Can pilocarpine cause fever in patients, particularly older adults or those with compromised immune systems?

Does Pilocarpine Cause Fever?

No, pilocarpine does not directly cause fever as a recognized adverse effect. Fever is not listed among the documented adverse reactions in the FDA drug label or major clinical guidelines addressing pilocarpine use, and the most common side effects are related to its cholinergic activity (sweating, nausea, rhinitis, flushing, and urinary frequency) rather than pyrogenic effects 1.

Evidence from FDA Drug Label and Clinical Guidelines

The FDA-approved pilocarpine drug label comprehensively documents adverse reactions from controlled trials involving over 600 patients and does not include fever as a reported adverse event 1. The most frequent adverse effects are:

• Sweating (40-68% of patients) - the most common side effect and leading cause of discontinuation 1
• Nausea (9-15%) 1
• Rhinitis (7-14%) 1
• Urinary frequency (10-12%) 1
• Flushing/vasodilation (9-13%) 1
• Chills (4-15%) - notably distinct from fever 1

Important distinction: While chills are reported in 4-15% of patients, these represent a cholinergic side effect rather than true fever and are not accompanied by documented temperature elevation 1.

Clinical Context: Chills vs. Fever

The occurrence of chills with pilocarpine does not indicate fever 1. Multiple ophthalmology and rheumatology guidelines addressing pilocarpine use in dry eye syndrome and Sjögren's syndrome extensively discuss adverse effects but never mention fever as a concern 2.

The 2024 EULAR recommendations for Sjögren's syndrome management specifically address pilocarpine and cevimeline as oral muscarinic agonists, noting that "cevimeline may have fewer adverse systemic side effects than oral pilocarpine," but fever is not among the discussed adverse effects 2.

Rare Adverse Events and Hyperthermia Considerations

In rare case reports (affecting <1% of patients), the FDA label documents "hypothermia" rather than fever, with causal relation listed as unknown 1. One pediatric case series found that pilocarpine iontophoresis sweat testing was used to diagnose oligohydrosis caused by topiramate, which led to hyperthermia in that context - but this represents pilocarpine as a diagnostic tool, not as a causative agent of fever 3.

Critical distinction: Hyperthermia from impaired heat dissipation (as seen with anticholinergic agents that reduce sweating) is mechanistically opposite to pilocarpine's effect, which is cholinergic and increases sweating 3.

Drug-Induced Fever: General Considerations

While drug-induced fever is a recognized phenomenon with certain medications (most commonly penicillins, cephalosporins, antituberculars, quinidine, procainamide, methyldopa, and phenytoin), pilocarpine is not among the agents associated with this reaction 4. Drug-induced fever typically:

• Occurs 7-10 days after drug initiation (mean lag time 21 days, median 8 days) 4
• Represents a hypersensitivity reaction 4
• Resolves upon drug discontinuation 4

Pilocarpine is not documented in the literature as causing drug-induced fever 4.

Clinical Recommendations

If a patient on pilocarpine develops fever:

• Do not attribute the fever to pilocarpine - investigate other causes including infection, underlying disease activity (particularly in Sjögren's syndrome patients), or other medications 2
• Continue pilocarpine unless other contraindications arise - fever alone is not an indication to discontinue 1
• Distinguish chills from fever - chills without documented temperature elevation ≥38°C (100.4°F) are an expected cholinergic effect and do not require intervention beyond patient reassurance 1

Common Pitfalls to Avoid

• Do not confuse chills with fever - chills are a documented cholinergic side effect occurring in 4-15% of patients but are not associated with temperature elevation 1
• Do not mistake sweating for fever - excessive sweating (40-68% incidence) is the most common pilocarpine side effect but represents cholinergic stimulation of sweat glands, not pyrexia 1, 5
• Do not overlook concurrent medications - if fever develops, consider other recently initiated drugs that are actually associated with drug-induced fever 4