SIDE EFFECTS
Immediate Release Capsules
In multiple-dose U.S. and foreign controlled studies
in which adverse reactions were reported spontaneously,
adverse effects were frequent but generally not serious
and rarely required discontinuation of therapy or dosage
adjustment. Most were expected consequences of the vasodilator
effects of nifedipine. (See TABLE -1.)
| TABLE 1 |
| |
Nifedipine (%) |
Placebo (%) |
| Adverse Effect |
(N=226) |
(N=235) |
| Dizziness, lightheadedness,
giddiness |
27 |
15 |
| Flushing,
heat sensation | 25 |
8 |
| Headache |
23 |
20 |
| Weakness |
12 |
10 |
| Nausea, heartburn |
11 |
8 |
| Muscle cramps, tremor |
8 |
3 |
| Peripheral edema |
7 |
1 |
| Nervousness,
mood changes | 7 |
4 |
| Palpitation |
7 |
5 |
| Dyspnea, cough, wheezing |
6 |
3 |
| Nasal
congestion, sore throat | 6 |
8 |
There is also a large uncontrolled experience in over
2100 patients in the United States. Most of the patients
had vasospastic or resistant angina pectoris, and about
half had concomitant treatment with beta-adrenergic blocking
agents. The most common adverse events were:
Incidence Approximately 10%:
Cardiovascular: Peripheral edema.
Central Nervous System: Dizziness or
lightheadedness.
Gastrointestinal: Nausea.
Systemic: Hadache and flushing, weakness.
Incidence Approximately 5%:
Cardiovascular: Transient hypotension.
Incidence 2% or Less:
Cardiovascular: Palpitation.
Respiratory: Nasal and chest congestion,
shortness of breath.
Gastrointestinal: Diarrhea, constipation,
cramps, flatulence.
Musculoskeletal: Inflammation, joint
stiffness, muscle cramps.
Central Nervous System: Shakiness, nervousness,
jitteriness, sleep disturbances, blurred vision, difficulties
in balance.
Other: Dermatitis, pruritus, urticaria,
fever, sweating, chills, sexual difficulties.
Incidence Approximately 0.5%:
Cardiovascular: Syncope (mostly with
initial dosing and/or an increase in dose), erythromelalgia.
Incidence Less Than 0.5%:
Hematologic: Thrombocytopenia, anemia,
leukopenia, purpura.
Gastrointestinal: Allergic hepatitis.
Face and Throat: Angioedema (mostly oropharyngeal
edema with breathing difficulty in a few patients), gingival
hyperplasia.
CNS: Depression, paranoid syndrome.
Special Senses: Transient blindness at
the peak of plasma level, tinnitus.
Urogenital: Nocturia, polyuria.
Otherl: Arthritis with ANA (+), exfoliative
dermatitis, gynecomastia.
Musculoskeletal: Myalgia.
Several of these side effects appear to be dose related.
Peripheral edema occurred in about one in 25 patients at
doses less than 60 mg per day and in about 1 patient in
8 at 120 mg per day or more. Transient hypotension, generally
of mild to moderate severity and seldom requiring discontinuation
of therapy, occurred in 1 of 50 patients at less than 60
mg per day and in one of 20 patients at 120 mg per day or
more.
Very rarely, introduction of nifedipine therapy was associated
with an increase in anginal pain, possibly due to associated
hypotension. Transient unilateral loss of vision has also
occurred.
In addition, more serious adverse events were observed,
not readily distinguishable from the natural history of
the disease in these patients. It remains possible, however,
that some or many of these events were drug related. Myocardial
infarction occurred in about 4% of patients and congestive
heart failure or pulmonary edema in about 2%. Ventricular
arrhythmias or conduction disturbances each occurred in
fewer than 0.5% of patients.
In a subgroup of over 1000 patients receiving nifedipine
with concomitant beta blocker therapy, the pattern and
incidence of adverse experiences was not different from
that of the entire group of nifedipine treated patients.
(See PRECAUTIONS.)
In a subgroup of approximately 250 patients with a diagnosis
of congestive heart failure as well as angina pectoris
(about 10% of the total patient population), dizziness
or lightheadedness, peripheral edema, headache or flushing
each occurred in 1 in 8 patients. Hypotension occurred
in about 1 in 20 patients. Syncope occurred in approximately
1 patient in 250. Myocardial infarction or symptoms of
congestive heart failure each occurred in about 1 patient
in 15. Atrial or ventricular dysrhythmias each occurred
in about one patient in 150.
In post-marketing experience, there have been rare reports
of exfoliative dermatitis caused by nifedipine. There
have been rare reports of exfoliative or bullous skin
adverse events (such as exfoliative dermatitis, erythema
multiforme, Stevens-Johnson Syndrome, and toxic epidermal
necrolysis) and photosensitivity reactions.
Extended Release Tablets
Over 1000 patients from both controlled and open trials
with nifedipine extended release tablets in hypertension
and angina were included in the evaluation of adverse
experiences. All side effects reported during nifedipine
extended release tablet therapy were tabulated independent
of their causal relation to medication. The most common
side effect reported with nifedipine was edema which was
dose related and ranged in frequency from approximately
10% to about 30% at the highest dose studied (180 mg).
Other common adverse experience reported in placebo-controlled
trials include those shown in TABLE 2.
| TABLE 2 |
| |
Nifedipine Extended Release
Tablets (%) |
Placebo (%) |
| Adverse Effect |
(N=707) |
(N=266) |
| Headache |
15.8 |
9.8 |
| Fatigue |
5.9 |
4.1 |
| Dizziness |
4.1 |
4.5 |
| Constipation |
3.3 |
2.3 |
| Nausea |
3.3 |
1.9 |
Of these, only edema and headache were more common in
nifedipine patients than placebo patients.
The following adverse reactions occurred with
an incidence of less than 3.0%. With the exception
of leg cramps, the incidence of these side effects was
similar to that of placebo alone.
Body as a Whole/Systemic: Asthenia,
flushing, pain.
Cardiovascular: Palpitations.
Central Nervous System: Insomnia, nervousness,
paresthesia, somnolence.
Dermatologic: Pruritus, rash.
Gastrointestinal: Abdominal pain, diarrhea,
dry mouth, dyspepsia, flatulence.
Musculoskeletal: Arthralgia, leg cramps.
Respiratory: Chest pain (nonspecific),
dyspnea.
Urogenital: Impotence, polyuria.
Other adverse reactions were reported sporadically
with an incidence of 1.0% or less. These include:
Body as a Whole/System: Face edema, fever, hot
flashes, malaise, periorbital edema, rigors.
Cardiovascular: Arrhythmia, hypotension, increased
angina, tachycardia, syncope.
Central Nervous System: Anxiety, ataxia,
decreased libido, depression, hypertonia, hypoesthesia,
migraine, paroniria, tenor, vertigo.
Dermatologic: Alopecia, increased sweating,
urticaria, purpura.
Gastrointestinal: Eructation, gastroesophageal
reflux, gum hyperplasia, melena, vomiting, weight increase.
Musculoskeletal: Back pain, gout, myalgias.
Respiratory: Coughing, epistaxis, upper
respiratory tract infection, respiratory disorder, sinusitis.
Special Senses: Abnormal lacrimation,
abnormal vision, taste perversion, tinnitus.
Urogenital/Reproductive: Breast pain,
dysuria, hematuria, nocturia.
Adverse experiences which occurred in less than 1 in 1000
patients cannot be distinguished from concurrent disease
states or medications.
The following adverse experiences, reported in less than
1% of patients, occurred under conditions (e.g., open
trials, marketing experience) where a causal relationship
is uncertain: gastrointestinal irritation, gastrointestinal
bleeding, gynecomastia.
There is also a large uncontrolled experience in over
2100 patients in the United States. Most of the patients
had vasospastic or resistant angina pectoris, and about
half had concomitant treatment with beta-adrenergic blocking
agents. The relatively common adverse events were similar
in nature to those seen with nifedipine.
In addition, more serious adverse events were observed,
not readily distinguishable from the natural history of
the disease in these patients. It remains possible, however,
that some or many of these events were drug related. Myocardial
infarction occurred in about 4% of patients and congestive
heart failure or pulmonary edema in about 2%. Ventricular
arrhythmias or conduction disturbances each occurred in
fewer than 0.5% of patients.
In a subgroup of over 1000 patients receiving nifedipine
with concomitant beta blocker therapy, the pattern and
incidence of adverse experiences was not different from
that of the entire group of nifedipine treated patients.
(See PRECAUTIONS.)
In a subgroup of approximately 250 patients with a diagnosis
of congestive heart failure as well as angina, dizziness
or lightheadedness, peripheral edema, headache or flushing
each occurred in 1 in 8 patients. Hypotension occurred
in about 1 in 20 patients. Syncope occurred in approximately
1 patient in 250. Myocardial infarction or symptoms of
congestive heart failure each occurred in about 1 patient
in 15. Atrial or ventricular dysrhythmias each occurred
in about one patient in 150.
In post-marketing experience, there have been rare reports
of exfoliative dermatitis caused by nifedipine. There
have been rare reports of exfoliative or bullous skin
adverse events (such as exfoliative dermatitis, erythema
multiforme, Stevens-Johnson Syndrome, and toxic epidermal
necrolysis) and photosensitivity reactions.
DRUG INTERACTIONS
Beta-adrenergic Blocking Agents: (See INDICATIONS AND
USAGE and WARNINGS.) Experience in over 1400 patients
in a non-comparative clinical trial has shown that concomitant
administration of nifedipine and beta-blocking agents
is usually well tolerated, but there have been occasional
literature reports suggesting that the combination may
increase the likelihood of congestive heart failure, severe
hypotension or exacerbation of angina.
Long Acting Nitrates: Nifedipine may
be safely co-administered with nitrates, but there have
been no controlled studies to evaluate the antianginal
effectiveness of this combination.
Digitalis: Immediate Release Capsules:
Since there have been isolated reports of patients with
elevated digoxin levels, and there is a possible interaction
between digoxin and nifedipine, it is recommended that
digoxin levels be monitored when initiating, adjusting,
and discontinuing nifedipine to avoid possible over- or
under-digitalization. Extended Release Tablets: Administration
of nifedipine with digoxin increased digoxin levels in
9 of 12 normal volunteers. The average increase was 45%.
Another investigator found no increase in digoxin levels
in 13 patients with coronary artery disease. In an uncontrolled
study of over 200 patients with congestive heart failure
during which digoxin blood levels were not measured, digitalis
toxicity was not observed. Since there have been isolated
reports of patients with elevated digoxin levels, it is
recommended that digoxin levels be monitored when initiating,
adjusting, and discontinuing nifedipine to avoid possible
over- or under-digitalization.
Quinidine: Immediate Release Capsules:
There have been rare reports of an interaction between
quinidine and nifedipine (with a decreased plasma level
of quinidine).
Coumarin Anticoagulants: There have
been rare reports of increased prothrombin time in patients
taking coumarin anticoagulants to whom nifedipine was
administered. However, the relationship to nifedipine
therapy is uncertain.
Cimetidine: A study in 6 healthy volunteers
has shown a significant increase in peak nifedipine plasma
levels (80%) and area-under-the-curve (74%) after a 1
week course of cimetidine at 1000 mg per day and nifedipine
at 40 mg per day. Ranitidine produced smaller, non-significant
increases. The effect may be mediated by the known inhibition
of cimetidine on hepatic cytochrome P-450, the enzyme
system probably responsible for the first-pass metabolism
of nifedipine. If nifedipine therapy is initiated in a
patient currently receiving cimetidine, cautious titration
is advised.
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