The Discontinuation of Tham
In May 2016, the only manufacturer of the brand-name drug Tham (tromethamine), Pfizer (through its Hospira division), made the decision to discontinue its production in the United States. This created a significant drug shortage, leaving medical professionals without a key therapeutic option for specific cases of metabolic acidosis. Unlike recalls, which are initiated due to safety concerns, this was a simple discontinuation by the manufacturer, though the precise reasons were not specified in public announcements.
The FDA's Crucial Determination
In a crucial step towards resolving the shortage, the Food and Drug Administration (FDA) conducted a review to ensure the discontinuation was not due to safety or effectiveness issues. The FDA concluded in July 2019 that tromethamine was not withdrawn for safety or effectiveness reasons. This determination was vital, as it cleared the path for other companies to seek approval for generic versions of the injectable drug. This decision enabled the eventual reintroduction of tromethamine into the market under a generic label, following the proper legal and regulatory pathways.
The Return of Generic Tromethamine
Following the FDA's ruling, several generic drug manufacturers pursued approval to produce and market tromethamine. In late 2024, the FDA approved abbreviated new drug applications (ANDAs) for tromethamine injectable from at least two manufacturers, B BRAUN MEDICAL and MILLA PHARMS. A press release from January 2025 further confirmed that Milla Pharmaceuticals had launched its generic version of tromethamine, explicitly addressing the need created by the prior shortage. This return of generic tromethamine has restored a valuable treatment option for hospitals and critical care units across the U.S..
What is Tromethamine?
Tromethamine, or tris(hydroxymethyl)aminomethane, is an inert amino alcohol used as a systemic alkalinizing agent. It works differently than sodium bicarbonate by directly binding to hydrogen ions ($H^+$), effectively neutralizing both metabolic and respiratory acids. This mechanism increases the bicarbonate ($HCO_3^−$) concentration and raises blood pH without producing the carbon dioxide ($CO_2$) that is a byproduct of bicarbonate administration.
It is typically administered via intravenous injection and is indicated for the prevention and correction of severe metabolic acidosis. This can occur in several critical care scenarios, such as:
- During cardiac bypass surgery: To correct metabolic acidosis that can develop during or after the procedure.
- Associated with cardiac arrest: To help correct the acidosis that is a nearly universal consequence of cardiac arrest, potentially helping the heart to respond to resuscitation efforts.
- In specific pediatric cases: To address metabolic acidosis with concurrent respiratory acidosis in neonates and infants, especially when hypernatremia is also a concern.
Comparison: Tromethamine vs. Sodium Bicarbonate
| Feature | Tromethamine (Generic) | Sodium Bicarbonate |
|---|---|---|
| Mechanism | Acts as a proton acceptor, neutralizing acids without producing $CO_2$. | Donates bicarbonate to bind hydrogen ions, which produces $CO_2$. |
| Indications | Severe metabolic acidosis in cardiac bypass surgery and cardiac arrest. | Most commonly used alkali therapy for acidosis. |
| $CO_2$ Production | Does not produce $CO_2$. | Produces $CO_2$, which can worsen hypercapnia. |
| Special Considerations | Historically reserved for patients intolerant to bicarbonate's $CO_2$ effects. | Standard of care for most severe acidosis cases; often preferred in neonates despite THAM's use. |
| Key Side Effects | Hyperkalemia, hypoglycemia, respiratory depression, tissue damage upon extravasation. | May cause hypernatremia due to high sodium load. |
| Elimination | Rapidly excreted by the kidneys. | Dependent on renal and respiratory function. |
Important Safety Considerations
Despite its clinical benefits, tromethamine carries important risks and requires careful administration and monitoring. Key safety considerations include:
- Respiratory Depression: High doses can suppress ventilation due to increased blood pH and reduced $CO_2$ concentration. Ventilatory support may be necessary.
- Hypoglycemia: Overdosage or rapid infusion can lead to prolonged low blood sugar, especially in neonates. Blood glucose levels must be frequently monitored.
- Extravasation Risk: Tromethamine is a vesicant, and leakage from the intravenous site can cause inflammation, tissue necrosis, and sloughing. Slow, careful infusion into a large vein is necessary.
- Hyperkalemia: Due to its potential to alter potassium levels, caution is advised in patients with renal disease or reduced urinary output, with frequent monitoring of serum potassium.
- Limited Duration of Use: Due to limited long-term experience, the drug is typically administered for no more than one day except in life-threatening emergencies.
Conclusion
While the original brand-name Tham was discontinued in 2016, the crucial FDA determination that it was not for safety reasons paved the way for generic manufacturers to reintroduce the active ingredient, tromethamine, to the market. The successful launch of generic tromethamine by companies like Milla Pharmaceuticals in 2025 has officially ended the long-term drug shortage. As a unique buffering agent for severe metabolic acidosis, the availability of tromethamine restores a valuable tool for critical care situations, particularly in patients who may not tolerate the carbon dioxide-generating effects of sodium bicarbonate. Medical professionals can once again utilize this medication, provided they adhere to the necessary precautions and monitoring guidelines associated with its use.
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