Compounded medicines and ‘off label’ prescribing

[Pages:5]THEME summer salad

Romano A Fois

BPharm, PhD, MPS, is Lecturer, Faculty of Pharmacy, University of Sydney, New South Wales. romanof@pharm.usyd.edu.au

Barry T Mewes

PhC, FPS, is Adjunct Lecturer, Faculty of Pharmacy, University of Sydney, New South Wales.

Andrew J McLachlan

BPharm(Hons), PhD, FPS, is Professor of Pharmacy (Aged Care), Faculty of Pharmacy, University of Sydney, New South Wales.

Compounded medicines and `off label' prescribing

A case for more guidance

Background Interest by prescribers and pharmacists in the provision of individualised pharmaceutical therapy in the form of compounded medicines has grown in recent times. However, there have also been a number of case reports of patient harm associated with these medicines.

Objective To highlight areas for clinicians and pharmacists to consider when prescribing or dispensing compounded medicines, which are consistent with quality use of medicines principles.

Discussion Regulators of pharmaceutical products have expressed concerns with the production, marketing and use of compounded medicines dispensed by pharmacists. This has prompted debate over the need for more regulation of these products. We propose an expansion of off label prescribing guidelines to include a risk based assessment of pharmaceutical quality, a consumer information/education strategy and the development of a code of practice for pharmacists engaging in compounding. These strategies recognise a shared responsibility among prescribers, dispensers and regulators to achieve contemporary quality, safety, and efficacy standards and support the quality use of compounded medicines.

There has been a recent rise in the prescribing and dispensing of compounded medicines both in Australia and overseas. These activities are proposed to offer benefits by individualising pharmaceutical therapy to patients' needs. However, case reports of patients coming to harm following the use of compounded medicines and the absence of regulated processes for evaluating these medicines for quality, safety and efficacy, warrant a review of the activities and responsibilities of prescribers, pharmacists and regulators concerning compounded medicines.

In February 2007, the United States Food and Drug Administration (FDA) issued a public health advisory warning of the hazards associated with the use of compounded high dose topical anaesthetic products.1 The FDA highlighted two cases of young women who had used these products to lessen the pain of laser hair removal. These women wrapped their legs in plastic wrap, as instructed, to increase the numbing effect of the creams, and subsequently died from the toxic effects of the local anaesthetic agents. In August 2007, an Australian report of three cases of endometrial cancer in patients using `bioidentical' hormone replacement therapy (BHRT) raised the possibility that the absorbed dose of the progesterone component of the BHRT troches was inadequate, thereby resulting in endometrial hyperplasia in response to the `unopposed' oestrogen component.2

These events raise questions about how compounded medicines are regulated and how those who prescribe and dispense these medicines can evaluate their quality, safety and efficacy.

Extemporaneous dispensing (compounding)

The Australian Pharmaceutical Formulary (APF) describes extemporaneous dispensing (compounding) as `the preparation and

16 Reprinted from Australian Family Physician Vol. 38, No. 1/2, January/February 2009

Iqbal Ramzan DipPharm, MSc, PhD, is Dean and Professor, Faculty of Pharmacy, University of Sydney, New South Wales.

supply of a single `unit of issue' of product which is intended for immediate use by a specific patient'.3

Regulation of therapeutic goods

The Therapeutic Goods Act, 1989 requires that applications for registration of therapeutic goods be evaluated `having regard to whether the quality, safety and efficacy of the goods for the purposes for which they are to be used have been satisfactorily established'.4

To ensure product quality, manufacturers must comply with the code of Good Manufacturing Practice (cGMP). The sponsor must also produce evidence that supports the efficacy and safety of their products and information for prescribers (product information [PI]) and consumers (consumer medicines information [CMI]) of medicines that support the quality use of medicines (QUM). Manufacturers must also comply with therapeutic goods and other legislation and codes that govern the promotion of their products to health professionals and consumers.5

The system that regulates the pharmaceutical manufacturing industry in Australia, and many other countries, seeks to ensure that industry's medicinal products are reasonably able to deliver on therapeutic claims without producing unacceptable harm and that their products are selected and used in a rational manner.

Exemption from therapeutic goods legislation

The preparation of compounded medicines by pharmacists in Australia is not regulated in the same way as manufacturing by the pharmaceutical industry due to an exemption for pharmacists and the medicines they compound from parts of the Therapeutic Goods Act, 1989. In particular, pharmacists are not required to comply with many of the processes included under cGMP when preparing an individual product prescribed by a medical practitioner for an individual patient.

In Australia, principles of quality, safety, efficacy and risk management are applied to compounded medicines under a system guided by professional practice standards6 and legislation governing the practice of pharmacy. Prescribers and dispensers of compounded medicines accept responsibility for evaluating and ensuring the quality, safety and efficacy of this class of medicines.

Indications for use and associated risks

Table 1 summarises some circumstances where prescribers may regard compounded medicines as offering an appropriate benefit-risk balance for their patients. Clearly, patients benefit from the availability of compounded medicines under any of the circumstances outlined in Table 1. A restriction on compounding could deprive patients of

Table 1. Circumstances where compounded medicines may be indicated

? A manufactured product contains inactive ingredients the patient can't tolerate (eg. dye allergy), no alternative therapeutic options exist and a compounded medicine can provide an acceptable standard of quality, safety and efficacy

? A manufactured pharmacopoeial product is not available (eg. for stability reasons)

? No product exists to deliver a registered medicine in the required form (eg. reformulation of capsules as a mixture for a child)

? Evidence supports an acceptable benefit-risk balance (eg. topical formulation for dermatological condition)

an important therapeutic option and a requirement for pharmacists to demonstrate compliance with cGMP in such circumstances would be impractical.

However, compounded medicines may carry unique risks associated with their formulation such as: ? uncertain bioavailability and stability, and ? adverse reactions to active ingredients or excipients associated with

unapproved use. They also carry a risk of dosage and formulation errors in prescribing or dispensing. On balance, the exemption from sections of the Therapeutic Goods Act, 1989 for pharmacists is a sensible approach based on risk management principles.

Regulator concerns with compounded medicines and their promotion

The USA employs a similar system to that which applies in Australia. However, recent incidents indicate that the FDA is concerned with the actions of some USA pharmacy operators. In January 2008, the FDA issued warning letters to seven pharmacy operators indicating that claims about the safety and effectiveness of their BHRT products are unsupported by medical evidence, and are considered false or misleading by the agency.7

More recently, the FDA has taken action to stop the inappropriate marketing of unapproved injectable products containing colchicine that were being used for the treatment of back pain, an indication that has not been evaluated by the FDA. This action included a number of compounding pharmacies.8

The FDA also regards certain other activities as being outside the legitimate practice of pharmacists under exemption from cGMP, labelling and new drug registration provisions of legislation.9 These include: ? commercial scale manufacturing ? compounding drugs that were withdrawn or removed from the market

for safety reasons ? compounding products from unregistered bulk active ingredients ? using drug substances without proof of supplier licences or evidence

of compliance with compendial standards, and ? wholesaling and copying existing FDA approved drug products.9

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theme Compounded medicines and `off label' prescribing ? a case for more guidance 18 Reprinted from Australian Family Physician Vol. 38, No. 1/2, January/February 2009

Table 2. Criteria for the assessment of risk from compounded medicines

Factor Patient population

Risk criteria

Is the medicine to be used in a high risk population?

Lower risk Healthy young adults

Site of action

Route of administration

Is the medicine intended to

Local effect

have a local or systemic effect?

Is the medicine intended for topical, enteral or parenteral administration?

Topical

Higher risk ? Infants ? Frail older people

? Systemic effect

? Enteral ? Parenteral

Pharmacodynamics Is there a wide or narrow safety ? Large difference between ? Small difference between

margin (therapeutic index)?

therapeutic and toxic doses therapeutic and toxic doses

Examples of factors contributing to risk

? Population more sensitive to pharmacodynamic effects ? Lack of acceptable level of evidence for safety and efficacy in

target population ? Altered pharmacokinetics (eg. reduced renal clearance)

? Formulation dependent variability in rate or extent of bioavailability

? Dosage or formulation error during prescribing or dispensing

? Formulation dependent variability in rate or extent of bioavailability

? Dosage or formulation error during prescribing or dispensing ? Microbial contamination ? Topical administration may carry increased risk of delayed

hypersensitivity reactions (eg. antihistamines)

? Formulation dependent variability in rate or extent of bioavailability

Biopharmaceutics

Is the dose response relationship steep or shallow? Do formulation factors affect the bioavailability or stability of the medicine?

Is bioavailability highly variable because of physicochemical properties of active ingredient?

? Small changes in response with changes in dose

? Dissolution, bioavailability and stability relatively insensitive to formulation factors

? Consistent bioavailability

? Large changes in response with changes in dose

? Dissolution, bioavailability or stability affected significantly by formulation factors

? Dosage or formulation error during prescribing or dispensing

? Variability among pharmacies in active ingredient or excipients with respect to particle size, crystal form or other critical physicochemical characteristics

? Inconsistent bioavailability

? Variability among pharmacies in method of manufacture

Is the formulation complexity rational for a compounded medicine and is dose uniformity guaranteed?

? Simple solution

? Solid dose forms ? Sustained release formulations ? Transdermal delivery of

systemic medications ? Inhaled formulations

? Failure of solid dose form to disintegrate or release active ingredients

? Dose `dumping' or high variability in dose delivery from nonvalidated sustained release products

? Failure in delivery of inhaled dose to intended site

Is quality assurance (QA) testing required and can it be performed?

? QA testing not required or is easily performed

? QA testing required and is not easily performed

? QA testing is not performed

? Nonpharmacopoeial formula prescribed in absence of evidence for quality, safety and efficacy

? Use in absence of evidence for quality, safety or efficacy ? Use when evidence exists raising quality, safety or efficacy

concerns

Clinical investigation formulation unknown

Nonpharmacopoeial formula

Acceptable level of evidence is lacking

Ingredients rejected or withdrawn for safety reasons or not approved for indication or dose form and acceptable level of evidence lacking for quality, safety and efficacy in patient population

Compounded medicines and `off label' prescribing ? a case for more guidance THEME

In Australia, the National Coordinating Committee on Therapeutic Goods (NCCTG) has been conducting a review of the regulation of extemporaneously prepared medicines by nonhospital pharmacies and is exploring a three tier regulatory system for pharmacies engaged in compounding.10 This system proposes to set levels of accreditation, licensing and compliance with manufacturing and other standards for pharmacies based on the types and quantities of compounded medicines being produced. The NCCTG review is a response to compounding and associated promotional activities by some pharmacies that are viewed as commercial scale pharmaceutical manufacturing and marketing rather than traditional extemporaneous dispensing.

Off label prescribing of compounded medicines

An important issue that emerges from these events is that of `off label' prescribing.11 Research conducted after marketing approval is granted may support the use of a medicine for an indication, at a dose, in a formulation or in a patient group not included in the original marketing application. Any of these deviations from the original marketing application are considered `off label' and prescribers may choose to follow the recommendations from this research. This may necessitate dispensing of a compounded medicine by a pharmacist.

Consensus recommendations for evaluating off label prescribing (using evidence level and risk management principles) are described by Gazarian et al.11 Three broad categories of appropriate off label use are described: ? use justified by high quality evidence ? use within the context of research, and ? exceptional use, justified by individual clinical circumstances. This guidance focuses primarily on clinical evidence for off label use. Off label prescribing of compounded nonpharmacopoeial medicines should also involve consideration of pharmaceutical quality. In these situations, prescribers and pharmacists must consider whether a proposed formulation is bio-equivalent to the formulation employed in the clinical literature and whether the ongoing stability and performance of the compounded medicine is established.

The professional practice standard of the Pharmaceutical Society of Australia (PSA) concerning compounding includes a recommendation to produce compounded medicines in accordance with pharmacopoeial formulations where possible or to adequately research nonpharmacopoeial formulae for issues such as stability and `appropriateness' of ingredients.6

Guidance on prescribing and dispensing

Guidance on nonpharmacopoeial formulae in PSA's practice standard is broad and pharmacists and prescribers would benefit from more specific guidance to assess nonpharmacopoeial formulae. An expansion of the existing guidance for evaluating off label use to include the risk based evaluation and classification of the factors outlined in Table 2 would be useful.

Under these criteria, many dermatological preparations intended for local effects (a significant segment of compounded nonpharmacopoeial

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Clinical investigation formulation known

Standard pharmacopoeial formula

Ingredients approved for indication and dose form or acceptable level of evidence exists for quality, safety and efficacy in compounded dose form in patient population Acceptable level of evidence exists

Is the complete formula for the product used in clinical investigations known?

Is the product described as a standard pharmacopoeial formula?

Are the active and inactive ingredients approved for pharmaceutical use in Australia? Have any of the ingredients been withdrawn or rejected from registration because of safety concerns? Is there an acceptable level of evidence supporting the quality, safety and efficacy of an extemporaneous formulation?

Regulatory Clinical and pharmaceutical evidence

theme Compounded medicines and `off label' prescribing ? a case for more guidance

medicines) would be regarded as having an appropriate benefit-risk balance. However, such criteria would require critical assessment of a sustained release formulation for systemic delivery of a potent low therapeutic index active ingredient. There is a need for research to evaluate nonpharmacopeial formulations for safety, efficacy and pharmaceutical quality. In particular, sources of variability in performance should be assessed.

A note on writing prescriptions

A prescription for a compounded pharmacopoeial or formulary medicine should state the name of the pharmacopeial formula (including the edition of the pharmacopoeia or formulary). If a nonpharmacopoeial formula is prescribed, the prescription should include the complete formula including quantities (absolute, percentage or parts based) of active ingredients and excipients. The formula should reflect that of the product used in generating clinical evidence for safety and efficacy or should be able to be justified using stability and bio-equivalence criteria.

Patient information

Consumers would benefit from balanced information about compounded formulations, including information about their therapeutic effects, potential adverse effects and appropriate use. This represents a challenge in the absence of CMIs for compounded medicines. A strategy for achieving this should be considered by prescribers, pharmacists and regulators.

Reporting adverse reactions

While adverse drug reaction (ADR) reporting is a legal obligation of the pharmaceutical manufacturing industry, the reporting of spontaneous ADRs by prescribers and dispensers of compounded medicines is not currently mandated. Previously unknown risks to patients from compounded medicines may be exposed by an active program requiring ADR reporting for compounded medicines by prescribers and pharmacists.

Code of practice for pharmacists

A code of practice in compounding would support pharmacists in these activities. This should encompass issues currently included in the PSA practice standard and guidance on issues currently addressed for pharmaceutical manufacturers in the Therapeutic Goods Act, 1989. These include: ? establishing, assuring and maintaining quality ? a risk management approach (Table 2) to achieve an acceptable

benefit-risk balance for compounded medicines ? ensuring that prescribers and consumers of compounded medicines

have evidence based information to support QUM ? complying with the spirit of the therapeutic goods advertising code in

relation to promotion to prescribers and consumers of compounded medicine ? engaging in reporting to the Therapeutic Goods Administration all ADR reports received that are associated with the use of compounded medicines.

Ultimately, prescribers and pharmacists must appreciate that there are

some medicines and some formulations that cannot be compounded to

acceptable quality, safety and efficacy standards. Both professions share

responsibility in ensuring compounded medicines meet these standards.

Conclusion

Prescribers of compounded medicines should evaluate the evidence

for efficacy, safety and quality and prescribe detailed formulae to

ensure consistency of performance with the evidence based formulae.

Prescribers should review all nonpharmacopoeial formulations for a

number of criteria to assess the potential risk associated with their use.

An expansion of off label prescribing guidelines to consider issues

of pharmaceutical quality would be beneficial. A consumer information/

education strategy and the development of a code of practice for

pharmacists engaging in compounding would also be helpful. The code

should be based on criteria that align with Australia's medicines policy

in delivering medicines within contemporary quality, safety, and efficacy

standards.

Conflict of interest: none declared.

References

1. US Department of Health and Human Services, Food and Drug Administration. FDA Public Health Advisory ? life-threatening side effects with the use of skin products containing numbing ingredients for cosmetic procedures, February 6, 2007. Available at Cder/drug/advisory/topical_anesthetics.htm [Accessed August 2008].

2. Eden JA, Hacker NF, Fortune M. Three cases of endometrial cancer associated with `bioidentical' hormone replacement therapy. Med J Aust 2007;187:244?5.

3. Sansom L, editor. Australian pharmaceutical formulary and handbook. 20th edn. Curtin, ACT: Pharmaceutical Society of Australia, 2006. Section A: Dispensing and advice to consumers. p. 23?5.

4. Therapeutic Goods Act 1989 (Cwlth), s25(1)(d). Available at austlii.edu.au/au/ legis/cth/consol_act/tga1989191/s25.html [Accessed April 2008].

5. Australian Government, Department of Health and Aging, Therapeutic Goods Administration. Advertising prescription medicines to healthcare professionals. Available at .au/advert/advpmhcp.htm [Accessed February 2008].

6. Sansom L, editor. Australian pharmaceutical formulary and handbook. 20th edn. Curtin, ACT: Pharmaceutical Society of Australia, 2006. Section G: Standards and guidelines. p. 468?71.

7. US Department of Health and Human Services, Food and Drug Administration. MedWatch, The Safety Information and Adverse Event Reporting Program, 2008. Safety alerts for drugs, biologics, medical devices and dietary supplements. Available at medwatch/safety/2008/safety08.htm#Menopause [Accessed January 2008].

8. US Department of Health and Human Services, Food and Drug Administration. FDA News ? FDA takes action to stop the marketing of unapproved injectable drugs containing colchicine'. Available at bbs/topics/NEWS/2008/NEW01791. html [Accessed February 2008].

9. US Department of Health and Human Services, Food and Drug Administration. Guidance for FDA staff and industry: Compliance policy guides manual, Sec 460.200 Pharmacy compounding, May 2002. Available at OHRMS/ DOCKETS/98fr/02D-0242_gdl0001.pdf [Accessed March 2008].

10. Australian Government Department of Health and Ageing, Therapeutic Goods Administration. A discussion paper on regulation of extemporaneously prepared medicines in non-hospital pharmacies. Available at .au/meds/extempcomp2.htm [Accessed August 2008].

11. Gazarian M, Kelly M, McPhee JR, et al. Off-label use of medicines: consensus recommendations for evaluating appropriateness. Med J Aust 2006;185:544?8.

correspondence afp@.au

20 Reprinted from Australian Family Physician Vol. 38, No. 1/2, January/February 2009

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