Why was orphenadrine discontinued? Unpacking the nitrosamine recall and safety concerns

October 8, 2025 •

3 min read

In March 2022, manufacturer Sandoz, Inc. issued a nationwide recall of 13 lots of orphenadrine citrate 100 mg extended-release tablets because of a potentially cancer-causing nitrosamine impurity. However, the story of why was orphenadrine discontinued is more complex, involving long-standing safety concerns and poor risk-benefit ratios that ultimately led to its removal from many markets.

Quick Summary

The discontinuation of orphenadrine was prompted by a 2022 manufacturer recall due to a nitrosamine impurity. This was a final step following decades of safety issues, including high overdose toxicity, pronounced anticholinergic side effects, abuse potential, and limited efficacy compared to modern alternatives.

Key Points

Nitrosamine Impurity Recall: In March 2022, manufacturer Sandoz recalled specific lots of orphenadrine citrate tablets due to unsafe levels of a nitrosamine impurity.
High Overdose Toxicity: The drug has a narrow therapeutic index and has been historically associated with a high mortality rate in overdose, primarily due to severe cardiac and neurological events.
Pronounced Anticholinergic Effects: Orphenadrine's anticholinergic properties cause significant side effects like dry mouth, confusion, and urinary retention, making it less suitable than modern alternatives, especially for older adults.
Long-Standing Safety Concerns: Over many years, concerns over its safety, limited efficacy compared to modern drugs, and abuse potential contributed to its withdrawal from many international markets.
FDA Did Not Issue Mandatory Withdrawal: The FDA determined that the brand-name Norflex was not withdrawn for official safety or effectiveness reasons, allowing for the potential approval of generic versions that meet current standards.
Safer Alternatives Exist: The development and widespread availability of other muscle relaxants with better safety profiles, such as cyclobenzaprine and methocarbamol, have reduced the clinical necessity for orphenadrine.

The 2022 Nitrosamine-Related Recall

On March 21, 2022, Sandoz, Inc. voluntarily recalled 13 lots of orphenadrine citrate 100 mg extended-release tablets nationwide. This action was taken because the tablets contained a nitrosamine impurity at levels exceeding the FDA's Acceptable Daily Intake limit.

The Nature of Nitrosamine Impurities

Nitrosamines are chemicals that can form during drug manufacturing and can increase cancer risk with high or prolonged exposure. The specific impurity found was NMOA. This discovery led to the recall and advice for patients to stop using the affected medication.

Beyond the Recall: Broader Safety and Efficacy Concerns

The nitrosamine recall was a recent factor in orphenadrine's market withdrawal by one manufacturer, but its discontinuation in various markets over the years stems from long-standing safety and efficacy issues.

Overdose Toxicity and Narrow Therapeutic Index

Medical literature has long noted orphenadrine's significant toxicity in overdose due to its narrow therapeutic index. Overdoses can cause severe, sometimes fatal, cardiac rhythm problems and neurological effects like seizures and respiratory depression. Accidental ingestion by children has also resulted in serious outcomes.

Significant Anticholinergic Side Effects

Orphenadrine's strong anticholinergic properties lead to numerous side effects, such as dry mouth, drowsiness, blurred vision, and urinary issues. These effects make it generally unsuitable for older adults.

Abuse Potential and Limited Efficacy

The drug has a documented potential for abuse due to euphoric effects. Its effectiveness as a muscle relaxant has also been questioned, with analyses suggesting only modest benefits for muscle spasm pain, particularly when considering the availability of safer alternatives.

The FDA's Official Determination

The FDA clarified in December 2022 that the brand-name Norflex was not withdrawn for reasons of safety or effectiveness, a regulatory distinction that permits generic versions to remain available if they meet requirements. This determination does not, however, negate the documented clinical concerns about the drug's risk-benefit profile.

Orphenadrine vs. Modern Muscle Relaxants


Feature	Orphenadrine (e.g., Norflex)	Cyclobenzaprine (e.g., Flexeril)	Methocarbamol (e.g., Robaxin)
Mechanism	Anticholinergic and centrally acting muscle relaxant.	Centrally acting muscle relaxant.	Centrally acting muscle relaxant.
Overdose Toxicity	Historically associated with high mortality in overdose due to cardiac and neurological effects.	Lower toxicity profile in overdose compared to orphenadrine.	Generally considered safer in overdose compared to orphenadrine.
Key Side Effects	Dry mouth, drowsiness, dizziness, blurred vision, urinary retention, cardiac arrhythmias.	Drowsiness, dry mouth, dizziness.	Drowsiness, dizziness, blurred vision.
Anticholinergic Burden	High.	Lower than orphenadrine.	Low.
Use in Elderly	Not generally recommended due to increased side effect risk.	Use with caution, higher risk of side effects.	Use with caution.
Abuse Potential	Documented potential for abuse.	Less potential for abuse compared to some others.	Minimal abuse potential.

Conclusion: A Multifaceted Discontinuation

The discontinuation of orphenadrine is not solely due to the 2022 nitrosamine recall. It is the result of decades of concerns regarding its safety, including significant overdose toxicity, problematic anticholinergic side effects, abuse potential, and limited efficacy when compared to newer muscle relaxants. The availability of safer and more effective alternatives has led to a decline in orphenadrine's use, solidifying its phased withdrawal from many markets.

This article is for informational purposes only and is not medical advice. Consult with a healthcare professional regarding any medical questions or concerns.

Frequently Asked Questions

In March 2022, a manufacturer voluntarily recalled specific lots of orphenadrine citrate extended-release tablets after discovering unacceptable levels of a nitrosamine impurity, which can potentially increase cancer risk over long-term exposure.

While the brand-name Norflex and specific generic lots were recalled, the FDA's determination did not preclude the existence of other generic versions. However, due to its poor risk-benefit profile, clinical use is now rare, and many countries have withdrawn or restricted it.

The FDA's statement was a regulatory distinction. It determined that the brand-name product was not removed for mandatory safety or effectiveness reasons, a finding that allows generic manufacturers to continue seeking approval for their versions that meet all standards. It does not negate the significant clinical safety concerns associated with the drug.

Prior safety issues included significant toxicity and high mortality in overdose (especially cardiac-related), a high burden of anticholinergic side effects, a narrow safety margin, and a documented potential for abuse.

Safer alternatives for treating muscle spasms include other muscle relaxants like cyclobenzaprine (Flexeril), tizanidine (Zanaflex), and methocarbamol (Robaxin). These options have better-defined safety profiles and are generally preferred by modern medical practice.

No, the nitrosamine recall was a final event in the drug's history. Its discontinuation in many regions was also driven by long-standing concerns regarding its high toxicity in overdose, significant side effects, abuse potential, and limited efficacy compared to newer, safer treatments.

Due to its potent anticholinergic effects, orphenadrine can cause confusion, sedation, and urinary issues, which are particularly dangerous for older adults. The higher risk of side effects means safer alternatives are generally recommended for this age group.