Label Changes for:

Caduet (amlodipine besylate/atorvastatin calcium) tablets

February 2010

Changes have been made to the CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS sections of the safety label.

Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER) – February 2010

CONTRAINDICATIONS

Caduet contains atorvastatin and is therefore contraindicated in patients with active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels.

Pregnancy and Lactation 
  • Caduet contains atorvastatin and is therefore contraindicated in women who are pregnant or may become pregnant. The atorvastatin component of Caduet may cause fetal harm when administered to a pregnant woman. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Atherosclerosis is a chronic process and discontinuation of lipid lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia.
  • There are no adequate and well-controlled studies of atorvastatin use during pregnancy; however in rare reports congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, atorvastatin revealed no evidence of teratogenicity. Caduet, WHICH INCLUDES ATORVASTATIN, SHOULD BE ADMINISTERED TO WOMEN OF CHILDBEARING AGE ONLY WHEN SUCH PATIENTS ARE HIGHLY UNLIKELY TO CONCEIVE AND HAVE BEEN INFORMED OF THE POTENTIAL HAZARDS. If the patient becomes pregnant while taking this drug, therapy should be discontinued immediately and the patient apprised of the potential hazard to the fetus.
  • It is not known whether atorvastatin or amlodipine are excreted into human milk; however a small amount of another statin does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women taking Caduet should not breastfeed their infants.
Skeletal Muscle
  • Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with the atorvastatin component of Caduet and with other statins. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects.
  • The atorvastatin component of Caduet, like other statins, occasionally causes myopathy, defined as muscle aches or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values >10 times ULN. The concomitant use of higher doses of atorvastatin with certain drugs such as cyclosporine and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole and HIV protease inhibitors) increases the risk of myopathy/rhabdomyolysis.
  • Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise...
  • ... Table 12 added...
Liver Dysfunction
  • Statins, like the atorvastatin component of CADUET and like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Persistent elevations (>3 times the upper limit of normal [ULN] occurring on 2 or more occasions) in serum transaminases 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.
  • In clinical trials in patients taking the atorvastatin component of Caduet, the following...

Increased Angina and/or 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.

PRECAUTIONS

Hypotension
  • Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension is unlikely
Use in Patients with Recent Stroke or TIA
  • Studies with atorvastatin: In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study where atorvastatin 80 mg vs. placebo was administered in 4,731 subjects without CHD who had a stroke or TIA within the preceding 6 months, 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 nonfatal 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.
Information for Patients (reworded)
  • Because of the risk of myopathy with statins, the drug class to which the atorvastatin component of Caduet belongs, advise patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.
Drug Interactions
  • the sentence “, which was not clinically meaningful.” was added to the last sentence of the first paragraph.
Studies with Atorvastatin (section revised)
Pregnancy
  • Caduet contains atorvastatin and is therefore contraindicated in women who are pregnant or may become pregnant. The atorvastatin component of Caduet may cause fetal harm when administered to a pregnant woman. Caduet should be administered to women of child-bearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the woman becomes pregnant while taking Caduet, it should be discontinued immediately and the patient advised again as to the potential hazards to the fetus, and the lack of known clinical benefit with continued use during pregnancy.
  • Serum cholesterol and triglycerides increase during normal pregnancy. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol products are essential for fetal development. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy.
Pregnancy/Studies with atorvastatin
  • There are no adequate and well-controlled studies of atorvastatin use during pregnancy. There have been rare reports of congenital anomalies following intrauterine exposure to statins. In a review of about 100 prospectively followed pregnancies in women exposed
    to other statins, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. However, this study was only able to exclude a three-to-four-fold increased risk of congenital anomalies over background incidence. In 89% of these cases, drug treatment started before pregnancy and stopped during the first trimester when pregnancy was identified.
Nursing Mothers
  • Studies with amlodipine: It is not known whether the amlodipine component of Caduet is excreted in human milk.
  • Studies with atorvastatin: It is not known whether the atorvastatin component of Caduet is excreted in human milk, but a small amount of another drug in this class does pass into breast milk. Nursing rat pups taking atorvastatin had plasma and liver drug levels of 50% and 40%, respectively, of that in their mother’s milk. Animal breast milk drug levels may not accurately reflect human breast milk levels. Because another drug in this class passes into human milk and because statins have a potential to cause serious adverse reactions in nursing infants, women taking Caduet, which includes atorvastatin, should be advised not to nurse their infants.
Geriatric Use/In studies with Atorvastatin
  • In studies with atorvastatin: Of the 39,828 patients who received Lipitor in clinical studies, 15,813 (40%) were ≥65 years old and 2,800 (7%) were ≥75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older adults cannot be ruled out. Advanced age (≥65 years) is a predisposing factor for myopathy.
ADVERSE REACTIONS

The Atorvastatin Component of Caduet (section entirely rewritten and information added).

PATIENT PACKAGE INSERT

What is Caduet?
  • Lipitor is also used to lower the risk for heart attack, stroke, certain types of heart surgery, and chest pain in patients who have heart disease of risk factors for heart disease such as: age, smoking, high blood pressure, low HDL-C, heart disease in the family.
  • Lipitor can lower the risk for heart attack or stroke in patients with diabetes and risk factors such as: diabetic eye or kidney problems, smoking, or high blood pressure.
What are possible side effects of Caduet?/Call your doctor right away if
  • allergic reactions including swelling of the face, lips, tongue, and/or throat that may
    cause difficulty in breathing or swallowing which may require treatment right away.
  • allergic skin reactions
Common side effects of Caduet include
  • Upset stomach
  • alterations in some laboratory blood tests
  • Additional side effects have been reported: tendon problems.
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