Download The Need and Importance of Dose Flexibility - Accu

Achieving Individualized Dosing and Dose Flexibility
through Tablet Splitting
Accu-Break Pharmaceuticals, Inc.
Achieving Individualized Dosing and Dose Flexibility
through Tablet Splitting
1. Introduction
Dose flexibility is a growing need for all segments of the population, especially the geriatric and pediatric
populations. The growth of >65 year old segment has been outpacing the growth of the overall U.S.
population. Over half of all elderly patients are currently on 3 or more medications and, by 2020, will
consume 40% of all prescriptions.1 By the same token, prescription drug spending for the >65 and for
children (0-19 years) is growing at a faster than average rate compared to other age groups.2
Individualized dosing to achieve treatment goals, adherence, cost containment and safety are among
the chief concerns of these age groups.
Lastly, dose flexibility translates into an efficient use of health care resources -- multiple dosage
strengths can be derived from one tablet, which translates into fewer prescriptions written (if a
medication is being titrated), fewer trips to the pharmacy and to the physician’s office, and fewer
medication refills.
2. Dose Flexibility Today
Dose adjustments are a common and everyday occurrence for many patients on acute or chronic
medications. The frequency of dose adjustments varies according to therapy. It is estimated that as
many as 86% of patients taking warfarin, a popular anticoagulant, are on alternating dosage regimens.3
Another prime example is statins, the largest prescribed class of cardiovascular medicines. Currently,
there are over 30 million Americans on statins.4 Dose adjustments during the first year are frequent as
patients are titrated (or dose-adjusted) according to their cholesterol goals and response to therapy.
Even after one full year of statin therapy, where “dose stabilization” has occurred, 17% of patients still
require up/down dose titration.5 Oxycodone, a frequently prescribed opioid analgesic, is adjusted both in
the short and long-term. In one study, approximately, 44 percent of patients taking oxycodone for the
treatment of non-cancer pain, required titration in the first three months, and 8-13% required dose
titration in the longer term (> 1 year).6
Achieving dose flexibility can be a challenge, depending on the formulation. Oral delivery systems
continue to dominate the drug delivery market due to convenience and cost-effectiveness. Capsules first
Achieving Individualized Dosing and Dose Flexibility through Tablet Splitting
Dose flexibility can be defined as the ability to easily and accurately deliver dosing according to a
patient’s individual needs. This has important clinical ramifications as health care providers can
customize drug therapy for their patients, titrating doses up and/or down, and help patients reach their
therapeutic goals in many chronic conditions such as hypertension, hyperlipidemia and diabetes. It also
allows physicians and patients to achieve doses that might not otherwise be available and to make fine
dose adjustments. This is important for medicines with narrow therapeutic indexes, such as anticoagulants, medications for cardiovascular and thyroid disorders, and those to treat conditions such as
pain, anxiety and depression. Additionally, as combination therapy becomes more commonplace, dose
flexibility for combination tablets is needed to manage side effects or to maximize therapeutic response.
1
appeared in the mid 19th century offering improvements in the palatability of medications. Later, they
were used as a means to individualize dosages through compounding. They have become increasingly
prevalent, comprising approximately 21% of all U.S. oral solid medications today.7 The principal
disadvantage of capsules, however, is the lack of flexibility, making dose adjustments impossible without
multiple daily dosages or multiple dosage strengths.
Tablets, on the other hand, are the most popular dosage form because of the advantages afforded to
both the manufacturer and the patient.8 They also offer the greatest opportunity for dose flexibility via
the presence of a score mark. It is estimated that over 50% of all oral dosage forms are produced as
compressed tablets. Nonetheless, approximately 15% of tablets bear a score mark(s), rendering the
majority of tablets dose inflexible.7 Of the tablets bearing score marks, many of these are more cosmetic
rather than functional. According to the Association of Pharmaceutical Scientists, there are 7 types of
score marks, ranging from the most functional to the purely cosmetic. Most tablets today are the E-Type,
or standard bisect, which are more cosmetic in nature and are not formulated or designed to break into
equal doses, despite the implication of the score mark. Experts in this field recommend avoiding the Etype and opting instead for the functional types (D, C or A), depending on the active ingredient.9
The only ways to achieve dose flexibility is via tablet subdivision, multiple dosage strengths or multiple
daily dosages. It is estimated that millions of people subdivide tablets every day, either for doseadjusting, cost savings or both. Unfortunately, this practice is not always safe, regardless of whether the
tablets are subdivided using a tablet-splitting device, a knife or by hand, as tablets break into imprecise
doses.
Many clinical trials have been conducted to assess the
ease of breakability and accuracy (variability) of scored
«It is estimated that millions
tablets. Peek et al assessed the ability of elderly men
of people subdivide tablets
to split tablets types using two different tablet
splitters. They found that doses deviated anywhere
every day, either for dosebetween 9 and 37% from those intended and
adjusting, cost savings or
concluded that these larger deviations could be
hazardous in medications with narrow therapeutic
both»
indexes.10 In another study, Cook et al found that
cyclobenzaprine hydrochloride tablet fragments, split
by pharmacists and doctor of pharmacy students, using tablet splitters or a kitchen knife, varied
considerably in weight and estimated drug content. Of these tablets fragments, 58% of those split using
a kitchen knife and 16% split using a tablet splitter deviated by more than 15% of their ideal weights.11
Rosenburg et al evaluated fragments split by pharmacists from 22 dispensed prescriptions and found
that 15 out of 22 (68%) of medicines failed the Uniformity of Dosage Unit standard of the United States
Pharmacopeia (USP) applied to the dose uniformity of the resulting split tablets. This standard requires
uniform drug content from tablet to tablet, ensuring the tablets contain between 85% and 115% of the
labeled dose, allowing for a 6% relative standard deviation in drug content. Rosenburg concluded that
tablet splitting results in an unacceptable high incidence of weight variation and that standards should
be developed to ensure dose uniformity of split tablets.12 Similar results were found with Teng et al in
2002 who concluded that visible tablet features (such as score marks) did not predispose a product’s
Achieving Individualized Dosing and Dose Flexibility through Tablet Splitting
3. Tablet Splitting as a Means of Dose Adjustment
2
ability to pass or fail the uniformity test, and that this did not vary between branded or generic
products.13
Proponents of tablet-splitting have advocated that strategies such as the use of tablet-splitters (vs.
breaking by hand or with other utensils) and better patient instruction will overcome the issues
associated with subdivision. However, as shown in several clinical studies, even trained personnel using
different types of tablet splitters were not able to accurately split scored tablets.11-13
Thus, it is difficult to imagine that elderly patients, who consume the majority of Rx drugs, would be able
to properly break a tablet with a standard score. One possible strategy is to pre-break tablets at the
pharmacy, as is done in some European countries. This is not a viable option as studies have shown that
trained pharmacists do not fare any better at subdividing tablets than end users (patients). Further, this
practice is actually illegal in many U.S. states.14
4. Tablet Subdivision: Challenges and Call to Action
Groups such as the American Medical Association, the Academy of Managed Care Pharmacy, and the
National Association of Boards of Pharmacy, among others, have opposed the practice of mandatory
tablet-splitting for safety reasons cited previously.15-17 Instead, they have advocated implementing
regulatory standards for scored tablets, similar
to the ones in Europe.
«Tablet-splitting has become
more prevalent in the past
decade due to rising
prescription drug costs»
The U.S. Pharmacopeia (USP) is the official
public standards-setting authority for all
prescription products manufactured and sold in
the U.S. Unlike its European counterpart, the
European Pharmacopeia (EP), no standards for
how accurately a scored tablet must subdivide
exist in the USP. Due to concerns over dosing in
accuracy upon tablet subdivision, the EP instituted standards for scored tablets in 2002 and relaxed
these standards in 2005 (Monograph 0478, 5th Edition, 5.5) due to comments received and the
difficulty of the pharmaceutical industry to meet these standards.18,19 According to the new standards,
all tablets in the European Union bearing score marks, and for which subdivision is authorized in their
respective package inserts, must now adhere to defined subdivision accuracy standards. Thus, tablet
fragments, upon subdivision, must not deviate by more than 15% of their ideal weight.
Besides the requirement for breaking into equal doses, increasing attention is being paid to the ease of
breaking by health authorities in Europe. Tablet subdivision researchers point out that there should be
limits on the amount of manual force that has to be applied to break a tablet. Tablets, in addition to
adhering to the accuracy of subdivision standards instituted in the EP, should be easy to break by hand
Achieving Individualized Dosing and Dose Flexibility through Tablet Splitting
Tablet-splitting has become more prevalent in the past decade due to rising prescription drug costs.
Because of the flat pricing practices of most pharmaceutical manufacturers (i.e. little variation in price
among different dosage strengths), many hospitals, pharmacy benefit managers (PBMs) and managed
care organizations (MCOs) have instituted table-splitting programs in an effort to save costs. These
programs, some mandatory and others voluntary, offer a number of incentives (free tablet-splitters,
reduced co-pays) to increase this practice. Some of the largest insurers have also adopted these
programs (Aetna, United, Cigna, Wellpoint, and Blue Cross/Blue Shield).
3
(without the use of any device) by a panel of elderly volunteers. This proposal was introduced in 2005
and has yet to be included in the EP.20,21
5. Dose Flexibility and Its Role in Patient Care
The issue of dose flexibility is only important when viewed in the light of a patient’s overall health.
Therapeutic inertia, or TI, is the failure to begin new medications or increase the dose of existing
medications when treatment goals are unmet. It is a term well-known to health care providers and
researchers alike. It is also the primary cause of treatment failure, especially among diabetic,
hypertensive and hyperlipidemic patients. Health-related expenditures in the U.S. alone due to TI are
approximately $200 billion annually.22,23 TI has been cited as a factor in other diseases such as chronic
depression. Core strategies to overcome TI are multi-faceted, involving a more effective management of
different disorders, educational programs and overcoming the practical complexities of treating to goal.
These complexities include “treating to goal” by dose titration, adding more medications or using fixeddose combination therapies to help reach therapeutic targets.24-26 Dose titration is difficult for providers
and patients alike due to fear of drug side effects or other dosing considerations (difficulty achieving or
unavailability of in-between doses). Likewise, fixed-dose combination therapies are limited in the
flexibility they can offer, and many times might not be available in tablet form due to incompatible APIs.
Thus, the lack of dose flexibility in current dosage forms actually contributes to TI.
Accu-Break technologies represent a solution to the long-standing problem of dose inflexibility. The
patented and patent-pending technologies are designed to provide easily divisible tablets that, when
subdivided, result in precise smaller doses for the ease of customized and precise dose adjustments
and titration. This is achieved through a drug-free break layer that delivers accuracy upon subdivision
well within the existing EP standards for subdivision of scored dosage forms. The technologies can be
applied to any product requiring titration or dose adjustment (e.g. cardiovasculars, opioids, antidepressants, anti-epileptics). They are especially suited to medications with a narrow therapeutic index,
where precise dosing is of the utmost clinical importance.
ACCU-TTM (tri-layer) tablets are manufactured in a deep fill multi-layer press. In the AIA version (figure 1),
“A” can be a single or combination agent drug which is separated by a drug-free break layer, allowing the
dose to be divided into exact halves. In the AIB version (figure 2), “B” can be a different drug or drug
combination which is likewise separated by a drug-free layer, allowing the two medications to be easily
separated from each other if medically indicated. The novel AIB design is especially suited for
combination products with compatible and/or incompatible APIs. The ACCU-T technology can also be
applied to controlled-release formulations, offering unprecedented flexibility for CR products – either for
pure CR tablets or in combination CR and immediate-release (IR) tablets, as shown in figure 3.
Figure 2
Figure 1
Figure 3
Achieving Individualized Dosing and Dose Flexibility through Tablet Splitting
6. The Accu-Break Solution
4
This is especially important as many CR medications are available as capsules or unscored tablets,
unsuitable for subdivision. Even for CR medications in scored tablet form, multiple studies have documented
that the pharmacokinetic properties are altered when CR tablets are subdivided.
ACCU-BTM tablets, for single agent drugs, are manufactured on a standard bi-layer press and can be
produced as bisected, trisected, or quadrisected tablets, rendering exact half, third or quarter doses
(figure 4).
Figure 4
Figure5
Accu-Break tablet technologies offer a variety of applications and benefits to the pharmaceutical and
healthcare industries. Among them are life cycle management opportunities to develop differentiated
line extensions (single and combination agent), reformulations, new intermediate doses or controlledrelease products in the Accu-Break format. The technologies are patented or patent-pending (Accu-Break
patents are valid until at least 2025).27,28
Ultimately, the principal advantages of the Accu-Break tablet technologies are for physicians and
patients. Physicians can finally deliver individualized care and dosing strategies during treatment
initiation, at various times throughout treatment and whenever dose titration is medically indicated.
They can achieve therapeutic goals, overcoming TI, and accomplish this with greater compliance from
their patients. Patients, especially the elderly and the young, can more easily and accurately obtain the
dose customization they require, while at the same time enjoying the economic benefits this technology
confers.
Achieving Individualized Dosing and Dose Flexibility through Tablet Splitting
Additionally, other configurations can be achieved such as pentasect or octasect tablets,
should the need arise (figure 5).
5
1. National Center for Health Statistics. Health, United States, 2007, With Chart book on Trends in the Health of
Americans. U.S. Department of Health and Human Services, Hyattsville, MD, 2007.
2. Medco Heatlh. Drug Trend Report 2008, Vol 10.
http://medco.mediaroom.com/file.php/162/2008+DRUG+TREND+REPORT.pdf. Accessed August 18, 2008
3. Hixson-Wallace J et al. Effect of Regimen Complexity on Patient Satisfaction and Compliance with Warfarin Therapy.
Clin Appl Thromb Hemost. 2001;7(1):33-37.
4. Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services. AHRQ website:
http://www.meps.ahrq.gov/mepsweb/data_stats/summ_tables/hc/drugs/2005/hcdrugest_totexp2005.shtml.
Accessed August 18, 2008.
5. Zhou Z et al. Effectiveness of Statins for secondary prevention in elderly patients after acute myocardial infarction:
an evaluation of class effect. CMAJ. 2005;172(9):1187–1194.
6. Portion R et al. Long-term Use of Controlled-release Oxycodone for Noncancer Pain: Results of a 3-year Registry
Study. Clin J Pain. 2007;23(4):287-299.
7. Physicians’ Desk Reference. 62nd ed. Montvale, NJ: Thomson PDR; 2008.
8. Drug Delivery Market: Vol 1: Oral Delivery. Kalorma Information, January 2007.
9. Tableting Specification Manual, 7th ed. American Pharmacists Associations.
10. Peek B et al. Accuracy of Tablet Splitting by Elderly Patients. JAMA. 2002;288(4): 451-452.
11. Cook T et al. Variability in Tablet Fragment Weights When Splitting Unscored Cyclobenzaprine 10 mg Tablets. J Am
Pharm Assoc. 2004;44(5):583-586.
12. Rosenburg J et al. Weight Variability of Pharmacist-Dispensed Split Tablets. J Am Pharm Assoc. 2002;42:200-205.
13. Teng J et al. Lack of Medication Dose Uniformity in Commonly Split Tablets. J Am Pharm Assoc. 2002, 42:195-199.
14. FDA Modernization Act of 1997. 21 U.S.C. 353 § 503A (b) (1)(D).
15. AMA Policy Finder page. American Medical Association Web site. http://www0.amaassn.org/apps/pf_new/pf_online?f_n=browse&n_p=T&&s_t=115.970&st_p=0&nth=1&catg=AMA/HnE&catg=AMA/
BnGnC&catg=AMA/DIR&prev_pol=policyfiles/HnE/H-115.971.HTM&nxt_pol=policyfiles/HnE/H-115.973.HTM&
Accessed September 11, 2008
16. AMCP Professional Practice Advisory. Association of Managed Care Professionals Web site.
http://www.amcp.org/data/nav_content/Tablet%20Splitting%20Memohead.pdf. Accessed August 6, 2008.
17. NABP Resolution pages. National Association of Board Pharmacies Web site.
http://www.nabp.net/ftpfiles/resolutions2001/RESOLUTIONS_2001_FINAL.pdf. Accessed August 6, 2008.
18. European Pharmacopeia Fourth Edition, Supplement 4.1. Strasbourg Cedex, France: Convention on the Elaboration
of a European Pharmacopoeia; 2002: Tablets, monograph 0478.
19. European Pharmacopeia Fifth Edition, Supplement 5.5. Strasbourg Cedex, France: Convention on the Elaboration of
a European Pharmacopoeia; 2006: Tablets, monograph 0478.
20. Barends D et al. Development of an in vivo Test Procedure for the Ease of Breaking of Scored Tablets. Pharmeur Sci
Notes. 2005;(1):27-30
21. Rodenhuis N et al. Patient Experiences with the performance of tablet score lines needed for dosing. Pharm World
Sci. 2003;25:173-176
22. Triplitt C et al. The Changing Landscape of Type 2 Diabetes: The Role of Incretin-Based Therapies in Managed Care
Outcomes. J Man Care Pharm. 2007;13(9),S-c.
23. Thom T et al. Heart Disease and Stroke Statistics—2006 Update. A Report From the American Heart Association
Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2006;113(6)e85-e15.1.
24. Bakris G et al. Achieving blood pressure goals globally: five core actions for health-care professionals. A Worldwide
call to action. J Hum Hypertens. 2008;22: 63-70.
25. Basile J et al. The Role of Therapeutic Inertia and the Use of Fixed-Dose Combination Therapy in the Management of
Hypertension. J Clin Hyper tens. 2007; 9(8):636-645.
26. Elliott, W. What Factors Contribute to the Inadequate Control of Elevated Blood Pressure? J Clin Hyper tens. 2008;
10(supply 1): 20–26.
27. USPTO Full Text and Image Database. Alexandria, VA: United States Patent and Trademark Office; 2008.
http://patft.uspto.gov/netacgi/nphParser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=
7,318,935.PN.&OS=PN/7,318,935&RS=PN/7,318,935. Accessed August 6, 2008.
28. USPTO Full Text and Image Database. Alexandria, VA: United States Patent and Trademark Office; 2008.
http://patft.uspto.gov/netacgi/nphParser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=
7,329,418.PN.&OS=PN/7,329,418&RS=PN/7,329,418. Accessed August 6, 2008.
Achieving Individualized Dosing and Dose Flexibility through Tablet Splitting
References
6