Increased Angina and/or Myocardial Infarction
Rarely, patients, particularly those with severe obstructive coronary artery disease,
have developed documented increased frequency, duration and/or severity of angina
or acute myocardial infarction on starting calcium channel blocker therapy or at
the time of dosage increase. The mechanism of this effect has not been elucidated.
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, and/or marked elevation of CPK. Patients should be advised to report promptly
unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or
fever. CADUET therapy should be discontinued if markedly elevated CPK levels occur or
myopathy is diagnosed or suspected.
The risk of myopathy during treatment with statins is increased with concurrent
administration of cyclosporine, fibric acid derivatives,
erythromycin, clarithromycin, combination of ritonavir plus saquinavir or lopinavir
plus ritonavir, niacin, or azole antifungals. Physicians considering combined therapy
with CADUET and fibric acid derivatives, erythromycin, clarithromycin, a combination
of ritonavir plus saquinavir or lopinavir plus ritonavir, immunosuppressive drugs,
azole antifungals, or lipid-modifying doses of niacin 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.
Lower starting and maintenance doses of atorvastatin should be considered when taken
concomitantly with the aforementioned drugs (See PRECAUTIONS, Drug Interactions).
Periodic creatine phosphokinase (CPK) determinations may be considered in such situations,
but there is no assurance that such monitoring will prevent the occurrence of severe myopathy.
Prescribing recommendations for atorvastatin, a component of CADUET, and interacting agents
are summarized in Table 12 (see DOSAGE AND ADMINISTRATION, PRECAUTIONS, Drug Interactions,
and CLINICAL PHARMACOLOGY).
In patients taking CADUET, therapy should be temporarily withheld or discontinued
in any patient with an acute, serious condition suggestive of a myopathy or having
a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis
(e.g., severe acute infection, hypotension, major surgery, trauma, severe metabolic,
endocrine and electrolyte disorders, and uncontrolled seizures).
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 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.
CADUET should be used with caution in patients who consume substantial quantities of alcohol and/or have
a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are
contraindications to the use of CADUET (see CONTRAINDICATIONS).