Caduet

Published data indicate that through inhibition of the cytochrome P450 system, grapefruit juice can increase plasma levels and augment pharmacodynamic effects of some dihydropyridine calcium channel blockers. Following oral administration of 10 mg amlodipine to 20 male volunteers, pharmacokinetics of amlodipine were similar when amlodipine was administered with and without grapefruit juice.

Established or Predicted Drug-Drug Interactions^a

Drugs known to be inhibitors of the cytochrome P450 system include: azole antifungals, cimetidine, cyclosporine, erythromycin, quinidine, warfarin.

Drugs known to be inducers of the cytochrome P450 system include: phenobarbital, phenytoin, rifampin.

Drugs known to be biotransformed via the cytochrome P450 system include: benzodiazepines, flecainide, imipramine, propafenone, and theophylline.

Concomitant administration of atorvastatin with inducers of cytochrome P450 3A4 (eg efavirenz, rifampin) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, (cytochrome P450 3A4 induction and inhibition of hepatocyte uptake transporter OATP1B1), simultaneous co-administration of atorvastatin with rifampin resulted in a mean increase in Cmax and AUC of atorvastatin of 12 and 190%, respectively. In contrast, a delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction (approximately 80%) in atorvastatin plasma concentrations.

Coadministration of grapefruit juice has the potential to increase plasma concentrations of HMG-CoA reductase inhibitors including LIPITOR. The equivalent of 1.2 L per day resulted in a 2.5 fold increase in AUC of atorvastatin.

Based on post-marketing surveillance, gemfibrozil, fenofibrate, other fibrates, and lipid lowering doses of niacin (nicotinic acid) may increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors, probably because they can produce myopathy when given alone (see Warnings and Precautions, Muscle Effects). Therefore, combined drug therapy should be approached with caution.

Pharmacokinetic interaction studies conducted with drugs in healthy subjects may not detect the possibility of a potential drug interaction in some patients due to differences in underlying diseases and use of concomitant medications (see also Warnings and Precautions, Geriatrics, Renal Insufficiency and Patients with Severe Hypercholesterolemia).

Data from a drug-drug interaction study involving 10 mg of amlodipine and 80 mg of atorvastatin in healthy subjects indicate that the pharmacokinetics of amlodipine are not altered when the drugs are coadministered. The effect of amlodipine on the pharmacokinetics of atorvastatin showed no effect on the C_max but the AUC of atorvastatin increased by 18% (90% confidence interval: 109 to 127%) in the presence of amlodipine.

No drug interaction studies have been conducted with CADUET and other drugs, although studies have been conducted in the individual amlodipine and atorvastatin components, as described below:

The recommended initial dose of the amlodipine component of CADUET in patients over 65 years of age or patients with impaired renal function is 5 mg once daily. If required, increasing the dose should be done gradually and with caution (see Warnings and Precautions).

If a patient misses taking their medicine, he/she should take it as soon as they can. If it is almost time for their next dose, then the patient can skip the missed dose and just take the next dose. Patients should not take a double dose.

The amlodipine component of CADUET has been safely administered in combination with diuretics, beta-blocking agents, and angiotensin converting enzyme inhibitors. CADUET has also been safely administered with the above medicines, in addition to angiotensin-II receptor blockers.

The atorvastatin component of CADUET may be used in combination with a bile acid binding resin for additive effect on lipid lowering. The combination of HMG-CoA reductase inhibitors and fibrates should generally be avoided (see Warnings and Precautions, Muscle Effects and Drug Interactions).

A broad dose-range of CADUET is available for titration to hypertension and/or angina and dyslipidemia goals. The starting dose and maintenance doses of CADUET should be individualized on the basis of both effectiveness and tolerance for each individual component and according to the level of risk and the baseline LDL-C and/or TG levels, the desired LDL-C and/or TG target, and/or TC/HDL-C target.

After initiation and/or upon titration of CADUET, blood pressure and lipid levels should be measured within 2-4 weeks. The dose should be adjusted to achieve treatment goals in hypertension and dyslipidemia guidelines. In patients with angina, if necessary, the amlodipine component of CADUET can be increased after 1-2 weeks to a maximum dose of 10 mg once daily. The maximum recommended daily dose of each component should not be exceeded.

Titration for blood pressure response and/or symptom control in angina response may proceed more rapidly, if clinically warranted, provided the patient is assessed frequently.

The dosage of CADUET must be individualized on the basis of both effectiveness and tolerance for each individual component in the treatment of hypertension and/or angina and dyslipidemia.

Consistent with goal-oriented therapy, if dose adjustment is necessary for one or both components, it is recommended to adjust the necessary component(s) using the flexible dose range of CADUET.

CADUET, amlodipine besylate/atorvastatin calcium is available as tablets of 5/10 mg, 5/20 mg, 5/40 mg, 5/80 mg, 10/10 mg, 10/20 mg, 10/40 mg, 10/80 mg respectively. CADUET can be administered once daily, at any time of the day, with or without food.

The patient should be placed on a standard cholesterol-lowering diet (at least equivalent to the Adult Treatment Panel III [ATP III] TLC diet) before or at the time of CADUET initiation, and should continue on this diet during treatment with CADUET. If appropriate, a program of weight control and physical exercise should be implemented.

Prior to initiating therapy with CADUET, secondary causes for elevations in plasma lipid levels should be excluded. A lipid profile should also be performed.

In patients with severe dyslipidemias, including homozygous and heterozygous familial hypercholesterolemia and dysbetalipoproteinemia (Type III), higher dosages of the atorvastatin component of CADUET (up to 80 mg/day) may be required (see Warnings and Precautions, Pharmacokinetic Interactions, Muscle Effects and Drug Interactions).

Consistent with goal-oriented therapy, when administered, the CADUET dose should be individualized based on level of risk.

In post-marketing 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 the use of amlodipine.

anorexia, constipation, dysphagia, vomiting, gingival hyperplasia.

conjunctivitis, diplopia, eye pain, tinnitus.

leucopenia, purpura, thrombocytopenia.

The following events occurred in <0.1% of patients: cardiac failure, skin discoloration, urticaria, skin dryness, Stevens-Johnson syndrome, alopecia, twitching, ataxia, hypertonia, migraine, apathy, amnesia, gastritis, pancreatitis, increased appetite, coughing, rhinitis, parosmia, taste perversion, and xerophthalmia.

Isolated cases of angioedema have been reported. Angioedema may be accompanied by breathing difficulty.

arthralgia, arthrosis, myalgia.

In the controlled clinical trials in 909 angina patients treated with amlodipine, adverse effects were reported in 30.5% of patients and required discontinuation of therapy due to side effects in 0.6% of patients. The most common adverse reactions reported in controlled clinical trials were: edema (9.9%) and headache (7.8%).

The following adverse reactions occurred at an incidence of >0.5% in the controlled clinical trials program (n=909):

pruritus*, rash erythematous, rash maculopapular, erythema multiforme.

The following adverse events have also been reported during post-marketing experience with the atorvastatin component of CADUET, regardless of causality assessment: Very rare reports: severe myopathy with or without rhabdomyolysis (see Warnings and Precautions, Muscle Effects, Renal Insufficiency and Drug Interactions). Isolated reports: Gynecomastia, thrombocytopenia, arthralgia and allergic reactions including urticaria, angioneurotic edema, anaphylaxis and bullous rashes (including erytheme multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis) and fatigue, back pain, chest pain, malaise, dizziness, amnesia, peripheral edema, weight gain, abdominal pain, insomnia, hypoesthesia, tinnitus, tendon rupture, and dysgeusia. These may have no causal relationship to atorvastatin.

sexual dysfunction (male* and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization.

hypoesthesia, peripheral neuropathy, tremor, vertigo.

muscle cramps (1.0%).

See Warnings and Precautions, Ophthalmologic.

allergic reaction, asthenia{*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.}, back pain, hot flushes, malaise, rigors, weight gain.

The incidence (%) of dose-related adverse events was consistent with those seen for amlodipine and/or atorvastatin.

In this clinical trial, the most frequently reported adverse events among patients who took concurrent amlodipine and atorvastatin were peripheral edema (9.9%), headache (5.3%), respiratory tract infection (4.9%), dizziness (2.4%), abdominal pain (2.3%), asthenia (2.1%), and vasodilatation (2.0%).

In this controlled clinical trial, similar percentages of patients who took concurrent amlodipine and atorvastatin (5.6%) versus patients who took placebo (4.5%), amlodipine only (5.4%), or atorvastatin only (4.1%) discontinued due to adverse safety experiences. Only 1 subject discontinued due to laboratory abnormalities. The most common safety-related reasons for discontinuation from the study in the combination treatment groups were peripheral edema (1.5%) and headache (1.4%), but these events led to the discontinuation of subjects in the combination treatment groups no more frequently than they did among subjects treated with either amlodipine alone or atorvastatin alone within this study.

The following information is based on the clinical experience with the parent compounds, NORVASC and LIPITOR.

epistaxis.

In the 805 hypertensive patients treated with amlodipine in controlled clinical trials, adverse effects were reported in 29.9% of patients and required discontinuation of therapy due to side effects in 1.9% of patients. The most common adverse reactions in controlled clinical trials were: edema (8.9%), and headache (8.3%).

The following adverse reactions were reported with an incidence of >0.5% in the controlled clinical trials program (n=805):

dry mouth, sweating increased.

hyperglycemia, thirst.

micturition frequency, micturition disorder, nocturia.

The following additional adverse events were reported in clinical trials; not all events listed below have been associated with a causal relationship to atorvastatin therapy: Muscle cramps, myositis, myopathy, paresthesia, peripheral neuropathy, pancreatitis, hepatitis, cholestatic jaundice, anorexia, vomiting, alopecia, pruritus, rash, impotence, hyperglycemia, and hypoglycemia.

Amlodipine has been evaluated for safety in about 11 000 patients with hypertension and angina. The following events occurred in <1% but >0.1% of patients in comparative clinical trials (double-blind comparative vs placebo or active agents; n=2615) or under conditions of open trials or marketing experience where a causal relationship is uncertain.

arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension, vasculitis.

Overdosage can cause excessive peripheral vasodilation with marked and probably prolonged hypotension and possibly a reflex tachycardia. In humans, experience with overdosage of the amlodipine component of CADUET is limited. When amlodipine was ingested at doses of 105-250 mg some patients remained normotensive with or without gastric lavage while another patient experienced hypotension (90/50 mmHg) which normalized following plasma expansion. A patient who took 70 mg of amlodipine with benzodiazepine developed shock which was refractory to treatment and died. In a 19-month old child who ingested 30 mg of amlodipine (about 2 mg/kg) there was no evidence of hypotension but tachycardia (180 bpm) was observed. Ipecac was administered 3.5 hrs after ingestion and on subsequent observation (overnight) no sequelae were noted.

Clinically significant hypotension due to overdosage requires active cardiovascular support, including frequent monitoring of cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and urine output. A vasoconstrictor (such as norepinephrine) may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Clearance of amlodipine is prolonged in elderly patients and in patients with impaired liver function. Since amlodipine absorption is slow, gastric lavage may be worthwhile in some cases.

There is no specific treatment for the atorvastatin component of CADUET overdosage. Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted as required. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin clearance.

Each white tablet, engraved with “Pfizer” on one side and CDT 054 on the other side, contains: amlodipine besylate 5 mg and atorvastatin calcium 40 mg. Nonmedicinal ingredients: calcium carbonate, colloidal silicon dioxide (anhydrous), croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, Opadry II White 85F28751, polysorbate 80, pregelatinized starch and purified water. High-density polyethylene (HDPE) bottles of 90, containing desiccant, with child-resistant closure.

Each white tablet, engraved with “Pfizer” on one side and CDT 051 on the other side, contains: amlodipine besylate 5 mg and atorvastatin calcium 10 mg. Nonmedicinal ingredients: calcium carbonate, colloidal silicon dioxide (anhydrous), croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, Opadry II White 85F28751, polysorbate 80, pregelatinized starch and purified water. High-density polyethylene (HDPE) bottles of 90, containing desiccant, with child-resistant closure.

Each blue tablet, engraved with “Pfizer” on one side and CDT 104 on the other side, contains: amlodipine besylate 10 mg and atorvastatin calcium 40 mg. Nonmedicinal ingredients: calcium carbonate, colloidal silicon dioxide (anhydrous), croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, Opadry II Blue 85F10919, polysorbate 80, pregelatinized starch and purified water. High-density polyethylene (HDPE) bottles of 90, containing desiccant, with child-resistant closure.

Each white tablet, engraved with “Pfizer” on one side and CDT 058 on the other side, contains: amlodipine besylate 5 mg and atorvastatin calcium 80 mg. Nonmedicinal ingredients: calcium carbonate, colloidal silicon dioxide (anhydrous), croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, Opadry II White 85F28751, polysorbate 80, pregelatinized starch and purified water. High-density polyethylene (HDPE) bottles of 90, containing desiccant, with child-resistant closure.

Each white tablet, engraved with “Pfizer” on one side and CDT 052 on the other side, contains: amlodipine besylate 5 mg and atorvastatin calcium 20 mg. Nonmedicinal ingredients: calcium carbonate, colloidal silicon dioxide (anhydrous), croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, Opadry II White 85F28751, polysorbate 80, pregelatinized starch and purified water. High-density polyethylene (HDPE) bottles of 90, containing desiccant, with child-resistant closure.

Each blue tablet, engraved with “Pfizer” on one side and CDT 102 on the other side, contains: amlodipine besylate 10 mg and atorvastatin calcium 20 mg. Nonmedicinal ingredients: calcium carbonate, colloidal silicon dioxide (anhydrous), croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, Opadry II Blue 85F10919, polysorbate 80, pregelatinized starch and purified water. High-density polyethylene (HDPE) bottles of 90, containing desiccant, with child-resistant closure.

Each blue tablet, engraved with “Pfizer” on one side and CDT 101 on the other side, contains: amlodipine besylate 10 mg and atorvastatin calcium 10 mg. Nonmedicinal ingredients: calcium carbonate, colloidal silicon dioxide (anhydrous), croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, Opadry II Blue 85F10919, polysorbate 80, pregelatinized starch and purified water. High-density polyethylene (HDPE) bottles of 90, containing desiccant, with child-resistant closure.

Each blue tablet, engraved with “Pfizer” on one side and CDT 108 on the other side, contains: amlodipine besylate 10 mg and atorvastatin calcium 80 mg. Nonmedicinal ingredients: calcium carbonate, colloidal silicon dioxide (anhydrous), croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, Opadry II Blue 85F10919, polysorbate 80, pregelatinized starch and purified water. High-density polyethylene (HDPE) bottles of 90, containing desiccant, with child-resistant closure.

The use of CADUET is not recommended in children since safety and efficacy have not been established with the amlodipine component of CADUET in that population.

In clinical trials with the atorvastatin component of CADUET, persistent increases in serum transaminases greater than 3 times the upper limit of normal occurred in <1% of patients who received atorvastatin. When the dosage of atorvastatin was reduced, or when drug treatment was interrupted or discontinued, serum transaminase levels returned to pretreatment levels. The increases were generally not associated with jaundice or other clinical signs or symptoms. Most patients continued treatment with a reduced dose of atorvastatin without clinical sequelae.

Liver function tests should be performed before the initiation of treatment, and periodically thereafter: Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients measurements should be repeated promptly and then performed more frequently.

If increases in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) show evidence of progression, particularly if they rise to greater than 3 times the upper limit of normal and are persistent, the dosage of the atorvastatin component of CADUET should be reduced or the drug discontinued.

CADUET, as well as other products containing HMG-CoA reductase inhibitors, should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver disease or unexplained transaminase elevations are contraindications to the use of the atorvastatin component of CADUET; if such a condition should develop during therapy, CADUET should be discontinued.

There are no adequate studies in patients with liver dysfunction and dosage recommendations have not been established. In a small number of patients with mild to moderate hepatic impairment in which a single dose of 5 mg of the amlodipine component of CADUET was given, half-life has been prolonged (see Action and Clinical Pharmacology, Pharmacokinetics and Metabolism). CADUET should therefore be administered with caution in these patients and careful monitoring should be performed. A lower starting dose of the amlodipine component of CADUET may be required (see Dosage and Administration).

Although amlodipine was not teratogenic in the rat and rabbit, some dihydropyridine compounds have been found to be teratogenic in animals. In rats, amlodipine has been shown to prolong both the gestation period and the duration of labor. There is no clinical experience with amlodipine in pregnant women.

In some patients, the beneficial effect of lowered total cholesterol and LDL-C levels may be partly blunted by a concomitant increase in Lp(a) lipoprotein concentrations. Present knowledge suggests the importance of high Lp(a) levels as an emerging risk factor for coronary heart disease. It is thus desirable to maintain and reinforce lifestyle changes in high risk patients placed on atorvastatin therapy.

Treatment experience in adults 70 years or older (N=221) with doses of atorvastatin up to 80 mg/day has demonstrated that the safety and effectiveness of atorvastatin in this population was similar to that of patients <70 years of age. Pharmacokinetic evaluation of atorvastatin in subjects over the age of 65 years indicates an increased AUC. As a precautionary measure, the lowest dose of the atorvastatin component of CADUET should be administered initially.

Elderly patients may be more susceptible to myopathy (see Muscle Effects, Pre-disposing Factors for Myopathy/Rhabdomyolysis).

The atorvastatin component of CADUET is contraindicated during pregnancy (see Contraindications).

There are no data on the use of atorvastatin during pregnancy. CADUET 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 CADUET, the drug should be discontinued and the patient apprised of the potential risk to the fetus.

The amlodipine component of CADUET gives no protection against the dangers of abrupt beta-blocker withdrawal and such withdrawal should be done by the gradual reduction of the dose of beta-blocker.

The atorvastatin component of CADUET may elevate serum transaminase and CPK levels (from skeletal muscle). In the differential diagnosis of chest pain in a patient on therapy with CADUET, cardiac and noncardiac fractions of these enzymes should be determined.

Mild to moderate peripheral edema was the most common adverse event in clinical trials with the amlodipine component of CADUET (see Adverse Reactions). The incidence of peripheral edema was dose-dependent and ranged in frequency from 3.0 to 10.8% in 5 to 10 mg dose range. Care should be taken to differentiate this peripheral edema from the effects of increasing left ventricular dysfunction.

Effects on skeletal muscle such as myalgia, myopathy and very rarely, rhabdomyolysis have been reported in patients treated with the atorvastatin component of CADUET.

Very rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria, have been reported with the atorvastatin component of CADUET and with other HMG-CoA reductase inhibitors.

Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine kinase (CK) values to greater than 10 times the upper limit of normal, should be considered in any patient with diffuse myalgia, 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. Patients who develop any signs or symptoms suggestive of myopathy should have their CK levels measured. CADUET therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.

Before instituting therapy with CADUET, an attempt should be made to control elevated serum lipoprotein levels with appropriate diet, exercise, and weight reduction in overweight patients, and to treat other underlying medical problems (see Indications and Clinical Use). Patients should be advised to inform subsequent physicians of the prior use of atorvastatin or any other lipid-lowering agents.

The use of HMG CoA reductase inhibitors like some other lipid-lowering therapies has been associated with severe myopathy, including rhabdomyolysis, which may be more frequent when they are co-administered with drugs that inhibit the cytochrome P450 enzyme system. The atorvastatin component of CADUET is metabolized by cytochrome P450 isoform 3A4 and, as such, may interact with agents that inhibit this enzyme. (See Muscle Effects and Drug Interactions, Cytochrome P-450 Mediated Interactions.)

Plasma concentrations and LDL-C lowering efficacy of the atorvastatin component of CADUET were shown to be similar in patients with moderate renal insufficiency compared with patients with normal renal function. However, since several cases of rhabdomyolysis have been reported in patients with a history of renal insufficiency of unknown severity, as a precautionary measure and pending further experience in renal disease, the lowest dose (10 mg/day) of atorvastatin should be used in these patients. Similar precautions apply in patients with severe renal insufficiency (creatinine clearance <30 mL/min [<0.5 mL/sec]); the lowest dosage should be used and implemented cautiously (see Muscle Effects; Drug Interactions and Dosage and Administration).

In elderly patients (>65 years), clearance of amlodipine is decreased with a resulting increase in AUC of approximately 40-60%. In general, dose selection of the amlodipine component of CADUET for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see Action and Clinical Pharmacology, Pharmacokinetics and Metabolism). In clinical trials, the incidence of adverse reactions in elderly patients was approximately 6% higher than that of younger population (<65 years). Adverse reactions include edema, muscle cramps and dizziness. The amlodipine component of CADUET should be used cautiously in elderly patients. Dosage adjustment is advisable (see Dosage and Administration).

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.

Although generally calcium channel blockers should only be used with caution in patients with heart failure, it has been observed that the amlodipine component of CADUET had no overall deleterious effect on survival and cardiovascular morbidity in both short-term and long-term clinical trials in these patients. While a significant proportion of the patients in these studies had a history of ischemic heart disease, angina or hypertension, the studies were not designed to evaluate the treatment of angina or hypertension in patients with concomitant heart failure.

CADUET should be used with caution in the presence of fixed left ventricular outflow obstruction (aortic stenosis).

The amlodipine component of CADUET may occasionally precipitate symptomatic hypotension. Careful monitoring of blood pressure is recommended, especially in patients with a history of cerebrovascular insufficiency, and those taking medications known to lower blood pressure.

HMG-CoA reductase inhibitors interfere with cholesterol synthesis and, as such, might theoretically blunt adrenal and/or gonadal steroid production. Clinical studies with the atorvastatin component of CADUET and other HMG-CoA reductase inhibitors have suggested that these agents do not reduce plasma cortisol concentration or impair adrenal reserve, and do not reduce basal plasma testosterone concentration. However, the effects of HMG-CoA reductase inhibitors on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown.

Patients treated with the atorvastatin component of CADUET who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients receiving other drugs (e.g. ketoconazole, spironolactone or cimetidine) that may decrease the levels of endogenous steroid hormones.

Significant decreases in circulating ubiquinone levels in patients treated with atorvastatin and other statins have been observed. The clinical significance of a potential long-term statin-induced deficiency of ubiquinone has not been established. It has been reported that a decrease in myocardial ubiquinone levels could lead to impaired cardiac function in patients with borderline congestive heart failure.

An apparent hypersensitivity syndrome has been reported with other HMG-CoA reductase inhibitors which has included 1 or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome. Although to date hypersensitivity syndrome has not been described as such, the atorvastatin component of CADUET should be discontinued if hypersensitivity is suspected.

The atorvastatin component of CADUET, as with other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with pre-disposing factors for myopathy/rhabdomyolysis. Such factors include: personal or family history of hereditary muscular disorders; previous history of muscle toxicity with another HMG-CoA reductase inhibitor; concomitant use of a fibrate, or niacin; hypothyroidism; alcohol abuse; excessive physical exercise; age >70 years; renal impairment; hepatic impairment; diabetes with hepatic fatty change; surgery and trauma; frailty; situations where an increase in plasma levels of active ingredient may occur.

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 (such as sepsis, severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).

The risk of myopathy and rhabdomyolysis during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of cyclosporine, fibric acid derivatives, erythromycin, clarithromycin, niacin (nicotinic acid), azole antifungals or nefazodone. As there is no experience to date with the use of atorvastatin given concurrently with these drugs, with the exception of pharmacokinetic studies conducted in healthy subjects with erythromycin and clarithromycin, the benefits and risks of such combined therapy should be carefully considered (see Pharmacokinetic Interactions and Drug Interactions).

Current long-term data from clinical trials do not indicate an adverse effect of the atorvastatin component of CADUET on the human lens.

Higher drug dosages (80 mg/day) required for some patients with severe hypercholesterolemia (including familial hypercholesterolemia) are associated with increased plasma levels of the atorvastatin component of CADUET. Caution should be exercised in such patients who are also severely renally impaired, elderly, or are concomitantly being administered digoxin or CYP 3A4 inhibitors (see Pharmacokinetic Interactions; Muscle Effects; Drug Interactions and Dosage and Administration).

It is not known whether the amlodipine component of CADUET is excreted in human milk. In rats, milk concentrations of atorvastatin are similar to those in plasma. It is not known whether the atorvastatin component of CADUET is excreted in human milk. Because of the potential for adverse reactions in nursing infants, women taking CADUET should not breast-feed (see Contraindications).

The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Plasma concentrations in the patients with moderate to severe renal failure were higher than in the normal subjects. Accumulation and mean elimination half-life in all patients were within the range of those observed in other pharmacokinetic studies with amlodipine in normal subjects.

Atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell-surface for enhanced uptake and catabolism of LDL.

Atorvastatin reduces LDL-C and the number of LDL particles. Atorvastatin also reduces VLDL-C, serum TG and IDL, as well as the number of apo B containing particles, but increases HDL-C. Elevated serum cholesterol due to elevated LDL-C is a major risk factor for the development of cardiovascular disease. Low serum concentration of HDL-C is an independent risk factor. Elevated plasma TG is also a risk factor for cardiovascular disease, particularly if due to increased IDL, or associated with decreased HDL-C or increased LDL-C.

Epidemiologic, clinical and experimental studies have established that high LDL-C, low HDL-C and high plasma TG promote human atherosclerosis, and are risk factors for developing cardiovascular disease. Some studies have also shown that the total (TC):HDL-C ratio (TC:HDL-C) is the best predictor of coronary artery disease. In contrast, increased levels of HDL-C are associated with decreased cardiovascular risk. Drug therapies that reduce levels of LDL-C or decrease TG while simultaneously increasing HDL-C have demonstrated reductions in rates of cardiovascular mortality and morbidity.

Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals, or man. In patients with chronic stable angina, intravenous administration of 10 mg of amlodipine and a further 10 mg of amlodipine after a 30-minute interval produced peripheral vasodilation and afterload reduction, but did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving amlodipine and concomitant beta-blockers. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed. In clinical trials with angina patients, amlodipine as monotherapy did not alter electrocardiographic intervals.

The lowering of total cholesterol, LDL-C and apo B have been shown to reduce the risk of cardiovascular events and mortality.

Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase. In both subjects and in patients with homozygous and heterozygous familial hypercholesterolemia, nonfamilial forms of hypercholesterolemia, mixed dyslipidemia, hypertriglyceridemia, and dysbetalipoproteinemia, atorvastatin has been shown to reduce levels of total-C, LDL-C, apo B and total TG, and raises HDL-C levels.

Epidemiologic and clinical studies have associated the risk of coronary artery disease (CAD) with elevated levels of total-C, LDL-C and decreased levels of HDL-C. These abnormalities of lipoprotein metabolism are considered as major contributors to the development of the disease. Like LDL, cholesterol-enriched lipoproteins, including VLDL, IDL and remnants can also promote atherosclerosis. Elevated plasma triglycerides are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease (metabolic syndrome). Clinical studies have also shown that serum triglycerides can be an independent risk factor for CAD. CAD risk is especially increased if the hypertriglyceridemia is due to increased intermediate density lipoproteins (IDL) or associated with decreased HDL or increased LDL-C. In addition, high TG levels are associated with an increased risk of pancreatitis. Although epidemiological and preliminary clinical evidence link low HDL-C levels and high triglyceride levels with coronary artery disease and atherosclerosis, the independent effect of raising HDL or lowering TG on the risk of coronary and cerebrovascular morbidity and mortality has not been demonstrated in prospective, well-controlled outcome studies. Other factors, e.g. interactions between lipids/lipoproteins and endothelium, platelets and macrophages, have also been incriminated in the development of human atherosclerosis and of its complications. Regardless of the intervention used (low-fat/low-cholesterol diet, partial ileal bypass surgery or pharmacologic therapy), effective treatment of hypercholesterolemia/dyslipidemia has consistently been shown to reduce the risk of CAD.

Atorvastatin reduces LDL-C and the number of LDL particles, lowersVLDL-C and serum TG, reduces the number of apo B containing particles, and also increases HDL-C. Atorvastatin is effective in reducing LDL-C in patients with homozygous familial hypercholesterolemia, a condition that rarely responds to any other lipid-lowering medication. In addition to the above effects, atorvastatin reduces IDL-C and apolipoprotein E (apo E) in patients with dysbetalipoproteinemia (Type III).

In patients with Type II dyslipidemia, atorvastatin improved endothelial dysfunction. Atorvastatin significantly improved flow-mediated endothelium-dependent dilatation induced by reactive hyperemia, as assessed by brachial ultrasound (p<0.01).

Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac and vascular smooth muscle tissues are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound and its kinetic interaction with the calcium channel receptor is characterized by the gradual association and dissociation with the receptor binding site.

• Hypertension: The mechanism by which amlodipine reduces arterial blood pressure involves direct peripheral arterial vasodilation and reduction in peripheral vascular resistance.

  
  

• Angina: The precise mechanism by which amlodipine relieves angina has not been fully delineated. Amlodipine is a dilator of peripheral arteries and arterioles which reduces the total peripheral resistance and, therefore, reduces the workload of the heart (afterload). The unloading of the heart is thought to decrease ischemia and relieve effort angina by reducing myocardial energy oxygen consumption and oxygen requirements.

Following administration of recommended doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by any significant change in heart rate or plasma catecholamine levels with chronic dosing. With chronic once daily oral administration (5 and 10 mg once daily), antihypertensive effectiveness is maintained throughout the 24-hour dose interval with minimal peak to trough differences in blood pressure reduction. Since the vasodilation induced by amlodipine is gradual in onset, acute hypotension has rarely been reported after oral administration of amlodipine. In normotensive patients with angina, amlodipine has not been associated with any clinically significant reductions in blood pressure or changes in heart rate.

Negative inotropic effects have not been observed when amlodipine was administered at the recommended doses to man, but has been demonstrated in animal models. Hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in angina patients with normal ventricular function have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume.

In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction.

Pharmacokinetic data in the pediatric population are not available.

Plasma concentrations and LDL-C lowering efficacy of atorvastatin are similar in patients with moderate renal insufficiency compared with patients with normal renal function. However, since several cases of rhabdomyolysis have been reported in patients with a history of renal insufficiency of unknown severity, as a precautionary measure and pending further experience in renal disease, the lowest dose (10 mg/day) of atorvastatin should be used in these patients. Similar precautions apply in patients with severe renal insufficiency (creatinine clearance <30 mL/min [<0.5 mL/sec]); the lowest dosage should be used and implemented cautiously (see Warnings and Precautions, Muscle Effects; Drug Interactions and Dosage and Administration).

CADUET (amlodipine besylate/atorvastatin calcium), is a combination tablet which combines 2 mechanisms of action: the dihydropyridine calcium antagonist (calcium entry blocker or calcium ion antagonist) action of amlodipine and the HMG-CoA reductase inhibition of atorvastatin. The amlodipine component of CADUET inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. The atorvastatin component of CADUET is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol.

Following oral administration of therapeutic doses of CADUET tablets, 2 distinct peak plasma concentrations are observed. The first peak is attributable to atorvastatin and occurs within 1 to 2 hours after dosing. The second peak is attributable to amlodipine and occurs between 6 and 12 hours after dosing. The rate and extent of absorption (bioavailability) of both amlodipine and atorvastatin from CADUET combination tablet are not significantly different from those observed during coadministration of separate amlodipine and atorvastatin tablets, as assessed by C_max: 101% (90% CI: 98, 104) and AUC: 100% (90% CI: 97, 103) for the amlodipine component and C_max: 94% (90% CI: 85, 104) and AUC: 105% (90% CI: 99, 111) for the atorvastatin component, respectively.

The bioavailability of amlodipine from the CADUET tablet was not affected under the fed state as assessed by C_max and AUC. Food decreases the rate and extent of absorption of atorvastatin from the CADUET tablets by approximately 32% and 11%, respectively. Similar reductions in plasma concentrations were observed with atorvastatin in the fed state without a reduction in LDL-C effect.