What medications cause peripheral edema (ankle swelling)?

From the Guidelines

Calcium channel blockers, particularly amlodipine and felodipine, are the most likely medications to cause ankle swelling due to their association with dose-related pedal edema, as noted in the 2018 ACC/AHA guideline 1.

Medications Causing Ankle Swelling

Several medications can cause ankle swelling as a side effect. Common culprits include:

• Blood pressure medications such as calcium channel blockers (amlodipine, nifedipine, diltiazem)
• ACE inhibitors (lisinopril, enalapril)
• Nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and naproxen can also cause fluid retention.
• Hormonal medications including estrogen-containing contraceptives, hormone replacement therapy, and testosterone supplements frequently cause edema.
• Diabetes medications like thiazolidinediones (pioglitazone, rosiglitazone) are known for this side effect.
• Certain antidepressants (particularly MAOIs and tricyclics), steroids (prednisone), and some chemotherapy drugs can also lead to ankle swelling.

Mechanism of Action

These medications typically cause swelling by altering kidney function, affecting sodium retention, changing blood vessel permeability, or disrupting hormonal balance that regulates fluid distribution.

Management

If you experience ankle swelling while taking any medication, don't stop taking it without consulting your healthcare provider, as they may adjust your dosage, switch to an alternative medication, or recommend lifestyle modifications like reducing salt intake, elevating your legs, or wearing compression stockings to manage the swelling, as suggested in the management of heart failure patients with diuretic resistance 1.

From the FDA Drug Label

Mild to moderate peripheral edema occurs in a dose-dependent manner with nifedipine extended-release tablets. The placebo subtracted rate is approximately 8% at 30 mg, 12% at 60 mg and 19% at 90 mg daily This edema is a localized phenomenon, thought to be associated with vasodilation of dependent arterioles and small blood vessels and not due to left ventricular dysfunction or generalized fluid retention Edema 1.8 3.0 10.8 0.6 For several adverse experiences that appear to be drug and dose related, there was a greater incidence in women than men associated with amlodipine treatment as shown in the following table: Amlodipine Placebo Male=% (N=1218) Female=% (N=512) Male=% (N=914) Female=% (N=336) Edema 5.6 14.6 1.4 5.1

Medications that cause ankle swelling

• Nifedipine: causes peripheral edema in a dose-dependent manner, with a placebo-subtracted rate of approximately 8% at 30 mg, 12% at 60 mg, and 19% at 90 mg daily 2
• Amlodipine: causes edema, with an incidence of 1.8% at 2.5 mg, 3.0% at 5 mg, and 10.8% at 10 mg, and a greater incidence in women than men 3

From the Research

Medications Causing Ankle Swelling

• Amlodipine is known to cause pedal oedema, but the frequency of this side effect can be reduced by using half of the maximum recommended dosage 4
• Dihydropyridine calcium channel blockers (DHPCCBs) can cause peripheral edema, particularly in the lower limbs, with nifedipine having the highest risk and lacidipine having the lowest risk 5
• Combination therapy with a calcium antagonist and an ACE inhibitor can reduce the risk of peripheral edema compared to calcium antagonist monotherapy 6
• Amlodipine and nifedipine can cause edema, with high-dose monotherapy having a higher incidence of edema compared to combination therapy with an ACE inhibitor 6
• Interactions between antidepressants and medications used to treat cardiovascular disorders can also cause ankle swelling, with combinations of fluoxetine, sertraline, and paroxetine with amlodipine resulting in intensified side effects such as swelling of the lower limbs 7

Management of Ankle Swelling

• Reducing the dosage of the medication can help minimize side effects 4
• Switching to a different medication, such as lercanidipine or lacidipine, can also help reduce the risk of peripheral edema 4, 5
• Adding or increasing the dosage of an ACE inhibitor or angiotensin II receptor blocker can help reduce the risk of peripheral edema 4, 5
• Administering the medication at night can also help minimize side effects 4