"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 a factorial study, combinations of enalapril at doses of 0, 5, and 20 mg and felodipine ER at doses of 0, 2.5, 5, and 10 mg were evaluated for safety in more than 700 patients with hypertension. In addition more than 500 patients received various combinations of enalapril (5 or 10 mg) and felodipine ER (2.5, 5, or 10 mg) with or without hydrochlorothiazide (12.5 mg) in an open-labeled study up to 52 weeks (mean 33 weeks). Adverse events were similar to those described with the individual components.
In general, treatment with enalapril maleate-felodipine ER was well tolerated and adverse events were mild and transient in nature. In the placebo-controlled, double-blind trial, discontinuation of therapy due to adverse events considered related (possibly, probably or definitely) occurred in 2.8% vs 1.3% of patients treated with the combination or placebo, respectively. The most frequently observed clinical adverse events considered related to treatment with the combination were headache, edema or swelling, and dizziness.
Clinical adverse events considered related (possibly, probably, or definitely) to treatment with enalapril-felodipine ER that occurred with an incidence of 1% or greater with the combination during the placebo-controlled, double-blind trial are compared to individual components and placebo in the table below:
|Percent of Patients with Adverse Events in the Double-Blind Trial (Percent discontinuation shown in parentheses)|
|Body System Adverse Event|| Enalaprila Felodipine ERb
| Felodipine ERb
|Body as a Whole|
| aCombination of dose of 5 and 20 mg daily
bCombination of dose 2.5, 5 and 10 mg daily
Other clinical adverse events considered related (possibly, probably, or definitely) to treatment with enalapril-felodipine ER that occurred with an incidence of less than 1% in the placebo-controlled, double-blind trial are listed below. These events are listed in order of decreasing frequency within each category. Body as a Whole: Syncope, facial edema, orthostatic effects, chest pain; Cardiovascular: Palpitation, hypotension, bradycardia, premature ventricular contraction, increased blood pressure; Digestive: Dry mouth, constipation, dyspepsia, flatulence, acid regurgitation, vomiting, diarrhea, nausea, anal/rectal pain; Metabolic: Gout; Musculoskeletal: Neck pain, joint swelling; Nervous/Psychiatric: Insomnia, nervousness, somnolence, ataxia, agitation, paresthesia, tremor; Respiratory: Dyspnea, respiratory congestion, pharyngeal discomfort, dry throat; Skin: Rash, angioedema, pruritus, alopecia, dry skin; Special Senses: Increased intraocular pressure; Urogenital: Impotence, hot flashes.
Other infrequently reported adverse events were seen in clinical trials with enalapril-felodipine ER (causal relationship unknown). These included: Body as a Whole: Abdominal pain, fever; Digestive: Dental pain; Metabolic: Increased ALT and AST, hyperglycemia; Musculoskeletal: Back pain, myalgia, foot pain, knee pain, shoulder pain, tendinitis; Respiratory: Upper respiratory infection, sinusitis, pharyngitis, bronchitis, nasal congestion, influenza, sinus disorder; Special Senses: Conjunctivitis; Urogenital: Proteinuria, pyuria, urinary tract infection.
Other adverse events that have been reported with enalapril, without regard to causality, are listed (in decreasing severity) below:
Angioedema- Angioedema has been reported in patients receiving enalapril maleate, with an incidence higher in black than in non-black patients. Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with LEXXEL (enalapril maleate-felodipine) should be discontinued and appropriate therapy instituted immediately. (See WARNINGS.)
Body as a Whole: Anaphylactoid reactions (see WARNINGS, Anaphylactoid and Possibly Related Reactions); Cardiovascular: Cardiac arrest, myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see WARNINGS, Hypotension), orthostatic hypotension, pulmonary embolism and infarction, pulmonary edema, rhythm disturbances including atrial tachycardia and bradycardia, atrial fibrillation, angina pectoris; Digestive: Ileus, pancreatitis, hepatic failure, hepatitis (hepatocellular [proven on rechallenge] or cholestatic jaundice) (see WARNINGS, Hepatic Failure), melena, anorexia, glossitis, stomatitis; Hematologic: Rare cases of neutropenia, thrombocytopenia and bone marrow depression; Musculoskeletal: Muscle cramps; Nervous/Psychiatric: Depression, confusion, peripheral neuropathy (eg paresthesia, dysesthesia), vertigo; Respiratory: Bronchospasm, rhinorrhea, sore throat and hoarseness, asthma, pneumonia, pulmonary infiltrates, eosinophilic pneumonitis; Skin: Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, pemphigus, herpes zoster, erythema multiforme, urticaria, diaphoresis, photosensitivity; Special Senses: Blurred vision, taste alteration, anosmia, tinnitus, dry eyes, tearing; Urogenital: Renal failure, oliguria, renal dysfunction (see PRECAUTIONS), flank pain, gynecomastia; Miscellaneous: A symptom complex has been reported which may include a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia/myositis, fever, serositis, vasculitis, leukocytosis, eosinophilia, photosensitivity rash and other dermatologic manifestations; Fetal/Neonatal Morbidity and Mortality: See WARNINGS, Fetal/Neonatal Morbidity and Mortality.
Felodipine as an Extended-Release Formulation
Other adverse events that have been reported with felodipine ER, without regard to causality, are listed (in decreasing severity) below:
Body as a Whole: Flu-like illness; Cardiovascular: Myocardial infarction, angina pectoris, arrhythmia, tachycardia, premature beats; Digestive: Gingival hyperplasia; Endocrine: Gynecomastia; Hematologic: Anemia; Musculoskeletal: Arthralgia, leg pain, muscle cramps, arm pain, hip pain; Nervous/Psychiatric: Depression, anxiety disorders, irritability, decreased libido; Respiratory: Upper respiratory infection, rhinorrhea, sneezing, pharyngitis, influenza, epistaxis, respiratory infection; Skin: Angioedema, contusion, erythema, urticaria, leukocytoclastic vasculitis; Special Senses: Visual disturbances; Urogenital: Urinary frequency, urinary urgency, dysuria, polyuria.
Laboratory Test Findings
In controlled clinical trials with enalapril-felodipine ER, clinically important changes in standard laboratory parameters associated with administration of LEXXEL (enalapril maleate-felodipine) were rare. No changes peculiar to the combination treatment were observed.
Serum Electrolytes- See PRECAUTIONS.
Creatinine- Minor reversible increases in serum creatinine were observed in patients treated with LEXXEL (enalapril maleate-felodipine) . Increases in creatinine are more likely to occur in patients with renal insufficiency or those pretreated with a diuretic and based on experience with other ACE inhibitors, would be expected to be especially likely in patients with renal artery stenosis (see PRECAUTIONS).
Other- Minor reversible increases or decreases in serum potassium were infrequently observed in patients treated with LEXXEL (enalapril maleate-felodipine) ; rarely were these measurements outside the normal range.
Read the Lexxel (enalapril maleate-felodipine) Side Effects Center for a complete guide to possible side effects
Hypotension - Patients on Diuretic Therapy: Patients on diuretics, and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with enalapril. The possibility of hypotensive effects with enalapril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with enalapril. If it is necessary to continue the diuretic, provide close medical supervision after the initial dose for at least two hours and until blood pressure has stabilized for at least an additional hour. (See WARNINGS and DOSAGE AND ADMINISTRATION.)
Agents Causing Renin Release- The antihypertensive effect of enalapril is augmented by antihypertensive agents that cause renin release (eg, diuretics).
Non-steroidal Anti-inflammatory Agents- In some patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs, the coadministration of enalapril may result in a further deterioration of renal function. These effects are usually reversible.
In a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving VASOTEC (enalapril maleate). In this study there was no evidence of a blunting of the antihypertensive action of VASOTEC (enalapril maleate). However, reports suggest that NSAIDs may diminish the antihypertensive effect of ACE- inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.
Agents Increasing Serum Potassium- Enalapril attenuates potassium loss caused by thiazide-type diuretics. Potassium- sparing diuretics (eg, spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum potassium.
Lithium- Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium, including ACE inhibitors. A few cases of lithium toxicity have been reported in patients receiving concomitant enalapril and lithium and were reversible upon discontinuation of both drugs. It is recommended that serum lithium levels be monitored frequently if enalapril is administered concomitantly with lithium.
CYP3A4 Inhibitors-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:
Itraconazole-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.
Erythromycin-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.
Grapefruit juice-Co-administration of felodipine 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-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.
Beta-Blocking Agents- Enalapril has been used concomitantly with beta adrenergic-blocking agents without evidence of clinically significant adverse interactions.
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- Enalapril has been used concomitantly with digoxin without evidence of clinically significant adverse interactions.
When given concomitantly with felodipine ER, 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 (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.
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.
Enalapril has been used concomitantly with methyldopa, nitrates, hydralazine, and prazosin without evidence of clinically significant adverse interactions.
Read the Lexxel Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 10/25/2007
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