Pheniramine maleate

What it is

Pheniramine maleate is a first-generation (sedating) H1-antihistamine with anticholinergic properties, sold as the maleate salt. In the United States it is almost entirely an ophthalmic product: a 0.3% eye drop combined with the vasoconstrictor naphazoline hydrochloride 0.025% for itchy, red allergic eyes. It also appears as an oral ingredient at 20 mg in United States cold and sore throat hot-drink packets alongside acetaminophen and phenylephrine. Outside the United States it is additionally given by injection for allergic reactions, and that intravenous form is the subject of a documented misuse and dependence literature, mostly from South Asia.

What the research says

The evidence base is thin and narrow, and it should be reported that way. The ophthalmic combination with naphazoline is the only use with randomised human trials behind it: two conjunctival allergen challenge studies, 83 and 72 subjects, both showing the combination beats placebo within 20 minutes, with pheniramine itself accounting for the relief of itching and naphazoline for the relief of redness. There is no long-term ophthalmic trial, no trial of pheniramine eye drops in real-world seasonal allergy over weeks, and no modern randomised trial of oral or intravenous pheniramine that we could find. What the literature does contain in volume is harm: a narrative review of misuse and dependence, a fatal rhabdomyolysis and acute kidney injury case at 4.077 g, supraventricular tachycardia at an ordinary therapeutic dose, hypersensitivity to pheniramine itself, and the label's warning that a child who swallows the eye drops may become comatose and hypothermic.

Evidence grade: Limited evidence.

How it works

Drug class: First-generation (sedating) H1-antihistamine with anticholinergic properties; the US product is a topical ocular antihistamine combined with a vasoconstrictor

Pheniramine blocks histamine H1-receptors, acting as an inverse agonist at them rather than a simple blocker. In the eye that blocks the histamine released by mast cells during an allergic reaction, which is what causes itching. It also has anticholinergic activity, which is why overdose produces a dry flushed skin, dilated pupils, a fast heart rate and urinary retention. In the ophthalmic product the antihistamine is paired with naphazoline, a vasoconstrictor, which is what reduces redness. (Source 1)

What it is used for

• Two randomised conjunctival allergen challenge trials support rapid onset: the combination scored significantly better than placebo at 7, 12 and 20 minutes and better than olopatadine at 12 and 20 minutes in one, and beat placebo, naphazoline alone and pheniramine alone for redness in the other. Both are short provocation studies in a laboratory model, not trials of a real allergy season, and neither ran beyond two hours. Evidence: limited. (Source 2)
• Cochrane found antihistamine-analgesic-decongestant combinations have at best a small general benefit in adults that is probably too small to matter for individual symptoms, no evidence of effectiveness in young children, and more adverse effects than control. No trial of this particular pheniramine combination was identified. Evidence: limited. (Source 3)
• Intravenous pheniramine is used outside the United States for allergic reactions, but we found no randomised trial of it. What the literature holds instead is harm: a narrative review of misuse and dependence concentrated in South Asia, a case of supraventricular tachycardia resistant to adenosine after a therapeutic dose, and reports of seizures and psychosis. Evidence: unknown. (Source 4)
• A 2026 case series is the only evidence. Its own author states that data supporting antihistamines as a treatment for hiccups are limited. A case series without a control group cannot show a drug works for a condition that is often self-limiting. Evidence: unknown. (Source 5)

Interactions

• Naphazoline, the vasoconstrictor it is formulated with (clinical trial): The two work on different symptoms. Pheniramine relieves the itch and naphazoline relieves the redness, and the combination was better than either alone for redness. The naphazoline also brings the risks of rebound redness with overuse and of coma and hypothermia if a child swallows the drops. (Source 6)
• Alcohol (label): The United States oral product label tells people to avoid alcoholic drinks while taking it and says alcohol, sedatives and tranquillisers may increase drowsiness. No study of pheniramine with alcohol was found; the nearest human experiment measured a different sedating antihistamine against alcohol in a driving simulator and found the antihistamine the more impairing of the two. Limit: This is a label position for the whole fixed combination of acetaminophen, pheniramine and phenylephrine, not for pheniramine alone, and it gives no rates. The same label also warns against 3 or more alcoholic drinks a day because of the acetaminophen. The ophthalmic label carries no alcohol warning. (Source 7)
• Monoamine oxidase inhibitors (MAOIs) (label): The United States oral combination label says not to use the product while taking a prescription MAOI, or for two weeks after stopping one. The label does not say which component the restriction is for. Limit: A do-not-use instruction for the fixed combination. The phenylephrine decongestant is the component usually behind an MAOI restriction, so this cannot be read as a pheniramine interaction on its own. (Source 7)
• Opioids and diazepam, in injection drug use (case reports): Pheniramine is reported to be mixed with opioids and diazepam and injected, particularly in South Asia, and the review that collected these reports lists seizures, psychosis and life-threatening toxicity among the complications. Limit: A narrative review of case reports and epidemiological surveys with no stated appraisal method; the comparison with lorazepam is asserted without a supporting figure in the abstract. (Source 4)
• Other anticholinergic medicines (clinical trial): Systemic pheniramine adds to total anticholinergic burden, which cohort studies associate with falls and fall-related injuries in older adults with impaired cognition. This is unlikely to apply to eye drops at labelled doses. Limit: A retrospective cohort rather than a trial; the closest honest design label is an observational study. Pheniramine is not named in it, and the quoted sentence is from the paper's Results section. (Source 8)
• Contact lenses (label): The ophthalmic label directs that contact lenses be removed before using the drops, and that the bottle tip not touch any surface, to avoid contamination. (Source 9)
• Food (theoretical): No food-effect study of pheniramine was found. The United States oral packet is dissolved in hot water and sipped while hot, which is a formulation instruction rather than a food interaction; the ophthalmic route bypasses the question. Limit: We searched Europe PMC for pheniramine pharmacokinetic and bioavailability work and found analytical chemistry methods rather than human food-effect studies. The absence of a study is the finding. (Source 7)
• Sedating supplements: valerian, melatonin, kava, St John's wort (theoretical): No human study of pheniramine with any sedating supplement exists in what we searched. Any concern is additive sedation with the systemic forms, inferred rather than measured, and would not be expected from eye drops at labelled doses. Limit: The source record prints "I-tryptophan" with a capital I where it means L-tryptophan, the amino acid; the quotation is faithful to the record and has not been corrected, but the substance named is L-tryptophan. Beyond that, the review covers those supplements taken alone, not with an antihistamine, and its search ran only to October 2002. (Source 10)

Stopping it

• The ophthalmic label gives no taper. It caps use at 4 times daily and tells people to stop and see a doctor if there is eye pain, a change in vision, or redness or irritation that worsens or lasts more than 72 hours. (Source 9)
• Continuing the drops past the labelled limit is counterproductive, because the label states that overuse makes eye redness worse. This rebound is attributed to the naphazoline decongestant rather than to pheniramine. (Source 9)
• The United States oral product gives no taper. Its label tells people to stop and ask a doctor if nervousness, dizziness or sleeplessness occurs, or if pain or nasal congestion gets worse or lasts more than 7 days. (Source 7)
• Dependence on pheniramine is documented, mainly with the injected form outside the United States, and the review that gathered those reports found the literature inadequate for judging how often withdrawal or dependence occurs. (Source 4)
• A 2026 scoping review of rebound itching and hives after stopping chronic antihistamines found reports only for cetirizine and levocetirizine and none for any other antihistamine, so a pheniramine discontinuation syndrome is neither documented nor excluded. (Source 11)

What goes wrong

A high oral dose of pheniramine caused fatal rhabdomyolysis with acute kidney injury despite haemodialysis and intensive care. (Source 12)

• Case report, Very low certainty.
• Size: 1 patient.
• Who: Young man after a very large single ingestion.
• How long: Index admission to death.
• Result: 4.077 g ingested; seizures, respiratory depression, non-traumatic rhabdomyolysis and acute kidney injury; death from multiorgan dysfunction syndrome.
• Funding: Not stated.

Limit of this finding: The same abstract states that pheniramine "has not been implicated as an important cause of rhabdomyolysis and acute kidney injury (AKI)" and then reports a fatal case of exactly that, and the paper is titled "Is it Fatal?" while describing a death. We have not corrected the source; read the case, not the framing.

We report a fatal case of a young male with a very high dose of consumption of pheniramine maleate (4.077 g), which was complicated by seizures, respiratory depression, nontraumatic rhabdomyolysis, and AKI.

The label records the anticholinergic toxic syndrome pheniramine produces at high dose. (Source 12)

• Case report, Very low certainty.
• Size: Background to a single case.
• Who: People taking pheniramine in overdose.
• How long: Not applicable.
• Result: Tachycardia, dilated pupils, urinary retention, dry flushed skin, decreased bowel sounds, confusion, mild temperature rise, cardiac arrhythmias and seizures at lethal doses.
• Funding: Not stated.

Limit of this finding: This is the introduction to a single case report, not a dose-response study. No incidence figures attach to any of these effects.

Pheniramine has antimuscarinic effect causing tachycardia, dilated pupils, urinary retention, and dry flushed skin, and decreased bowel sounds, confusion, mild increase in body temperature, cardiac arrhythmias, and seizures at lethal doses.

Supraventricular tachycardia resistant to adenosine occurred after an ordinary therapeutic dose of pheniramine. (Source 13)

• Case report, Very low certainty.
• Size: 1 patient.
• Who: 22-year-old woman given pheniramine for a food allergy.
• How long: Acute presentation.
• Result: Adenosine-resistant supraventricular tachycardia; the authors state the incidence of this at adult clinical doses is unknown.
• Funding: Not stated.

Limit of this finding: A single case. The authors themselves say the incidence is currently unknown, so this establishes that it can happen, not how often.

It is crucial to know that symptomatic SVT could occur with therapeutic doses of pheniramine.

Pheniramine misuse and dependence are documented, with misuse potential the review compares to lorazepam, and comorbid use reported in 15% to 80% of injection drug users in South Asian studies. (Source 4)

• Expert review, not systematic, Very low certainty.
• Size: More than 8 case reports plus epidemiological data, mostly South Asian.
• Who: People with substance use disorders, particularly injection drug users.
• How long: Literature to the review's search date.
• Result: Comorbid pheniramine use reported from around 15% to 80% in injection drug users; complications included seizures, psychosis and life-threatening toxicity.
• Funding: Not stated in the abstract.

Limit of this finding: A narrative review with no stated appraisal method and a 15-to-80% range so wide it mainly shows the underlying studies disagree. The review's own words are that pheniramine misuse "is not adequately studied in existing literature", and the comparison to lorazepam is asserted in the abstract without a supporting figure.

Studies on extent of its use are mainly from South Asia, which report comorbid use of pheniramine ranging from around 15% to 80% in injection drug users.

The review's own appraisal is that pheniramine misuse is not adequately studied and is under-reported by patients. (Source 4)

• Expert review, not systematic, Very low certainty.
• Size: Literature search of PubMed, Google Scholar and MedSearch.
• Who: People misusing pheniramine.
• How long: Not stated.
• Result: No quantitative estimate; the review reports under-reporting and easy accessibility as contributing factors.
• Funding: Not stated in the abstract.

However, pheniramine misuse is not adequately studied in existing literature.

Immediate hypersensitivity to pheniramine itself is possible, though the authors describe hypersensitivity to antihistamines as extremely rare. (Source 14)

• Case report, Very low certainty.
• Size: 1 patient.
• Who: Patient with multiple drug hypersensitivity syndrome who had reacted to diclofenac, paracetamol, an mRNA COVID-19 vaccine, clarithromycin and pheniramine.
• How long: Diagnostic workup with skin and provocation testing.
• Result: Diagnosis of multiple drug hypersensitivity with pheniramine allergy confirmed on skin and provocation testing.
• Funding: Not stated.

Limit of this finding: A single case in a patient already reacting to several unrelated drugs, so it is weak evidence about pheniramine specifically. The authors' own appraisal is that this is extremely rare.

While non-steroidal anti-inflammatory drugs and antibiotics are the most commonly implicated agents, hypersensitivity to antihistamines is extremely rare.

The ophthalmic label warns that a child who swallows the drops may become comatose and markedly hypothermic. (Source 9)

• Official position, Certainty not rated.
• Size: Not quantified.
• Who: Infants and children who accidentally swallow the eye drops.
• How long: Not applicable.
• Result: No rates given.
• Funding: Regulatory record, label effective 2024-03-27.

Limit of this finding: The naphazoline component is the agent usually blamed for coma and hypothermia after imidazoline ingestion; the label attributes the effect to the product, not to pheniramine alone.

If swallowed, get medical help or contact a Poison Control Center right away. Accidental swallowing by infants and children may lead to coma and marked reduction in body temperature.

The ophthalmic label warns that overuse of the product makes eye redness worse, and that pupils may enlarge temporarily causing light sensitivity. (Source 9)

• Official position, Certainty not rated.
• Size: Not quantified.
• Who: People using the drops more than directed.
• How long: Not applicable.
• Result: No rates given; the label caps use at 4 times daily and tells people to stop if redness lasts more than 72 hours.
• Funding: Regulatory record, label effective 2024-03-27.

Limit of this finding: Rebound redness from decongestant eye drops is attributed to the naphazoline, not to the antihistamine.

pupils may become enlarged temporarily causing light sensitivity overuse may cause more eye redness

In a Cochrane review, more people on antihistamine-decongestant cold combinations reported an adverse effect than on control, though the review’s own odds ratio for that comparison was not statistically significant. (Source 3)

• Systematic review, Moderate certainty.
• Size: 842 participants in the antihistamine-decongestant adverse-effect analysis within a review of 30 studies and 6,304 participants.
• Who: Children and adults with the common cold.
• How long: 3 to 10 days.
• Result: 128/419 versus 100/423 participants suffered one or more adverse effects, odds ratio 1.58 (95% CI 0.78 to 3.21)
• Funding: Cochrane review; indexed as Research Support, Non-U.S. Gov't.

Limit of this finding: None of the pooled trials is identified as using pheniramine, so this is evidence about the product category, not this ingredient. The review also prints the control figure as "100/423 (13%)" when 100 of 423 is 23.6 per cent, and it calls the difference "more adverse effects" although its own 95% confidence interval, 0.78 to 3.21, includes 1. Quoted as printed; read the fractions and treat the comparison as not statistically significant.

Adverse effects: the antihistamine-decongestant group experienced more adverse effects than the control group: 128/419 (31%) versus 100/423 (13%) participants suffered one or more adverse effects (OR 1.58, 95%CI 0.78 to 3.21; moderate certainty of evidence).

Sedating first-generation antihistamines impair driving more than alcohol at roughly the legal limit. (Source 15)

• Randomized trial, Moderate certainty.
• Size: 40 licensed drivers.
• Who: Licensed drivers aged 25 to 44 with seasonal allergic rhinitis.
• How long: Four single-dose periods a week apart, 1 hour of simulated driving each.
• Result: Overall driving performance poorest after diphenhydramine 50 mg, worse than after alcohol at about 0.1% blood alcohol concentration; self-reported drowsiness did not predict impairment.
• Funding: Research Support, Non-U.S. Gov't and Research Support, U.S. Gov't, P.H.S.; the trial compares a non-sedating competitor product.

Limit of this finding: Diphenhydramine, not pheniramine, and systemic dosing rather than eye drops. This applies to oral and intravenous pheniramine as class evidence and is of doubtful relevance to the eye drops.

After participants took diphenhydramine, driving performance was poorest, indicating that diphenhydramine had a greater impact on driving than alcohol did.

Older inpatients cared for by physicians prescribing first-generation antihistamines more often had higher odds of in-hospital delirium. (Source 16)

• Survey study, Low certainty.
• Size: 328,140 admissions, 755 physicians.
• Who: General medicine inpatients aged 65 and over, 17 Ontario hospitals, 2015-2022.
• How long: 7 years of admissions.
• Result: Delirium in 32.3% of admissions in the lowest-prescribing quartile versus 36.6% in the highest; adjusted OR 1.41 (95% CI 1.28-1.56) highest versus lowest quartile.
• Funding: Research Support, Non-U.S. Gov't.

Limit of this finding: Exposure is measured as a physician's prescribing rate rather than individual patient exposure, and the agents are not broken out, so pheniramine's own contribution is unknown. Pheniramine is also not commonly used as a systemic drug in Ontario.

Delirium occurred in 32.3% of admissions to the lowest-prescribing quartile and 36.6% of the highest-prescribing quartile of physicians.

A systematic review of over-the-counter medicine misuse found antihistamines among the drugs that can induce psychotic symptoms when abused. (Source 17)

• Systematic review, Very low certainty.
• Size: 46 studies from an initial 2,677 articles.
• Who: People misusing over-the-counter antihistamines, cough medicines and decongestants.
• How long: Varied; mostly case material.
• Result: Paranoia, hallucinations and thought disorders reported.
• Funding: Not stated in the abstract; PROSPERO CRD42024527558.

Limit of this finding: The review's stated search terms were diphenhydramine, promethazine, chlorpheniramine and dimenhydrinate; pheniramine was not among them. The pheniramine misuse review separately reports psychosis among the complications in its case reports.

Key findings indicate that antihistamines, dextromethorphan, and other OTC drugs can induce psychotic symptoms, such as paranoia, hallucinations, and thought disorders when abused.

A professional body holds that first-generation antihistamines have an unfavourable risk-benefit profile and should not be first-line for allergy. (Source 18)

• Official position, Certainty not rated.
• Size: Not applicable.
• Who: People with allergic rhinitis and chronic urticaria.
• How long: Not applicable.
• Result: No rates given; the statement reports deaths from accidents, overdoses and sudden cardiac death with this class and recommends newer agents instead.
• Funding: Canadian Society of Allergy and Clinical Immunology position statement, 2019.

Limit of this finding: A position dated 2019, not a measurement, and it addresses oral antihistamines for rhinitis and urticaria rather than ophthalmic pheniramine. Its examples are diphenhydramine and hydroxyzine.

High-quality trials have proven that newer generation AHs are superior in safety compared to older first-generation AHs.

The Beers Criteria exist as a dated expert list of medicines generally best avoided in people 65 and over, which is the framework under which sedating antihistamines are usually judged in older adults. (Source 19)

• Official position, Certainty not rated.
• Size: Not applicable.
• Who: Adults 65 years and older in ambulatory, acute and institutional care, excluding hospice and end-of-life care.
• How long: Not applicable.
• Result: No effect estimate; the criteria are an explicit list, updated on a cycle, with the 2023 update reviewing evidence published since 2019.
• Funding: Produced by an interprofessional expert panel convened by the American Geriatrics Society.

Limit of this finding: The abstract of the 2023 update does not itself name pheniramine or any other drug, so we cannot and do not assert from this source that pheniramine appears on the list. It is recorded here only as the dated position that frames the question, and the cohort studies on dementia, delirium and falls are the evidence behind it.

The AGS Beers Criteria® is an explicit list of PIMs that are typically best avoided by older adults in most circumstances or under specific situations, such as in certain diseases or conditions.

What the evidence supports

In a conjunctival allergen challenge trial, pheniramine with naphazoline relieved the signs and symptoms of ocular allergy better than placebo and, at 12 and 20 minutes, better than olopatadine. (Source 2)

• Randomized trial, Low certainty.
• Size: 83 subjects.
• Who: Adults aged 20 to 70 (mean 42.5 years), 61.4% female, 94.0% white, single centre, with an established ocular allergic reaction.
• How long: Single dose given 10 minutes before challenge; outcomes at 7, 12 and 20 minutes.
• Result: Ocular allergy index significantly lower than placebo at all 3 time points (all P < 0.001); significantly lower than olopatadine at 12 minutes (P = 0.005) and 20 minutes (P = 0.001)
• Funding: Indexed as Research Support, Non-U.S. Gov't; a comparison of an over-the-counter product against a prescription competitor, with no funder named in the abstract.

Limit of this finding: A 20-minute laboratory provocation model designed to test onset of action. It says nothing about how the drops perform over a day, a week or an allergy season, and it compares onset only, which is the end point that favours a vasoconstrictor-containing product.

Both pheniramine/naphazoline and olopatadine were associated with significantly lower OAI scores than placebo at all 3 time points (all, P < 0.001). OAI scores were significantly lower with pheniramine/naphazoline than with olopatadine at 12 and 20 minutes (P = 0.005 and P = 0.001, respectively).

What the evidence does not support

Cochrane found the benefit of antihistamine-analgesic-decongestant cold combinations probably too small to be clinically relevant, with no evidence of effectiveness in young children. (Source 20)

• Systematic review, Low certainty.
• Size: 30 studies, 6,304 participants.
• Who: Children and adults with the common cold.
• How long: Varied.
• Result: Pooled global effect 52% on active treatment versus 34% on placebo, equivalent to less than one point on a four- or five-point scale; OR of treatment failure 0.47 (95% CI 0.33 to 0.67, low certainty), NNTB 5.6 (95% CI 3.8 to 10.2)
• Funding: Cochrane review.

We found a lack of data on the effectiveness of antihistamine-analgesic-decongestant combinations for the common cold. Based on these scarce data, the effect on individual symptoms is probably too small to be clinically relevant.

Where the evidence is mixed

In a second randomised challenge trial, the combination beat pheniramine alone for redness, while pheniramine alone accounted for the relief of itching. (Source 6)

• Randomized trial, Low certainty.
• Size: 72 patients, 24 per group.
• Who: Patients with a documented positive skin test or radioallergosorbent test, contralateral-eye design.
• How long: Single dose; outcomes at 10, 30 and 120 minutes, with rechallenge at 120 minutes.
• Result: The combination was significantly more effective than placebo, naphazoline and pheniramine at reducing redness; the combination and pheniramine alone were equally effective for itching.
• Funding: Indexed as Research Support, Non-U.S. Gov't; a study of the branded combination, funder not named in the abstract.

Limit of this finding: This is the clearest statement in the literature of what pheniramine itself does and does not do: it treats the itch, not the redness. The abstract gives no numbers or confidence intervals for either comparison, only the direction of the result, so the size of the effect cannot be checked.

Naphcon-A was significantly more effective than placebo, naphazoline, and pheniramine in reducing redness. Naphcon-A and pheniramine were equally effective in relieving itching.

The only published evidence for intravenous pheniramine in persistent hiccups is a case series whose author states the supporting data are limited. (Source 5)

• Case series, Very low certainty.
• Size: A case series; the abstract does not state how many patients.
• Who: Patients with persistent hiccups.
• How long: Not stated in the abstract.
• Result: No effect estimate is given in the abstract.
• Funding: Not stated.

Limit of this finding: A case series with no control group, for a condition that is usually self-limiting, so improvement cannot be attributed to the drug. The abstract does not even state the number of patients.

there is limited data in the literature to support antihistamines as an effective treatment modality, and clinical data supporting their use are also limited.

Where the research disagrees

What pheniramine itself contributes to the eye drop, as distinct from the naphazoline it is combined with

• Dockhorn and Duckett, who tested the components separately, Double-masked randomised parallel-group placebo-controlled challenge study, 72 patients, contralateral-eye design, with each component tested alone: Naphcon-A was significantly more effective than placebo, naphazoline, and pheniramine in reducing redness. Naphcon-A and pheniramine were equally effective in relieving itching. (Source 6)
• Greiner and Udell, and the product label, which treat the fixed combination as the unit, Randomised double-masked contralateral challenge study of the fixed combination against a prescription comparator and placebo, 83 subjects, no single-component arm: Two treatment options currently indicated for acute ocular allergic reaction are pheniramine maleate 0.3%/naphazoline hydrochloride 0.025% ophthalmic solution, an over-the-counter antihistamine/vasoconstrictor combination (Source 21)

Whether pheniramine is an important cause of rhabdomyolysis and acute kidney injury

• Venugopal and colleagues, in their own introduction, Background assertion in a case report, with no cited frequency data: It has not been implicated as an important cause of rhabdomyolysis and acute kidney injury (AKI). Rhabdomyolysis causing AKI is rarely reported in the literature. (Source 12)
• The same authors, in the case they then report, Single fatal case report with haemodialysis and ventilator support: We report a fatal case of a young male with a very high dose of consumption of pheniramine maleate (4.077 g), which was complicated by seizures, respiratory depression, nontraumatic rhabdomyolysis, and AKI. (Source 12)

How much

• Reference intake: Dosing is set by the package or the prescriber. As a position, the Naphcon-A Drug Facts label effective 2024-03-27 directs 1 or 2 drops in the affected eye up to 4 times daily for adults and children 6 years and over, with children under 6 told to ask a doctor. The United States oral Drug Facts label effective 2016-03-31 directs one packet of acetaminophen 325 mg, pheniramine maleate 20 mg and phenylephrine hydrochloride 10 mg every 4 hours for adults and children 12 and over. No reference intake exists because pheniramine is a drug, not a nutrient. (Source 9)
• Upper limit: As a position, the ophthalmic label caps use at 4 times daily and directs people to stop and ask a doctor if redness or irritation lasts more than 72 hours. The United States oral label caps use at 6 packets in 24 hours and says the product is not to be used in a child under 4 years. No tolerable upper intake level exists because this is a drug. (Source 7)
• Studied: The conjunctival allergen challenge trial against olopatadine used pheniramine maleate 0.3% with naphazoline hydrochloride 0.025% ophthalmic solution, a single dose 10 minutes before challenge. (Source 21)
• Studied: The component-comparison challenge trial used one drop of naphazoline HCl 0.025% with pheniramine maleate 0.3%, or one drop of naphazoline, pheniramine or placebo in the other eye. (Source 6)
• Studied: The fatal overdose case involved an oral ingestion of 4.077 g of pheniramine maleate, which is more than 200 times a single 20 mg oral dose. (Source 12)

A common belief, and what the research shows

The belief: Allergy eye drops relieve redness because of the antihistamine in them.

What the research shows: In the one trial that separated the two ingredients, it was the other way round for redness. Dockhorn and Duckett gave 72 patients the combination in one eye and either naphazoline, pheniramine or placebo in the other, then challenged both eyes with ragweed, and reported that "Naphcon-A was significantly more effective than placebo, naphazoline, and pheniramine in reducing redness. Naphcon-A and pheniramine were equally effective in relieving itching." Pheniramine is what treats the itch; the naphazoline vasoconstrictor is what takes the red out, and it is also the component behind the label's warnings that "overuse may cause more eye redness" and that a child who swallows the drops may become comatose and hypothermic. The abstract gives no numbers for either comparison, only the direction, so this reads the result as published rather than as a measured effect size.

Questions and answers

What is it?

Pheniramine maleate is a medicine, not a nutrient: a first-generation sedating antihistamine with anticholinergic activity. In the United States you will almost always meet it as a 0.3% eye drop paired with the vasoconstrictor naphazoline 0.025% for itchy, red allergic eyes, and sometimes as a 20 mg oral ingredient in cold and sore throat hot-drink packets. Outside the United States it is also given by injection. (Source 21)

What does it do in the body?

It blocks histamine H1-receptors. In the eye that blocks the histamine released during an allergic reaction, which is what relieves itching; in the one trial that tested the ingredients separately, pheniramine accounted for the relief of itching while the naphazoline accounted for the relief of redness. It also has an anticholinergic action, which is why overdose produces a fast heart rate, dilated pupils, dry flushed skin, urinary retention and confusion. (Source 6)

Is it good or bad for you?

For short-term relief of allergic eye itching the evidence is favourable but narrow: two randomised challenge trials showing the combination works within 20 minutes, with no trial beyond two hours and none across a real allergy season. For colds, the combination products it appears in give at best a benefit Cochrane calls probably too small to be clinically relevant, with more adverse effects than control. For intravenous use there is no trial at all, and the published literature is dominated by harm: misuse and dependence, a fatal rhabdomyolysis case at 4.077 g, and supraventricular tachycardia after an ordinary therapeutic dose. (Source 4)

How do you get more of it?

There is no food or behaviour that increases it; it only enters the body as a medicine. In the United States that means the over-the-counter eye drops, used 1 or 2 drops up to 4 times daily in adults and children 6 and over, or an oral cold and sore throat hot-drink packet. This describes how it is supplied, not a recommendation to use it. (Source 9)

If it is harmful, what reduces it?

There is no antidote. The ophthalmic label directs anyone who swallows the drops to get medical help or call a poison control centre, and warns that in infants and children this can cause coma and a marked drop in body temperature. In the published oral overdose case, treatment was symptomatic and supportive with haemodialysis and ventilation, and the patient still died, so there is no reliable way to undo a large ingestion. (Source 12)

Why might someone be low in it or missing it?

The question does not apply in the form it takes for a nutrient. Pheniramine is synthetic, is not made by the body and is not present in food, so nobody can be deficient in it. For the systemic forms, how much of a dose reaches the blood does vary with age, sex and cytochrome P450 genetics, as a review of anticholinergic drug handling describes for the class. (Source 22)

Which whole foods contain it or feed it?

No whole food contains pheniramine. We found no study of whether food changes its absorption, and the only oral-formulation instruction we found is to dissolve the packet in hot water and sip it while hot, which is not an interaction with a meal. The ophthalmic route makes the question moot. (Source 7)

We searched: Europe PMC for pheniramine pharmacokinetic, bioavailability and food-effect studies, and the full DailyMed Drug Facts labels for the Naphcon-A ophthalmic solution and the United States Wal-Flu Cold and Sore Throat oral packet; only analytical chemistry and protein-binding work was found, with no human food-effect study.

What happens if you do not have it?

Nothing happens from not having pheniramine, because it is not a nutrient. Stopping it is only an issue after prolonged misuse, which is documented mainly for the injected form outside the United States. A 2026 scoping review of rebound itching and hives after stopping chronic antihistamines found reports only for cetirizine and levocetirizine and none for any other antihistamine, so a pheniramine withdrawal syndrome is neither documented nor ruled out. (Source 11)

How can you test for it?

There is no clinical test for pheniramine and no reference range to be low or high against. It can be measured in urine by gas chromatography as part of de-addiction monitoring and in alternative biological matrices by liquid chromatography tandem mass spectrometry, and analytical chemistry methods exist for quality control of the formulations, but these are forensic and laboratory assays rather than diagnostic ones. Nothing is gained by testing it in ordinary use. (Source 4)

We searched: Europe PMC for pheniramine assay, therapeutic drug monitoring, urine detection and alternative-matrix literature; the hits were analytical and forensic methods, including a gas chromatography urine method used in a de-addiction programme, with no validated clinical diagnostic test or reference interval.

References

1. Indian J Dermatol. Pharmacology of antihistamines.. 2013. PMID 23723474, DOI 10.4103/0019-5154.110832. Read the source
2. Clin Ther. A comparison of the clinical efficacy of pheniramine maleate/naphazoline hydrochloride ophthalmic solution and olopatadine hydrochloride ophthalmic solution in the conjunctival allergen challenge model (RESULTS section of the abstract). 2005. PMID 15978305, DOI 10.1016/j.clinthera.2005.04.011. Read the source
3. Cochrane Database Syst Rev. Oral antihistamine-decongestant-analgesic combinations for the common cold (MAIN RESULTS section of the abstract). 2022. PMID 35060618, DOI 10.1002/14651858.CD004976.pub4. Read the source
4. Int J Risk Saf Med. Current status of pheniramine misuse among substance use disorder patients: A narrative review of extent, patterns, and clinical implications.. 2026. PMID 40843532, DOI 10.1177/09246479251370587. Read the source
5. Cureus. Clinical Experience With Combined Pantoprazole and Pheniramine in the Treatment of Persistent Hiccups: A Case Series.. 2026. PMID 42147647, DOI 10.7759/cureus.107185. Read the source
6. Curr Eye Res. Comparison of Naphcon-A and its components (naphazoline and pheniramine) in a provocative model of allergic conjunctivitis.. 1994. PMID 8055694, DOI 10.3109/02713689409167294. Read the source
7. DailyMed (US National Library of Medicine), SPL effective 2016-03-31. Walgreens Wal-Flu Cold and Sore Throat Lemon Flavor (acetaminophen 325 mg, pheniramine maleate 20 mg, phenylephrine hydrochloride 10 mg) granules for solution, United States OTC Drug Facts label: the label text of every Drug Facts content section, transcribed in document order from the SPL XML, excluding the principal display panel. This SPL carries no section title elements, so no heading has been added; the headings that appear ("Uses", "Warnings", "Do not use:", "When using this product", "Directions", "Other Information" and the rest) are the label's own printed words. Line breaks follow the label's own line-break elements, and the Directions age/dose table is given as its own cells, one per line, with no punctuation added between them. 2016. Read the source
8. Drugs Aging. Drugs Contributing to Anticholinergic Burden and Risk of Fall or Fall-Related Injury among Older Adults with Mild Cognitive Impairment, Dementia and Multiple Chronic Conditions: A Retrospective Cohort Study (RESULTS section of the abstract). 2019. PMID 30652263, DOI 10.1007/s40266-018-00630-z. Read the source
9. DailyMed (US National Library of Medicine), SPL effective 2024-03-27. NAPHCON A (naphazoline hydrochloride 0.025% and pheniramine maleate 0.3%) ophthalmic solution, OTC Drug Facts label: the label text of every Drug Facts content section, in document order from the SPL XML, excluding the three principal display panels. The active-ingredient/purpose table is given as its own cells, one per line, with no punctuation added between them. 2024. Read the source
10. J Clin Sleep Med. Oral nonprescription treatment for insomnia: an evaluation of products with limited evidence (RESULTS AND CONCLUSIONS section of the abstract). 2005. PMID 17561634, DOI 10.5664/jcsm.26314. Read the source
11. Clin Exp Allergy. Rebound Pruritus and Urticaria After Discontinuation of Chronic Antihistamine Use-A Scoping Review (RESULTS section of the abstract). 2026. PMID 41911848, DOI 10.1111/cea.70291. Read the source
12. Toxicol Int. Pheniramine Maleate-Induced Rhabdomyolysis and Aki: Is it Fatal?. 2014. PMID 25948974, DOI 10.4103/0971-6580.155384. Read the source
13. Annals of Medicine and Surgery. Pheniramine induced supraventricular tachycardia resistant to adenosine: A case report and review.. 2022. PMID 35600167, DOI 10.1016/j.amsu.2022.103621. Read the source
14. Cureus. Immediate Hypersensitivity Reaction to Pheniramine in a Case of Multiple Drug Hypersensitivity Syndrome.. 2025. PMID 40125237, DOI 10.7759/cureus.79259. Read the source
15. Ann Intern Med. Effects of fexofenadine, diphenhydramine, and alcohol on driving performance. A randomized, placebo-controlled trial in the Iowa driving simulator (CONCLUSIONS section of the abstract). 2000. PMID 10691585, DOI 10.7326/0003-4819-132-5-200003070-00004. Read the source
16. J Am Geriatr Soc. Association of Inpatient Prescribing of First-Generation Antihistamines With Delirium in Older Adults: A Cross-Sectional Study (RESULTS section of the abstract). 2025. PMID 41121962, DOI 10.1111/jgs.70121. Read the source
17. Curr Neuropharmacol. Over-the-counter Psychosis: A Systematic Review of the Misuse of Antihistamines, Cough Medicines, and Decongestants and the Risk of Developing Psychosis (RESULTS section of the abstract). 2025. PMID 39976040, DOI 10.2174/011570159X344365250114064248. Read the source
18. Allergy Asthma Clin Immunol. CSACI position statement: Newer generation H1-antihistamines are safer than first-generation H1-antihistamines and should be the first-line antihistamines for the treatment of allergic rhinitis and urticaria.. 2019. PMID 31582993, DOI 10.1186/s13223-019-0375-9. Read the source
19. Journal of the American Geriatrics Society. American Geriatrics Society 2023 updated AGS Beers Criteria® for potentially inappropriate medication use in older adults.. 2023. PMID 37139824, DOI 10.1111/jgs.18372. Read the source
20. Cochrane Database Syst Rev. Oral antihistamine-decongestant-analgesic combinations for the common cold (AUTHORS' CONCLUSIONS section of the abstract). 2022. PMID 35060618, DOI 10.1002/14651858.CD004976.pub4. Read the source
21. Clin Ther. A comparison of the clinical efficacy of pheniramine maleate/naphazoline hydrochloride ophthalmic solution and olopatadine hydrochloride ophthalmic solution in the conjunctival allergen challenge model (BACKGROUND section of the abstract). 2005. PMID 15978305, DOI 10.1016/j.clinthera.2005.04.011. Read the source
22. Pharmacol Res Perspect. The role of sex, age and genetic polymorphisms of CYP enzymes on the pharmacokinetics of anticholinergic drugs.. 2021. PMID 34003603, DOI 10.1002/prp2.775. Read the source