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:
|
Adverse Event
|
amlodipine
|
|
|
|
|
|
2.5 mg N=275
|
5.0 mg N=296
|
10.0 mg N=268
|
Placebo N=520
|
|
Edema
|
1.8
|
3.0
|
10.8
|
0.6
|
|
Dizziness
|
1.1
|
3.4
|
3.4
|
1.5
|
|
Flushing
|
0.7
|
1.4
|
2.6
|
0.0
|
|
Palpitations
|
0.7
|
1.4
|
4.5
|
0.6
|
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
|
Adverse Event
|
amlodipine (%)
(N=1730)
|
Placebo (%)
(N=1250)
|
|
Headache
|
7.3
|
7.8
|
|
Fatigue
|
4.5
|
2.8
|
|
Nausea
|
2.9
|
1.9
|
|
Abdominal Pain
|
1.6
|
0.3
|
|
Somnolence
|
1.4
|
0.6
|
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:
|
Adverse Event
|
amlodipine
|
Placebo
|
|
|
|
|
M=%
(N=1218)
|
F=%
(N=512)
|
M=%
(N=914)
|
F=%
(N=336)
|
|
Edema
|
5.6
|
14.6
|
1.4
|
5.1
|
|
Flushing
|
1.5
|
4.5
|
0.3
|
0.9
|
|
Palpitations
|
1.4
|
3.3
|
0.9
|
0.9
|
|
Somnolence
|
1.3
|
1.6
|
0.8
|
0.3
|
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
The following serious adverse reactions are discussed in greater detail in other sections of the label:
Rhabdomyolysis and myopathy (see
WARNINGS, Skeletal Muscle)
Liver enzyme abnormalities (see
WARNINGS, Liver Dysfunction)
Clinical Adverse Experiences
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 (see CLINICAL PHARMACOLOGY, Clinical Studies, Clinical Studies
with Atorvastatin) 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 (see CLINICAL PHARMACOLOGY, Clinical Studies, Clinical Studies with Atorvastatin)
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 (see CLINICAL PHARMACOLOGY, Clinical Studies) 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
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 (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 x ULN twice within 4–10 days) in the atorvastatin group (0.9%) compared to placebo (0.1%). Elevations of CK (>10 x 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 (see PRECAUTIONS).
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%).
Postintroduction Reports with Atorvastatin
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.
Pediatric Patients (ages 10-17 years)
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 (see CLINICAL PHARMACOLOGY, Clinical Studies section
and PRECAUTIONS, Pediatric Use).