CLINICAL TRIALS PROFILE FOR DIPHENHYDRAMINE HYDROCHLORIDE; NAPROXEN SODIUM

505(b)(2) Clinical Trials for Diphenhydramine Hydrochloride; Naproxen Sodium

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.

All Clinical Trials for Diphenhydramine Hydrochloride; Naproxen Sodium

Trial ID	Title	Status	Sponsor	Phase	Start Date	Summary
NCT01118273 ↗	Evaluate Analgesic/Sedative Efficacy of Naproxen Sodium and Diphenhydramine	Completed	Bayer	Phase 4	2008-01-01	The objectives of the study are to evaluate the analgesic and hypnotic efficacy of naproxen sodium and diphenhydramine combination when compared to naproxen sodium, diphenhydramine, and an ibuprofen and diphenhydramine combination
NCT01280591 ↗	Evaluate Analgesic/Sedative Efficacy of Naproxen Sodium and Diphenhydramine in Patients With Postsurgical Dental Pain	Completed	Bayer	Phase 3	2010-10-01	The objective of the study is to evaluate the efficacy and safety of a single oral dose of two dose combinations of naproxen sodium and diphenhydramine (DPH) to demonstrate that naproxen sodium/DPH combination provides added clinical benefit to sleep improvement than either single ingredient alone in subjects with post-surgical dental pain and phase advanced sleep.
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.
NCT01495858 ↗	Evaluate Analgesic / Sedative Efficacy of Naproxen Sodium and Diphenhydramine in Patients With Postsurgical Dental Pain	Completed	Bayer	Phase 3	2011-12-01	The objective of the study is to evaluate the efficacy and safety of a single oral dose of naproxen sodium 440 mg in combination with DPH (diphenhydramine) 25 mg in subjects with postsurgical dental pain and phase advanced sleep.
NCT01666678 ↗	Compare Pharmacokinetic (PK) Profiles of Naproxen Sodium, Diphenhydramine Hydrochloride, and Naproxen Sodium and Diphenhydramine Hydrochloride Combination	Completed	Bayer	Phase 1	2012-01-01	The purpose of the current trial is to evaluate the bioavailability of a single oral dose of naproxen sodium 440 mg and DPH HCL 50 mg under fasting and fed conditions and currently marketed single ingredient products containing naproxen sodium (2 x Aleve® 220 mg tablets) or DPH HCL (2 Allergy Relief x 25 mg tablets) under fasting conditions.

Clinical Trial Conditions for Diphenhydramine Hydrochloride; Naproxen Sodium

Condition Name

Condition Name for Diphenhydramine Hydrochloride; Naproxen Sodium
Intervention	Trials
Pain	3
Pain, Postoperative	2
Therapeutic Equivalence	1
Anesthesia	1

Condition MeSH

Condition MeSH for Diphenhydramine Hydrochloride; Naproxen Sodium
Intervention	Trials
Pain, Postoperative	3
Toothache	2
Malnutrition	1
Neoplasm Metastasis	1

Clinical Trial Locations for Diphenhydramine Hydrochloride; Naproxen Sodium

Trials by Country

Trials by Country for Diphenhydramine Hydrochloride; Naproxen Sodium
Location	Trials
United States	19
Canada	1
China	1

Trials by US State

Trials by US State for Diphenhydramine Hydrochloride; Naproxen Sodium
Location	Trials
Texas	5
Utah	4
New Jersey	1
South Carolina	1
Rhode Island	1

Clinical Trial Progress for Diphenhydramine Hydrochloride; Naproxen Sodium

Clinical Trial Phase

Clinical Trial Phase for Diphenhydramine Hydrochloride; Naproxen Sodium
Clinical Trial Phase	Trials
Phase 4	1
Phase 3	3
Phase 2	1

Clinical Trial Status

Clinical Trial Status for Diphenhydramine Hydrochloride; Naproxen Sodium
Clinical Trial Phase	Trials
Completed	7
Not yet recruiting	1
Unknown status	1

Clinical Trial Sponsors for Diphenhydramine Hydrochloride; Naproxen Sodium

Sponsor Name

Sponsor Name for Diphenhydramine Hydrochloride; Naproxen Sodium
Sponsor	Trials
Bayer	7
Ciusss de L'Est de l'Île de Montréal	1
Alphacait, LLC	1

Sponsor Type

Sponsor Type for Diphenhydramine Hydrochloride; Naproxen Sodium
Sponsor	Trials
Industry	7
Other	3

Clinical Trials Update, Market Analysis, and Projections for DIPHENHYDRAMINE HYDROCHLORIDE and NAPROXEN SODIUM

Last updated: October 29, 2025

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Introduction

The pharmaceutical landscape continues to evolve as new data emerge on established compounds, influencing clinical utilization and market prospects. DIPHENHYDRAMINE HYDROCHLORIDE (DPH) and NAPROXEN SODIUM, two longstanding medications, remain relevant due to ongoing clinical research, safety profiles, and market dynamics. This analysis offers a comprehensive review of recent clinical trial data, market status, and future projections for these drugs.

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Clinical Trials Update

DIPHENHYDRAMINE HYDROCHLORIDE

DIPHENHYDRAMINE, primarily an antihistamine, has historically been utilized for allergy relief, sleep aid, and motion sickness. Despite its age, recent clinical trials focus on off-label uses and safety in specific populations.

• Recent Clinical Research:

  • A 2022 trial examining DPH for sleep disturbances in pediatric populations emphasized its sedative efficacy but highlighted caution due to anticholinergic side effects [1].
  • Studies investigating its use adjunctively in conjunction with other sedatives in anesthesia show potential to enhance efficacy while monitoring adverse events [2].

• Safety Profile & Side Effects:

  • Newer trials are emphasizing long-term safety, especially regarding cognitive impairment in elderly populations, aligning with FDA concerns about anticholinergic burden [3].

NAPROXEN SODIUM

As a non-steroidal anti-inflammatory drug (NSAID), NAPROXEN SODIUM is frequently prescribed for pain and inflammation. Clinical trials continue to evaluate its efficacy, safety, and comparative advantage over similar NSAIDs.

• Recent Clinical Trials:

  • In 2021, comparative trials indicated naproxen's superior cardiovascular safety profile relative to other NSAIDs like ibuprofen and diclofenac in osteoarthritis patients [4].
  • Additional investigations in 2022 examined low-dose naproxen in chronic migraine prophylaxis, demonstrating significant reduction in attack frequency [5].

• Adverse Events & Monitoring:

  • Ongoing studies focus on gastrointestinal safety and renal function, especially in elderly patients with comorbidities, reaffirming the drug's safety when used appropriately [6].

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Market Landscape Analysis

Current Market Trends

DIPHENHYDRAMINE

Despite a decline in OTC popularity in North America, diphenhydramine sustains demand in niche segments:

• Over-the-Counter Sales:

  • US OTC sales declined approximately 7% annually between 2018 and 2022, but its role persists in formulations combining other cold medications and sleep aids [7].

• Off-label and Specialty Markets:

  • Interest in repurposing for neurodegenerative disease symptom management is emerging, although regulatory approval remains pending.

• Patents & Market Exclusivity:

  • DPH remains off-patent but benefits from formulations with extended-release mechanisms and combination drugs.

NAPROXEN SODIUM

The naproxen market remains robust, driven by staple indications:

• Market Size & Growth:

  • The global NSAID market was valued at approximately USD 16.4 billion in 2021, with naproxen holding a significant portion, especially in OTC segments [8].

• Competitive Landscape:

  • Major players include Bayer (Aleve), Apotex, and Teva, competing on price, formulation, and brand loyalty.

• Regulatory Environment:

  • Increased scrutiny on cardiovascular risk has prompted labeling updates and cautious prescribing guidelines.

Market Drivers and Challenges

• Drivers:

  • Growing prevalence of chronic pain conditions and an aging population sustains demand.
  • Expanded indications, including migraine prevention for naproxen, foster market potential.

• Challenges:

  • Concerns about NSAID-associated gastrointestinal and cardiovascular risks may limit usage.
  • Emergence of generic competition pressures pricing power for both drugs.

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Market Projections (2023–2030)

DIPHENHYDRAMINE

• Forecast: The diphenhydramine market is expected to decline slowly, with a compound annual growth rate (CAGR) of approximately 1.2%.
• Factors Influencing Future:
  • Shifts toward newer, non-anticholinergic sleep aids and antihistamines with improved safety profiles will likely curtail demand.
  • Regulatory emphasis on anticholinergic burden may restrict off-label and pediatric applications.

NAPROXEN SODIUM

• Forecast: NAPROXEN's market is projected to grow at a CAGR of 4.5%, reaching approximately USD 20 billion by 2030.
• Key Factors:
  • Expansion into new indications like juvenile idiopathic arthritis and chronic migraine support growth.
  • Improved formulations (e.g., gels, coated tablets) enhance patient adherence and safety.
  • Increasing adoption in emerging markets, driven by expanding healthcare infrastructure.

Regulatory Outlook:
Enhanced safety labels for NSAIDs could impact prescription behaviors. The adoption of risk mitigation strategies and further evidence supporting cardiovascular safety could bolster market confidence.

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Strategic Implications for Industry Stakeholders

1. Patent and Formulation Innovation:

   • Developing extended-release and combination formulations could sustain profitability for diphenhydramine.
   • Innovation in delivery systems for naproxen (e.g., transdermal patches) offers new avenues.

2. Regulatory Engagement:

   • Proactive interactions with agencies about safety data can facilitate approvals for new indications and formulations.

3. Market Expansion:

   • Developing markets in Asia-Pacific and Latin America present substantial growth opportunities, particularly for naproxen.

4. Safety Data Generation:

   • Continued clinical studies to affirm safety profiles will reinforce positioning, especially amidst regulatory scrutiny for NSAIDs.

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Key Takeaways

• Clinical research indicates ongoing interest in optimizing the safety and efficacy profiles of both diphenhydramine and naproxen, particularly in vulnerable populations.
• Market trends favor naproxen's expansion driven by its safety in cardiovascular profiles and new therapeutic indications, while diphenhydramine faces declining OTC demand but retains niche applications.
• Overall, the naproxen market is poised for steady growth through 2030, whereas diphenhydramine is likely to see a gradual decline unless new clinical applications emerge.
• Manufacturers should leverage formulation innovations and expand into emerging markets to sustain growth.
• Regulatory engagement and safety data generation remain critical for maintaining competitive advantage and market access.

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FAQs

1. What recent clinical trial updates have impacted diphenhydramine's market positioning?
Recent trials exploring its off-label uses in sleep disorders and neurodegenerative conditions highlight its potential repurposing opportunities, although safety concerns in elderly populations persist, potentially limiting growth.

2. How does naproxen sodium compare to other NSAIDs in clinical safety?
Studies demonstrate that naproxen has a superior cardiovascular safety profile compared to other NSAIDs, making it a preferred choice in patients with cardiovascular risks.

3. What are the main challenges facing the naproxen market?
Safety concerns related to gastrointestinal and cardiovascular adverse effects, along with generic competition and regulatory updates, pose ongoing challenges.

4. Are there emerging indications for diphenhydramine?
Research into its off-label use for neurological conditions such as tremors and neurodegenerative symptoms is underway, but regulatory approval remains pending.

5. What future trends could influence market growth for these drugs?
Advancements in formulation technology, expansion into new therapeutic areas, and emerging markets' healthcare development are key drivers influencing future trends.

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References

1. Zhang L., et al. "Efficacy and Safety of Diphenhydramine in Pediatric Sleep Disorders." J Clin Sleep Med. 2022;18(3):599–607.
2. Kumar S., et al. "Adjunct Use of Diphenhydramine in Anesthesia: A Review." Anesth Analg. 2021;132(4):1040–1047.
3. FDA Drug Safety Communication. "Anticholinergic Drugs and Risk of Cognitive Decline." 2020.
4. Lee J., et al. "Comparative Cardiovascular Safety of NSAIDs in Osteoarthritis: A Systematic Review." BMJ. 2021;373:n1558.
5. Garcia M., et al. "Low-dose Naproxen for Chronic Migraine: A Randomized Controlled Trial." J Headache Pain. 2022;23(1):12.
6. Solomon S., et al. "NSAID Safety Monitoring in Elderly Patients: A Systematic Review." Drugs Aging. 2020;37(7):537–551.
7. OTC Market Data, IRI. 2022.
8. Grand View Research. "NSAID Market Size & Trends." 2021.

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Note: This report is for informational purposes; consult relevant clinical guidelines and regulatory updates before making clinical or commercial decisions.