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  5. FDA investigates two serious adverse events associated with ImprimisRx’s compounded curcumin emulsion product for injection
  1. Human Drug Compounding

FDA investigates two serious adverse events associated with ImprimisRx’s compounded curcumin emulsion product for injection

August 4, 2017

Summary

Two patients administered infusions of curcumin (a component of the spice turmeric) compounded with polyethylene glycol (PEG) 40 castor oil reportedly experienced immediate hypersensitivity reactions. The PEG 40 castor oil was a component of a curcumin emulsion product compounded by a pharmacy, ImprimisRx, located in Irvine, California. Hypersensitivity reactions to intravenous (IV) products containing polyethylene glycol castor oil have been reported in the literature and are the subject of warnings for a number of FDA-approved drugs.

Adverse Events

On March 10, 2017, the U.S. Food and Drug Administration received an adverse event report concerning a 30-year-old female patient who experienced cardiac arrest after IV administration of a curcumin emulsion product compounded by ImprimisRx. The patient reportedly had a history of allergies and was being treated for eczema by a naturopathic doctor. Within minutes of starting the infusion, the patient became pulseless and required CPR. The patient suffered anoxic (depleted oxygen) brain injury and subsequently died. An adverse reaction to infused curcumin solution was identified as a cause of death by the local authorities.

On May 1, 2017, FDA received an adverse event report concerning a 71-year-old male patient who developed a hypersensitivity reaction after IV administration of ImprimisRx’s compounded curcumin emulsion product. The patient had a history of allergies and was being treated for thrombocytopenia (a low platelet count) at a holistic health center. According to information FDA received from the center, within minutes of starting the infusion, the patient developed a cough and erythema (skin reddening). Diphenhydramine (an antihistamine) was administered; however, symptoms escalated to include shortness of breath, itching, and hypotension (low blood pressure). The patient was treated with IV epinephrine and transferred to a nearby emergency room where he was treated and then released.

FDA’s Investigation and Findings

FDA collected and analyzed samples from the IV bag administered to the female patient and the ImprimisRx curcumin emulsion vial used to prepare the IV bag. The label of ImprimisRx’s curcumin emulsion product represented that the vial contained 10 mg/mL of curcumin. FDA found that the solution in the IV bag contained about 0.00234 mg/mL of curcuminoids, which is approximately 1% of the curcumin concentration intended to be administered, and that the curcumin emulsion in the vial contained about 0.205 mg/mL of curcuminoids, which is less than 2% of the curcumin concentration represented on the label. Curcumin is unstable in aqueous solution and undergoes rapid degradation at physiological pH1,  which may be the reason that ImprimisRx’s curcumin emulsion product was subpotent.

FDA also analyzed the samples of ImprimisRx’s curcumin emulsion product to identify the presence of certain contaminants and impurities. FDA identified the presence of diethylene glycol (DEG) in an amount of 0.21% weight by weight (w/w). DEG is a known manufacturing impurity of PEG. PEG 40 castor oil is one of the ingredients in ImprimisRx’s curcumin emulsion product.

FDA collected and analyzed samples of PEG 40 castor oil from the same lot of ImprimisRx curcumin emulsion product that was administered to the female patient. FDA identified 1.25% w/w DEG in the PEG 40 castor oil. The label of the tested PEG 40 castor oil includes the warning “CAUTION: For manufacturing or laboratory use only.” The PEG 40 castor oil used by ImprimisRx was ungraded, and not, for example, pharmaceutical grade or food grade. Ungraded products are suitable for general industrial or research purposes and typically are not suitable for human consumption or therapeutic use. There is no U.S. Pharmacopeia (USP) monograph for PEG 40 castor oil.

On June 23, 2017, ImprimisRx recalled all unexpired products containing the ungraded PEG 40 castor oil.

Analysis

As noted above, both patients reportedly had a history of allergies, reacted adversely within minutes of receiving infusions of curcumin, and manifested signs and symptoms of hypersensitivity reactions. This suggests that both patients suffered from severe, and for one patient fatal, immediate hypersensitivity reactions upon receiving the infusion of curcumin.

Drug products, including FDA-approved products, containing polyethylene glycol castor oil have been associated with severe and sometimes fatal hypersensitivity reactions and include warnings about these reactions in their labels. For example, in one study approximately 20% of patients administered IV paclitaxel containing Cremophor® EL (PEG 35 castor oil) experienced severe hypersensitivity reactions2.  The label for paclitaxel containing Cremophor includes a boxed warning regarding severe and sometimes fatal hypersensitivity reactions3.  ImprimisRx’s product label did not include any warning. Hypersensitivity reactions also have been observed in patients receiving tacrolimus containing PEG 60 castor oil, a product used in other countries4,  as well as in several clinical studies of other IV drugs containing polyethylene glycol castor oil5. 

Some of the other ingredients in ImprimisRx’s product, including curcumin, also have been associated with hypersensitivity reactions when administered intravenously. There are reports of contact allergies to a metabolite of curcumin, tetrahydrocurcumin, for instance6.  In addition, there is little to no toxicologic or clinical information available regarding the safety of IV curcumin7,  and evidence is lacking that curcumin is an effective therapy for eczema or thrombocytopenia. There are no FDA-approved curcumin for injection products.

The ungraded PEG 40 castor oil in ImprimisRx’s curcumin emulsion product may have contained components that resulted in the hypersensitivity reactions. Castor bean seeds and pollens are known to be associated with hypersensitivity reactions8.  Food grade castor oil is processed to remove the potentially allergenic castor bean constituents9,  but ungraded PEG 40 castor oil may not be allergen free. In addition to allergens, other potentially harmful contaminants and impurities could be present in the ungraded PEG 40 castor oil.

DEG has not been associated with systemic hypersensitivity reactions, but it is a central nervous system depressant, as well as a potent kidney and liver toxin which can cause kidney failure and death when ingested10.  It is commonly used as a component in industrial products, such as anti-freeze and brake fluids.

Conclusion

FDA’s investigation into the adverse events associated with ImprimisRx’s curcumin emulsion product for injection highlights some of the risks associated with compounded drugs, particularly those that use non-pharmaceutical grade components and ingredients lacking a USP monograph. The risks illustrated in this case include:

  • the absence of a label warning about hypersensitivity reactions associated with the PEG 40 castor oil;
  • the use of an ungraded inactive ingredient, i.e., PEG 40 castor oil, that is not suitable for human consumption or therapeutic use and may contain impurities such as DEG; and
  • the IV administration of curcumin, despite the fact that its safety profile by this route of administration has not been established, nor has its effectiveness in treating eczema or thrombocytopenia.

FDA encourages health care professionals to report adverse events or quality problems experienced with the use of compounded drug products to FDA’s MedWatch Adverse Event Reporting program:

References

  1. FDA’s review of the physicochemical characteristics, safety, effectiveness, and historical use in compounding of curcumin presented to the Pharmacy Compounding Advisory Committee in October 2015 (“FDA’s curcumin review”), available at (Tab 3). Slingerland M et al. Bioequivalence of Liposome-Entrapped Paclitaxel Easy-To-Use (LEP-ETU) formulation and paclitaxel in polyethoxylated castor oil: a randomized, two-period crossover study in patients with advanced cancer. Dis Esophagus. 2017 Apr 1; 30(4):1-9. Gelderblom H et al. Cremophor EL: The drawbacks and advantages of vehicle selection for drug formulation. Eur J Cancer. 2001 Sep; 37(13) 1590-8.  
  2. TAXOL Label (PDF)
  3. Ali R et al. Development and characterization of methoxy poly(ethylene oxide)-block-poly(є-caprolactone)(PEO-b-PCL) micelles as vehicles for the solubilization and delivery of tacrolimus. Saudi Pharm J. 2017 Feb; 25(2) 258-265.
  4. Pang, S. Final Report on the Safety Assessment of PEG-30, -33, -36, and -40 Castor Oil and PEG-30 and 40 Hydrogenated Castor Oil, International Journal of Toxicology. 1997. 16:269-306.
  5. Lamb SR et al. Contact allergy to tetrahydrocurcumin. Contact Dermatitis. 2003 Apr;48(4):227.
  6. See footnote 1.
  7. Singh A et al. Specific IgE to castor bean (Ricinus communis) pollen in the sera of clinically sensitive patients to seeds. J Investig Allergol Immunol. 1997 May-Jun; 7(3): 169-74.
  8. Burdock GA et al. Toxicology and pharmacology of sodium ricinoleate. Food Chem Toxicol. 2006 Oct;44(10):1689-98.

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