Caduet Side Effects

Please note - some side effects for Caduet may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Caduet - for the Consumer

Caduet

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Caduet:

Constipation; diarrhea; dizziness; drowsiness; flushing; gas; headache; nausea; stomach upset or pain; tiredness; weakness.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); change in the amount of urine produced or increased urination; changes in vision; dark urine; fainting; fast or irregular heartbeat; increased frequency, duration, or severity of chest pain; joint pain; muscle aches, pain, tenderness, or weakness, especially with fever, unusual tiredness, or general body discomfort; numbness of an arm or leg; pale stools; red, swollen, blistered, or peeling skin; severe or persistent stomach pain; sharp or crushing chest pain; sudden leg pain; sudden severe headache, vomiting, dizziness, or fainting; sudden shortness of breath; swelling of your feet or legs; tender, bleeding, or swollen gums; unexplained weight gain; yellowing of eyes or skin.

Caduet Side Effects - for the Professional

Caduet

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:

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,2 dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia.

General: allergic reaction, asthenia,2 back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease.

Musculoskeletal System: arthralgia, arthrosis, muscle cramps,2 myalgia.

Psychiatric: sexual dysfunction (male2 and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization.

Respiratory System: dyspnea,2 epistaxis.

Skin and Appendages: angioedema, erythema multiforme, pruritus,2 rash,2 rash erythematous, rash maculopapular.

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 the adverse event profile was similar to that reported previously, 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.

2

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.

The Atorvastatin Component of Caduet

The following serious adverse reactions are discussed in greater detail in other sections of the label:
Rhabdomyolysis and myopathy
Liver enzyme abnormalities

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

In the LIPITOR placebo-controlled clinical trial database of 16,066 patients (8755 LIPITOR vs. 7311 placebo; age range 10–93 years, 39% women, 91% Caucasians, 3% Blacks, 2% Asians, 4% other) with a median treatment duration of 53 weeks, 9.7% of patients on LIPITOR and 9.5% of the patients on placebo discontinued due to adverse reactions regardless of causality. The five most common adverse reactions in patients treated with LIPITOR that led to treatment discontinuation and occurred at a rate greater than placebo were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), alanine aminotransferase increase (0.4%), and hepatic enzyme increase (0.4%).

The most commonly reported adverse reactions (incidence ≥ 2% and greater than placebo) regardless of causality, in patients treated with LIPITOR in placebo controlled trials (n=8755) were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), pain in extremity (6.0%), and urinary tract infection (5.7%).

Table 13 summarizes the frequency of clinical adverse reactions, regardless of causality, reported in ≥ 2% and at a rate greater than placebo in patients treated with LIPITOR (n=8755), from seventeen placebo-controlled trials.

Other adverse reactions reported in placebo-controlled studies include:
Body as a whole: malaise, pyrexia; Digestive system: abdominal discomfort, eructation, flatulence, hepatitis, cholestasis; Musculoskeletal system: musculoskeletal pain, muscle fatigue, neck pain, joint swelling; Metabolic and nutritional system: transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, creatine phosphokinase increase, hyperglycemia; Nervous system: nightmare; Respiratory system: epistaxis; Skin and appendages: urticaria; Special senses: vision blurred, tinnitus; Urogenital system: white blood cells urine positive.

Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)

In ASCOT involving 10,305 participants (age range 40–80 years, 19% women; 94.6% Caucasians, 2.6% Africans, 1.5% South Asians, 1.3% mixed/other) 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 involving 2838 subjects (age range 39–77 years, 32% women; 94.3% Caucasians, 2.4% South Asians, 2.3% Afro-Caribbean, 1.0% other)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 reactions or serious adverse reactions 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 involving 10,001 subjects (age range 29–78 years, 19% women; 94.1% Caucasians, 2.9% Blacks, 1.0% Asians, 2.0% other) with clinically evident CHD treated with LIPITOR 10 mg daily (n=5006) or LIPITOR 80 mg daily (n=4995), there were more serious adverse reactions and discontinuations due to adverse reactions 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 × 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 × 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 involving 8,888 subjects (age range 26–80 years, 19% women; 99.3% Caucasians, 0.4% Asians, 0.3% Blacks, 0.04% other) 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 reactions or serious adverse reactions between the treatment groups during a median follow-up of 4.8 years.

Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)

In SPARCL involving 4731 subjects (age range 21–92 years, 40% women; 93.3% Caucasians, 3.0% Blacks, 0.6% Asians, 3.1% other) without clinically evident CHD but with a stroke or transient ischemic attack (TIA) within the previous 6 months treated with LIPITOR 80 mg (n=2365) or placebo (n=2366) for a median follow-up of 4.9 years, there was a higher incidence of persistent hepatic transaminase elevations (≥ 3 × ULN twice within 4–10 days) in the atorvastatin group (0.9%) compared to placebo (0.1%). Elevations of CK (>10 × ULN) were rare, but were higher in the atorvastatin group (0.1%) compared to placebo (0.0%). Diabetes was reported as an adverse reaction in 144 subjects (6.1%) in the atorvastatin group and 89 subjects (3.8%) in the placebo group.

In a post-hoc analysis, LIPITOR 80 mg reduced the incidence of ischemic stroke (218/2365, 9.2% vs. 274/2366, 11.6%) and increased the incidence of hemorrhagic stroke (55/2365, 2.3% vs. 33/2366, 1.4%) compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17 LIPITOR vs. 18 placebo). The incidence of non-fatal hemorrhagic strokes was significantly greater in the atorvastatin group (38 non-fatal hemorrhagic strokes) as compared to the placebo group (16 non-fatal hemorrhagic strokes). Subjects who entered the study with a hemorrhagic stroke appeared to be at increased risk for hemorrhagic stroke [7 (16%) LIPITOR vs. 2 (4%) placebo].

There were no significant differences between the treatment groups for all-cause mortality: 216 (9.1%) in the LIPITOR 80 mg/day group vs. 211 (8.9%) in the placebo group. The proportions of subjects who experienced cardiovascular death were numerically smaller in the LIPITOR 80 mg group (3.3%) than in the placebo group (4.1%). The proportions of subjects who experienced non-cardiovascular death were numerically larger in the LIPITOR 80 mg group (5.0%) than in the placebo group (4.0%).

The following adverse reactions have been identified during postapproval use of the atorvastatin component of Caduet. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions 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, tendon rupture, hepatic failure, dizziness, memory impairment, depression, and peripheral neuropathy.

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.

Side Effects by Body System

Cardiovascular

Worsened angina has been rarely associated with the use of amlodipine (as with other calcium channel blockers).

Bradycardia, hypotension, and syncope have been reported in less than 1% of patients receiving amlodipine.

Cardiovascular side effects associated with amlodipine are dose-related, are usually the result of vasodilation, and include flushing in less than 1% and peripheral edema in 2% of patients. Peripheral edema may become a chronic problem, and may occur in up to 10% of patients who are receiving 10 mg doses. Palpitations occur 1% to 5% (10 mg) of patients. Recent data have shown that the use of amlodipine in patients with NYHA Class III or IV heart failure is not associated with worsened heart failure.

Cardiovascular side effects occurring since market introduction of atorvastatin have included angioneurotic edema, peripheral edema, and chest pain. Atorvastatin may also increase the incidence of hemorrhagic stroke in patients with a history of recent stroke or TIA.

Endocrine

Endocrine side effects including a single case of gynecomastia has been associated with the use of amlodipine. The patient's gynecomastia resolved upon substitution of amlodipine with an unrelated antihypertensive agent. The use of amlodipine has not been associated with adverse effects on glucose metabolism or serum lipids.

Endocrine adverse effects associated with the use of other HMG-CoA reductase inhibitors have included hypospermia, gynecomastia and thyroid dysfunction.

Gastrointestinal

Gastrointestinal side effects associated with amlodipine include nausea in 3% of patients.

Gastrointestinal symptoms have been the most common adverse effects and have included constipation, flatulence, dyspepsia and abdominal pain. These effects occurred in less than 4% of patients. Diarrhea has been reported in up to 5.3% of patients and may be dose-related.

Anorexia, constipation, dyspepsia, vomiting, flatulence, and diarrhea have been reported in less than 1% of patients receiving amlodipine. As with some other calcium channel blockers, rare cases of gingival hyperplasia have been associated with amlodipine.

Other gastrointestinal side effects observed with HMG-CoA reductase inhibitors have included pancreatitis, anorexia and vomiting. Most effects tended to be mild and transient.

Hematologic

A case study reports a 34-year-old woman with a history of chronic renal failure secondary to glomerulonephritis, who was started on amlodipine for uncontrolled hypertension. Three days later the patient developed severe thrombocytopenia. After discontinuation of the drug, the platelet count returned to normal.

Hematological side effects have included isolated cases of thrombocytopenia during amlodipine therapy.

Hematologic side effects including hemolytic anemia, thrombocytopenia, and leukopenia have occurred with HMG-CoA reductase inhibitors. These effects may be manifestations of a hypersensitivity reaction.

Hypersensitivity

A 62-year-old man with hypertension and psoriasis developed erythema multiforme within three days after starting amlodipine. The rash resolved upon substitution with nifedipine.

Hypersensitivity reactions have rarely been reported, although experience with amlodipine is limited. A single case of erythema multiforme during amlodipine therapy has been reported.

Hypersensitivity reactions have been observed rarely with HMG-CoA reductase inhibitors. Symptoms have included anaphylaxis, angioedema, allergic reaction, urticaria, fever, chills, flushing, malaise and dyspnea.

Nervous system

Nervous system side effects associated with amlodipine include headache in 8%, dizziness in 3%, and fatigue in 5% of patients. Vertigo, tremors, and paresthesias have been reported in less than 1% of patients receiving amlodipine.

Nervous system side effects of headache and weakness have occurred with HMG-CoA reductase inhibitors.

Other

A single case of acute porphyria exacerbation has been associated with the use of amlodipine, and confirmed upon rechallenge in the same patient. Calcium channel blockers have been suggested as possibly unsafe in patients with this condition.

Other side effects reported during clinical trials with atorvastatin (in greater than or equal to 2% of patients) include infection, accidental injury, flu syndrome, abdominal pain and back pain. Fatigue has also been reported in postmarketing studies with atorvastatin.

Dermatologic

Dermatologic reactions have occurred rarely during atorvastatin therapy. In premarketing trials up to 3.8% of patients complained of a rash. Since market introduction, bullous rashes including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have occurred.

General

Atorvastatin generally has been well tolerated. Less than 2% of patients in premarketing clinical studies discontinued treatment due to adverse effects.

Genitourinary

Genitourinary adverse effects associated with other HMG-CoA reductase inhibitors have included erectile dysfunction and impotence. Gynecomastia has been reported in postmarketing experience with amlodipine, although causality has not been determined.

Immunologic

Immunologic side effects including a possible case of atorvastatin-induced reversible positive antinuclear antibodies have been reported.

Psychiatric

Psychiatric side effects of HMG-CoA reductase inhibitors have included decreases in libido, anxiety, depression and insomnia.

Renal

Renal side effects including acute renal failure secondary to rhabdomyolysis has been reported with HMG-CoA reductase inhibitors.

Respiratory

Respiratory symptoms reported since market introduction have included bronchitis, rhinitis, pharyngitis, and sinusitis.

Hepatic

Hepatic side effects including altered liver function have been observed with all HMG-CoA reductase inhibitors. In premarketing clinical trials, up to 0.7% of patients experienced persistent, elevated AST and/or ALT values greater than three times the upper normal limits on two or more occasions. Elevations of liver enzymes may be dose-related. Other hepatic side effects of the HMG-CoA class have included hepatitis, cholestatic jaundice, fatty changes in the liver, cirrhosis and fulminant hepatic necrosis.

In clinical trials, liver enzyme elevations returned to pretreatment levels upon discontinuation or dose reduction of atorvastatin. Liver function tests should be closely monitored as most patients remain asymptomatic with elevated liver enzymes. Treatment should be discontinued if values remain elevated. Nawrocki and colleagues reported elevated bilirubin levels in 2/30 patients and elevated AST and ALT levels in 1/30 patients.

Musculoskeletal

Some drugs in the HMG-CoA reductase inhibitor class have been associated with rare cases of severe myopathy and rhabdomyolysis, accompanied by increases in creatine kinase, myoglobinuria, proteinuria and renal failure. The risk of myopathy is increased with concurrent administration of cyclosporine, fibric acid derivatives, erythromycin, niacin, or azole antifungals.

Patients should be instructed to promptly report symptoms of muscle pain, weakness, or tenderness. If such symptoms develop, creatine kinase should be measured, and if markedly elevated, atorvastatin should be discontinued. The value of routine creatine kinase monitoring is not known.

Musculoskeletal side effects have included uncomplicated myalgia and arthralgia during atorvastatin therapy. Rhabdomyolysis and myopathy related to HMG-CoA reductase inhibitor use have been reported rarely. One case of atorvastatin-induced dermatomyositis has been reported. Tendon rupture has also been reported in postmarketing studies.

In addition, some data have suggested that exposure to HMG-CoA reductase inhibitors is associated with a decreased risk of bone fractures in persons older than 50 years of age.

Ocular

Ocular side effects including a case of reversible ophthalmoplegia as well as a case of ocular myasthenia have been reported during atorvastatin use.

A 60-year-old woman with hypercholesterolemia treated with atorvastatin developed painless horizontal diplopia, vertigo, blurry vision, elevated anti-acetylcholine receptor (anti-AchR) antibodies levels, ataxia, and paresthesia of the upper extremities. No other medications were reported. Neurological exam revealed generalized hyperreflexia and finger-nose and gait ataxia. Ptosis was present in both upper eyelids. Discontinuation of atorvastatin resulted in symptom resolution and anti-AchR levels within normal limits.

A 67-year-old women treated for hypercholesterolemia with atorvastatin developed myogenic ptosis and variable incomitant horizontal and vertical strabismus consistent with ocular myasthenia. Following discontinuation of atorvastatin, the patient experienced significant clinical improvement with only mild residual aponeurotic ptosis after 2 months.

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