CLINICAL TRIALS PROFILE FOR DIPHENHYDRAMINE HYDROCHLORIDE

505(b)(2) Clinical Trials for diphenhydramine hydrochloride

This table shows clinical trials for potential 505(b)(2) applications. See the next table for all clinical trials

Trial Type	Trial ID	Title	Status	Sponsor	Phase	Start Date	Summary
OTC	NCT01365052 ↗	Safety Trial of Naproxen Sodium/ Diphenhydramine	Completed	Bayer	Phase 3	2011-05-01	The purpose of this trial is to see how safe the combination of naproxen sodium 440 mg and diphenhydramine hydrochloride (DPH) 50 mg (the investigational product) is compared to placebo (capsules containing no drug) when taken for 10 days.
OTC	NCT02229539 ↗	Doxepin and a Topical Rinse in the Treatment of Acute Oral Mucositis Pain in Patients Receiving Radiotherapy With or Without Chemotherapy	Completed	National Cancer Institute (NCI)	Phase 3	2014-11-01	The purpose of this study is to test whether a mouthwash made with a drug called doxepin can reduce the pain caused by mouth sores resulting from radiation therapy. A number of mouth rinse preparations exist for patients with treatment-related oral mucositis pain such as the DLA rinse, an over-the-counter medication. This study will evaluate the effects of doxepin compared to DLA (diphenhydramine, lidocaine and antacids) and placebo.Doxepin is approved by the Food and Drug Administration (FDA) for the treatment of depression, anxiety, long-term pain management, as well as management of rash.
OTC	NCT02229539 ↗	Doxepin and a Topical Rinse in the Treatment of Acute Oral Mucositis Pain in Patients Receiving Radiotherapy With or Without Chemotherapy	Completed	Alliance for Clinical Trials in Oncology	Phase 3	2014-11-01	The purpose of this study is to test whether a mouthwash made with a drug called doxepin can reduce the pain caused by mouth sores resulting from radiation therapy. A number of mouth rinse preparations exist for patients with treatment-related oral mucositis pain such as the DLA rinse, an over-the-counter medication. This study will evaluate the effects of doxepin compared to DLA (diphenhydramine, lidocaine and antacids) and placebo.Doxepin is approved by the Food and Drug Administration (FDA) for the treatment of depression, anxiety, long-term pain management, as well as management of rash.
OTC	NCT02474199 ↗	Donor Alloantigen Reactive Tregs (darTregs) for Calcineurin Inhibitor (CNI) Reduction	Completed	Clinical Trials in Organ Transplantation in Children	Phase 1/Phase 2	2016-06-06	This research study is for liver transplant recipients and their respective living donors. The purpose of this study is: 1. To see if it is safe for liver recipients to receive one dose of donor reactive T regulatory cells (Tregs) 2. To see if the Tregs allows a liver recipient to take less, or completely stop medications normally taken after receiving an organ transplant.
OTC	NCT02474199 ↗	Donor Alloantigen Reactive Tregs (darTregs) for Calcineurin Inhibitor (CNI) Reduction	Completed	Rho Federal Systems Division, Inc.	Phase 1/Phase 2	2016-06-06	This research study is for liver transplant recipients and their respective living donors. The purpose of this study is: 1. To see if it is safe for liver recipients to receive one dose of donor reactive T regulatory cells (Tregs) 2. To see if the Tregs allows a liver recipient to take less, or completely stop medications normally taken after receiving an organ transplant.
OTC	NCT02474199 ↗	Donor Alloantigen Reactive Tregs (darTregs) for Calcineurin Inhibitor (CNI) Reduction	Completed	National Institute of Allergy and Infectious Diseases (NIAID)	Phase 1/Phase 2	2016-06-06	This research study is for liver transplant recipients and their respective living donors. The purpose of this study is: 1. To see if it is safe for liver recipients to receive one dose of donor reactive T regulatory cells (Tregs) 2. To see if the Tregs allows a liver recipient to take less, or completely stop medications normally taken after receiving an organ transplant.

All Clinical Trials for diphenhydramine hydrochloride

Trial ID	Title	Status	Sponsor	Phase	Start Date	Summary
NCT00011804 ↗	Topiramate in the Treatment of Sciatica	Completed	National Institute of Dental and Craniofacial Research (NIDCR)	Phase 2	2001-02-01	This study will test the effectiveness of topiramate to treat pain caused by lumbar radiculopathy, or sciatica. Sciatica results from damage to the lumbar nerve roots, typically causing back pain and sharp, shooting pain down one or both legs. Although sciatica is common, there are no good treatments for it. Topiramate belongs to a group of medications commonly used to treat pain caused by nerve damage. Patients between 18 and 75 years of age who have had sciatica pain daily for at least 3 months may be eligible for this study. (This is taken from the first paragraph of the Qualification Criteria in the consent form. The inclusion criteria on page 6 of the protocol say "low back pain of 3 months duration or longer present at least 5 out of 7 days a week" and signs and symptoms of lumbar radiculopathy. Which is correct?) Participants will provide a medical history, as well as occupational and social information. They will undergo a standard neurological examination, including a test of cognitive (thinking) abilities, muscular function, reflexes and a sensory examination. The latter involves testing with a pin placed on the surface of the skin. Participants will also have routine blood tests and will fill out questionnaires on their daily functioning and psychological well being. Additional procedures may include magnetic resonance imaging (MRI) scans and possible referral to a psychiatrist for evaluation of depression or emotional difficulties. This "cross-over" study consists of two parts. In one part, patients will receive topiramate and in the other, an active placebo. An active placebo is a drug that does not work for the problem being studied but whose side effects are like those of the test drug. Diphenhydramine (Benadryl) is the active placebo used in this study. Diphenhydramine is an allergy medication with very mild side effects, such as drowsiness. During both parts of the study-topiramate and placebo-patients will keep a daily log in which they rate their pain, record other procedures they undergo, such as injections and manipulations, and record medication side effects. In the first week of the study, patients will remain on their current medications and record pain levels once a day. After the first week, they will begin taking the study drugs-either topiramate in increasing doses ranging from 50 to 400 mg. or diphenhydramine in doses ranging from 6.25 to 50 mg. The drug doses will be increased gradually over 4 weeks to minimize possible side effects. Increases will continue until the maximum tolerated dose is reached. Patients will continue on the highest tolerated dose for two weeks and then be tapered off gradually over 12 days. They will remain off drugs completely for a 2-day washout period and then begin the next treatment. Those who took topiramate for the first part will take diphenhydramine for the second part and vice versa. A study nurse will call patients twice a week throughout the study to check for problems and answer questions. A physician will see patients 6 weeks after the start of each treatment. During the last visit, at the end of the study, patients will repeat the questionnaires they filled out at the beginning of the study. Patients and their doctors will be informed of the medications that were effective in each individual's care.
NCT00030992 ↗	BMS 247550 to Treat Kidney Cancer	Completed	National Cancer Institute (NCI)	Phase 2	2002-02-01	This study will examine whether the experimental drug BMS 247550 (Ixabepilone) is an effective treatment for kidney cancer. BMS 247550 belongs to a class of drugs called epothilones that interfere with the ability of cancer cells to divide. In the way they kill cells, they are very similar to a class of compounds known as the taxanes, which include the drug Taxol. Other characteristics of the epothilones, however, enable them to work in cells that are resistant to Taxol. Patients 18 years of age or older with kidney cancer that has not spread to the central nervous system (unless the brain tumor has remained stable for at least six months after surgical or radiation treatment) may be eligible for this study. Pregnant or nursing women may not participate. Candidates are screened with various tests that may include blood and urine tests, electrocardiogram (EKG), and chest x-ray. Computerized tomography (CT) scans or X-rays, and possibly nuclear medicine studies may be done to determine the extent of disease. Participants receive BMS 247550 by a 1-hour infusion into a vein for 5 consecutive days (days 1, 2, 3, 4 and 5) of each 21-day treatment cycle. Patients must stay in the National Institutes of Health (NIH) area near Bethesda, Maryland, for 7 to 8 days during the first treatment cycle and for the 5 days of treatment in subsequent cycles. The total number of cycles will vary among patients, depending on their individual clinical situation. The drug dose may be increased gradually in subsequent cycles in patients who can tolerate such increases. In addition, participants undergo the following tests and procedures: - Periodic physical examinations and frequent blood tests - X-ray and other imaging studies to determine if the tumor is responding to the treatment. - Tumor biopsies to confirm the diagnosis or spread of tumor and to examine the reaction of certain proteins in cancer cells to BMS 247550. Two biopsies will be done. For this procedure, a small piece of tumor tissue is withdrawn through a needle under local anesthetic. Treatment will be stopped in patients whose tumor grows while receiving BMS 247550. Patients whose tumor disappears completely will be followed at NIH periodically for examinations and tests. Patients whose disease does not completely resolve or whose disease recurs may be advised of other appropriate research protocols at NIH or, if none are available, will be returned to the care of their local doctor.
NCT00038402 ↗	Evaluation of the Addition of Herceptin to Standard Chemotherapy in the Neoadjuvant Setting for Operable Breast Cancer	Completed	Genentech, Inc.	Phase 3	2001-04-01	The purpose of this study is to evaluate the addition of Herceptin to standard chemotherapy treatment of patients newly diagnosed with operable breast cancer. Other objectives: 1) to evaluate the potential of this therapy to reduce the size of the tumor and increase the possibility of breast conservative surgery, 2) evaluate the ability of this regimen to prevent recurrence of breast cancer and impact on survival, 3) determine side effect profile with the addition of Herceptin, and 4) evaluate significance of HER2 expression by two different methods.
NCT00038402 ↗	Evaluation of the Addition of Herceptin to Standard Chemotherapy in the Neoadjuvant Setting for Operable Breast Cancer	Completed	M.D. Anderson Cancer Center	Phase 3	2001-04-01	The purpose of this study is to evaluate the addition of Herceptin to standard chemotherapy treatment of patients newly diagnosed with operable breast cancer. Other objectives: 1) to evaluate the potential of this therapy to reduce the size of the tumor and increase the possibility of breast conservative surgery, 2) evaluate the ability of this regimen to prevent recurrence of breast cancer and impact on survival, 3) determine side effect profile with the addition of Herceptin, and 4) evaluate significance of HER2 expression by two different methods.
NCT00038623 ↗	Study Of Yttrium-ibritumomab (Zevalin) For the Treatment Of Patients With Relapsed And Refractory Mantle Cell Lymphoma	Completed	Biogen	Phase 2	2002-04-01	Study of Yttrium-ibritumomab (Zevalin) For the treatment of Patients with Relapsed & Refractory Mantle Cell Lymphoma
NCT00038623 ↗	Study Of Yttrium-ibritumomab (Zevalin) For the Treatment Of Patients With Relapsed And Refractory Mantle Cell Lymphoma	Completed	M.D. Anderson Cancer Center	Phase 2	2002-04-01	Study of Yttrium-ibritumomab (Zevalin) For the treatment of Patients with Relapsed & Refractory Mantle Cell Lymphoma

Clinical Trial Conditions for diphenhydramine hydrochloride

Condition Name

Condition Name for diphenhydramine hydrochloride
Intervention	Trials
Leukemia	18
Lymphoma	14
Healthy	8
Chronic Lymphocytic Leukemia	8

Condition MeSH

Condition MeSH for diphenhydramine hydrochloride
Intervention	Trials
Leukemia	32
Lymphoma	23
Leukemia, Lymphoid	20
Headache	19

Clinical Trial Locations for diphenhydramine hydrochloride

Trials by Country

Trials by Country for diphenhydramine hydrochloride
Location	Trials
United States	633
China	36
Canada	36
Italy	18
Spain	15

Trials by US State

Trials by US State for diphenhydramine hydrochloride
Location	Trials
Texas	112
New York	43
California	37
Florida	25
Ohio	24

Clinical Trial Progress for diphenhydramine hydrochloride

Clinical Trial Phase

Clinical Trial Phase for diphenhydramine hydrochloride
Clinical Trial Phase	Trials
PHASE4	2
PHASE3	3
PHASE2	4

Clinical Trial Status

Clinical Trial Status for diphenhydramine hydrochloride
Clinical Trial Phase	Trials
Completed	158
Recruiting	51
Terminated	35

Clinical Trial Sponsors for diphenhydramine hydrochloride

Sponsor Name

Sponsor Name for diphenhydramine hydrochloride
Sponsor	Trials
M.D. Anderson Cancer Center	66
National Cancer Institute (NCI)	20
Genentech, Inc.	15

Sponsor Type

Sponsor Type for diphenhydramine hydrochloride
Sponsor	Trials
Other	322
Industry	155
NIH	41

Diphenhydramine Hydrochloride Clinical Trials Update, Market Analysis, and Revenue Projection (2026-2035)

Last updated: July 27, 2026

Executive summary: Diphenhydramine hydrochloride (Benadryl and generics) is an established, largely off-patent antihistamine with extensive generic availability across the U.S. and major markets. Clinical development is niche (reformulations, pediatrics, decongestant combinations, abuse-deterrent or dose-form refinements), and the near-term commercial outlook is driven by volume growth in OTC channels plus periodic product-cycle refreshes rather than new molecular entity approvals. Revenue is projected to track OTC demand growth and mix shifts, with downside sensitivity to retail price compression and competitive intensity from low-cost generics.

What is diphenhydramine hydrochloride, and what clinical trials are currently active or recently completed?

Short answer: Diphenhydramine hydrochloride is an OTC first-generation H1 antihistamine with long-standing indications for allergic symptoms and urticaria, and off-label use for insomnia and motion sickness. “Clinical trials” activity is concentrated in formulation work (bioavailability, stability, taste/mouthfeel, pediatric dosing, and combination products) and in safety/pharmacokinetic studies rather than pivotal efficacy trials for a new indication.

Where do diphenhydramine hydrochloride trials cluster (U.S. and global registries)?

Clinical trial visibility tends to concentrate in:

• Bioequivalence (BE) studies for generic tablet, capsule, liquid, and oral-dissolving formulations.
• Formulation/palatability studies for pediatric liquid or chewable formats.
• PK/safety studies comparing salt form, excipients, or dissolution profiles.
• Combination-product trials (e.g., decongestant + antihistamine combinations), which use diphenhydramine as a component rather than as a standalone new active.

Data note: A complete, accurate “currently active” and “recently completed” list requires up-to-date registry extraction from ClinicalTrials.gov and equivalent WHO/ICTRP sources. Without that registry-level pull in this session, any enumerated trial list would risk being incomplete or inaccurate.

Which diphenhydramine hydrochloride indications drive market demand?

Short answer: The largest demand segments are OTC allergy and sleep-adjacent use. U.S. revenue concentration is typically highest in OTC antihistamine categories, with additional volume from nighttime/“PM” formats, cold-and-allergy combination products, and generics in mass retail.

Core commercial demand drivers

• Allergy season repeat purchase: Diphenhydramine is a familiar OTC option used during seasonal peaks.
• Nighttime symptom relief: “PM” labeling and consumer perception of sedative benefit support higher-mix nighttime products.
• Form factor convenience: Liquid, fast-dissolve, capsule, and multi-symptom cold products affect shelf conversions.
• Price compression dynamics: Generic penetration shifts revenue toward volume and away from brand-like pricing.

Key regulatory context affecting clinical development

Because diphenhydramine is widely marketed, new clinical programs are typically tied to:

• Generic approvals through BE rather than new clinical efficacy.
• Switches in excipient systems or formulation redesigns that require supportive data.
• Label updates where FDA requires additional support.

What is the current market size and growth outlook for diphenhydramine hydrochloride?

Short answer: Diphenhydramine hydrochloride is a mature, high-volume OTC drug with growth typically in line with OTC antihistamine category demand, moderated by generic price erosion and substitution effects.

Market segmentation most relevant to projections

• Product type: tablets/capsules vs liquids vs oral-dissolving or fast-dissolve
• OTC channel: mass retail, club stores, online pharmacies, and pharmacy chains
• Geography: U.S. and high-income OECD markets show the best visibility for revenue forecasting; other regions are frequently less transparent and more supplier-diverse.
• Label positioning: allergy-focused vs nighttime/sleep-adjacent vs combination cold-and-allergy

Competitive landscape

• Generic incumbency: Multiple manufacturers supply the same strength and dosage forms, driving price competition.
• Substitution within antihistamines: Second-generation antihistamines (e.g., loratadine/cetirizine/fexofenadine) can pressure volume, but diphenhydramine retains share when sedative benefit is valued or when price is decisive.
• Combination products: Addition of decongestants or analgesics can stabilize unit demand even when pure antihistamine categories are pressured.

How do we project diphenhydramine hydrochloride revenues from 2026 to 2035?

Short answer: A practical projection model for diphenhydramine should be volume-led with mix and price-down adjustments. In a generic OTC environment, revenue typically follows:

• Category unit growth (consumer demand and channel expansion)
• Offset by average selling price (ASP) erosion from generics
• Partially offset by mix (nighttime formats, multi-symptom combinations) and periodic formulation shifts

Projection framework (equation form)

Annual revenue = (Projected units × Weighted average net price)
Weighted net price = baseline OTC price – generic erosion – retailer/promotional effects + mix uplift (PM, combination)

Base case (directional) projection

Without registry and pricing inputs in this session, the most defensible projection is a directional scenario range:

• Base case: low single-digit revenue growth or flat-to-slight decline driven by price compression offset by steady unit demand.
• Bull case: stronger nighttime and combination mix plus channel growth yields modest positive revenue growth.
• Bear case: continued intense pricing competition and substitution to second-generation antihistamines leads to revenue contraction.

Important: Generating numeric dollar forecasts requires current market sizing, ASP history, and unit sell-through data. In absence of those inputs, numeric “market projection numbers” would be speculative.

How strong is the patent estate for diphenhydramine hydrochloride?

Short answer: Diphenhydramine hydrochloride is a long-established molecule with no meaningful remaining composition-of-matter exclusivity in most major markets. Commercial exclusivity generally does not come from patents on the active but from:

• formulation-specific protection (where it exists for specific dosage forms/excipients)
• packaging or process claims (rarely the basis for broad commercial barriers for a commodity OTC ingredient)
• brand-specific regulatory exclusivity, which is not the default for diphenhydramine

What typically protects specific diphenhydramine products (not the active ingredient)

• Formulation patents: modified-release, rapid-dissolve, taste-masking systems
• Manufacturing/process patents: granulation or dissolution processes
• Method-of-use patents: far less common for a widely used OTC antihistamine

Data note: A complete patent estate map by jurisdiction (USPTO/EP register/WO) requires live patent database extraction. This session does not include that extraction, so a precise count of active patents and their expiration dates cannot be provided reliably.

What clinical trial patterns matter most for generic diphenhydramine entry risk?

Short answer: For OTC generics, the dominant risk is not “clinical success” but regulatory/CMC execution for BE and consistent manufacturing.

Key execution risks

• Bioequivalence strategy: dissolution profile and absorption for different dosage forms
• Stability and shelf-life compliance: especially for liquids and combination products
• Labeling and consumer safety requirements: pediatric dosing accuracy and warning language compliance
• Supply continuity: scale-up and raw material qualification

What generic or biosimilar risks exist for diphenhydramine hydrochloride?

Short answer: “Biosimilar” is not applicable. Generic entry risk is low from a clinical trial standpoint because diphenhydramine is not biologic and BE is routine. The main friction is operational, regulatory labeling, and supply chain rather than IP in most markets.

What could still delay or block entry

• lingering formulation-specific IP for certain products
• regulatory refusals tied to CMC or labeling deficiencies
• supply chain constraints for key excipients

Which companies compete in diphenhydramine hydrochloride OTC products?

Short answer: Competition includes large generic and OTC-focused manufacturers and private label suppliers. The market is structurally fragmented with many SKUs across dosage forms.

Data note: A company-by-company ranking and SKU ownership table requires retail/wholesale share data and regulatory label ownership. This session does not include those market share datasets.

How does diphenhydramine hydrochloride compare with second-generation antihistamines in clinical and commercial terms?

Short answer: Second-generation antihistamines typically trade away sedation for improved tolerability. Diphenhydramine’s differentiator is sedative effect and low price, which supports persistent use in nighttime and value-seeking segments.

Clinical and consumer fit

• Diphenhydramine: sleep-adjacent benefit, allergy symptom control, motion sickness use (commonly off-label)
• Second-generation antihistamines: less sedation, often preferred for daytime allergy management

What is the Orange Book status of diphenhydramine hydrochloride products?

Short answer: Diphenhydramine hydrochloride products are widely available as generics and typically do not show active, broadly constraining Orange Book listings for the active substance in modern categories. Exact Orange Book listings vary by NDA and dosage form.

Data note: A precise Orange Book table (patent numbers, expiry, exclusivity codes, and listed drug products) requires a direct Orange Book pull for each relevant NDA. This session does not include that dataset.

What litigation or Paragraph IV challenges affect diphenhydramine hydrochloride?

Short answer: Paragraph IV litigation is less central for diphenhydramine in most contexts due to commodity status and limited remaining enforceable patent coverage. When litigation occurs, it often relates to specific branded formulations, packaging, or minor improvements rather than the base molecule.

Data note: A litigation docket summary with case numbers and filing outcomes requires a live search of FDA-Orange Book-linked cases and court databases. Without that, any list would risk inaccuracies.

What is the regulatory pathway for diphenhydramine hydrochloride in new products?

Short answer: For new generic entrants, the typical route is abbreviated pathways grounded in BE and labeling. For new dosage forms, CMC and BE drive approval more than new clinical efficacy.

Typical submission components

• BE studies (waiver possible in certain scenarios)
• dissolution and formulation characterization
• stability data
• labeling compliance and OTC monograph or FDA OTC framework alignment

Formulations and dosage forms: what product categories offer the most upside?

Short answer: Mix-shift opportunities are in:

• nighttime (“PM”) positioning and sedative-benefit formats
• rapid-dissolve or convenience formats
• cold-and-allergy combination products that sustain use during respiratory seasons

Key CMC levers affecting market performance

• shelf-life retention in liquids
• uniformity and dissolution consistency across lots
• taste masking and palatability for pediatric markets

Key Takeaways

• Diphenhydramine hydrochloride is a mature OTC antihistamine with an active commercial base, driven by allergy seasonality and nighttime use.
• Clinical development is not anchored in new pivotal efficacy programs; it is dominated by formulation and BE-linked trials and CMC-related studies.
• Revenue outlook from 2026-2035 is volume-led with price erosion counterbalanced by mix (nighttime/combination formats) and channel expansion. Net growth is likely flat to modest unless mix shifts materially.
• Competitive barriers are primarily operational and regulatory (BE/CMC/supply), not biologic development complexity.
• Patent-driven exclusivity is generally limited at the molecule level, with any remaining protection usually tied to specific formulations or packaging rather than the core active ingredient.

FAQs

1. Do diphenhydramine hydrochloride generics require clinical efficacy trials?
2. What formulation types (liquid vs tablet vs fast-dissolve) tend to face the highest bioequivalence scrutiny?
3. How do nighttime and “PM” product positioning change market mix for diphenhydramine products?
4. Are there any remaining formulation patents that block specific diphenhydramine dosage forms in the U.S.?
5. What are the main regulatory CMC requirements for new diphenhydramine OTC product approvals?

References (APA)

1. U.S. Food and Drug Administration. (n.d.). Drugs@FDA.
2. U.S. Food and Drug Administration. (n.d.). Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations.
3. U.S. National Library of Medicine. (n.d.). ClinicalTrials.gov.