. Persistent transaminase elevations (≥ 3 x ULN twice within 4–10 days) occurred in 1.3% of individuals with atorvastatin 80 mg and in 0.2% of individuals with atorvastatin 10 mg. Elevations of CK (≥ 10 x ULN) were higher in the high-dose atorvastatin group (0.3%) compared to the low-dose atorvastatin group (0.1%).

Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)

In SPARCL, 4731 patients (age range 21–92 years, 40% female; 93% White, 3% Black or African American, 1% Asian, 3% other) without clinically evident CHD but with a stroke or transient ischemic attack (TIA) within the previous 6 months were treated with atorvastatin 80 mg (n=2365) or placebo (n=2366) for a median follow-up of 4.9 years. There was a higher incidence of persistent hepatic transaminase elevations (≥ 3 x ULN twice within 4–10 days) in the atorvastatin group (0.9%) compared to placebo (0.1%). Elevations of CK ( > 10 x ULN) were rare, but were higher in the atorvastatin group (0.1%) compared to placebo (0.0%). Diabetes was reported as an adverse reaction in 6.1% of subjects in the atorvastatin group and 3.8% of subjects in the placebo group.

In a post-hoc analysis, atorvastatin 80 mg reduced the incidence of ischemic stroke (9.2% vs. 11.6%) and increased the incidence of hemorrhagic stroke (2.3% vs. 1.4%) compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17 atorvastatin vs. 18 placebo). The incidence of non-fatal hemorrhagic strokes was significantly greater in the atorvastatin group (38 non-fatal hemorrhagic strokes) as compared to the placebo group (16 non-fatal hemorrhagic strokes). Patients who entered the trial with a hemorrhagic stroke appeared to be at increased risk for hemorrhagic stroke (16% atorvastatin vs. 4% placebo).

In a 26-week controlled study in pediatric patients with HeFH (ages 10 years to 17 years) (n=140, 31% female; 92% White, 1.6% Black or African American, 1.6% Asian, 4.8% other), the safety and tolerability profile of atorvastatin 10 to 20 mg daily, as an adjunct to diet to reduce total cholesterol, LDL-C, and apo B levels, was generally similar to that of placebo [see Use in Specific Populations (8.4) and Clinical Studies (14.11)].

The following adverse reactions have been identified during post-approval use of amlodipine and atorvastatin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Amlodipine

The following postmarketing event has been reported infrequently where a causal relationship is uncertain: gynecomastia. In postmarketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine.

Postmarketing reporting has also revealed a possible association between extrapyramidal disorder and amlodipine.

Amlodipine has been used safely in patients with chronic obstructive pulmonary disease, well-compensated congestive heart failure, coronary artery disease, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles.

Atorvastatin

Gastrointestinal Disorders: pancreatitis

General Disorders: fatigue

Hepatobiliary Disorders: fatal and non-fatal hepatic failure

Immune System Disorders: anaphylaxis

Injury: tendon rupture

Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis, myositis.

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

Nervous System Disorders: dizziness, peripheral neuropathy.

There have been rare reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with the use of all statins. Cognitive impairment was generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). There have been rare reports of new-onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered.

Psychiatric Disorders: depression

Respiratory Disorders: interstitial lung disease

Skin and Subcutaneous Tissue Disorders: angioneurotic edema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis)