Felodipine (Page 3 of 4)

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 1 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 1 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 1 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 (1100 times 1 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 1 the maximum recommended human dose on a mg/m2 basis) showed no significant effect of felodipine on reproductive performance.

Pregnancy

Pregnancy Category C.

Teratogenic Effects

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 1 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 1 the maximum human dose on a mg/m2 basis) and above.

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 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.


1
Based on patient weight of 50 kg

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 3000 patients were treated with felodipine as either the extended-release or the immediate-release formulation.

The most common clinical adverse events reported with felodipine 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, 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, 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 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 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).

Percent of Patients with Adverse Events in Controlled Trials * of felodipine (N=861) as Monotherapy without Regard to Causality (Incidence of discontinuations shown in parentheses)
Body SystemAdverse Events PlaceboN=334 2.5 mgN=255 5 mgN=581 10 mgN=408
*
Patients in titration studies may have been exposed to more than one dose level of felodipine.
Body as a Whole
Peripheral Edema 3.3 (0.0) 2.0 (0.0) 8.8 (2.2) 17.4 (2.5)
Asthenia 3.3 (0.0) 3.9 (0.0) 3.3 (0.0) 2.2 (0.0)
Warm Sensation 0.0 (0.0) 0.0 (0.0) 0.9 (0.2) 1.5 (0.0)
Cardiovascular
Palpitation 2.4 (0.0) 0.4 (0.0) 1.4 (0.3) 2.5 (0.5)
Digestive
Nausea 1.5 (0.9) 1.2 (0.0) 1.7 (0.3) 1.0 (0.7)
Dyspepsia 1.2 (0.0) 3.9 (0.0) 0.7 (0.0) 0.5 (0.0)
Constipation 0.9 (0.0) 1.2 (0.0) 0.3 (0.0) 1.5 (0.2)
Nervous
Headache 10.2 (0.9) 10.6 (0.4) 11.0 (1.7) 14.7 (2.0)
Dizziness 2.7 (0.3) 2.7 (0.0) 3.6 (0.5) 3.7 (0.5)
Paresthesia 1.5 (0.3) 1.6 (0.0) 1.2 (0.0) 1.2 (0.2)
Respiratory
Upper Respiratory Infection 1.8 (0.0) 3.9 (0.0) 1.9 (0.0) 0.7 (0.0)
Cough 0.3 (0.0) 0.8 (0.0) 1.2 (0.0) 1.7 (0.0)
Rhinorrhea 0.0 (0.0) 1.6 (0.0) 0.2 (0.0) 0.2 (0.0)
Sneezing 0.0 (0.0) 1.6 (0.0) 0.0 (0.0) 0.0 (0.0)
Skin
Rash 0.9 (0.0) 2.0 (0.0) 0.2 (0.0) 0.2 (0.0)
Flushing 0.9 (0.3) 3.9 (0.0) 5.3 (0.7) 6.9 (1.2)

Adverse events that occurred in 0.5 up to 1.5% of patients who received felodipine 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 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.

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