Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)
- added...Postmarketing reporting has also revealed a possible association between extrapyramidal disorder and amlodipine.
Impact of Other Drugs on Amlodipine
- 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)].
- 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.
- Monitor for hypotension when sildenafil is co-administered with amlodipine [see Clinical Pharmacology (12.2)].
Impact of Amlodipine on Other Drugs
- 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)].
USE IN SPECIAL POPULATIONS
- Amlodipine - There are no adequate and well-controlled studies in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
WARNINGS AND PRECAUTIONS
Myopathy and Rhabdomyolysis
- The risk of myopathy during treatment with statins is increased with concurrent administration of …., the hepatitis C protease inhibitor telaprevir, combinations of HIV protease inhibitors, including ritonavir plus saquinavir plus ritonavir, , tipranavir plus ritonavir,darunavir plus ritonavir, fosamprenavir, and fosamprenavir plus ritonavir.
- Physicians considering combined therapy with Caduet and…. darunavir plus ritonavir,fosamprenavir, or fosamprenavir plus ritonavir,should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly
- during the initial months of therapy and during any periods of upward dosage titration of either drug.
- Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin coadministered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine.
- It is recommended that liver enzyme tests be obtained prior to initiating therapy with atorvastatin and repeated as clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with CADUET, promptly interrupt therapy. If an alternateive etiology is not found, do not restart CADUET.
- Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin.
- Edema, flushing, palpitations, and somnolence appear to be more common in women than in men.
- 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
- 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).
- Co-administration of 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine
- Co-administration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive patients resulted in a 1.6-fold 60% increase in amlodipine systemic exposure. Erythromycin co-administration in healthy volunteers did not significantly change amlodipine systemic exposure. However, strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A4 inhibitors.
- No information is available on the quantitative effects of CYP3A4 inducers on amlodipine. Patients should be monitored for adequate clinical effect when amlodipine is co-administered with CYP3A4 inducers. Blood pressure should be closely monitored when amlodipine is coadministered with CYP3A4 inducers.
Combination of Protease Inhibitors
- In patients taking the HIV protease inhibitors tipranavir plus ritonavir, or the hepatitis C protease inhibitor telaprevir, concomitant use of atorvastatin should be avoided. In patients taking the HIV protease inhibitor lopinavir plus ritonavir, caution should be used when prescribing atorvastatin and the lowest dose necessary should be used. In patients taking the HIV protease inhibitors saquinavir plus ritonavir, darunavir plus ritonavir,fosamprenavir, or fosamprenavir plus ritonavir, the dose of atorvastatin should not exceed 20 mg
- The co-administration of atorvastatin with cyclosporine should be avoided
- Because of an increased risk of myopathy/rhabdomyolysis when HMGCoA reductase inhibitors are co-administered with gemfibrozil, avoid concomitant administration of atorvastatin with gemfibrozil
- The risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates
- The risk of skeletal muscle effects may be enhanced when atorvastatin is used in combination with niacin; consider a reduction in atorvastatin dosage in this setting
- Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin co-administered with colchicine
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.
- section revised
- 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 has been observed. One patient in clinical trials developed jaundice. Increases in liver function tests (LFT) 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 LFT elevations continued treatment with a reduced dose of atorvastatin.
- It is recommended that liver function tests be performed prior to and at 12 weeks following both the initiation of therapy and any elevation of dose, and periodically (e.g., semiannually) thereafter. Liver enzyme changes generally occur in the first 3 months of treatment with the atorvastatin component of Caduet. Patients who develop increased transaminase levels should be monitored until the abnormalities resolve. Should an increase in ALT or AST of >3 times ULN persist, reduction of dose or withdrawal of Caduet is recommended.
- Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of Caduet.
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.
- 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
- 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.
Studies with Atorvastatin
- section reorganized
- 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.
- 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
- section reworded
The Atorvastatin Component of Caduet
- section changed