"The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has recommended the marketing of selexipag (Uptravi, Actelion Registration Ltd) for the treatment of adults with pulmonary arterial hypertension (PAH)./"...
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 PLENDIL 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 PLENDIL, 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 (PLENDIL, 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 PLENDIL 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 PLENDIL 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
PLENDIL (N=861) as Monotherapy without Regard to Causality (Incidence of
discontinuations shown in parentheses)
|Body System Adverse Events||Placebo
|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)|
|Palpitation||2.4 (0.0)||0.4 (0.0)||1.4 (0.3)||2.5 (0.5)|
|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)|
|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)|
|Upper Respiratory Infection|
|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)|
|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)|
|*Patients in titration studies may have been exposed to more than one dose level of PLENDIL.|
Adverse events that occurred in 0.5 up to 1.5% of patients who received PLENDIL 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 PLENDIL 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.
Clinical Laboratory Test Findings
No significant effects on serum electrolytes were observed during short- and long-term therapy (see CLINICAL PHARMACOLOGY, Renal/Endocrine Effects).
No significant effects on fasting serum glucose were observed in patients treated with PLENDIL in the U.S. controlled study.
1 of 2 episodes of elevated serum transaminases decreased once drug was discontinued in clinical studies; no follow-up was available for the other patient.
Read the Plendil (felodipine) Side Effects Center for a complete guide to possible side effects
Felodipine is metabolized by CYP3A4. Co-administration of CYP3A4 inhibitors (eg, 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 co-administration of itraconazole (a potent CYP3A4 inhibitor). Caution should be used when CYP3A4 inhibitors are co-administered with felodipine. A conservative approach to dosing felodipine should be taken. The following specific interactions have been reported:
Co-administration 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.
Co-administration of felodipine (PLENDIL) 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.
Co-administration of felodipine with grapefruit juice resulted in more than 2fold increase in the AUC and Cmax, but no prolongation in the half-life of felodipine.
Co-administration 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.
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.
When given concomitantly with PLENDIL the pharmacokinetics of digoxin in patients with heart failure were not significantly altered.
In a pharmacokinetic study, maximum plasma concentrations of felodipine were considerably lower in epileptic patients on long-term anticonvulsant therapy (eg, 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.
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.
Read the Plendil Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 11/9/2012
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