Archives of Physical Medicine and Rehabilitation
Volume 90, Issue 11 , Pages 1815-1820, November 2009

Potential Clinical Impact of Compounded Versus Noncompounded Intrathecal Baclofen

Presented to the American Academy of Physical Medicine and Rehabilitation, September 26, 2007, Boston, MA.

  • Elizabeth Moberg-Wolff, MD, FAAPMR

      Affiliations

    • Corresponding Author InformationReprint requests to Elizabeth Moberg-Wolff, MD, FAAPMR, 999 N 92nd St, Ste 350 CCC, Milwaukee, WI 53201

Department of Physical Medicine and Rehabilitation, Medical College of Wisconsin, Milwaukee, WI

Article Outline

Abstract 

Moberg-Wolff E. Potential clinical impact of compounded versus noncompounded intrathecal baclofen.

Objective

To assess the differences between commercial and pharmacy-compounded preparations of baclofen for intrathecal administration.

Design

Random sample.

Setting

Pharmacies in the United States advertising compounded intrathecal baclofen preparation.

Participants

Not applicable.

Interventions

Intrathecal baclofen (ITB) samples were collected from 1 Food and Drug Administration–approved commercial source and 6 compounding pharmacies. An independent analysis of drug concentration and density was conducted. Information regarding ordering process, manufacturing, packaging, storage, and expiration was collected.

Main Outcome Measure

Comparison of concentration and density variations.

Results

Twenty-nine ITB samples in concentrations of 2000, 3000, 4000, 5000, and 6000μg/mL were analyzed. Over 40% of compounded samples were more than 5% above or below labeled concentration. Twenty-two percent of compounded samples were more than 10% above or below labeled concentration. The only samples with no concentration deviation and consistent drug density were the commercially available, noncompounded products.

Conclusions

Compounding pharmacies have variable practices in the provision of ITB. A high incidence of concentration inaccuracy existed. The use of compounded ITB may result in unintended dose alterations. Variable clinical efficacy, or life-threatening overdose or withdrawal may occur in patients who are sensitive to slight dose fluctuations. Given the variability of these compounded ITB samples, informed consent to use these products and understanding of potential side effects should be reviewed with patients.

Key Words: Pharmacy, Rehabilitation

List of Abbreviations: FDA, Food and Drug Administration, ITB, intrathecal baclofen, USP, United States Pharmacopeia

 

INTRATHECAL BACLOFEN is used to reduce severe spasticity resulting from a wide variety of disorders including cerebral palsy, brain injury, spinal cord injury, multiple sclerosis, and stroke.1, 2, 3, 4, 5, 6 The U.S. FDA first approved its administration by means of a programable implanted infusion pumpa in 1992, and, since that time, over 50,000 drug delivery devices have been implanted worldwide.7 The pump has a reservoir into which the medication is instilled via transdermal needle puncture and depending on patient usage is typically refilled every 1 to 6 months. ITB is then released directly into the intrathecal space via a silastic catheter that attaches to the pump on 1 end and extends into the intrathecal space on the other. The fenestrated tip is then placed at whatever vertebral level will result in the functional effect desired.

ITB is commercially available as baclofen injection (Lioresal Intrathecal) in 500-μg/mL and 2000-μg/mL concentrations. The sole manufacturer labels the stability of Lioresal Intrathecal for up to 6 months in a Synchromed II delivery device. They analyzed concentrations greater than 2000μg/mL and concluded that the higher concentrations did not meet stability requirements without the formation of precipitates.8 In contrast, compounding pharmacies advertise concentrations up to 8000μg/mL for physicians who seek to reduce the frequency of patient refills and/or reduce cost.

The FDA Modernization Act of 1997 introduced “compounding guidelines” with the intent to exclude pharmacies from reproducing commercially available drugs or from creating dangerous or unstable products.9 In a 2001 FDA study, 31% of compounded injectable drugs randomly obtained via Internet order from compounding pharmacies failed to meet USP quality standards.10 Multiple warnings for misbranding, mislabeling, and manufacturing in volumes not consistent with compounding have been issued, and several compounding pharmacies have been closed. Nationally, several deaths attributed to contaminated or erroneously concentrated compounded products have also raised concerns.11, 12, 13, 14 Because individual state boards of pharmacy, not the FDA, are in charge of regulation of compounding pharmacies within their states, oversight is inconsistent.15, 16 In 2004, the first FDA-enforceable practice standards for sterile pharmacy compounding were released by the USP.17 These standards may be adopted and enforced by state boards of pharmacy and surveyable by accreditation organizations, but it is not mandatory that all compounding pharmacies comply.18 Perhaps in part because of the administrative and financial repercussions that meeting these guidelines can create, many U.S. pharmacies were not USP 797 compliant in a 2006 survey.19, 20 For patients receiving ITB, variability in either stability or concentration could make titrating to an effective dose difficult and could result in unintended life-threatening withdrawal or overdose.21, 22, 23, 24

The purpose of this study was to analyze samples from compounding pharmacies and the commercial manufacturer and to compare drug delivery, packaging, storage, cost, labeling, expiration date, stability, concentration (actual vs labeled), drug density, and internal consistency between each pharmacies' samples. Institutional review board review was obtained before study implementation.

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Methods 

Six pharmacies located in different geographic regions of the US who regionally or nationally advertised compounded ITB in concentrations that ranged between 500 and 8000μg/mL were selected. Data regarding individual pharmacy compounding practices, including self-reported compliance with USP 797 guidelines, were obtained by telephone interview by a list of standardized questions, before ordering medication.

At least 2 samples of each concentration were ordered from each compounder and from the manufacturer. At least 2 different concentrations were also obtained from each compounding pharmacy. No samples of the same concentration were ordered from the same pharmacy within 3 weeks of each other to avoid potentially obtaining samples from the same product batch. The manufacturer samples had different lot numbers.

The compounding pharmacies and manufacturer were unaware that their products were being sent for independent testing. Sample delivery method, timeliness of order receipt, storage instructions, labeling, cost, sterility testing, product expiration date, and concentration were recorded upon sample receipt. Original pharmacy labeling was removed or covered, and then samples were coded, returned to their original packaging following their enclosed storage instructions, and sent unopened by FedEx to Medtox Laboratories.a The chain of custody was documented, and samples were processed with forensic handling. Drug density was analyzed at 37°C, samples were inspected for precipitate, and concentration analysis was performed in triplicate by high-performance liquid chromatography by National Medical Services (Willow Grove, PA).

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Results 

Sample Delivery, Storage, Cost, Labeling, and Expiration Date 

A total of 29 samples with concentrations varying from 2000μg/mL to 6000μg/mL were analyzed (table 1). Twenty-seven samples of compounded ITB were received from 6 national compounding pharmacies, and 2 samples of commercially available Lioresal Intrathecal 2000μg/mL were received from the manufacturer. We did not test 500-μg/mL concentration baclofen because it is not as commonly compounded or used. We tested more samples of 4000 concentration because it is more commonly ordered.

Table 1. Baclofen for Intrathecal Administration Samples
Samples (n=29)Concentration (μg/mL)
72000
43000
114000
45000
36000

All compounding pharmacies indicated that they conducted a large-volume, mail order ITB business and were skilled at ITB preparation. References from physicians or hospitals currently using their products were provided. All pharmacies quoted 48-hour delivery on receipt of a faxed prescription. Five of 6 compounding pharmacies provided delivery within the quoted timeframe, and the sixth was 1 day late (table 2).

Table 2. Pharmacy Compounded Sample Information (n=6)
Timeliness of pharmacy samplesOn time: 5 pharmacies (24 samples) Late: 1 pharmacy (3 samples)
Packaging
5 of 6 pharmacies sent in sealed syringes

1 sent in sealed glass

Expiration date “in syringe/glass” from preparation date
2 weeks (2 pharmacies)

30 days (2 pharmacies)

90 days (2 pharmacies)

Expiration date “in pump” from preparation date
90 days (5 pharmacies)

30 days (1 pharmacy)

Mailed and delivery storage instructions
1 pharmacy: mailed with ice pack, refrigeration suggested

1 pharmacy: mailed with ice pack, no refrigeration after delivery

1 pharmacy: room temperature mailing and storage

3 pharmacies: room temperature mailing, no storage instructions

Compounded baclofen cost (10mL)
$60 (2000μg/mL) to $385 (6000μg/mL)

All samples arrived via UPS or FedEx enclosed in protective wrap and in either vials or prefilled syringes. Two pharmacies used freezer packs to cool samples en route, but only 1 of these included instructions for future storage (continue refrigeration, not freezing). Three additional pharmacies provided no storage instructions. One pharmacy, along with the manufacturer, suggested room temperature storage, with the manufacturer's recommendation based on the possibility of precipitates forming outside of the designated temperature range. Cost of samples varied significantly, with the most concentrated samples typically more expensive (see table 2).

All samples were labeled clearly and corresponded to the concentrations that had been ordered. Expiration dates of compounded baclofen not yet placed in a pump varied from 14 days to 90 days from preparation date (see table 2). Five out of 6 pharmacies indicated that once the medication was placed in an implanted delivery system, it was stable for 90 days. No compounding pharmacies could provide independent documentation of this prolonged drug stability only when in the pump but simply referenced Lioresal Intrathecal's 90-day in-pump stability data. Lioresal Intrathecal's expiration dates were 3 years from manufacture, with stability for 6 months in a 40-mL delivery device.

Drug Concentration 

Only 1 pharmacy identified their diluent on the packaging, and none identified the grade of baclofen powder that they used. None reported testing each product batch for sterility or concentration accuracy. They were willing to test an individual batch if it was requested, but results would be provided after product shipment, and there was an extra cost for this.

Significant variability was noted between actual versus labeled sample concentrations. Forty-one percent of compounded ITB samples were inaccurate by at least 5%. At a 10% variation interval, 22% of samples were inaccurate (table 3, fig 1). Samples varied from –35% to 12% from labeled concentration, and all 6 compounding pharmacies had at least 1 significant concentration discrepancy. Only the Lioresal Intrathecal samples had no concentration deviation.

Table 3. Concentration and Failure Rates of Compounded ITB
Expected Concentration (μg/mL)Failure Rate %
2000402/5
3000502/4
4000182/11
5000753/4
6000672/3
Overall (compounded samples)4111/27
Lioresal (2000)00/2

Drug Density 

All compounded ITB samples varied in density between samples of the same concentration, both inter- and intrapharmacy (fig 2). Lioresal Intrathecal samples did not vary in density.

Drug Precipitation 

Two of the 3 compounded samples of 6000μg/mL had visible particulate matter (fig 3). Spectral analysis was not conducted.

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Discussion 

Over 250 million compounded prescriptions are filled each year in the US. Compounded preparations may provide value in instances when no commercial product exists in a specific dosage or form (ie, liquid or reduced concentration for pediatric needs), when a product without specific allergenic ingredients is needed, or when limited demand makes the medication commercially nonviable.10

Although higher concentrations of ITB may benefit some patients by reducing refill frequency, the impact of variable concentration or stability refill to refill for many of these patients could be significant. In light of the fact that commercial sources have failed in their attempts to manufacture concentrations higher than the commercially available 2000μg/mL, the risks and benefits of using compounded preparations need to be examined.

Previous Reports 

In the FDA's 2001 survey of compounded products, over half the samples that failed potency assays measured less than 70% of the labeled values.15 Several other studies also have shown serious quality gaps. From 2003 to 2005, Missouri's State Board of Pharmacy randomly tested a variety of compounded products and found a 19.8% failure rate of potency. A few samples contained no medication at all, whereas another's concentration tested over 500% above intended concentration.25 A 2003 American Society of Health-System Pharmacists survey of 182 hospital pharmacies showed low compliance with sterility guidelines for compounding even though hospital pharmacies typically undergo much more stringent accreditation procedures than independent compounding pharmacies might.26 Canadian hospitals found similar concerns; a survey of 306 hospital-based compounding pharmacies noted a need for comprehensive quality control guidelines and improved training of personnel.27 Even the veterinary medicine community expressed concern about the issue after the FDA published guidelines for veterinary compounds in 2003.28 USP guidelines were introduced to assist with some of these problems, but compliance with the guidelines can have administrative and financial impact on pharmacies that follow them.18, 20

Intrathecal Baclofen 

Timeliness, storage, and expiration 

Although nearly all samples arrived safely and on time, damage during shipping or late delivery could result in patient inconvenience and/or withdrawal. The lack of storage directions provided in nearly all compounded ITB samples was concerning given that the solubility of pharmaceutical agents can be impacted by temperature. Expiration dates provided varied greatly not just between pharmacies but also within a single pharmacy's samples. They varied not only by the concentration but whether the medication was in or out of an implanted pump. In some instances, the expiration of the compounded drug was far shorter on the shelf than if it were in the pump, although they could not verify how they had determined this. This is the opposite of the commercially manufactured product.

Sterility 

All pharmacies stated they were in compliance with USP 797 and used barrier hoods and laminar flow clean rooms for drug preparation. Yet, no compounding ITB batches were routinely tested for sterility by the compounding pharmacies. When we requested documentation of sterility, it was offered only at our expense, and results were promised after the samples had been shipped and presumably used. Routine random pyrogen and endotoxin testing was offered instead by several pharmacies as proof of sterility. USP guidelines are specific that microbial and pyrogenicity testing are distinct and exclusive concepts, especially for high-risk compounded products such as ITB.19

Concentration 

FDA guidelines allow a 10% deviation from labeled concentration in compounded products, but we also chose to examine at ±5% potency specification because commercial Lioresal Intrathecal is manufactured according to those guidelines and there is a narrow therapeutic window for many ITB patients. Only 1 compounding pharmacy indicated that they routinely tested each batch of drug for concentration accuracy. However, they shipped the product before the results were back and did not report the results to the consumer. On request, 1 pharmacy sent their annual concentration testing data reporting a 15% variance between monthly samples. Another provided a report that averaged their “high” and “low” batch variations throughout the year to report that there was virtually no deviation annually from desired concentration in their samples. None reported if they used USP grade baclofen powder. Because of baclofen's bipolarity as a molecule and its zwitterionic effects, the purity of product and its diluent can impact its solubility and the product's final concentration.

Overall, there were significant differences in actual versus labeled concentration in 40.7% of the samples. Although the highest error rates were noted in the higher concentration solutions, even the lowest concentrations had variable results. Two of 5 samples of 2000μg/mL ITB deviated by more than 5% from labeled concentration.

Drug density 

Minor changes in the density of a drug affect how it will be distributed in the cerebrospinal fluid, and slight variations from 1 infusion to the next may result in variable clinical efficacy.29, 30 The compounded ITB samples had a variation in density between 0.994g/cm3and 1.002g/cm3. For samples of the same concentration from the same pharmacy, variation ranged from 0.002g/cm3 to no variance. The density of Lioresal Intrathecal samples did not vary.

Precipitation 

The commercial provider of Lioresal Intrathecal, has not been able to successfully manufacture stable concentrations of ITB greater than 2000μg/mL, even when changing pH and increasing manufacturing temperatures. They found that higher concentrations produced precipitates.8 Two nonrefrigerated 6000μg/mL compounded samples in this study had visible particulate matter. Any drug precipitate not only reduces the presumed baclofen concentration but also could potentially alter pump mechanics. Intrathecal delivery devices such as the SynchroMed IIb have two 0.22-μm antimicrobial filters, which if occluded could cause the pump to cease delivery of the medication. When the compounding pharmacies were questioned as to how they were able to produce such concentrated solutions without precipitate, none could provide a clear explanation. The effect of storage temperature on ITB may also impact solubility, yet storage information was not addressed by 4 of 6 pharmacies in this study.

Patient Impact 

To understand the impact of these compounded products, one must consider the variations that concentration produces for a patient whose pump is programmed to provide 800μg of 5000μg/mL ITB per day. With medication provided for this study, it would have been possible for them to actually receive 620μg/d from 1 refill and 1080μg/d the next, without a change in programming. This would be possible given the 35% variability rate in 1 pharmacy's samples. These wide variations in efficacy could result in significant withdrawal or overdose symptoms, both of which can be life threatening. Such variation can also cause great confusion to the programming physician and may ultimately put patients at risk.

Numerous patient deaths have been reported nationally, not just from erroneous concentrations of various compounded products but also from contaminated compounds.11, 13, 14 Infected intrathecal betamethasone and methylprednisolone acetate compounds resulted in 15 infections and 4 deaths from meningitis in 2001.12

The integrity of intrathecal preparations is especially important given the risk of meningitis, which can result in permanent neurologic damage or death. Although we did not test sample sterility, the fact that no pharmacy did before shipping was concerning.

Liability 

The liability of pharmacies and physicians creating, ordering, and using compounded medications may not be fully understood by the pharmacy, physician, or the patient. Providing compounded medication that is commercially available (500 and 2000μg/mL) or producing it in large volumes (manufacturing) is outside legitimate practice per the FDA Modernization Act of 1997. Fines and pharmacy closure can result if the FDA intervenes.15

The pharmacy creating or ordering compounded products bears responsibility for the clinical impact that erroneous concentrations or contaminated products may have. The American Society of Health System Pharmacists guidelines state that “the pharmacy director must take complete responsibility for patient outcomes from all medication related activities performed at or for the organizations work sites, whether they are carried out by the organization or contractors staff on or off site.”31 If patients are unaware that their physicians are using noncommercial products when commercial product is available, legal recourse, especially if ill effects or death from a contaminated or erroneously concentrated product occur, could be significant. Thus, all risks should be explained and informed consent should be obtained from the patient to use a compounded product.

Study Limitations 

Although the compounding pharmacies we obtained samples from were geographically diverse, specifically advertised regionally or nationally regarding baclofen compounding, and were known suppliers of many office or hospital practices, their products may not be representative of all compounding pharmacies. Increasing the number of samples tested from each pharmacy might also have strengthened the study results.

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Conclusions 


1.The delivery of intrathecal baclofen for spasticity related to spinal cord injury, stroke, cerebral palsy, multiple sclerosis, and brain injury is commonplace.

2.Compounding pharmacies have variable practices in provision of compounded ITB and a high incidence (41%) of concentration inaccuracy varying more than 5% from labeled value. The reliability of compounded product varied regardless of concentration, although more variability was typically seen with higher concentrations.

3.Drug density varied among compounded samples, which may impact drug distribution in the CSF.

4.Patients using ITB therapy to manage severe spasticity are often sensitive to slight fluctuations in dose. Fluctuations in concentration may result in suboptimal therapeutic response, complicating patient management and reducing satisfaction.

5.Variability in concentration from refill to refill may also result in life-threatening drug overdose or withdrawal.

6.A clear understanding of potential side effects should be reviewed with all patients, and, if compounded product is used, informed consent should be obtained.

Suppliers

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References 

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  • a Medtox Laboratories, 402 County Road D W, New Brighton, St Paul, MN 55112.
  • b Medtronic Inc, 710 Metronic Pkwy, Minneapolis, MN 55432.

 Medical College of Wisconsin was supported by grant funding from Medtronic Neurologic, Inc, for independent testing of the samples in this study.

 No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit on the authors or on any organization with which the authors are associated. Moberg-Wolff discloses involvement with Medtronic Neurologic, Inc as a teaching consultant.

PII: S0003-9993(09)00466-3

doi:10.1016/j.apmr.2009.05.018

Archives of Physical Medicine and Rehabilitation
Volume 90, Issue 11 , Pages 1815-1820, November 2009

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