High-Value Medications: Preserving Value after a Frosty Flounder

The pharmaceutical industry continually develops novel therapeutics, many of which require refrigeration and are associated with high costs. In the event of such temperature excursions as a breach in the cold chain protocol, pharmacists are looked upon as experts who can deter- mine whether medications are still viable. Besides resulting in a quantifiable loss, temperature excursions can expose medications to temperature insults that lead to chemical (eg, potency, antigenic) and physical (eg, dissolution, particulates)¹ changes in the properties of the drug product. The clinical implications of excursions include a subpotent product, packaging contamination, patient harm, and therapeutic failure.^2,3

For medication stability inquiries during temperature excursions above 8oC, many resources are available, including medication package inserts that typically indicate recommended storage environments (Table5-24). Peer-reviewed articles, such as “Room-Temperature Storage of Medications Labeled for Refrigeration” by Cohen et al² from 2007, are also an asset when determining the viability of high-cost refrigerated medications. An abundance of guidance for storage conditions above manufacturers’ recommendations was noted in our research. However, it was challenging to find published information on temperature excursions below recommended refrigeration temperatures.

In the event of a break in the cold chain process used to maintain high-cost medications, a privileged pool of data, beyond what is required for package labeling, typically exists for reference. Federal regulations mandate that manufacturers ensure product'quality, essentially until'patient treatment.⁴ Because'of the immense aggregate'cost of a medication passed'through full drug development and supply chain'processes, manufacturers'of high-cost medications'routinely conduct additional distribution stability studies to ascertain a'product’s temperature limitations with respect to product integrity and quality.¹ This information is generally reserved for “in-house” use during distribution and transport to ensure drug products endure temperature excursions during shipping and handling, as well as meet meticulous distribution protocols. If used, this unpublished data could help your pharmacy recoup over $200,000 in pharmaceutical products, including medications for which there is a national shortage.

Recent breaches in the cold chain process of select high-cost medications led to their exposure to freezing temperatures for more than 4 hours, which prompted preemptive action to ensure patient safety and product quality. After taking inventory, a clinical specialist from each manufacturer of a product affected by the breach was contacted with an inquiry into “temperature excursions.” Specifics (ie, lot number, expiration date, exposure temperature, duration of exposure, return time to refrigerator temperature) were provided at the request of the manufacturer. With each conversation, the manufacturer was asked to send a letter stating its temperature excursion data for the medication in question. This written confirmation of stability should not be over- looked. Once all manufacturer conversations had been properly documented, the medications deemed unaffected by the breach were specially marked in case they might need to be re-pulled from hospital supply. This process is an example of how health systems can use resources just behind the curtain. All it takes is a few good ideas, a few good people, and a few good hours.

Generic Name

(Brand Name)

Stability at Temperature

Excursions Below 2°C^a

(For specific information,

contact the manufacturer^b)

Manufacturer

Contact Information

Beractant (Survanta)

Based on information provided, product use supported by manufacturer

AbbVie, Inc

800-633-9110

Travoprost (Travatan Z)

Manufacturer gave verbal in-house temperature excursion data to support use of product after site-specific breach

Alcon

800-757-9785

Botulinum Toxin Type A (Botox)

Prior to 2012, Botox was approved for storage in the freezer; product use supported by manufacturer

Allergan

714-246-4500

Filgrastim (Neupogen)

Based on site-specific breach details, product use supported by manufacturer

Amgen

800-772-6436

Phenylephrine 2.5% and 10% Drops

Product found to be stable after a freeze-thaw cycle

Paragon Bio Teck, Inc

503-465-3802

Crotalidae Immune Fab (CroFab)

Unreconstituted vials remain stable if exposed to —10°C to +2°C during 1 continuous excursion of ≤12 hr

BTG International, Inc

877-377-3784

Digoxin Immune Fab (DigiFab)

Unreconstituted vials remain stable if exposed to —25°C to +25°C during 1 continuous excursion of ≤7 days

Rh_o(D) Immune Globulin

(Rhophylac)

Specific breach conditions will have NEGATIVE impact on product

CSL Behring

800-504-5434

Alteplase

(Activase)

NO DATA on stability of unreconstituted vials exposed to negative temperature excursions; controlled room temperature (8°C-30°C) is OK

Genentech, Inc

800-821-8590

Rabies Immune Globulin (HyperRAB S/D)

Data indicate freezing point of Hyperimmune products to be —19°C; at temperatures <2°C, container closure integrity due to product expansion is a potential risk

Grifols, Inc

800-520-2807

Risperidone Long-acting Injection

(Risperdal Consta)

Manufacturer gave verbal in-house temperature excursion data to support use of product after site-specific breach

Janssen Pharmaceuticals, Inc

800-526-7736

Daptomycin

(Cubicin)

Unreconstituted vials did not show any significant change following weekly freeze-thaw cycling over 4 wk

Merck & Co, Inc

800-672-6372

Eptifibatide

(Integrilin)

Based on site-specific breach details, the product would not be adversely affected; may be stored at room temperature (25°C) for up to 2 months

Interferon Alfa-2b recombinant (Intron A)

Based on site-specific breach details, the product would not be adversely affected

Tobramycin Inhalation Solution

(Tobi)

Data support no change in stability after 3 freeze cycles to —20°C;

may be stored at room temperature (25°C) for up to 28 days

Novartis Pharmaceuticals Corporation

855-275-4642

Penicillin G benzanthine + penicillin G procaine injectable suspension

(Bicillin C-R and Bicillin C-R 900/300)

Data indicate the product failed to meet quality specifications when freeze/thaw testing was conducted

Pfizer, Inc

800-438-1985

Penicillin G benzanthine injectable suspension

(Bicillin L-A)

Rabies Vaccine

(Imovax Rabies IM)

Based on site-specific breach details, the product would not be adversely affected

Sanofi Pasteur

800-822-2463

Bacitracin

(Baciim)

Manufacturer indicates nature of freez-dried product has no stability issues based on site-specific breach details

X-GEN Pharmaceuticals, Inc

866-390-4411

Neomycin/Polymyxin B GU Irr — Amp (Neosporin GU Irrigant)

Freezing study indicates no stability issues based on site-specific breach details

^aRecommended storage conditions are refrigerate at 2°C to 8°C based upon package labeling, unless otherwise indicated.

^bTemperature stability determined on a case-by-case basis. Contact manufacturer and provide lot number and expiration date, length of time exposed to room temperature, and maximum exposure temperature. The authors of this article do not recommend the use of any pharmaceutical product that is in any way inconsistent with its prescribing information. Clinical judgment should be used regarding the use of material that has been subject to temperatures outside of those recommended by the manufacturer.

References

• Lucas TI, Bishara RH, Seevers RH. A stability program for the distribution of drug products. Pharm Tech. 2004;July:68-73.
• Cohen V, Jellinek SP, Teperikidis L, Berkovits E, Goldman WM. Room-temperature storage of medications labeled for refrigeration. Am J Health Syst Pharm. 2007;64:1711-1715.
• Stability of refrigerated and frozen drugs. Pharmacist’s Letter/Prescriber’s Letter. 2008;24(10):241001.
• Ammann C. Stability studies needed to define the handling and transport conditions of sensitive pharmaceutical or biotechnological products. AAPS PharmSciTech. 2011;12:1264-1275.
• Survanta [package insert]. North Chicago, IL: AbbVie; 2012.
• Travatan Z [package insert]. Mississauga, Ontario: Alcon; 2010.
• Botox [package insert]. Irvine, CA: Allergan; 2015.
• Neupogen [package insert]. Thousand Oaks, CA: Amgen; 2015.
• Phenylephrine HCL [package insert]. Portland, OR: Paragon BioTeck, Inc; 2013.
• CroFab [package insert]. West Conshohocken, PA: BTG International Inc; 2012.
• DigiFab [package insert]. West Conshohocken, PA: BTG International Inc; 2014.
• Rophylac [package insert]. Bern, Switzerland: CSL Behring AG; 2052.
• Activase [package insert]. South San Francisco, CA: Genentech, Inc; 2015.
• HyperRAB S/D [package insert]. Research Triangle Park, NC: Grifols, Inc; 2012.
• Risperdal Consta [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2014.
• Cubicin [package insert]. North Wales, PA: Merck; 2014.
• Integrilin [package insert]. North Wales, PA: Merck; 2014.
• Intron A [package insert]. North Wales, PA: Merck; 2015.
• Tobi [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015.
• Bicillin C-R [package insert]. New York, NY: Pfizer; 2014.
• Bicillin L-A [package insert]. New York, NY: Pfizer; 2014.
• Imovax® Rabies IM [package insert]. Swiftwater, PA: Sanofi Pasteur; 2013.
• Baciim [package insert]. Big Flats, NY: X-GEN; 2012.
• Neosporin GU Irrigant [package insert]. Big Flats, NY: X-GEN; 2010.

Jillian J. Bishop is an intern pharmacy student at the Denver Health & Hospital Authority and a PharmD candidate, class of 2017, at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences.

Michelle Then, PharmD, MBA, is the acute care pharmacy operations manager at the Denver Health & Hospital Authority.