CADUET

CADUET (amlodipine besylate/atorvastatin calcium) has been evaluated for safety in 1092 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 experiences have been mild or moderate in severity. In clinical trials with CADUET, no adverse experiences peculiar to this combination have been observed. Adverse experiences 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.

The Amlodipine Component of CADUET

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=1730) in doses up to 10 mg to placebo (N=1250), discontinuation of amlodipine due to adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). The most common side effects are headache and edema. The incidence (%) of side effects which occurred in a dose related manner are as follows:

Other adverse experiences which were not clearly dose related but which were reported with an incidence greater than 1.0% in placebo-controlled clinical trials include the following:

Placebo-Controlled Studies

For several adverse experiences that appear to be drug and dose related, there was a greater incidence in women than men associated with amlodipine treatment as shown in the following table:

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, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension, vasculitis.

Central and Peripheral Nervous System: hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo.

Gastrointestinal: anorexia, constipation, dyspepsia,** dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia.

General: allergic reaction, asthenia,** back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease.

Musculoskeletal System: arthralgia, arthrosis, muscle cramps,** myalgia.

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

Respiratory System: dyspnea,** epistaxis.

Skin and Appendages: angioedema, erythema multiforme, pruritus,** rash,** rash erythematous, rash maculopapular.

**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.

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.

The following events occurred in ≤ 0.1% of patients treated with amlodipine in controlled clinical trials or under conditions of open trials or marketing experience: cardiac failure, pulse irregularity, extrasystoles, skin discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, coughing, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, and xerophthalmia.

Other reactions occurred sporadically and cannot be distinguished from medications or concurrent disease states such as myocardial infarction and angina.

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.

In the CAMELOT and PREVENT studies (see CLINICAL PHARMACOLOGY, Clinical Studies, Clinical Studies with Amlodipine) the adverse event profile was similar to that reported previously (see above), with the most common adverse event being peripheral edema.

The following postmarketing event has been reported infrequently with amlodipine treatment 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.

Amlodipine has been used safely in patients with chronic obstructive pulmonary disease, well-compensated congestive heart failure, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles.

The Atorvastatin Component of CADUET

Atorvastatin is generally well-tolerated. Adverse reactions have usually been mild and transient. In controlled clinical studies of 2502 patients, < 2% of patients were discontinued due to adverse experiences attributable to atorvastatin calcium. The most frequent adverse events thought to be related to atorvastatin calcium were constipation, flatulence, dyspepsia, and abdominal pain.

Clinical Adverse Experiences

Adverse experiences reported in ≥ 2% of patients in placebo-controlled clinical studies of atorvastatin, regardless of causality assessment, are shown in Table 12.

Table 12. Adverse Events in Placebo-Controlled Studies (% of Patients)

Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)

In ASCOT (see CLINICAL PHARMACOLOGY, Clinical Studies, Clinical Studies with Atorvastatin) involving 10,305 participants treated with atorvastatin 10 mg daily (n=5,168) or placebo (n=5,137), the safety and tolerability profile of the group treated with atorvastatin was comparable to that of the group treated with placebo during a median of 3.3 years of follow-up.

Collaborative Atorvastatin Diabetes Study (CARDS)

In CARDS (see CLINICAL PHARMACOLOGY, Clinical Studies, Clinical Studies with Atorvastatin) involving 2838 subjects with type 2 diabetes treated with LIPITOR 10 mg daily (n=1428) or placebo (n=1410), there was no difference in the overall frequency of adverse events or serious adverse events between the treatment groups during a median follow-up of 3.9 years. No cases of rhabdomyolysis were reported.

Treating to New Targets Study (TNT)

In TNT (see CLINICAL PHARMACOLOGY, Clinical Studies) involving 10,001 subjects with clinically evident CHD treated with LIPITOR 10 mg daily (n=5006) or LIPITOR 80 mg daily (n=4995), there were more serious adverse events and discontinuations due to adverse events in the high-dose atorvastatin group (92, 1.8%; 497, 9.9%, respectively) as compared to the low-dose group (69, 1.4%; 404, 8.1%, respectively) during a median follow-up of 4.9 years. 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%).

Incremental Decrease in Endpoints Through Aggressive Lipid Lowering Study (IDEAL)

In IDEAL (see CLINICAL PHARMACOLOGY, Clinical Studies) involving 8,888 subjects treated with LIPITOR 80 mg/day (n=4439) or simvastatin 20-40 mg daily (n=4449), there was no difference in the overall frequency of adverse events or serious adverse events between the treatment groups during a median follow-up of 4.8 years.

The following adverse events were reported, regardless of causality assessment, in patients treated with atorvastatin in clinical trials. The events in italics occurred in ≥ 2% of patients and the events in plain type occurred in < 2% of patients.

Body as a Whole: Chest pain, face edema, fever, neck rigidity, malaise, photosensitivity reaction, generalized edema.

Digestive System: Nausea, gastroenteritis, liver function tests abnormal, colitis, vomiting, gastritis, dry mouth, rectal hemorrhage, esophagitis, eructation, glossitis, mouth ulceration, anorexia, increased appetite, stomatitis, biliary pain, cheilitis, duodenal ulcer, dysphagia, enteritis, melena, gum hemorrhage, stomach ulcer, tenesmus, ulcerative stomatitis, hepatitis, pancreatitis, cholestatic jaundice.

Respiratory System: Bronchitis, rhinitis, pneumonia, dyspnea, asthma, epistaxis.

Nervous System: Insomnia, dizziness, paresthesia, somnolence, amnesia, abnormal dreams, libido decreased, emotional lability, incoordination, peripheral neuropathy, torticollis, facial paralysis, hyperkinesia, depression, hypesthesia, hypertonia.

Musculoskeletal System:Arthritis, leg cramps, bursitis, tenosynovitis, myasthenia, tendinous contracture, myositis.

Skin and Appendages: Pruritus, contact dermatitis, alopecia, dry skin, sweating, acne, urticaria, eczema, seborrhea, skin ulcer.

Urogenital System: Urinary tract infection, hematuria, albuminuria, urinary frequency, cystitis, impotence, dysuria, kidney calculus, nocturia, epididymitis, fibrocystic breast, vaginal hemorrhage, breast enlargement, metrorrhagia, nephritis, urinary incontinence, urinary retention, urinary urgency, abnormal ejaculation, uterine hemorrhage.

Special Senses: Amblyopia, tinnitus, dry eyes, refraction disorder, eye hemorrhage, deafness, glaucoma, parosmia, taste loss, taste perversion.

Cardiovascular System: Palpitation, vasodilatation, syncope, migraine, postural hypotension, phlebitis, arrhythmia, angina pectoris, hypertension.

Metabolic and Nutritional Disorders: Peripheral edema, hyperglycemia, creatine phosphokinase increased, gout, weight gain, hypoglycemia.

Hemic and Lymphatic System:Ecchymosis, anemia, lymphadenopathy, thrombocytopenia, petechia.

Postintroduction Reports with Atorvastatin

Adverse events 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, fatigue and tendon rupture

Pediatric Patients (ages 10-17 years)

In a 26-week controlled study in boys and postmenarchal girls (n=140), the safety and tolerability profile of atorvastatin 10 to 20 mg daily was generally similar to that of placebo (see CLINICAL PHARMACOLOGY, Clinical Studies section and PRECAUTIONS, Pediatric Use).

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 Cmax: 91% (90% confidence interval: 80 to 103%), 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:

Studies with Amlodipine

In vitro data in human plasma indicate that amlodipine has no effect on the protein binding of drugs tested (digoxin, phenytoin, warfarin, and indomethacin).

Cimetidine: Co-administration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.

Maalox® (antacid): Co-administration of the antacid Maalox with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.

Sildenafil:A single 100 mg dose of sildenafil (Viagra®) in subjects with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.

Digoxin: Co-administration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.

Ethanol (alcohol): Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol.

Warfarin: Co-administration of amlodipine with warfarin did not change the warfarin prothrombin response time.

In clinical trials, amlodipine has been safely administered with thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, non-steroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.

Studies with Atorvastatin

The risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of fibric acid derivatives, lipid-modifying doses of niacin or cytochrome P450 3A4 inhibitors (e.g. cyclosporine, erythromycin, clarithromycin, and azole antifungals) (see WARNINGS, Skeletal Muscle).

Inhibitors of cytochrome P450 3A4: Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant administration of atorvastatin with inhibitors of cytochrome P450 3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects depends on the variability of effect on cytochrome P450 3A4.

Clarithromycin: Concomitant administration of atorvastatin 80 mg with clarithromycin (500 mg twice daily) resulted in a 4.4-fold increase in atorvastatin AUC (see WARNINGS, Skeletal Muscle, and DOSAGE AND ADMINISTRATION).

Erythromycin: In healthy individuals, plasma concentrations of atorvastatin increased approximately 40% with co-administration of atorvastatin and erythromycin, a known inhibitor of cytochrome P450 3A4 (see WARNINGS, Skeletal Muscle).

Combination of Protease Inhibitors: Concomitant administration of atorvastatin 40 mg with ritonavir plus saquinavir (400 mg twice daily) resulted in a 3-fold increase in atorvastatin AUC. Concomitant administration of atorvastatin 20 mg with lopinavir plus ritonavir (400 mg+100 mg twice daily) resulted in a 5.9-fold increase in atorvastatin AUC (see WARNINGS, Skeletal Muscle, and DOSAGE AND ADMINISTRATION).

Itraconazole: Concomitant administration of atorvastatin (20 to 40 mg) and itraconazole (200 mg) was associated with a 2.5-3.3-fold increase in atorvastatin AUC.

Diltiazem hydrochloride: Co-administration of atorvastatin (40 mg) with diltiazem (240 mg) was associated with higher plasma concentrations of atorvastatin.

Cimetidine: Atorvastatin plasma concentrations and LDL-C reduction were not altered by co-administration of cimetidine.

Grapefruit juice: Contains one or more components that inhibit CYP 3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption ( > 1.2 liters per day).

Cyclosporine: Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g. cyclosporine) can increase the bioavailability of atorvastatin. Concomitant administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day resulted in an 8.7-fold increase in atorvastatin AUC. In cases where co-administration of atorvastatin with cyclosporine is necessary, the dose of atorvastatin should not exceed 10 mg (see WARNINGS, Skeletal Muscle).

Inducers of cytochrome P450 3A4: 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, simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.

Antacid: When atorvastatin and Maalox TC suspension were coadministered, plasma concentrations of atorvastatin decreased approximately 35%. However, LDL-C reduction was not altered.

Antipyrine: Because atorvastatin does not affect the pharmacokinetics of antipyrine, interactions with other drugs metabolized via the same cytochrome isozymes are not expected.

Colestipol: Plasma concentrations of atorvastatin decreased approximately 25% when colestipol and atorvastatin were coadministered. However, LDL-C reduction was greater when atorvastatin and colestipol were coadministered than when either drug was given alone.

Digoxin: When multiple doses of atorvastatin and digoxin were coadministered, steady-state plasma digoxin concentrations increased by approximately 20%. Patients taking digoxin should be monitored appropriately.

Oral Contraceptives: Coadministration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol by approximately 30% and 20%. These increases should be considered when selecting an oral contraceptive for a woman taking CADUET.

Warfarin: Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.

Amlodipine: In a drug-drug interaction study in healthy subjects, co-administration of atorvastatin 80 mg and amlodipine 10 mg resulted in an 18% increase in exposure to atorvastatin which was not clinically meaningful

Drug/Laboratory Test Interactions

None known.

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