Overview
Diphenhydramine - perhaps known most commonly as its brand name formulation Benadryl - is a first-generation H1 receptor antihistamine that is used extensively for the treatment of seasonal allergies, insect bites and stings, and rashes . However, it also has antiemetic, antitussive, hypnotic, and antiparkinson properties . As histamine receptors exist both peripherally and in the central nervous system, diphenhydramine has been shown to cause sedation due to its competitive antagonism of histamine H1 receptors within the central nervous system . While its use in allergy therapy can sometimes fall out of favor due to its sedative effect, diphenhydramine has been repurposed for use within many non-prescription over-the-counter sleep aids and cough-and-cold medications that have been marketed for "night time" use . Diphenhydramine is also used in combination with 8-chlorotheophylline as the anti-nausea drug Dimenhydrinate where it is utilized primarily for its antagonism of H1 histamine receptors within the vestibular system . Diphenhydramine has also been shown to be implicated in a number of neurotransmitter systems that affect behaviour including dopamine, norepinephrine, serotonin, acetylcholine, and opioid . As a result, diphenhydramine is being investigated for its anxiolytic and anti-depressant properties.
Indication
Diphenhydramine is a first-generation histamine H1 receptor antagonist (H1 antihistamine) that is widely available as a non-prescription, over-the-counter (OTC) medication. As an OTC medication, diphenhydramine is typically formulated as tablets and creams indicated for use in treating sneezing, runny nose, itchy/watery eyes, itching of nose or throat, insomnia, pruritis, urticaria, insect bites/stings, allergic rashes, and nausea . Additionally, when the use of oral diphenhydramine is impractical, there are also prescription-only formulations such as diphenhydramine injection products that are effective in adults and pediatric patients (other than premature infants and neonates) for: i) the amelioration of allergic reactions to blood or plasma, in anaphylaxis as an adjunct to epinephrine and other standard measures after acute allergic reaction symptoms have been controlled, and for other uncomplicated allergic conditions of the immediate type when oral therapy is impossible or contraindicated ; ii) the active treatment of motion sickness ; and iii) use in parkinsonism when oral therapy is impossible or contraindicated, as follows: parkinsonism in the elderly who are unable to tolerate more potent agents; mild cases of parkinsonism in other age groups, and in other cases of parkinsonism in combination with centrally acting anticholinergic agents .
Associated Conditions
- Allergic Reaction
- Allergic Rhinitis (AR)
- Allergic cough
- Allergy to Tree Pollen
- Anaphylaxis
- Angioedema
- Common Cold
- Conjunctival irritation
- Cough
- Cough Variant Asthma
- Cough caused by Common Cold
- Eye allergy
- Fever
- Insect Bites
- Insect Stings
- Insomnia
- Irritative cough
- Itching of the nose
- Itching of the throat
- Motion Sickness
- Nasal Congestion
- Oral Mucositis
- Pain
- Parkinsonian Syndromes
- Productive cough
- Pruritus
- Rash
- Rhinorrhoea
- Sinus Congestion
- Sinus headache
- Skin Irritation
- Sneezing
- Sunburn
- Symptoms of Acute Bronchitis Accompanied by Coughing
- Upper respiratory tract hypersensitivity reaction, site unspecified
- Urticaria
- Cold or flu syndrome
- Dermatographism
- Dry cough
- Watery itchy eyes
Research Report
A Comprehensive Monograph on Diphenhydramine (DB01075): Pharmacology, Clinical Utility, and Safety Profile
Executive Summary
Diphenhydramine is a first-generation ethanolamine-derivative antihistamine that, since its initial approval in 1946 [1], has become one of the most widely available and recognized over-the-counter (OTC) medications worldwide.[2] While primarily known for its role in treating acute allergic reactions, its diverse pharmacological profile lends it to a broad spectrum of uses, including as an antiemetic for motion sickness, an antitussive in cold preparations, and a hypnotic agent for short-term insomnia.[2]
The drug's primary mechanism of action is potent inverse agonism at the histamine H1 receptor. However, its clinical effects and extensive side-effect profile are profoundly influenced by its ability to readily cross the blood-brain barrier and its significant antagonism of muscarinic acetylcholine receptors.[2] This dual central and peripheral activity, combined with actions on other neurotransmitter systems, is responsible for both its therapeutic versatility and its hallmark sedative and anticholinergic adverse effects.
A central theme of this report is the profound dichotomy between Diphenhydramine's ubiquitous OTC availability and the growing body of evidence and clinical guidelines that caution against its use, particularly in vulnerable populations such as the elderly and young children.[3] Its inclusion in the American Geriatrics Society Beers Criteria as a potentially inappropriate medication for older adults underscores a significant risk profile—including cognitive impairment, delirium, and falls—that is often underappreciated by consumers and even some clinicians.[9]
Clinical Trials
Title | Posted | Study ID | Phase | Status | Sponsor |
|---|---|---|---|---|---|
2025/04/04 | Phase 3 | Not yet recruiting | |||
2024/11/26 | Phase 3 | Not yet recruiting | |||
2024/11/25 | Phase 2 | Not yet recruiting | |||
2024/04/10 | Phase 2 | Recruiting | |||
2024/04/03 | Not Applicable | ENROLLING_BY_INVITATION | |||
2024/03/15 | Phase 4 | Completed | |||
2024/01/22 | Phase 4 | Recruiting | |||
2024/01/16 | Phase 1 | Recruiting | |||
2023/12/26 | Not Applicable | Recruiting | |||
2023/10/16 | Phase 2 | Recruiting |
FDA Drug Approvals
Approved Product | Manufacturer | NDC Code | Route | Strength | Effective Date |
|---|---|---|---|---|---|
| Wal-Mart Stores Inc | 49035-164 | ORAL | 25 mg in 1 1 | 5/28/2025 | |
| P & L Development, LLC | 49580-0314 | ORAL | 50 mg in 30 mL | 3/24/2025 | |
| Meijer, Inc. | 79481-0174 | ORAL | 25 mg in 1 1 | 8/5/2025 | |
| HF Acquisition Co LLC, DBA HealthFirst | 51662-1218 | INTRAMUSCULAR, INTRAVENOUS | 50 mg in 1 mL | 2/19/2020 | |
| REMEDYREPACK INC. | 70518-3685 | INTRAVENOUS, INTRAMUSCULAR | 50 mg in 1 mL | 4/2/2024 | |
| NuCare Pharmaceuticals,Inc. | 68071-3877 | ORAL | 25 mg in 1 1 | 8/12/2025 | |
| Softgel Healthcare Pvt Ltd | 35916-0472 | ORAL | 50 mg in 1 1 | 4/8/2025 | |
| Cardinal Health 110, LLC. DBA Leader | 70000-0701 | ORAL | 12.5 mg in 5 mL | 4/28/2025 | |
| CHAIN DRUG MARKETING ASSOCIATION INC. | 83324-280 | ORAL | 25 mg in 1 1 | 7/7/2025 | |
| Fresenius Kabi USA, LLC | 63323-664 | INTRAVENOUS, INTRAMUSCULAR | 50 mg in 1 mL | 10/3/2019 |
EMA Drug Approvals
Approved Product | Authorization Holder | Status | Issued Date |
|---|---|---|---|
| No EMA approvals found for this drug. | |||
HSA Drug Approvals
Approved Product | Manufacturer | Approval Number | Dosage Form | Strength | Approval Date |
|---|---|---|---|---|---|
| BENOCTEN TABLET 50 mg | SIN00362P | TABLET | 50 mg | 4/23/1988 | |
| PAXIDORM TABLETS 25 mg | SIN10851P | TABLET, SUGAR COATED | 25 mg | 4/1/1999 | |
| PHENEXPECT SYRUP | SIN09014P | SYRUP | 12.5 mg/5 ml | 11/28/1996 | |
| DIPHEN 10 EXPECTORANT | SIN08799P | SYRUP | 10 mg/5 ml | 7/3/1996 | |
| SUNTUSS SYRUP | SIN03491P | SYRUP | 10 mg/5 ml | 6/24/1989 | |
| UNIDRYL CD EXPECTORANT | SIN02917P | SYRUP | 14mg/5ml | 5/22/1989 | |
| HOVA EXPECTORANT | SIN03251P | SYRUP | 14 mg/5 ml | 6/12/1989 | |
| DIPRODIN ELIXIR | SIN07830P | ELIXIR | 12.5 mg/5 ml | 9/1/1994 | |
| DIPRODIN ELIXIR | SIN07830P | ELIXIR | 12.5 mg/5 ml | 9/1/1994 | |
| SW-BENA PAEDIATRIC EXPECTORANT | SIN07609P | SYRUP | 5 mg/5 ml | 1/14/1994 |
NMPA Drug Approvals
Approved Product | Company | Approval Number | Drug Type | Dosage Form | Approval Date |
|---|---|---|---|---|---|
| No NMPA approvals found for this drug. | |||||
PPB Drug Approvals
Approved Product | Registration No. | Company | Licence No. | Strength | Registration Date |
|---|---|---|---|---|---|
| BACAMINE LOTION | N/A | N/A | N/A | 3/25/1982 | |
| LONGAXON CREAM | N/A | N/A | N/A | 1/14/1997 | |
| CALAMINE-D LOTION | N/A | N/A | N/A | 7/3/1979 | |
| AICADRYL LOTION | N/A | N/A | N/A | 9/30/1981 | |
| RAPIDERM CREAM | N/A | N/A | N/A | 8/23/1999 | |
| CALAMINE WITH D.P.H CREAM | N/A | N/A | N/A | 12/10/1983 | |
| TRIDAZINE-FORTE CREAM | N/A | N/A | N/A | 9/28/2009 | |
| LAMEBA CREAM | N/A | N/A | N/A | 3/21/2000 | |
| F-HANSONE CREAM | N/A | N/A | N/A | 12/14/1998 | |
| CALOX CREAM | N/A | N/A | N/A | 2/22/1980 |
TGA Drug Approvals
Approved Product | ARTG ID | Sponsor | Registration Type | Status | Registration Date |
|---|---|---|---|---|---|
| PHARMACY CHOICE NIGHT PAIN RELIEF film-coated tablet blister pack | 294150 | Medicine | A | 9/20/2017 | |
| SNUZAID TABS diphenhydramine hydrochloride 50mg tablet blister pack | 129483 | H W Woods Pty Ltd | Medicine | A | 7/14/2006 |
| PRICELINE PHARMACY NIGHT PAIN RELIEF tablet blister pack | 450607 | Medicine | A | 6/3/2024 | |
| MERSYNONIGHT NIGHT TIME PAIN RELIEF tablet blister pack | 301428 | Medicine | A | 3/29/2018 | |
| BENADRYL COUGH MEDICINE FOR DRY COUGHS oral liquid bottle (reformulation) | 57233 | Medicine | A | 11/27/1996 | |
| PANADOL NIGHT capsule-shaped tablet blister pack (reformulation) | 167596 | Medicine | A | 12/16/2009 | |
| PHARMACY HEALTH NIGHT PAIN RELIEF tablet blister pack | 450606 | Medicine | A | 6/3/2024 | |
| COMBOLIEVE NIGHT PAIN RELIEF paracetamol 500 mg and diphenhydramine hydrochloride 25 mg tablet blister pack | 373152 | Medicine | A | 8/19/2021 | |
| VIDALIFE NIGHT PAIN tablet blister pack | 356972 | Medicine | A | 3/18/2021 | |
| NEOCOMBO DAY & NIGHT PAIN RELIEF tablet blister pack | 371305 | Medicine | A | 7/19/2021 |
Health Canada Drug Approvals
Approved Product | Company | DIN | Dosage Form | Strength | Market Date |
|---|---|---|---|---|---|
| CALMEX TAB 25MG | novopharm limited | 00479764 | Tablet - Oral | 25 MG | 12/31/1981 |
| ADVIL COLD & FLU | glaxosmithkline consumer healthcare ulc | N/A | Tablet - Oral | 38 MG | 10/27/2011 |
| LOTION CALAMINE AVEC ANTIHISTAMINIQUE | laboratoire atlas inc | 02241462 | Suspension - Topical | 1 % | 10/13/2000 |
| DIPHENHYDRAMINE HYDROCHLORIDE 25MG | pharma strides canada corporation | 02258250 | Capsule - Oral | 25 MG | N/A |
| SUDAFED PE COLD AND COUGH | mcneil consumer healthcare division of johnson & johnson inc | 02274493 | Tablet - Oral | 12.5 MG | N/A |
| EXTRA STRENGTH TYLENOL FLU NIGHTTIME GELCAP | mcneil consumer healthcare division of johnson & johnson inc | 02167670 | Tablet - Oral | 25 MG | 12/31/1995 |
| CALAMINE LOTION WITH ANTIHISTAMINE | cellchem pharmaceuticals inc. | 02310783 | Suspension - Topical | 1 % / W/V | N/A |
| DORM-L TAB 25MG | nutribon (1986) inc. | 01943723 | Tablet - Oral | 25 MG / TAB | 12/31/1995 |
| DIPHENHYDRAMINE HCL INJECTION, USP | Sterimax Inc | 01997025 | Solution - Intramuscular
,
Intravenous | 50 MG / ML | 12/31/1994 |
| EXTRA STRENGTH SLEEP AID LIQUID GELS | 02431203 | Capsule - Oral | 50 MG | N/A |
CIMA AEMPS Drug Approvals
Approved Product | Company | Registration Number | Pharmaceutical Form | Prescription Type | Status |
|---|---|---|---|---|---|
| No CIMA AEMPS (Spain) approvals found for this drug. | |||||
Philippines FDA Drug Approvals
Approved Product | Company | License Number | Dosage Form | Strength | Approval Date |
|---|---|---|---|---|---|
| No Philippines FDA approvals found for this drug. | |||||
Saudi SFDA Drug Approvals
Approved Product | Company | License Number | Dosage Form | Strength | Approval Date |
|---|---|---|---|---|---|
| No Saudi SFDA approvals found for this drug. | |||||
Malaysia NPRA Drug Approvals
Approved Product | Company | Registration Number | Dosage Form | Strength | Approval Date |
|---|---|---|---|---|---|
| No Malaysia NPRA approvals found for this drug. | |||||
UK EMC Drug Information
Medicine Name | MA Holder | MA Number | Pharmaceutical Form | Active Ingredient | Authorization Date |
|---|---|---|---|---|---|
| No UK EMC drug information found for this drug. | |||||
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