Felodipine: Package Insert and Label Information (Page 2 of 3)

Drug Interactions

CYP3A4 Inhibitors
Felodipine is metabolized by CYP3A4. Coadministration of CYP3A4 inhibitors
(e.g., ketoconazole, itraconazole, erythromycin, grapefruit juice, cimetidine)
with felodipine may lead to several-fold increases in the plasma levels of
felodipine, either due to an increase in bioavailability or due to a decrease in
metabolism. These increases in concentration may lead to increased effects,
(lower blood pressure and increased heart rate). These effects have been
observed with coadministration of itraconazole (a potent CYP3A4 inhibitor).
Caution should be used when CYP3A4 inhibitors are coadministered with
felodipine. A conservative approach to dosing felodipine should be taken. The
following specific interactions have been reported:
Itraconazole
Coadministration of another extended-release formulation of felodipine with
itraconazole resulted in approximately 8-fold increase in the AUC, more
than 6-fold increase in the Cmax, and 2-fold prolongation in the half-life of
felodipine.
Erythromycin
Coadministration of felodipine extended-release tablets with erythromycin
resulted in approximately 2.5-fold increase in the AUC and Cmax, and about
2-fold prolongation in the half-life of felodipine.
Grapefruit Juice
Coadministration of felodipine extended-release tablets with grapefruit
juice resulted in more than 2-fold increase in the AUC and Cmax, but no
prolongation in the half-life of felodipine.
Cimetidine
Coadministration of felodipine with cimetidine (a non-specific CYP-450 inhibitor)
resulted in an increase of approximately 50% in the AUC and the Cmax, of
felodipine.
Beta-Blocking Agents
A pharmacokinetic study of felodipine in conjunction with metoprolol demonstrated
no significant effects on the pharmacokinetics of felodipine. The AUC and
Cmax of metoprolol, however, were increased approximately 31 and 38%,
respectively. In controlled clinical trials, however, beta-blockers including
metoprolol were concurrently administered with felodipine and were well
tolerated.
Digoxin
When given concomitantly with felodipine extended-release tablets the
pharmacokinetics of digoxin in patients with heart failure were not significantly
altered.
Anticonvulsants
In a pharmacokinetic study, maximum plasma concentrations of felodipine
were considerably lower in epileptic patients on long-term anticonvulsant
therapy (e.g. phenytoin, carbamazepine, or phenobarbital) than in healthy
volunteers. In such patients, the mean area under the felodipine plasma
concentration-time curve was also reduced to approximately 6% of that
observed in healthy volunteers. Since a clinically significant interaction may
be anticipated, alternative antihypertensive therapy should be considered in
these patients.
Tacrolimus
Felodipine may increase the blood concentration of tacrolimus. When given
concomitantly with felodipine, the tacrolimus blood concentration should be
followed and the tacrolimus dose may need to be adjusted.
Other Concomitant Therapy
In healthy subjects there were no clinically significant interactions when
felodipine was given concomitantly with indomethacin or spironolactone.
Interaction with Food
See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2 year carcinogenicity study in rats fed felodipine at doses of 7.7, 23.1
or 69.3 mg/kg/day (up to 61 times** the maximum recommended human dose
on a mg/m2 basis), a dose related increase in the incidence of benign
interstitial cell tumors of the testes (Leydig cell tumors) was observed in
treated male rats. These tumors were not observed in a similar study in mice
at doses up to 138.6 mg/kg/day (61 times** the maximum recommended
human dose on a mg/m2 basis). Felodipine, at the doses employed in the 2
year rat study, has been shown to lower testicular testosterone and to produce
a corresponding increase in serum luteinizing hormone in rats. The Leydig
cell tumor development is possibly secondary to these hormonal effects
which have not been observed in man.
In this same rat study a dose related increase in the incidence of focal
squamous cell hyperplasia compared to control was observed in the esophageal
groove of male and female rats in all dose groups. No other drug-related
esophageal or gastric pathology was observed in the rats or with chronic
administration in mice and dogs. The latter species, like man, has no anatomical
structure comparable to the esophageal groove.
Felodipine was not carcinogenic when fed to mice at doses up to 138.6 mg/kg/day
(61 times** the maximum recommended human dose on a mg/m2 basis) for
periods of up to 80 weeks in males and 99 weeks in females.
Felodipine did not display any mutagenic activity in vitro in the Ames
microbial mutagenicity test or in the mouse lymphoma forward mutation
assay. No clastogenic potential was seen in vivo in the mouse micronucleus
test at oral doses up to 2500 mg/kg (1,100 times** the maximum recommended
human dose on a mg/m2 basis) or in vitro in a human lymphocyte chromosome
aberration assay.
A fertility study in which male and female rats were administered doses of
3.8, 9.6 or 26.9 mg/kg/day (up to 24 times** the maximum recommended
human dose on a mg/m2 basis) showed no significant effect of felodipine on
reproductive performance.
**Based on patient weight of 50 kg

Pregnancy

Teratogenic Effects. Pregnancy Category C
Studies in pregnant rabbits administered doses of 0.46, 1.2, 2.3 and 4.6 mg/kg/day
(from 0.8 to 8 times** the maximum recommended human dose on a mg/m2
basis) showed digital anomalies consisting of reduction in size and degree
of ossification of the terminal phalanges in the fetuses. The frequency and
severity of the changes appeared dose related and were noted even at the
lowest dose. These changes have been shown to occur with other members
of the dihydropyridine class and are possibly a result of compromised uterine
blood flow. Similar fetal anomalies were not observed in rats given felodipine.
In a teratology study in cynomolgus monkeys, no reduction in the size of the
terminal phalanges was observed, but an abnormal position of the distal
phalanges was noted in about 40% of the fetuses.
Nonteratogenic Effects
A prolongation of parturition with difficult labor and an increased frequency
of fetal and early postnatal deaths were observed in rats administered doses
of 9.6 mg/kg/day (8 times** the maximum human dose on a mg/m2 basis) and
above.
**Based on patient weight of 50 kg
Significant enlargement of the mammary glands, in excess of the normal
enlargement for pregnant rabbits, was found with doses greater than or equal
to 1.2 mg/kg/day (2.1 times the maximum human dose on a mg/m2 basis).
This effect occurred only in pregnant rabbits and regressed during lactation.
Similar changes in the mammary glands were not observed in rats or
monkeys.
There are no adequate and well controlled studies in pregnant women. If
felodipine extended-release tablet is used during pregnancy, or if the
patient becomes pregnant while taking this drug, she should be apprised
of the potential hazard to the fetus, possible digital anomalies of the infant,
and the potential effects of felodipine on labor and delivery and on the
mammary glands of pregnant females.

Nursing Mothers

It is not known whether this drug is secreted in human milk and because of
the potential for serious adverse reactions from felodipine in the infant, a
decision should be made whether to discontinue nursing or to discontinue
the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of felodipine did not include sufficient numbers of subjects
aged 65 and over to determine whether they respond differently from younger
subjects. Other reported clinical experience has not identified differences in
responses between the elderly and younger patients. Pharmacokinetics,
however, indicate that the availability of felodipine is increased in older
patients (see CLINICAL PHARMACOLOGY: Geriatric Use). In general, dose
selection for an elderly patient should be cautious, usually starting at the low
end of the dosing range, reflecting the greater frequency of decreased
hepatic, renal, or cardiac function, and of concomitant disease or other drug
therapy.

ADVERSE REACTIONS

In controlled studies in the United States and overseas, approximately 3,000
patients were treated with felodipine as either the extended-release or the
immediate-release formulation.
The most common clinical adverse events reported with felodipine extendedrelease
tablets administered as monotherapy at the recommended dosage
range of 2.5 mg to 10 mg once a day were peripheral edema and headache.
Peripheral edema was generally mild, but it was age and dose related and
resulted in discontinuation of therapy in about 3% of the enrolled patients.
Discontinuation of therapy due to any clinical adverse event occurred in
about 6% of the patients receiving felodipine extended-release tablets,

principally for peripheral edema, headache, or flushing.
Adverse events that occurred with an incidence of 1.5% or greater at any of
the recommended doses of 2.5 mg to 10 mg once a day (felodipine extendedrelease
tablets, N = 861; Placebo, N = 334), without regard to causality, are
compared to placebo and are listed by dose in the table below. These events are
reported from controlled clinical trials with patients who were randomized to
a fixed dose of felodipine extended-release tablets or titrated from an initial
dose of 2.5 mg or 5 mg once a day. A dose of 20 mg once a day has been
evaluated in some clinical studies. Although the antihypertensive effect of
felodipine extended-release tablets is increased at 20 mg once a day,
there is a disproportionate increase in adverse events, especially those associated with vasodilatory effects (see DOSAGE AND ADMINISTRATION).

table 2
(click image for full-size original)

Adverse events that occurred in 0.5% up to 1.5% of patients who received
felodipine extended-release tablets in all controlled clinical trials at the
recommended dosage range of 2.5 mg to 10 mg once a day, and serious
adverse events that occurred at a lower rate, or events reported during
marketing experience (those lower rate events are in italics) are listed
below. These events are listed in order of decreasing severity within each
category, and the relationship of these events to administration of felodipine
extended-release tablets is uncertain:
Body as a Whole: Chest pain, facial edema, flu-like illness
Cardiovascular: Myocardial infarction, hypotension, syncope, angina pectoris,
arrhythmia, tachycardia, premature beats
Digestive: Abdominal pain, diarrhea, vomiting, dry mouth, flatulence, acid
regurgitation
Endocrine: Gynecomastia
Hematologic: Anemia
Metabolic: ALT (SGPT) increased
Musculoskeletal: Arthralgia, back pain, leg pain, foot pain, muscle cramps,
myalgia, arm pain, knee pain, hip pain
Nervous/Psychiatric: Insomnia, depression, anxiety disorders, irritability,
nervousness, somnolence, decreased libido
Respiratory: Dyspnea, pharyngitis, bronchitis, influenza, sinusitis, epistaxis,
respiratory infection
Skin: Angioedema, contusion, erythema, urticaria, leukocytoclastic vasculitis
Special Senses: Visual disturbances
Urogenital: Impotence, urinary frequency, urinary urgency, dysuria, polyuria.
Gingival Hyperplasia: Gingival hyperplasia, usually mild, occurred in < 0.5%
of patients in controlled studies. This condition may be avoided or may regress
with improved dental hygiene. (See PRECAUTIONS: Information for Patients.)
Clinical Laboratory Test Findings
Serum Electrolytes
No significant effects on serum electrolytes were observed during short- and
long-term therapy (see CLINICAL PHARMACOLOGY: Renal/Endocrine
Effects).
Serum Glucose
No significant effects on fasting serum glucose were observed in patients
treated with felodipine extended-release tablets in the U.S. controlled study.
Liver Enzymes
One of two episodes of elevated serum transaminases decreased once drug
was discontinued in clinical studies; no follow-up was available for the other
patient.

OVERDOSAGE

Oral doses of 240 mg/kg and 264 mg/kg in male and female mice, respectively,
and 2390 mg/kg and 2250 mg/kg in male and female rats, respectively,
caused significant lethality.
In a suicide attempt, one patient took 150 mg felodipine together with 15 tablets
each of atenolol and spironolactone and 20 tablets of nitrazepam. The patient’s
blood pressure and heart rate were normal on admission to hospital; he
subsequently recovered without significant sequelae.
Overdosage might be expected to cause excessive peripheral vasodilation
with marked hypotension and possibly bradycardia.
If severe hypotension occurs, symptomatic treatment should be instituted.
The patient should be placed supine with the legs elevated. The administration
of intravenous fluids may be useful to treat hypotension due to overdosage
with calcium antagonists. In case of accompanying bradycardia, atropine
(0.5 mg to 1 mg) should be administered intravenously. Sympathomimetic
drugs may also be given if the physician feels they are warranted.
It has not been established whether felodipine can be removed from the
circulation by hemodialysis.
To obtain up-to-date information about the treatment of overdose, consult
your Regional Poison-Control Center. Telephone numbers of certified poisoncontrol
centers are listed in the Physicians’ Desk Reference (PDR). In managing
overdose, consider the possibilities of multiple-drug overdoses, drug-drug
interactions, and unusual drug kinetics in your patient.

DOSAGE AND ADMINISTRATION

The recommended starting dose is 5 mg once a day. Depending on the patient’s
response, the dosage can be decreased to 2.5 mg or increased to 10 mg
once a day. These adjustments should occur generally at intervals of not less
than 2 weeks. The recommended dosage range is 2.5 mg to 10 mg once
daily. In clinical trials, doses above 10 mg daily showed an increased blood
pressure response but a large increase in the rate of peripheral edema and
other vasodilatory adverse events (see ADVERSE REACTIONS). Modification
of the recommended dosage is usually not required in patients with renal
impairment.
Felodipine extended-release tablets should regularly be taken either without
food or with a light meal (see CLINICAL PHARMACOLOGY, Pharmacokinetics
and Metabolism). Felodipine extended-release tablets should be swallowed
whole and not crushed or chewed.

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