Amlodipine Besylate, Atorvastatin Calcium

Atorvastatin is in a group of drugs called HMG CoA reductase inhibitors, or "statins." Atorvastatin reduces levels of "bad" cholesterol (low-density lipoprotein, or LDL) and triglycerides in the blood, while increasing levels of "good" cholesterol (high-density lipoprotein, or HDL).

Amlodipine is in a group of drugs called calcium channel blockers. Amlodipine relaxes the blood vessels, improving blood flow and making it easier for the heart to pump.

The combination of amlodipine and atorvastatin is used to treat high blood pressure (hypertension) or chest pain (angina), and to lower the risk of stroke, heart attack, and other heart complications in people with type 2 diabetes, coronary heart disease, or other risk factors.

Amlodipine and atorvastatin is used in adults and children who are at least 10 years old.

Amlodipine and atorvastatin may also be used for purposes not listed in this medication guide.

You should not use this medication if you are allergic to amlodipine (Norvasc) or atorvastatin (Lipitor), if you are pregnant or breast-feeding, or if you have liver disease.

To make sure amlodipine and atorvastatin is safe for you, tell your doctor if you have:

• history of liver disease;
• history of kidney disease;
• heart disease;
• diabetes;
• a thyroid disorder; or
• if you drink more than 2 alcoholic beverages daily.

Tell your doctor about all other medications you use. Certain other drugs can increase your risk of serious muscle problems, and it is very important that your doctor knows if you are using any of them:

• cyclosporine;
• gemfibrozil, fenofibric acid, fenofibrate;
• telaprevir;
• antibiotics--clarithromycin, erythromycin;
• antifungal medication--itraconazole, ketoconazole, voriconazole;
• HIV medications--atazanavir, darunavir, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, tipranavir; or
• medicines that contain niacin (Advicor, Niaspan, Niacor, Simcor, Slo-Niacin, and others).

In rare cases, amlodipine and atorvastatin can cause a condition that results in the breakdown of skeletal muscle tissue, leading to kidney failure. This condition may be more likely to occur in older adults and in people who have kidney disease or poorly controlled hypothyroidism (underactive thyroid).

FDA pregnancy category X. This medication can harm an unborn baby or cause birth defects. Do not take amlodipine and atorvastatin if you are pregnant.Stop taking this medication and tell your doctor right away if you become pregnant. Use effective birth control to avoid pregnancy while you are taking amlodipine and atorvastatin.

It is not known whether amlodipine and atorvastatin passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Your pharmacist can provide more information about amlodipine and atorvastatin.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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The following serious adverse reactions are discussed in greater detail in other sections of the label: Rhabdomyolysis and myopathy [see WARNINGS AND PRECAUTIONS] Liver enzyme abnormalities [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, 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 besylate/atorvastatin calcium) 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 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=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 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 triglycerides, total cholesterol, HDL cholesterol, 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- 93 years, 39% women, 91% Caucasians, 3% Blacks, 2% Asians, 4% other) with a median treatment duration of 53 weeks, 9.7% of patients on atorvastatin and 9.5% of the patients on placebo discontinued because of adverse reactions regardless of causality. The five 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%).

The most commonly reported adverse reactions (incidence ≥ 2% and greater than placebo) regardless of causality, in patients treated with atorvastatin in placebo-controlled trials (n=8,755) were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), pain in extremity (6.0%), and urinary tract infection (5.7%).

Table 3 summarizes the frequency of clinical adverse reactions, regardless of causality, reported in ≥ 2% and at a rate greater than placebo in patients treated with atorvastatin (n=8,755), from seventeen placebo-controlled trials.

Table 3: Clinical Adverse Reactions Occurring in ≥ 2% in Patients Treated with Any Dose of Atorvastatin and at an Incidence Greater than Placebo Regardless of Causality (% of Patients)

Other adverse reactions reported in placebo-controlled studies 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.

In TNT [see Clinical Studies] involving 10,001 subjects (age range 29-78 years, 19% women; 94.1% Caucasians, 2.9% Blacks, 1.0% Asians, 2.0% other) with clinically evident CHD treated with atorvastatin 10 mg daily (n=5,006) or atorvastatin 80 mg daily (n=4,995), serious adverse reactions and discontinuations because of adverse reactions increased with dose. Persistent transaminase elevations ( ≥ 3 x ULN twice within 4-10 days) occurred in 62 (1.3%) individuals with atorvastatin 80 mg and in nine (0.2%) individuals with atorvastatin 10 mg. Elevations of CK ( ≥ 10 x ULN) were low overall, but were higher in the high-dose atorvastatin treatment group (13, 0.3%) compared to the low-dose atorvastatin group (6, 0.1%).

In SPARCL involving 4,731 subjects (age range 21-92 years, 40% women; 93.3% Caucasians, 3.0% Blacks, 0.6% Asians, 3.1% other) without clinically evident CHD but with a stroke or transient ischemic attack (TIA) within the previous 6 months treated with atorvastatin 80 mg (n=2,365) or placebo (n=2,366) 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 144 subjects (6.1%) in the atorvastatin group and 89 subjects (3.8%) in the placebo group [see WARNINGS AND PRECAUTIONS].

In a post-hoc analysis, atorvastatin 80 mg reduced the incidence of ischemic stroke (218/2365, 9.2% vs. 274/2366, 11.6%) and increased the incidence of hemorrhagic stroke (55/2365, 2.3% vs. 33/2366, 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 nonfatal hemorrhagic strokes). Subjects who entered the study with a hemorrhagic stroke appeared to be at increased risk for hemorrhagic stroke [7 (16%) atorvastatin vs. 2 (4%) placebo].

There were no significant differences between the treatment groups for all-cause mortality: 216 (9.1%) in the atorvastatin 80 mg/day group vs. 211 (8.9%) in the placebo group. The proportions of subjects who experienced cardiovascular death were numerically smaller in the atorvastatin 80 mg group (3.3%) than in the placebo group (4.1%). The proportions of subjects who experienced non-cardiovascular death were numerically larger in the atorvastatin 80 mg group (5.0%) than in the placebo group (4.0%).

Pediatrics: In a 26-week controlled study in boys and postmenarchal girls (n=140, 31% female; 92% Caucasians, 1.6% Blacks, 1.6% Asians, 4.8% other), the safety and tolerability profile of atorvastatin 10 to 20 mg daily was generally similar to that of placebo [see Clinical Studies and Use in Specific Populations].

Postmarketing Experience

The following adverse reactions have been identified during post-approval 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.

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.

Adverse reactions associated with atorvastatin therapy reported since market introduction that are not listed above, regardless of causality assessment, include the following: anaphylaxis, angioneurotic edema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis), rhabdomyolysis, myositis, fatigue, tendon rupture, fatal and non-fatal hepatic failure, dizziness, depression, peripheral neuropathy, pancreatitis and interstitial lung disease.

There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see WARNINGS AND PRECAUTIONS].

There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

Read the entire FDA prescribing information for Caduet (Amlodipine Besylate, Atorvastatin Calcium)