Drug-Induced Edema

(Full update April 2024)

Awareness of medication-induced edema among clinicians is important to reduce unnecessary testing or treatments.15 For drug-induced edema caused by sodium and fluid retention, diuretics may be an option. But for drugs that cause edema through other mechanisms (e.g., drugs causing peripheral edema) diuretics may worsen the problem by causing volume depletion and associated stimulation of the renin-aldosterone system (resulting in sodium/water retention).16 Drugs that cause sodium and fluid retention can cause or exacerbate heart failure, and peripheral edema may lead to nonadherence or reduce quality of life.1,2,15 The chart below lists select drugs associated with edema. Mechanism, incidence, risk factors, onset, and clinical presentation are described if available. Management suggestions are also provided. In general, for dose-dependent edema, reduce the dose if possible, and look for interacting drugs that may be increasing the drug’s levels. Nonspecific interventions that may be appropriate for peripheral edema include limb elevation, use of compression stockings, and movement.11 Advise patients to protect edematous areas from pressure or injury, and to contact their prescriber in the event of pain, discoloration, sores, or shortness of breath.11

Clinically Pertinent Information for Select Drugs or Drug Class Associated with Edema

Abemaciclib (Verzenio)

  • Mild peripheral edema in 12% of patients when used with fluvestrant.8

Abiraterone (Zytiga)

  • Increases mineralocorticoid production via inhibition of CYP17, leading to sodium and water retention.8
  • Edema (general or peripheral) occurs in >25% of patients.13
  • Consider co-administration with a corticosteroid to suppress adrenocorticotropic hormone production.8

Alpha-blockers (doxazosin, prazosin, terazosin, tamsulosin)

  • May stimulate renin-angiotensin aldosterone system, resulting in sodium and fluid retention.1 Incidence of edema (usually described as peripheral) may be as high as 5%.8
  • Caution using with diuretic; may increase risk of orthostatic hypotension.14
  • May cause or worsen heart failure.1

Antibiotics (parenteral ampicillin/sulbactam, azithromycin, metronidazole, nafcillin, oxacillin, piperacillin/tazobactam, ticarcillin/clavulanate potassium; oral erythromycin ethylsuccinate)1

  • Sodium load (e.g., piperacillin/tazobactam 256 mg [11 mEq]/4.5 g)1
  • A sodium chloride-containing intravenous solution, if used to administer the antibiotic, is an additional source of sodium.1

Antidepressants

  • Peripheral edema incidence may be as high as 2% to 3% with mirtazapine and trazodone, respectively.9 Reported with all antidepressant classes.9
  • Risk factors may include older age, female gender, rapid titration, and higher dose.9
  • Mechanism may involve vasodilation caused by antagonism of alpha adrenergic and serotonin 5-HT2Areceptors.9
  • Consider dose reduction or discontinuation.9

Aromatase inhibitors (e.g., anastrozole, letrozole)

  • Peripheral edema incidence about 5%.8 May also cause generalized edema. Unspecified edema incidence may approach 20% with extended letrozole therapy.8 
  • Reports of heart failure with letrozole.8

Buprenorphine

  • Incidence of peripheral edema may be as high as 5%.8
  • Mechanism unknown. Consider dose reduction. Look for interacting medications (e.g., CYP3A4 inhibitors) that may increase levels.

Calcium channel blockers, dihydropyridine (e.g., amlodipine, etc)

  • Dose-dependent.2 Incidence of peripheral edema may be as high as 80% with high doses.2
  • Major cause of non-adherence.2
  • Mechanism is thought to be arteriolar dilatation.2 The resulting pressure gradient between arteriole and venule capillaries pushes fluid into the interstitial space.2
  • Red blood cells may leak into interstitial space, causing a petechial rash or skin discoloration.2
  • Add an ACEI or ARB (if otherwise clinically appropriate) to a dihydropyridine CCB to balance pressure gradient [Evidence level A-2].2 Diuretics are ineffective.2 Screen for drugs that may increase dihydropyridine CCB levels (e.g., CYP3A4 inhibitors).8

Dopamine agonists for Parkinson’s disease (e.g., pramipexole)

  • Incidence of peripheral edema is approximately 15%.15 Coronary artery disease may be a risk factor.15
  • Most common with pramipexole.6 Incidence increases with duration of use.6 Seems to be dose-dependent.17
  • Mechanism may involve dopaminergic effects on the sympathetic nervous system or sodium transport.9
  • Consider dose reduction.17 Diuretics generally ineffective.17

Docetaxel

  • Lower extremity edema and redness may progress to desquamation or scleroderma-like skin reactions.8 Peripheral edema might also present in the upper extremity on the mastectomy side.8 May also cause generalized edema.8
  • Incidence is related to cumulative dose.8
  • Mechanism may be capillary leak syndrome.8
  • Consider corticosteroid premedication to delay onset and reduce severity.8 Consider salt restriction and diuretics.8

Gabapentinoids (pregabalin, gabapentin)

  • Mechanism of peripheral edema may be calcium channel blockade.1
  • Dose-dependent.8,19 With gabapentin, risk is higher with daily doses ≥1,800 mg (7.4% vs 1.7% with doses <1,800 mg/day).19 With pregabalin, risk is as high as about 27% at daily doses of 300 to 600 mg.8
  • May occur within the first week of use.1
  • May cause or worsen heart failure.1

Gastrointestinal Drugs (omeprazole/sodium bicarbonate, polyethylene glycol powder bowel preps, ranitidine injection pre-mix, sodium phosphates enema, sodium polystyrene sulfonate suspension, sodium zirconium cyclosilicate)1,5

  • Sodium load (e.g., ranitidine 225 mg [9.8 mEq]/50 mg)1
  • May cause or worsen heart failure.1
  • Also see proton pump inhibitors, below.

Insulin

  • Rare.3 May cause peripheral (more common) or generalized edema.3
  • Occurs shortly after starting or intensifying insulin.3
  • Patients with lower body weight may be at higher risk.3
  • May be caused by an antinatriuretic effect of insulin in the face of increased capillary permeability caused by chronic hyperglycemia.3
  • Consider salt and fluid restriction, and diuretic.3 May resolve spontaneously.3

Interleukin-2 (Aldesleukin [Proleukin])

  • Causes increased capillary permeability.8 Administered in an inpatient setting by a specialized team, with cardiac monitoring.12
  • Can result in peripheral edema, pulmonary edema, hypotension, and decreased organ perfusion.8
  • Patients may experience a 5% to 10% increase in body weight during the week of administration (e.g., one to two pounds per day is expected).7 Daily weights are important to ensure adequate fluid replacement to maintain renal perfusion.7
  • Hypotension (nadir four to six hours post-dose) is managed by experienced team with vasopressors, and judicious fluid administration, and holding the next dose.7,12
  • Peripheral edema is usually just a patient comfort issue, but it may cause upper extremity peripheral nerve entrapment.7 Can be managed with elevation, compression, and reduced fluid administration in later cycles.7
  • Diuretics may be used to treat pulmonary edema, or peripheral edema if patients are uncomfortable.7 Some centers administer diuretics before discharge, with a goal weight within 5 pounds of admission weight; others send patients home with a diuretic prescription.7 Diuretics are generally not effective until six to eight hours after the last interleukin-2 dose.7

Methyldopa

  • Can cause sodium and fluid retention.8
  • Generally use with a diuretic.8,10

NSAIDs (COX-2 selective and nonselective)1

  • Prostaglandin inhibition causing sodium and water retention. Blunted response to diuretics.1
  • May occur within the first week of use.1
  • May cause or worsen heart failure.1 Even over-the-counter NSAIDs, especially at high doses, can worsen heart failure, necessitating hospitalization.1

Pemetrexed (Alimta,Pemfexy, generics)

  • Peripheral edema may involve redness, pain, itching, hyperpigmentation, purpura, and/or erysipelas-like lesions.4,21
  • May be caused by movement of drug into the interstitial space, causing hypersensitivity and vasculitis.4
  • Consider dose reduction, topical corticosteroids, systemic corticosteroids (prophylaxis or treatment).4,22 To mobilize the fluid, consider elevation, compression, massage, and physical therapy.4

Proton pump inhibitors

  • Peripheral edema reported in females who are slow metabolizers.20
  • Appears to be dose-dependent.20
  • Mechanism may involve interference with female hormone-mediated fluid regulation.20
  • Consider dose reduction. Look for interacting medications (e.g., CYP2C19 inhibitors) that may increase levels.

Raloxifene

  • Peripheral edema may occur in up to about 15% of patients.8

Thiazolidinediones (pioglitazone, rosiglitazone)

  • Fluid retention, perhaps due to calcium channel blockade.1
  • Edema is dose-dependent.18 Peripheral edema may be accompanied by macular edema.8 For pioglitazone, edema (includes peripheral edema), occurs in 2.5% of patients treated with 15 mg as monotherapy up to 26.1% of patients treated with 45 mg plus insulin.18
  • Consider dose reduction. Look for interacting medications (e.g., CYP3A4 inhibitors) that may increase levels.
  • May cause or worsen heart failure.1

Vasodilators

  • Minoxidil and hydralazine are potent arterial vasodilators causing edema (including peripheral edema, and even ascites).8
  • Generally use with a diuretic.8,10

Abbreviations: ACEI = angiotensin-converting enzyme inhibitor, ARB = angiotensin receptor blocker; CCB = calcium channel blocker

Levels of Evidence

In accordance with our goal of providing Evidence-Based information, we are citing the LEVEL OF EVIDENCE for the clinical recommendations we publish.

Level

Definition

Study Quality

A

Good-quality patient-oriented evidence.*
  1. High-quality randomized controlled trial (RCT)
  2. Systematic review (SR)/Meta-analysis of RCTs with consistent findings
  3. All-or-none study

B

Inconsistent or limited-quality patient-oriented evidence.*
  1. Lower-quality RCT
  2. SR/Meta-analysis with low-quality clinical trials or of studies with inconsistent findings
  3. Cohort study
  4. Case control study

C

Consensus; usual practice; expert opinion; disease-oriented evidence (e.g., physiologic or surrogate endpoints); case series for studies of diagnosis, treatment, prevention, or screening.

*Outcomes that matter to patients (e.g., morbidity, mortality, symptom improvement, quality of life).

[Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69:548-56. https://www.aafp.org/pubs/afp/issues/2004/0201/p548.html.]

References

  1. Page RL 2nd, O'Bryant CL, Cheng D, et al. Drugs That May Cause or Exacerbate Heart Failure: A Scientific Statement From the American Heart Association. Circulation. 2016 Aug 9;134(6):e32-69. Erratum in: Circulation. 2016 Sep 20;134(12):e261.
  2. Makani H, Bangalore S, Romero J, et al. Effect of renin-angiotensin system blockade on calcium channel blocker-associated peripheral edema. Am J Med. 2011 Feb;124(2):128-35.
  3. Vasigh M, Hopkins R. Insulin edema after initiation of hybrid closed-loop insulin pump therapy with continuous glucose monitoring: a case report. Clin Diabetes Endocrinol. 2022 Sep 30;8(1):6.
  4. Doyle T, Fay CJ, Pisano C, LeBoeuf NR. Edema of the face and extremities secondary to pemetrexed. JAAD Case Rep. 2023 May 18;38:20-22.
  5. Product information for Lokelma. AstraZeneca. Wilmington, DE 19850. February 2024.
  6. Kim R, Jeon B. Nonmotor Effects of Conventional and Transdermal Dopaminergic Therapies in Parkinson's Disease. Int Rev Neurobiol. 2017;134:989-1018.
  7. Dutcher JP, Schwartzentruber DJ, Kaufman HL, et al. High dose interleukin-2 (Aldesleukin) - expert consensus on best management practices-2014. J Immunother Cancer. 2014 Sep 16;2(1):26.
  8. Clinical Pharmacology powered by ClinicalKey. Tampa (FL): Elsevier. 2024. http://clinicalkey.com. (Accessed March 30, 2024).
  9. Joseph JT, Vishwanath R, Praharaj SK. Peripheral edema associated with antidepressant use: Systematic review of case reports. Hum Psychopharmacol. 2023 Nov;38(6):e2884.
  10. Cheng JW. Essential hypertension. In: Zeind CS, Carvalho MG, editors. Applied Therapeutics: the Clinical Use of Drugs. 11th ed. Philadelphia, PA: Wolters Kluwer Health, 2018: 132-61.
  11. Cleveland Clinic. Edema. Last reviewed May 17, 2022. https://my.clevelandclinic.org/health/diseases/12564-edema. (Accessed April 2, 2024).
  12. Weber JS, Yang JC, Atkins MB, Disis ML. Toxicities of Immunotherapy for the Practitioner. J Clin Oncol. 2015 Jun 20;33(18):2092-9.
  13. Product information for Zytiga. Janssen Biotech. Horsham, PA 19044. August 2021.
  14. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. U.S. Department of Health and Human Services. August 2004. https://www.nhlbi.nih.gov/sites/default/files/media/docs/jnc7full.pdf. (Accessed April 2, 2024).
  15. Kleiner-Fisman G, Fisman DN. Risk factors for the development of pedal edema in patients using pramipexole. Arch Neurol. 2007 Jun;64(6):820-4.
  16. Trayes KP, Studdiford JS, Pickle S, Tully AS. Edema: diagnosis and management. Am Fam Physician. 2013 Jul 15;88(2):102-10.
  17. Tan EK, Ondo W. Clinical characteristics of pramipexole-induced peripheral edema. Arch Neurol. 2000 May;57(5):729-32.
  18. Prescribing information for Actos. Takeda Pharmaceuticals America. Lexington, MA 02421. June 2020.
  19. Parsons B, Tive L, Huang S. Gabapentin: a pooled analysis of adverse events from three clinical trials in patients with postherpetic neuralgia. Am J Geriatr Pharmacother. 2004 Sep;2(3):157-62.
  20. Brunner G, Athmann C, Boldt JH. Reversible pheripheral edema in female patients taking proton pump inhibitors for peptic acid diseases. Dig Dis Sci. 2001 May;46(5):993-6.
  21. Galetta D, Silvestris N, Catino A, Colucci G. Peripheral skin edema as unusual toxicity in three patients with advanced non-small cell lung cancer treated with pemetrexed alone or in combination with cisplatin. J Thorac Oncol. 2011 Nov;6(11):1964.
  22. Horton LA, Lyons AB, Kwa MC, et al. Pemetrexed-Induced Pseudocellulitis: A Diagnostic Conundrum. Cureus. 2024 Jan 11;16(1):e52114.

Cite this document as follows: Clinical Resource, Drug-Induced Edema. Pharmacist’s Letter/Pharmacy Technician’s Letter/Prescriber Insights. April 2024. [400462]


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