Felodipine
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Essential hypertension | Adults | Monotherapy or combination with other antihypertensives | FDA Approved |
Felodipine is FDA-approved solely for the management of essential hypertension. It lowers blood pressure through selective peripheral arterial vasodilation, reducing systemic vascular resistance with a modest reflex increase in heart rate. Felodipine demonstrates comparable efficacy to other first-line antihypertensives including thiazide diuretics, beta-blockers, ACE inhibitors, and other calcium channel blockers. It was the backbone antihypertensive in the landmark HOT (Hypertension Optimal Treatment) trial involving over 18,700 patients, which established optimal diastolic blood pressure targets for cardiovascular risk reduction.
Stable angina pectoris — used outside the United States as an antianginal, particularly in combination with beta-blockers; reduces afterload and myocardial oxygen demand (Evidence: Moderate)
Raynaud phenomenon — limited evidence supports use as an alternative to nifedipine for reducing attack frequency (Evidence: Low)
Heart failure with preserved ejection fraction (HFpEF) — some data suggest safety in compensated heart failure with concurrent hypertension; amlodipine and felodipine are the preferred dihydropyridines in this setting (Evidence: Low)
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Hypertension — initial monotherapy | 5 mg ER once daily | 2.5–10 mg once daily | 10 mg/day | Titrate at intervals of ≥2 weeks; take without food or with a light meal Swallow whole; do not crush or chew |
| Hypertension — add-on to existing regimen | 2.5–5 mg ER once daily | 5–10 mg once daily | 10 mg/day | May combine with beta-blockers, ACE-I, ARB, or diuretics HOT trial used felodipine as base therapy with step-up additions |
| Hypertension — mild or low-risk profile | 2.5 mg ER once daily | 2.5–5 mg once daily | 10 mg/day | Lower starting dose for patients sensitive to vasodilatory effects or with smaller body weight |
| Stable angina (off-label) | 5 mg ER once daily | 5–10 mg once daily | 10 mg/day | Not FDA-approved for angina; use concurrently with beta-blocker to offset reflex tachycardia |
Special Population Dosing
| Population | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Elderly (≥65 years) | 2.5 mg ER once daily | 2.5–10 mg once daily | 10 mg/day | AUC ~2.5-fold higher than young adults; clearance reduced to ~45% of young volunteers (FDA PI) |
| Hepatic impairment | 2.5 mg ER once daily | Lowest effective dose | Individualize | Clearance reduced to ~60% of normal; monitor BP closely during titration |
| Renal impairment | 5 mg ER once daily | Standard dosing | 10 mg/day | No dose adjustment required; inactive metabolites accumulate but have no pharmacologic effect |
Although 20 mg once daily has been evaluated in clinical studies and shows additional blood pressure lowering, the FDA PI explicitly notes a disproportionate increase in vasodilatory adverse events at this dose, particularly peripheral edema (up to 30% in elderly patients), flushing, and tachycardia. The recommended therapeutic range remains 2.5–10 mg/day. If blood pressure remains inadequately controlled at 10 mg, combination therapy with another antihypertensive class is preferred over escalating beyond 10 mg.
Pharmacology
Mechanism of Action
Felodipine is a dihydropyridine calcium channel blocker that reversibly inhibits voltage-dependent L-type calcium channels in vascular smooth muscle with high vascular selectivity (approximately 12-fold selectivity for vascular over cardiac tissue in vitro). By blocking transmembrane calcium influx required for smooth muscle contraction, felodipine produces potent peripheral arterial vasodilation and reduces systemic vascular resistance. This vasodilation lowers blood pressure with a modest reflex increase in heart rate, typically 5–10 beats per minute during the first week of therapy, which attenuates with continued treatment. Unlike verapamil and diltiazem, felodipine has no clinically significant effects on cardiac conduction (PR interval, AV conduction) or sinoatrial node function at therapeutic doses. A mild diuretic and natriuretic effect has been observed in the first week of therapy but does not persist. Felodipine has also been found to act as an antagonist of the mineralocorticoid receptor, though the clinical significance of this property remains under investigation.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Almost completely absorbed; Tmax 2.5–5 h (ER); bioavailability ~20% due to extensive first-pass metabolism; high-fat meal increases Cmax ~60% (AUC unchanged); grapefruit juice doubles AUC and Cmax | Low bioavailability makes felodipine highly sensitive to CYP3A4 interactions. Take consistently without food or with a light meal only. Avoid grapefruit entirely. |
| Distribution | Vd ~10 L/kg; protein binding >99% (primarily albumin) | Extensive tissue distribution. Crosses blood-brain barrier and placenta. Very high protein binding means hemodialysis is ineffective for drug removal. |
| Metabolism | Extensive hepatic metabolism via CYP3A4 to six inactive water-soluble metabolites (accounting for 23% of oral dose recovered) | Highly susceptible to CYP3A4 drug interactions. Hepatic impairment reduces clearance to ~60% of normal; elderly clearance only ~45% of young adults. No active metabolites. |
| Elimination | ~70% urine, ~10% feces (as metabolites); <0.5% unchanged in urine or feces; terminal t½ 11–16 h (oral); systemic clearance ~0.8 L/min | Long half-life supports once-daily dosing with the ER formulation. Renal impairment does not alter pharmacokinetics of the parent drug. Steady-state peak concentrations ~20% higher than after single dose. |
Side Effects
Adverse effect data below are from controlled clinical trials of Plendil (N=861 active, N=334 placebo) at the recommended dose range of 2.5–10 mg once daily. Incidence is dose-dependent and age-dependent, with peripheral edema particularly increasing in patients over 60.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Peripheral edema | 17.4% at 10 mg (vs 3.3% placebo) | Dose- and age-dependent: 2.0% at 2.5 mg, 8.8% at 5 mg, 17.4% at 10 mg; up to ~30% at 20 mg in elderly patients. Localized vasodilatory effect, not fluid overload. Onset typically within 2–3 weeks. |
| Headache | 14.7% at 10 mg (vs 10.2% placebo) | Dose-related: 10.6% at 2.5 mg, 11.0% at 5 mg, 14.7% at 10 mg. Vasodilatory mechanism; usually self-limiting within first 1–2 weeks. Placebo rate also substantial (10.2%). |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Flushing | 6.9% at 10 mg (vs 0.9% placebo) | Dose-related (3.9% at 2.5 mg, 5.3% at 5 mg); direct vasodilatory effect; typically transient and diminishes with continued therapy |
| Dizziness | 3.7% at 10 mg (vs 2.7% placebo) | Modest increase over placebo; recommend slow position changes during initial titration |
| Asthenia / fatigue | 3.9% at 2.5 mg (vs 3.3% placebo) | Not clearly dose-related; rates similar to placebo across all dose levels |
| Palpitations | 2.5% at 10 mg (vs 2.4% placebo) | Reflex sympathetic activation; attenuates over first week; concurrent beta-blocker mitigates |
| Nausea | 1.7% at 5 mg (vs 1.5% placebo) | Not clearly drug-related given similar placebo rate |
| Warm sensation | 1.5% at 10 mg (vs 0% placebo) | Vasodilatory effect; dose-related; generally mild |
| Upper respiratory infection / cough | 1.7% at 10 mg (vs 0.3% placebo) | Mechanism unclear; not considered ACE-I class cough; evaluate for alternative causes |
| Constipation | 1.5% at 10 mg (vs 0.9% placebo) | Less prominent than with non-dihydropyridine CCBs; dietary measures usually sufficient |
| Gingival hyperplasia | ~1–2% | Calcium-mediated fibroblast proliferation; risk increased by poor oral hygiene and concurrent cyclosporine or phenytoin |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Symptomatic hypotension | Uncommon | Initial titration or dose increase | Reduce dose or discontinue; IV fluids if symptomatic; higher risk with concurrent antihypertensives |
| Syncope | Rare | First days of therapy | Evaluate for excessive BP lowering; dose reduction; consider alternative agent |
| Exacerbation of angina pectoris | Rare | Initiation, dose increase, or beta-blocker withdrawal | Reflex tachycardia increases myocardial oxygen demand; add or resume beta-blocker; if persistent, discontinue felodipine |
| Myocardial infarction | Very rare | Variable | Emergency cardiac evaluation; discontinue; not distinguishable from disease progression in high-risk patients |
| Tachycardia / arrhythmia | Rare | First week of therapy | ECG monitoring; add beta-blocker if clinically appropriate; dose reduction |
| Hepatotoxicity | Very rare (post-marketing) | Weeks to months | Check LFTs; discontinue if significant elevation; usually resolves after cessation |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Peripheral edema | ~3% | Leading cause; dose-dependent; more common at 10 mg (2.5%) than 5 mg (2.2%) |
| Headache | ~2% | Higher at 10 mg (2.0%) and 5 mg (1.7%); usually early in therapy |
| Flushing | ~1% | Dose-related; 1.2% at 10 mg, 0.7% at 5 mg; typically self-limiting |
Felodipine-induced peripheral edema reflects localized precapillary arteriolar vasodilation and is not a sign of heart failure or generalized fluid retention. Concurrent use of an ACE inhibitor or ARB can reduce the edema by dilating postcapillary venules, thereby equalizing capillary pressures. Diuretics are generally ineffective because the edema is not sodium-mediated. In patients with concurrent heart failure, always differentiate drug-induced edema from decompensation before adjusting therapy.
Drug Interactions
Felodipine is extensively metabolized by CYP3A4 with a low bioavailability (~20%), making it exceptionally sensitive to CYP3A4 inhibitors and inducers. Even modest changes in first-pass metabolism can produce large swings in plasma concentrations. The interaction magnitude with felodipine is often greater than with other dihydropyridines due to its low baseline bioavailability.
Monitoring
-
Blood Pressure
Baseline, each titration, then regularly
Routine Close monitoring during initial titration and dose changes, particularly in elderly patients (higher plasma concentrations) and those with hepatic impairment. Seated and standing BP recommended. -
Heart Rate
Baseline, first weeks
Routine Reflex tachycardia (5–10 bpm increase) common in first week; attenuates with continued therapy. More pronounced without concurrent beta-blocker. -
Peripheral Edema
Each visit
Routine Dose- and age-dependent. Onset typically within 2–3 weeks. Distinguish from heart failure in at-risk patients. Consider adding ACE-I/ARB before discontinuing felodipine. -
Dental Health
Every 6 months
Routine Gingival hyperplasia reported; encourage meticulous oral hygiene and regular dental visits. FDA PI specifically instructs patients about this risk. -
Liver Function Tests
If symptoms arise
Trigger-based Hepatotoxicity very rare but reported post-marketing. Check LFTs if jaundice, malaise, or right upper quadrant pain develops. In patients with baseline hepatic impairment, monitor BP closely as a surrogate for drug accumulation. -
Tacrolimus Levels
At initiation and changes
Trigger-based In transplant recipients on tacrolimus; felodipine can raise tacrolimus blood concentrations. Adjust dose accordingly.
Contraindications & Cautions
Absolute Contraindications
- Known hypersensitivity to felodipine or any formulation component
Relative Contraindications (Specialist Input Recommended)
- Severe aortic stenosis — afterload reduction in fixed outflow obstruction risks hemodynamic instability
- Acute heart failure / cardiogenic shock — although felodipine has not shown negative inotropy clinically, safety in acute HF is not established
- Unstable angina or acute MI — reflex tachycardia may worsen myocardial ischemia
- Moderate to severe hepatic impairment — substantially increased drug exposure; requires specialist-supervised low-dose initiation
- Pregnancy — Category C; digital anomalies in rabbit offspring and prolonged parturition in rats at supratherapeutic doses
Use with Caution
- Heart failure with reduced or preserved ejection fraction — no proven negative inotropic effects in clinical studies, but safety not fully established; felodipine (along with amlodipine) is considered safer than other CCBs in this context
- Elderly patients (≥65 years) — AUC approximately 2.5-fold higher than young adults; start 2.5 mg
- Concurrent potent CYP3A4 inhibitors — up to 8-fold increase in felodipine exposure possible
- Concurrent CYP3A4 inducers (anticonvulsants, rifampin) — may render felodipine therapeutically ineffective; consider alternative antihypertensive
In preclinical studies, felodipine produced dose-related digital anomalies (reduction in size and ossification of terminal phalanges) in rabbit fetuses at doses as low as 0.8 times the maximum recommended human dose on a body-surface-area basis. Prolonged parturition and increased fetal and early postnatal death were observed in rats. Abnormal distal phalanx positioning was noted in ~40% of fetuses in a cynomolgus monkey study. These findings are considered a class effect of dihydropyridine CCBs and are possibly related to compromised uterine blood flow. There are no adequate studies in pregnant women. Felodipine should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.
Patient Counselling
Purpose of Therapy
Felodipine is prescribed to lower blood pressure and reduce the long-term risk of stroke, heart attack, and kidney damage. It works by relaxing blood vessels so the heart does not need to work as hard. Blood pressure control is a lifelong commitment, and this medication should be taken consistently even when feeling well.
How to Take
Take felodipine once daily, consistently either on an empty stomach or with a light meal (avoid taking with a heavy or high-fat meal, as this can increase the amount of medication absorbed and cause more side effects). Swallow the tablet whole and never crush, chew, or split it. Take it at the same time each day to maintain steady blood levels.
Sources
- Plendil (felodipine) Extended-Release Tablets. Full Prescribing Information. AstraZeneca LP. Revised October 2012. accessdata.fda.gov Primary FDA-approved label for felodipine ER; source of all dosing, adverse effects, pharmacokinetics, interactions, and contraindications data in this monograph.
- Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998;351(9118):1755-1762. doi:10.1016/S0140-6736(98)04311-6 Landmark trial of 18,790 hypertensive patients using felodipine-based therapy demonstrating optimal cardiovascular protection at DBP 80–85 mmHg and aspirin benefit for MI reduction.
- Staessen JA, Wang JG, Thijs L. Cardiovascular protection and blood pressure reduction: a meta-analysis. Lancet. 2001;358(9290):1305-1315. doi:10.1016/S0140-6736(01)06411-X Meta-analysis confirming that CCBs including felodipine provide cardiovascular protection primarily through blood pressure reduction.
- Neaton JD, Grimm RH Jr, Prineas RJ, et al. Treatment of Mild Hypertension Study (TOMHS): final results. JAMA. 1993;270(6):713-724. doi:10.1001/jama.1993.03510060059034 Comparative trial showing that CCBs, diuretics, beta-blockers, ACE-I, and alpha-blockers all effectively control mild hypertension with acceptable tolerability profiles.
- Black HR, Elliott WJ, Weber MA, et al. One-year study of felodipine or placebo for stage 1 isolated systolic hypertension. Hypertension. 2001;38(5):1118-1123. doi:10.1161/hy1101.095000 RCT demonstrating felodipine reduces LV hypertrophy incidence and improves quality of life in stage 1 isolated systolic hypertension.
- Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults. Hypertension. 2018;71(6):e13-e115. doi:10.1161/HYP.0000000000000065 Current US hypertension guideline placing CCBs as first-line therapy, particularly for Black patients and older adults.
- Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH guidelines for the management of arterial hypertension. Eur Heart J. 2018;39(33):3021-3104. doi:10.1093/eurheartj/ehy339 European hypertension guideline supporting CCBs as first-line antihypertensives with particular utility in combination regimens.
- Godfraind T. Discovery and development of calcium channel blockers. Front Pharmacol. 2017;8:286. doi:10.3389/fphar.2017.00286 Comprehensive pharmacological review of CCB development including felodipine’s vascular selectivity profile (12:1 vascular-to-cardiac ratio).
- Todd PA, Faulds D. Felodipine: a review of the pharmacology and therapeutic use of the extended release formulation in cardiovascular disorders. Drugs. 1992;44(2):251-277. doi:10.2165/00003495-199244020-00008 Foundational pharmacology review of felodipine covering mechanism, PK, clinical efficacy, and tolerability of the ER formulation.
- Bansal AB, Patel P, Khandelwal G. Felodipine. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026. Updated January 31, 2024. ncbi.nlm.nih.gov Comprehensive overview including mechanism, PK across special populations, adverse effects, and current clinical role of felodipine in hypertension management.
- Edgar B, Regardh CG, Johnsson G, et al. Felodipine kinetics in healthy men. Clin Pharmacol Ther. 1985;38(2):205-211. doi:10.1038/clpt.1985.160 Seminal PK study establishing felodipine’s triexponential elimination kinetics, bioavailability, and volume of distribution in healthy volunteers.
- Navadiya K, Tiwari S. Pharmacology, efficacy and safety of felodipine with a focus on hypertension and angina pectoris. Curr Drug Saf. 2015;10(3):194-201. doi:10.2174/1574886310666150529100401 Safety and efficacy review consolidating clinical trial data for felodipine in hypertension and its off-label use in angina.