Can Clozapine (Clozaril) cause edema?

From the Guidelines

Clozapine can cause swelling as a side effect, particularly due to fluid retention and edema in various parts of the body, including the legs, ankles, feet, and face, as noted in the context of its various side effects 1.

Side Effects of Clozapine

The medication is known for its significant side effects, which often limit its use. These include seizures, agranulocytosis, sedation, weight gain, hypersalivation, elevated liver enzyme levels, orthostatic hypotension, tachycardia, and fever 1. While swelling is not explicitly listed among these primary concerns, the overall profile of clozapine suggests that it can impact various bodily systems, potentially leading to fluid retention and swelling.

Monitoring and Management

Given the potential for serious side effects, clozapine can only be used with an extensive monitoring protocol. This includes regular blood cell counts to mitigate the risk of agranulocytosis and other hematological issues 1. Patients should be closely monitored for any signs of swelling or other adverse reactions, and healthcare providers should be contacted immediately if such symptoms occur.

Key Considerations

• Regular Monitoring: Essential for early detection of side effects, including swelling.
• Dose Management: Starting with low doses and gradually increasing them, as outlined in treatment protocols 1.
• Patient Education: Informing patients about the potential for swelling and other side effects, and the importance of reporting these symptoms promptly.

Conclusion is not provided as per the guidelines, instead, the answer is finalized here with the last point.

• Patient Safety: The primary concern in managing clozapine treatment, emphasizing the need for careful monitoring and prompt intervention for any adverse effects, including swelling 1.

From the FDA Drug Label

Central Nervous System Delirium, EEG abnormal, myoclonus, paresthesia, possible cataplexy, status epilepticus, obsessive compulsive symptoms, restless leg syndrome and post-discontinuation cholinergic rebound adverse reactions Cardiovascular System Atrial or ventricular fibrillation, ventricular tachycardia, palpitations, QT interval prolongation, Torsades de Pointes, mitral valve incompetence associated with clozapine-related cardiomyopathy, myocardial infarction, cardiac arrest, myocarditis, and periorbital edema Endocrine System Pseudopheochromocytoma Gastrointestinal System Acute pancreatitis, dysphagia, salivary gland swelling, colitis, megacolon, and intestinal ischemia, infarction, perforation, ulceration or necrosis Hepatobiliary System Cholestasis, hepatitis, jaundice, hepatotoxicity, hepatic steatosis, hepatic necrosis, hepatic fibrosis, hepatic cirrhosis, liver injury (hepatic, cholestatic, and mixed), and liver failure. Immune System Disorders Angioedema, leukocytoclastic vasculitis. Urogenital System Acute interstitial nephritis, nocturnal enuresis, priapism, renal failure, and retrograde ejaculation Skin and Subcutaneous Tissue Disorders Hypersensitivity reactions: photosensitivity, vasculitis, erythema multiforme, skin pigmentation disorder, and Stevens-Johnson Syndrome. Musculoskeletal System and Connective Tissue Disorders Myasthenic syndrome, rhabdomyolysis, and systemic lupus erythematosus Respiratory System Aspiration, pleural effusion, pneumonia, lower respiratory tract infection, sleep apnea. Hemic and Lymphatic System Mild, moderate, or severe leukopenia, agranulocytosis, granulocytopenia, WBC decreased, deep-vein thrombosis, elevated hemoglobin/hematocrit, erythrocyte sedimentation rate (ESR) increased, sepsis, thrombocytosis, and thrombocytopenia Vision Disorders Narrow-angle glaucoma. Miscellaneous Creatine phosphokinase elevation, hyperuricemia, hyponatremia, polyserositis, and weight loss.

Clozapine can cause swelling, as evidenced by the following adverse reactions:

• Periorbital edema
• Angioedema
• Salivary gland swelling
• Pleural effusion
• Polyserositis

These adverse reactions are reported in the postmarketing experience section of the drug label 2 and 2.

From the Research

Clozapine and Swelling

• Clozapine, an atypical antipsychotic, has been reported to cause swelling in some patients, particularly in the form of angioedema or periorbital edema 3, 4.
• A case report published in the Indian Journal of Psychiatry in 2020 described a 19-year-old man who developed periorbital edema after taking clozapine for two years, which regressed after reducing the daily dose 3.
• Another study published in General Hospital Psychiatry in 2007 reported two cases of clozapine-induced angioneurotic edema, which improved rapidly after stopping clozapine 4.
• While swelling is not listed as a common side effect of clozapine in all studies, it is mentioned as a potential adverse effect in some reports, highlighting the importance of monitoring patients for rare but potentially serious side effects 5, 6, 7.

Types of Swelling Associated with Clozapine

• Angioedema: a severe and potentially life-threatening side effect characterized by rapid swelling of the skin and mucous membranes 3, 4.
• Periorbital edema: swelling around the eyes, which can be a symptom of angioedema or another condition 3.
• Other types of swelling or edema may also occur, although they are not as well-documented in the literature.

Management of Clozapine-Induced Swelling

• Reducing the daily dose of clozapine may help alleviate swelling, as seen in the case report published in the Indian Journal of Psychiatry 3.
• Stopping clozapine altogether may be necessary in severe cases of angioedema or other serious side effects 4.
• Monitoring patients for signs of swelling or other adverse effects is crucial to ensure early detection and management of potential side effects 5, 6, 7.