HA Injection Safety: 25+ Years of FDA Post-Market Data

Key Safety Findings

Over 25 years of FDA post-market surveillance demonstrate an excellent safety profile:

FDA approved since 1997 - Synvisc was first; multiple products followed
Millions of injections administered in the US
MAUDE database: Low adverse event reporting rate
No systemic toxicity - HA is a natural body substance
No cumulative damage - Safe for repeat courses
Local reactions only - Most side effects are injection-site related
Rare serious events - Much lower risk than NSAIDs or surgery

The FDA Approval History

Timeline of US Approvals

Hyaluronic acid products for knee OA have been FDA-approved for over 25 years:^[1]

FDA Approval Timeline:

Year	Product	Manufacturer	Source
1997	Synvisc	Sanofi	Avian (rooster comb)
1997	Hyalgan	Fidia	Avian
2001	Supartz	Bioventus	Avian
2004	Orthovisc	Anika	Avian
2004	Euflexxa	Ferring	Bacterial fermentation
2009	Synvisc-One	Sanofi	Avian
2011	Gel-One	Zimmer	Avian
2012	Monovisc	Anika	Avian
2017	Durolane	Bioventus	Bacterial fermentation
2023	Visco-3	Anika	Avian

What FDA Approval Means

Pre-market review: Safety and efficacy demonstrated in clinical trials

Manufacturing standards: GMP-compliant facilities

Labeling requirements: Clear indications and warnings

Ongoing surveillance: Adverse event reporting required

The MAUDE Database: Post-Market Safety

What Is MAUDE?

The Manufacturer and User Facility Device Experience (MAUDE) database is the FDA’s system for collecting adverse event reports for medical devices:^[2]

Mandatory reporting by manufacturers
Voluntary reporting by healthcare providers and patients
Publicly searchable
Updated regularly

MAUDE Data for HA Injections

Adverse Event Analysis (Representative Period):

Category	Finding
Total reports (2014-2019)	~63 reports across all HA products
Reporting rate	Very low relative to millions of procedures
Serious outcomes	Rare; most reports describe local reactions
Deaths reported	8 (causality unconfirmed; often comorbidities)

Note: MAUDE captures reported events; actual causality often undetermined.

Context for MAUDE Numbers

Millions of HA injections performed annually in the US

~63 MAUDE reports over 5 years is an extremely low rate

Many reports describe expected, minor reactions

Deaths often occurred in patients with multiple comorbidities

Types of Adverse Events

Common (Expected) Side Effects

These occur in some patients and are not considered serious:^[3]

Local Injection-Site Reactions:

Reaction	Frequency	Duration
Pain at injection site	10-20%	Hours to 1-2 days
Swelling	5-10%	1-3 days
Warmth/redness	5-10%	1-2 days
Stiffness	5-15%	1-2 days

These are self-limiting and typically resolve without treatment.

Uncommon Side Effects

Joint effusion (increased fluid) - Uncommon; usually resolves

Allergic-type reaction - Rare; more common with avian-derived products in egg-allergic patients

Pseudoseptic reaction - Very rare; inflammatory response mimicking infection

Rare Serious Events

Very Rare Events (MAUDE reports):

Event	Context
Infection	Any injection carries small infection risk
Severe allergic reaction	Extremely rare; managed with standard allergy protocols
Deaths reported	8 reports (2014-2019); causality not established; patients had comorbidities

Important: The presence of a MAUDE report does not prove the product caused the event. Many reports involve patients with multiple health conditions where causality cannot be determined.

Comparison to Other OA Treatments

Safety Profile Comparison

Relative Safety of OA Treatments:

Treatment	Major Safety Concerns	Risk Level
HA injections	Local reactions; rare allergic response	Very Low
Acetaminophen	Liver toxicity at high doses	Low-Moderate
NSAIDs (oral)	GI bleeding (1-2%/yr in 65+); CV risk (25% increase); renal effects	Moderate-High
Cortisone injections	Cartilage damage; blood sugar spikes; limited frequency	Moderate
Opioids	Addiction; constipation; falls; cognitive effects	High
Knee replacement	Surgical risks; revision risk; anesthesia; DVT/PE	Higher (for surgery)

The NSAID Comparison

NSAIDs are often the default OA treatment, but chronic use carries significant risks:

Cardiovascular: 25% increased risk of heart attack/stroke

GI bleeding: 1-2% annual rate in 65+

Renal: Can accelerate kidney disease

Drug interactions: Multiple with common medications

HA injections avoid all of these systemic risks because they work locally in the joint.

Why HA Is Inherently Safe

HA Is Natural

Hyaluronic acid is a naturally occurring substance in the body:

Present in synovial (joint) fluid

Present in skin, eyes, and connective tissues

Body recognizes and metabolizes it naturally

No known cumulative toxicity

Local Administration

Unlike oral medications, HA stays in the joint:

Doesn’t circulate systemically

No liver/kidney metabolism concerns

No drug-drug interactions

Safe for patients on multiple medications

No Cumulative Effects

Can be repeated every 6+ months indefinitely

No evidence of joint damage from HA (unlike cortisone)

Patients have used HA for 10+ years safely

Avian vs. Non-Avian Safety

The Allergy Question

Some HA products are derived from rooster combs (avian source), raising allergy concerns for some patients:

Product Sources:

Product	Source	Allergy Consideration
Synvisc, Synvisc-One	Avian	Caution with egg/poultry allergy
Hyalgan	Avian	Caution with egg/poultry allergy
Supartz	Avian	Caution with egg/poultry allergy
Orthovisc	Avian	Caution with egg/poultry allergy
Euflexxa	Bacterial fermentation	Safe for egg/poultry allergies
Durolane	Bacterial fermentation	Safe for egg/poultry allergies

Safety for Allergic Patients

Egg/poultry allergic patients can safely use Euflexxa or Durolane

Allergic reactions to avian-derived HA are rare even in allergic patients

Inform your provider of any allergies before treatment

Contraindications and Precautions

Who Should Not Receive HA

Contraindications:

Situation	Reason
Active knee infection	Risk of worsening infection
Skin infection at injection site	Risk of introducing bacteria
Known HA allergy	Prior allergic reaction to HA products
Egg/poultry allergy	Use non-avian product (Euflexxa, Durolane)

Precautions

Anticoagulants: Not a contraindication but may increase bruising

Pregnancy/nursing: Safety not established (typically not needed in this population)

Lymphedema: Theoretical concern; discuss with provider

Long-Term Safety Evidence

What 25+ Years Tells Us

No new safety signals have emerged since 1997 approval

No black box warnings added (unlike NSAIDs)

No product withdrawals for safety reasons

Medicare continues coverage - affirms safety and efficacy

New products continue approval - market remains active

Ongoing Surveillance

FDA continues to monitor HA products through:

MAUDE database adverse event reports
Post-marketing study requirements
Annual manufacturer reports
Periodic safety reviews

The Bottom Line

25+ Years of Safety Data

The evidence is clear:

FDA-approved since 1997 with continuous market presence
Millions of injections with very low adverse event rate
No systemic toxicity - HA is a natural body substance
No cumulative damage - safe for long-term repeated use
Much safer than NSAIDs - avoids CV, GI, and renal risks
Local reactions only - mild and self-limiting when they occur
Rare serious events - lower risk than most OA treatment alternatives

What this means for you:

HA injections have one of the best safety profiles of any OA treatment. With over 25 years of post-market surveillance confirming their safety, concerns about HA being “experimental” or “risky” are not supported by the evidence.

If you’re considering HA injections, the safety data should provide reassurance. The main questions are efficacy for your specific situation—not safety.

Find Safe, Evidence-Based Treatment

Locate providers who offer FDA-approved HA products with proper technique.

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References

FDA Premarket Approval Database. Device Approvals for Viscosupplementation Products. FDA
FDA MAUDE Database. Adverse Event Reports for Viscosupplementation Devices. FDA MAUDE
Synvisc-One Prescribing Information. Sanofi. FDA Label
Euflexxa Prescribing Information. Ferring Pharmaceuticals.
Comprehensive review of viscosupplementation safety. Orthopedic Reviews. Full Text

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