A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Caduet Side Effects, and Drug Interactions - Amlodipine besylate/atorvastatin
Caduet Side Effects, and Drug Interactions - Amlodipine besylate/atorvastatin
SIDE EFFECTS
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:
|
AE
|
amlodipine
|
| |
2.5mg
|
5.0mg
|
10.0mg
|
Placebo
|
| |
N=275
|
N=296
|
N=268
|
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
|
|
Palpitation
|
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
|
| |
amlodipine (%)
|
PLACEBO(%)
|
| |
(N=1730)
|
(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:
|
ADR
|
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.
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 ³2%
of patients in placebo-controlled clinical studies of atorvastatin, regardless
of causality assessment, are shown in Table 10.
|
TABLE 10. ADVERSE EVENTS IN PLACEBO- CONTROLLED STUDIES
(% of Patients)
|
| |
|
atorvastatin
|
|
|
Body System/
|
Placebo
|
10mg
|
20mg
|
40mg
|
80mg
|
|
Adverse Event
|
N=270
|
N=863
|
N=36
|
N=79
|
N=94
|
|
BODY AS A WHOLE
|
|
Infection
|
10.0
|
10.3
|
2.8
|
10.1
|
7.4
|
|
Headache
|
7.0
|
5.4
|
16.7
|
2.5
|
6.4
|
|
Accidental Injury
|
3.7
|
4.2
|
0.0
|
1.3
|
3.2
|
|
Flu Syndrome
|
1.9
|
2.2
|
0.0
|
2.5
|
3.2
|
|
Abdominal Pain
|
0.7
|
2.8
|
0.0
|
3.8
|
2.1
|
|
Back Pain
|
3.0
|
2.8
|
0.0
|
3.8
|
1.1
|
|
Allergic Reaction
|
2.6
|
0.9
|
2.8
|
1.3
|
0.0
|
|
Asthenia
|
1.9
|
2.2
|
0.0
|
3.8
|
0.0
|
|
DIGESTIVE SYSTEM
|
|
Constipation
|
1.8
|
2.1
|
0.0
|
2.5
|
1.1
|
|
Diarrhea
|
1.5
|
2.7
|
0.0
|
3.8
|
5.3
|
|
Dyspepsia
|
4.1
|
2.3
|
2.8
|
1.3
|
2.1
|
|
Flatulence
|
3.3
|
2.1
|
2.8
|
1.3
|
1.1
|
|
RESPIRATORY SYSTEM
|
|
Sinusitis
|
2.6
|
2.8
|
0.0
|
2.5
|
6.4
|
|
Pharyngitis
|
1.5
|
2.5
|
0.0
|
1.3
|
2.1
|
|
SKIN AND APPENDAGES
|
|
Rash
|
0.7
|
3.9
|
2.8
|
3.8
|
1.1
|
|
MUSCULOSKELETAL SYSTEM
|
|
Arthralgia
|
1.5
|
2.0
|
0.0
|
5.1
|
0.0
|
|
Myalgia
|
1.1
|
3.2
|
5.6
|
1.3
|
0.0
|
The following adverse events were reported, regardless of causality
assessment in patients treated with atorvastatin in clinical trials. The events
in italics occurred in ³2% 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, urinary
frequency, cystitis, hematuria, impotence, dysuria, kidney calculus, nocturia,
epididymitis, fibrocystic breast, vaginal hemorrhage, albuminuria, 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), and rhabdomyolysis.
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).
DRUG INTERACTIONS
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. 17
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 drugs of the HMG-CoA
reductase class is increased with concurrent administration of cyclosporine,
fibric acid derivatives, niacin (nicotinic acid), erythromycin, azole antifungals
(see WARNINGS, Skeletal Muscle).
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.
Cimetidine: Atorvastatin plasma concentrations
and LDL-C reduction were not altered by coadministration of cimetidine.
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.
Erythromycin: In healthy individuals, plasma
concentrations of atorvastatin increased approximately 40% with coadministration
of atorvastatin and erythromycin, a known inhibitor of cytochrome P450 3A4 (see
WARNINGS, Skeletal Muscle).
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.
Drug/Laboratory Test Interactions None known.
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