Note: Descriptions are shown in the official language in which they were submitted.
CA 02272099 1999-OS-17
WO 98!22072 PCT/US97120577
COMPLIANCE PACKAGE AND METHOD OF IMPROVING
OR AIDING PATIENT COMPLIANCE FOR COMPLEX DRUG REGIMENS
BACKGROUND OF THE INVENTION
The present invention relates to a pharmaceutical package for aiding or
increasing
patient compliance for the administration of peroral complex pharmaceutical
drug
regimens. Further, the present invention relates to a method of aiding and/or
improving
patient compliance for complex peroral drug regimens by the use of an
effective
compliance packaging.
Patient compliance has been defined as "the extent to which an individual's
behavior coincides with medical or health advise. Compliance with therapy
implies a
positive behavior in which the patient is motivated sufficiently to adhere to
the prescribed
treatment because of a perceived self benefit and a positive outcome {e.g.
enhanced daily
functioning and well-being." Remington's Pharmaceutical Sciences, Chpt. 103,
Vol. II; p.
179b ( 19th Ed.1995).
Most physicians assume that, when they a diagnosis a condition and select a
therapeutic agent and regimen for a patient to treat that condition, the
patient will follow
their recommendation and take the therapeutic agent according to instructions.
However,
patient compliance studies indicate otherwise. Studies indicate a high
incidence of
medication errors and non-compliance with respect to taking prescription
drugs. Stewart,
R. B., and Cluff, L.E. A review of medication errors and compliance in
ambulant patients.
Clin Pharm Ther) 1972, 13, 463-468.
In fact the problem of non-compliance can increase health-care costs. For
example, it is estimated that over 50% of patients taking antihypertensive
medication are
non-compliant and/or stop taking their medications within the first 12 months
of treatment.
Each year, thousands of deaths and hospital admissions result from over or
undermedicating. In addition about 25% of nursing home admissions are a result
of the
patient's inability to take his or her medications correctly. This can result
in added costs for
additional prescriptions, additional physician visits, hospitalization for
consequences of
untreated diseases or rehabilitation cost and/or home health care costs for
untreated or
undertreated diseases. Of course, the consequence of non-compliance with
antihypertensives can be life threatening, and can result in strokes,
myocardial infarction,
etc. Eraker, S.A., et al., Understanding and Improving Patient Compliance, Ann
Intern
Med, i 00, 258 ( 1984}. Forcinio, H. Packaging Solutions That Heip Patient
Compliance,
Pharmaceutical Technology, March 1993, p. 44-50.
CA 02272099 1999-OS-17
WO 98122072 PCT/US97/20577
2
Increased health care cost is also associated with antimicrobial therapy non-
compliance. In particular, non-compliance with antimicrobial treatment can
increase cost
due to the need to prescribe additional medications to retreat the infection,
additional lab
work to re-diagnose the infection, etc. Moreover, antimicrobial non-compliance
can also
S contribute to the development of resistance.
Non-compliance encompasses a variety of behaviors. Acts of omission include
drug underuse. For example the patient may take less medicine or take it less
frequently
than prescribed and may even take drug "holidays." The patient may not obtain
the initial
or a refill prescription, or may stop taking the medication too soon. Acts of
commission
include drug overuse, taking too high a dose or taking a dose too frequently.
They also
include taking too low a dose such as skipping a dose. The patient may even
share
medication with family members or knowingly consume a food, beverage, or other
drug
that can interact with one's prescription drug. Prescription Medicine
Compliance: A
Review of the Baseline of Knowledge, NCPIE Report, Aug. 1995
Numerous factors determine the probability for compliance and explain why
patients do not comply with prescribed drug therapy. One factor is the type of
illness
involved. For example, patients having chronic illness or illnesses that are
not associated
with significant symptomatology, such as hypertension and
hypercholesterolemia, are
likely to display higher medication non-compliance rates. It is somewhat
understandable
for patients to become discouraged with extended therapeutic drug regimens
that do not
eventually "cure" the disease. However, one can expect that compliance will
increase
where increased disability results from non-compliance.
Another reason that many patients stop taking prescribed medication too soon,
involves the disappearance of symptoms. In particular patients who are
prescribed
antibiotics often stop taking the antibiotic on the fourth day of treatment.
It is at this point
that the symptoms start to disappear and the patient feels better. This
problem may even be
further compounded where the antibiotic treatment involves the administration
of more
than one antibiotic agent. An example of this type of regimen is triple-
therapy regimen for
the treatment of H. pylori infections, consisting of: ( 1 ) a bismuth salt
(e.g., bismuth
subsalicylate), (2) metronidazole and (3) amoxicillin or tetracycline. Mohler,
D.N. et al.,
Studies in the Home Treatment of Streptococcal Disease, I. Failure of Patients
to Take
Penicillin as Prescribed, New Engl JMed, 252, 1116 (1955). Mattar, M.E. et
al.,
Pharmaceutic Factors Affecting Pediatric Compliance, Pediatrics, 55, lUl
(1975). U.S.
Pat. No. 5,256,684, Marshall, issued October 26, 1993, The Procter & Gamble
Company.
In addition, other factors, related to non-compliance, include the age of the
patient.
Non-compliance with the elderly population is generally higher than other
groups. This
can be attributed to a variety of factors such as declining mental
functioning, increasing
CA 02272099 1999-OS-17
WO 98/22072 PCT/iJS97/20577
3
numbers of medication prescribed and the increase in side effects and/or drug
interactions
associated with these multiple drug regimens. Also, improper dosing leading to
side effects
may also contribute to non-compliance. In addition non-compliance among the
elderly is
associated with taking more than five prescription medications concurrently,
an inability to
read prescription labels and difficulty opening flip-off type medication
container lids.
Murray, M.D. et al., DICP 20:146 { 1986.)
The physician's and pharmacist's relationship with the patient will influence
medication compliance. For example, how clearly the physician and/or
pharmacist
explains the treatment regimen to the patient being treated will influence how
likely the
patient will comply with the drug therapy prescribed.
Multiple medication administration, complex treatment regimens, frequent dose
regimens and the physical characteristics of the dosage form (tablet v.
capsule v. liquid),
can contribute to non-compliance. Studies have reported that non-compliance
increases
when the number of tablets or capsules taken daily increases from one to four
times daily.
Gatley, M.S. To be taken as directed. JI R Coll Gen Pract, 1968, 16, 39-44.
Eisen, S.A. et
al., Arch Intern Med 150, p. 1881, 1990. "The administration of medication at
frequent
intervals makes it more likely that the patient's normal routine or work
schedule will have
to be interrupted to take a dose of medication and in many cases the patient
wilt forget, not
want to be inconvenienced or be embarrassed to do so." Remir~gton's
Pharmaceutical
Sciences, Chpt. 103, Vol. II, p. 1800 ( 19th Ed.1995).
A specific example of a complex treatment regimen includes the treatment for
H.
pylori mediated upper gastrointestinal disorders or infections. Currently,
single agent
antimicrobiai approaches designed to eradicate infection by H. pylori provide
unacceptable
eradication rates (i.e., < 80%). As a result, treatment comprises the
administration of more
than one therapeutic agent. Examples of such combination therapy include the
administration of 1 ) at least one antimicrobial agents) used in combination
with a proton
pump inhibitor; and 2) at least one antimicrobial agents) used in combination
with bismuth
or a bismuth salt. An example of a particularly preferred combination includes
a triple-
therapy regimen consisting of: ( 1 ) a bismuth salt (e.g., bismuth
subsalicylate), (2)
metronidazole and (3) amoxicillin or tetracycline. These types of treatment
regimens, due
to their complexity, are particularly vulnerable to patient non-compliance.
A number of strategies have been proposed and developed to enhance medication
compliance by patients. In addition to oral and written
communication/counseling of
patients by the physician and/or the pharmacist, audiovisual materials and
improvement in
the patient/physician or pharmacist relationship may enhance patient
compliance.
Moreover, medication compliance aids have been developed to enhance
compliance. One example is a compliance package. A compliance package is
defined as
CA 02272099 1999-OS-17
WO 98/22072 PCT/US97/20577
4
"a prepackaged unit that provides one treatment cycle of the medication to the
patient in a
ready-to-use package." Remington's Pharmaceutical Sciences, Chpt. 103, Vol.
fi, p. 1804
( 19th Ed.1995). D.L. Smith, Compliance Packaging: A Patient Education Tool,
Amer
Pharm, Vol. NS29, No. 2, p. 42-53,1989.
Packages for oral contraceptives were possibly the first packaging of this
type to be
introduced and continue to be used extensively for these agents. Specific
examples of oral
contraceptive compliance packaging are listed in the Physicians' Desk
Reference, p. 306,
322, 323, 49 ed. 1995.
For example, Ovcon~ 35 and 50 (Bristol-Meyers Squibb), Ortho-Novum~ Dialpak
1/35, 1/50, 10/11 and 7/7/7 (Ortho Pharmaceutical Corp.), Loestrin~ Fe 1120
and 1.5/30
(Parke-Davis), etc. are oral contraceptives packaged in blister cards. These
packages are
generally a single blister card, with 21 or 28 day regimens. Each tablet is
labeled with a
particular day of the week so that the patient can tell if any doses have been
missed.
Written patient information, which informs the patient of risks and benefits
of therapy, is a
mandatory requirement for oral-contraceptive packaging.
Additional examples of compliance packaging include Rheumatrex~ Dose Packs
made by Lederle Laboratories, containing four blister-pack cards each
containing either 2,
3, 4, 5, or 6 tablets (for S mg, 7.5 mg, 10 mg, 12.5 mg, or 15 mg per week,
respectively)
for 1-week's therapy of methotrexate.
Medrol~ Dosepak (Upjohn Company), is a packaging designed for the
administration of steroids, (i.e. methylprednisolone) which require staggered
dosing. For
each day of drug treatment the number of tablets {and total dose) that the
patient must take,
decreases. For example, the Medrol Dosepak contains 21, 4mg tablets for 6 days
of
treatment where for each day of treatment, the total daily dose decreases by
one tablet.
Axid~ Convenience Pak previously made by Eli Lilly & Company, which
contained a 30-day supply of nizatidine in a single medication blister card,
is another
example. This medication is to be taken once a day and is for the treatment of
duodenal
ulcers.
Zithromax~ Z-Pak made by Pfizer Laboratories, contains a single medication
blister card with 6, 250mg capsules. Each blister medication card is labeled
with "Day 1 to
Day 5" for each dose, the first dose being two, 250 mg capsules labeled "Day I
." Each
subsequent capsule is labeled with "Day 2" to "Day 5."
A further example of a compliance package includes "MacPac~" made by Norwich
Eaton. Although no longer available on the market, this package contained an
information
booklet and seven blister-pack cards each card containing a daily dose (i.e.
four capsules)
of Macrodantin (nitrofurantoin macrocrystals.) Each dose (capsule) was labeled
"Breakfast," "Lunch," "Dinner," and "Bedtime." The MacPac also contained two
stickers
CA 02272099 1999-OS-17
WO 98!22072 PCT/US97/20577
for the pharmacist to apply to the package upon dispensing. These stickers
contained the
information: "Take with food or milk" and "Complete the full time of treatment
prescribed
by your physician." Furthermore, this package contained a reminder card
between the third
and forth medication cards, i.e between the third and forth day of treatment.
5 Despite the development of the above types of compliance packaging,
additional
improvements are needed to further enhance patient compliance, especially for
complex
peroral drug regimens. Further improvements are needed in order to ensure that
the
patients understand drug information provided in compliance packaging and to
ensure that
they are sufficiently motivated, through compliance packaging to complete a
full course of
drug treatment.
SUMMARY OF THE INVENTION
The present invention relates to a pharmaceutical package for aiding or
increasing
patient compliance for the administration of a peroral complex pharmaceutical
drug
regimen, comprising:
(a) at least one blister card,
wherein each blister card comprises the total daily dose of the peroral
complex drug
regimen; wherein the blister card is divided into sections, preferably
perforated sections,
separating each complex drug regimen dose; wherein each dose section comprises
an
indicia denoting the time the dose is to be administered; and wherein
preferably each blister
card comprises an indicia denoting each separate day of treatment;
{b) a patient information booklet comprising dosing information, side effect
information, information describing the disease being treated, and patient
incentive
information;
(c) a daily calendar comprising dosing information, side effect information,
information describing the disease being treated, and patient incentive
information; and
(d) preferably a reminder aid selected from the group consisting of:
I ) one or more reminder cards comprising information to remind the patient
when to take a dose of the complex drug regimen;
2) one or more adhesive stickers comprising information to remind the patient
when to take a dose of the complex drug regimen;
CA 02272099 1999-05-17
WO 98!22072 PCT/US97/20577
6
3) a case of the size to contain a single blister card, the case comprising an
alarm
which can be set by the patient to sound at the time that the next dose is to
be
administered; and
4) combinations thereof.
Preferably the complex drug regimen comprises varying the dosage level or the
dosage interval for a single therapeutic agent, the simultaneous
administration of more than
one therapeutic agent, or the concurrent administration of more than one
therapeutic agent.
It is understood that all of the above listed elements of the compliance
package of
the present invention are housed in a container made of any suitable material.
Preferably
the container is made of any suitable paper and/or plastic material.
Preferably the blister package is child resistant and "senior friendly."
Also, preferably the blister cards are separated, at approximately one-fourth
to
three-fourths of the way between the start and the finish of the complex drug
regimen, by a
card comprising patient information and patient incentive information. This
card
preferably contains a statement on the importance of completing the full
course of drug
therapy to avoid disease or symptom reoccurrence.
Preferably the compliance package comprises a number of reminder cards or
adhesive stickers equal to the number of daily doses to be administered by the
patient.
Preferably the reminder aid is one or more adhesive stickers.
Preferably each reminder aid (adhesive stickers or reminder card) is provided
in a
form to allow the patient to place the sticker or card at a location that the
patient will be, at
the time a dose of the complex drug regimen is due to be taken by the patient.
Further, the present invention relates to a method of aiding and/or improving
patient compliance for complex peroral drug regimens by the use of an
effective
compliance packaging.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a pharmaceutical package for aiding or
increasing
patient compliance. In particular the present invention reduces the risk of
omission of
doses, dosage errors (amount of individual dose), drug administration errors,
errors in the
time of administration and/or premature discontinuation, for peroral complex
drug
regimens. Specifically the present invention relates to a pharmaceutical
package for aiding
or increasing patient compliance for the administration of a peroral complex
pharmaceutical drug regimen, comprising:
(a) at least one blister card,
CA 02272099 1999-OS-17
WO 98122072 PCT/LTS97I20577
wherein each blister card comprises the total daily dose of the peroral
complex drug
regimen to be administered by the patient; wherein the blister card is divided
into sections,
preferably perforated sections, separating each complex drug regimen dose;
wherein each
dose section comprises an indicia denoting the time the dose is to be
administered; and
wherein preferably each blister card comprises an indicia denoting each
separate day of
treatment;
(b) a patient information booklet comprising dosing information, side effect
information, information describing the disease being treated, and patient
incentive
information;
(c) a daily calendar comprising dosing information, side effect information,
information describing the disease being treated, and patient incentive
information; and
(d) preferably a reminder aid selected from the group consisting of:
1 ) one or more reminder cards comprising information to remind the patient
when to take a dose of the complex drug regimen;
2) one or more adhesive stickers comprising information to remind the patient
when to take a dose of the complex drug regimen;
3) a case of the size to contain a single blister card, the case comprising an
alarm
which can be set by the patient to sound at the time that the next dose is to
be
administered; and
4) combinations thereof;
wherein preferably the complex drug regimen comprises varying the dosage level
or the
dosage interval for a single therapeutic agent, the simultaneous
administration of more than
one therapeutic agent, or the concurrent administration of more than one
therapeutic agent.
It is understood that all of the above listed elements of the compliance
package of
the present invention are housed in a container made of any suitable material.
Preferably
the container is made of any suitable paper and/or plastic material. Also,
this container is
preferably of square or rectangular dimensions. Preferably the outer container
for the
above listed components is of a size and dimension to accommodate standard
pharmacy
prescription labels.
Preferably the blister package is child resistant and senior friendly.
Also, preferably the blister cards are separated, at approximately one-fourth
to
three-fourths of the way between the start and the finish of the complex drug
regimen, by a
card comprising patient information (side effect, dosing, and/or disease
information) and
CA 02272099 1999-OS-17
WO 98122072 PCT/US97/20577
8
patient incentive information. This card preferably contains a statement on
the importance
of completing the full course of drug therapy to avoid disease or symptom
reoccurrence.
The methods and packages of the present invention comprise a safe and
effective
amount of one or more therapeutically active agent(s). The phrase "safe and
effective
amount," as used herein, means an amount of therapeutically active agent high
enough to
provide a significant positive modification of the condition to be treated,
but low enough to
avoid serious side effects (at a reasonable benefidrisk ratio), within the
scope of sound
medical judgment. A safe and effective amount of therapeutically active agents
will vary
with the particular condition being treated, the age and physical condition of
the patient
being treated, the severity of the condition, the duration of the treatment,
the nature of
concurrent therapy, the specific therapeutic agent selected, and like factors.
As used herein "administering" refers to any method which, in sound medical
practice, delivers the therapeutically active agents or compositions
containing the
therapeutically active agents, used in the compliance package of the present
invention, to
the patient to be treated in such a manner to be effective in the treatment of
the disorder.
As used herein the term "therapeutic agent" includes any pharmaceutical agent
useful for the treatment of a disease or condition, to alleviate symptoms,
etc.
The term "peroral complex drug regimen" includes any peroral drug regimen
which
requires the administration by the patient being treated, of:
1. Varying dosage regimens for a single therapeutic agent (i.e. where the dose
of
a single therapeutic agent is varied over the course of the drug treatment or
where the
intervals between dosage administration for a single therapeutic agent is
varied over the
course of the drug treatment.)
2. The administration of more than one therapeutic agent simultaneously. As
used herein the term "simultaneous" means that the two or more therapeutic
agents are
given at the same time, beginning and ending on the same day.
3. The administration of more than one therapeutic agent concurrently. The
term
"concurrently" as used herein means that the administration of two or more
therapeutic
agents are overlapping.
4. The administration of more than one therapeutically active agent
consecutively. The term "consecutively" herein means that the administration
of two or
more therapeutic agents are sequential, but substantially continuous, i.e. the
administration
of two or more agents is separated by no more than about 24 to 48 hours.
Specific examples of peroral complex drug regimens include those described in
U.S. Pat. No. 5,256,684, Marshall, issued October 26, 1993, The Procter &
Gamble
Company, which describes a method for the treatment of humans and lower animal
patients
having a gastrointestinal disorder associated with H. pylori, comprising
administering
_..__.,.w_.,.....~..._,~. __. .. . _.._..
CA 02272099 1999-OS-17
WO 98!22072 PCTIUS97/20577
9
bismuth and at least one antimicrobiai, the administration
being simultaneous, concurrent
or consecutive. The Marshall reference is incorporated
herein by reference in its entirety.
Particularly preferred peroral complex drug regimens include
those for the
treatment of H. pylori mediated upper gastrointestinal
disorders or infections. In particular,
such gastrointestinal disorders are those affecting the
upper-gastrointestinal tract, and those
mediated by H. pylori (herein referred to as "H. pylori-mediated
gastrointestinal
disorder(s)." Such gastrointestinal disorders include,
for example: H. pylori -mediated
disorders not manifested by presence of ulcerations in
the gastric mucosa (herein "non-
ulcerative gastrointestinal disorder"), including chronic
or atrophic gastritis, non-ulcer
dyspepsia, esophogeal reflux disease and gastric motility
disorders; and "peptic ulcer
disease", i.e., gastric, duodenal and jejuna! ulcers. H.
pylori treatment comprises the
administration of more than one therapeutic agent. Examples
of such combination therapy
include the administration of 1 ) at least one antimicrobial
agents) used in combination
with a proton pump inhibitor and 2) at least one antimicrobial
agents) used in combination
with bismuth or a bismuth salt.
Proton pump inhibitors include, but are not limited to
omeprazole (known under
the tradename of Prilosec~ available from Astra Merck),
lansoprazole (known under the
tradename of Prevacid~ available from TAP Pharm), pantoprazole,
and mixtures thereof.
Bismuth salts include, but are not limited to, bismuth
aluminate, bismuth citrate,
bismuth subcitrate, bismuth nitrate, bismuth subnitrate,
bismuth tartrate, bismuth
subcarbonate, bismuth subgallate, bismuth subsalicylate,
and tripotassium dicitrato
bismuthate, bismuth subgallate, and mixtures thereof. A
particularly preferred bismuth salt
is bismuth subsalicylate.
A variety of compositions containing bismuth salts are
commercially-available,
including, for example, DeNol~, containing tripotassium
dicitrato bismuthate (sold by
Gist-Brocades N.V.), Noralac~, containing bismuth aluminate,
alginic acid, and
magnesium carbonate (manufactured by North American Pharmaceuticals),
Roter bismuth,
containing bismuth subnitrate (sold by Roter Laboratories),
Fensobar Polvo, containing
bismuth subcarbonate among other materials (manufactured
by USV Pharmaceutical
Corporation), Pepto-Bismol~, containing bismuth subsalicylate
(sold by The Procter &
Gamble Company) and ranitidine bismuth citrate (Tritec~
available from Glaxo Wellcome
( p.l.c.).
A wide variety of antimicrobials are useful in this invention. As used herein,
such
"antimicrobials" refer to any naturally-occurring, synthetic or semi-synthetic
compound or
composition, or mixture thereof, which is safe for human use as used in the
packages and
methods of this invention, and is effective in killing or substantially
inhibiting the growth
of H. pylori when used in the methods/package of this invention. Antibiotics
are among
CA 02272099 1999-OS-17
WO 98/22072 PCT/US97/20577
the preferred antimicrobiais useful herein. Such antibiotics can be generally
classified by
chemical composition, into the following principal groups: the
aminogfycosides, such as
gentamicin, neomycin, kanamycin, and streptomycin; the macrolides, such as
erythromycin, clarithromycin, azithromycin, dirithromycin, troleandomycin,
clindamycin,
5 and rifampin; the penicillins, such as penicillin G, penicillin V,
ampicillin and amoxicillin;
the polypeptides, such as bacitracin and polymyxin; the tetracyclines, such as
tetracycline,
chlortetracycline, oxytetracycline and doxycycline; the cephalosporins, such
as cephalexin
and cephalothin; and such miscellaneous antibiotics as chloramphenicol and
clindamycin.
These antibiotics can be generally said to function in one of four ways:
inhibition of cell
10 walls synthesis, alteration of cell wall permeability, inhibition of
protein synthesis, or
inhibition of nucleic and synthesis.
Other antimicrobials useful herein include the sulfonamides; nitrofurans, such
as
nitrofurazone nitrofurantoin, and furozolidone; and metronidazole, tinidazole,
and
nimorazole. Antimicrobials among those useful herein are described in the
following
publications, incorporated by reference herein: Remington's Pharmaceuticals
Sciences
( 15th edition 1975); F.H. Meyers, et al., Review of Medical Pharmacology (7th
edition
1980); Gaddum's Pharmacology (8th edition 1978); and A. Goodman, A.G. Goodman
and
L.S. Gilman, The Pharmacological Basis of Therapeutics (6th edition 1980).
While any of these antimicrobials may be used, penicillin, erythromycin,
tetracycline, doxycycline, metronidazole, tinidazole, amoxicillin, ampicillin,
clarithromycin, and nitrofurantoin are among the preferred antimicrobials for
use in the
present invention.
Examples of particularly preferred peroral complex drug regimen include
regimens
such as: 1) a bismuth salt (e.g., bismuth subsalicylate), metronidazole, and
amoxicillin or
tetracycline; 2) iansoprazole, amoxicilIin, and clarithromycin; 3) ranitidine
bismuth citrate
(TritecOO available from Glaxo Wellcome p.l.c.); 4) omeprazole and
clarithromycin; and S)
ranitidine bismuth citrate and amoxicillin and/or clarithromycin.
Other preferred peroral complex drug regimens are disclosed in U.S. Pat. No.
5,256,684, Marshall, issued Oct. 26, 1993, The Procter & Gamble Co., which is
herein
incorporated by reference in its entirety.
The specific method of aiding and/or improving patient compliance by
administering one or more therapeutically active agent(s), according to the
packaging or
process of this invention, may depend upon such factors as the particular
therapeutic agent
used, the site of action desired, the amount of therapeutic agent to be
administered per day,
the presence or potential of any adverse side effects, and the potential for
any interactions
between therapeutic agents used. Thus the therapeutic agents) can be
administered by
single daily doses, or be administered in two, three, or four or more doses
per day.
CA 02272099 1999-OS-17
WO 98/22072 PCT/US97/20577
11
Whether two or more therapeutic agents are administered simultaneously,
concurrently or
sequentially depend on potential interactions between these agents, which are
known to
those skilled in the art.
The Blister Card
The compliance package of the present invention comprises at least one blister
card. Each blister blister card comprises the total daily dose of the peroral
complex drug
regimen to be administered by the patient. The blister card is divided into
sections,
preferably perforated sections, separating each complex drug regimen dose;
wherein each
dose section comprises an indicia denoting the time in which the dose is to be
administered,
i.e. "Breakfast " "Lunch " "Dinner " "Bedtime " etc.
> > ,
Also, preferably if the daily dose of the complex peroral drug regimen varies
throughout the course of therapy, the blister cards are arranged in sequential
order of
administration. For example the blister card can comprise an indicia denoting
each
1 ~ separate day of treatment ("Day I ," "Day 2," "Day 3 ", or "Monday,"
"Tuesday,"
"Wednesday," etc.) or an indicia denoting the order that each separate blister
card is to be
administered ("I," "2," "3," or "Card I," "Card 2," "Card 3," etc.) Preferably
for these
varying dosage regimens, the first card to be used will be placed at the
beginning of the
blister card stack in the compliance package container.
Preferably the blister card and/or compliance package is child resistant
and/or
tamper evident, which, while providing easy access to the end user, has child-
resistant
features.
Child resistant blister packages are disclosed in U.S. Pat. No. 3,809,221,
Compere,
issued May 7, 1974; U.S. Pat. No. 4,398,634, McClosky, issued Aug. 16, 1983,
Wrapade
Machine Company, Inc.; U.S. Pat. No. 3,809,220, Arcudi, issued May 7, 1974,
Becton
Dickinson and Company; U.S. Pat. No. 3,503,493, Nagy, issued March 31, 1970;
U.S. Pat.
No. 3,924,746, Haines, issued December 9, 1975, Paco Packaging; U.S. Pat. No.
4,011,949,
Braber, et al., issued March 15, 1977, The Lehigh Press; U.S. Pat. No.
3,924,747, Gerner,
issued Dec. 9, 1975, Packaging Coordinators, inc.; U.S. Pat. No. 4,537,312,
Intini, issued
Aug. 27, 1985. All of the above references are incorporated herein by
reference, in their
entirety.
Preferably the following information is printed on the blister card:
1. Preferably each dose is labeled with the time of day that the dose is to be
administered, for example, "Breakfast," "Lunch," "Dinner," and "Bedtime." This
is to help
patients take the medication at the correct times. In addition this will help
the patients to
recognize when and if they have missed a dose.
CA 02272099 1999-OS-17
WO 98/22072 PCT/US97/20577
12
2. Preferably if the daily dose of the complex peroral drug regimen varies
throughout the course of therapy, the blister cards are arranged in sequential
order of
administration. Therefore, preferably each blister card comprises an indicia
denoting the
order that each separate blister card is to be administered. For example the
blister card can
be optional ly marked with "Day I ," "Day 2," "Day 3 ", or " l ," "2," "3," or
"Card I ," "Card
2," "Card 3," etc.
3. The names of the therapeutic agent or agents and the doses contained in the
blister card and dose section of the blister card.
Each blister card of the present invention contains a full daily dose of the
peroral
complex drug regimen. Therefore, the patient can carry a I -day supply with
them during
the day, in either their purse or pocket, etc. Preferably the blister card is
approximately
3.75 X 4.75 inches or is a size that a single card will fit into a standard
size shirt pocket. If
the blister card is larger, it can be folded in half to reduce its dimension
so than it will
easily fit into a purse, pocket, etc., if necessary.
In addition one preferred embodiment of the present invention is a compliance
package or kit also comprising a separate cover or case to hold a single-
blister card. This
case will protect the blister card from damage. In addition this case is
another way for the
patient to transport the blister card during the day so that the doses of the
complex drug
regimen are readily accessible to patient.
In another embodiment of the present invention, this blister card cover or
case will
also comprise an alarm as the reminder aid. Therefore, the patient can set.the
alarm to
sound when the next scheduled dose is to be administered by the patient.
The portability of the single blister cards eliminates the need for the
patient to carry
the entire kit or compliance package. It also eliminates the need to transfer
the complex
drug regimen to another unlabeled vial or container. The transportability of
the single
blister cards allows the patient to have the dose at hand when the patient is
away from
home.
Preferably, the single dose sections on the blister cards are arranged in
order of the
time of administration intervals. For example if the peroral drug regimen
comprises 4 daily
doses of one or more therapeutic agent(s), then the blister card will
preferably comprise
four does sections, preferably of equal dimensions, and preferably separated
by
perforations.
If the peroral complex drug regimen has more than one therapeutic agent to be
given as part of the same dose of the regimen, preferably the blister card has
only one
medication per blister cavity. However these units of medication will be
located in the
same dose section of the blister card. This will avoid any potential physical
interactions
between two or more different therapeutic agents.
CA 02272099 1999-OS-17
WO 98/22072 PCT/US97/20577
13
The blister cards provide positive (or negative) feedback to the patient or
physician
since they can look at the blister cards to see whether all of the doses of
the complex
peroral drug regimen have been taken by the patient.
J Daily Calendar) Patient Information Booklet and Reminder Aid
' The compliance package of the present invention additionally comprises the
following:
( 1 ) a patient information booklet comprising dosing information, side effect
information, information describing the disease being treated, and patient
incentive
information;
(2) a daily calendar comprising dosing information, side effect information,
information describing the disease being treated, and patient incentive
information;
(3) preferably a reminder aid selected from the group consisting of:
1 ) one or more reminder cards comprising information to remind the patient
when to take a dose of the complex drug regimen;
2) one or more adhesive stickers comprising information to remind the
patient when to take a dose of the complex drug regimen;
3) a case of the size to contain a single blister card, the case comprising an
alarm which can be set by the patient to sound at the time that the next dose
is
to be administered; and
4) combinations thereof.
"Information" as used herein includes, but is not limited to, anticipated
benefits of
the therapy with the peroral complex drug regimen, the importance of complying
with the
dosage and administration instructions, side effect information, the point in
time during
therapy that side effects occur, dosage information, and information regarding
the disease
or condition being treated.
The multiple components of the compliance package of the present invention are
critical in that they provide repetition of the information (dosing
information, side effect
information, disease information, and patient incentive information) to the
patient. This is
to ensure that the patient remembers the information and is sufficiently
motivated to
complete the full course of treatment. In addition the multiple components,
such as the
booklet, calendar, indicia and other printed information on the blister cards,
reminder aids.
etc. provides a continuous source of information to the patient. Preferably,
the side effect
information, dosing information, disease information, and patient incentive
information is
repeated at least two times, more preferably at least 3 times in the
compliance package.
As used herein "information, dosing information, side effect information,
information describing the disease being treated and patient incentive
information" means
CA 02272099 1999-OS-17
WO 98122072 PCT/US97/20577
14
educational information that the patient is able to understand and use.
Preferably the this
information is written at a low readability level, i.e. is written such that
the average patient
or consumer can understand the information. Complex and difficult medical
terminology
should be translated into more simple words. The readability level of the
patient
information is very important since it has been reported that patients do not
understand
many medical terms used in patient information materials. D.L. Smith,
Compliance
Packaging: A Patient Education Tool, Amer Pharm, Vol. NS29, No. 2, p. 42-
53,1989.
Preferably this information also includes graphics and illustrations for
providing
further repetition and reinforcement of the written information.
The side effect information should not only list the possible side effects but
should
be complete enough to allow the patient to manage side effects. For example,
the statement
"bismuth may darken the stool or tongue but this darkening will go away after
the therapy
is complete," helps the patient manage this side effect. Also, the side effect
information
can instruct the patient to contact the prescriber if side effects are
bothersome to the patient.
Furthermore, for medications causing hypersensitivity of the patient's skin to
sun exposure,
the patient is instructed to avoid the sun and sunlamps as much as possible
and to wear a
high numbered SPF sunscreen.
Additionally the patient is instructed how and when to made up any missed
doses
of the medication.
The information of the compliance package and methods of the present invention
is
preferably not coercive, threatening or demeaning to the patient being
treated. Although
one can provide the patient with very comprehensive information about the
complex drug
regimen and the disease or condition being treated, this information will not
be effective if
the patient is not motivated to use the information and comply with
instructions for using
and administering the complex drug regimen.
Therefore, the compliance packages and methods of the present invention also
comprise "patient incentive information." "Patient incentive information" as
used herein
means specific written material or instructions which provides cues for
appropriate
behavior or prompting of the patient to comply with the therapeutic drug
regimen. Patient
incentive information includes statements providing positive feedback and/or
encouragement such as congratulatory statements, statements complementing the
patient
during various intervals of the complex drug regimen for complying with the
regimen,
statements that encourage compliance by highlighting the benefits of properly
administered
medication (i.e. lower chance of side effects, lower chance of the
reoccurrence of infection,
lower chance of the development of antimicrobial resistance, lower chance of
re-treatment,
etc.) statements that encourage compliance by highlighting the benefits of
completing the
therapy (i.e. reduction or elimination of the disease symptoms), statements
indicating that
CA 02272099 1999-OS-17
WO 98/22072 PCT/US97120577
the patient has some control over the treatment and that the patient has
chosen to participate
in the regimen and is therefore involved in the decision making process
concerning the
regimen, etc.
Patient incentive information can also inform the patient that compliance with
the
5 proper dosage administration may save the patient time and money as well. In
particular,
patient incentive information can inform the patient that by complying with
proper dosing
instruction and finishing the full course of complex drug regimen, the patient
may reduce
the number of trips to his or her physician, decrease the number of
medications prescribed
due to re-treatment of conditions due to non-compliance and due to recurrence
of infections
10 (in the case of antimicrobial non-compliance), etc. Furthermore, complying
with the
proper dosage regimen may avoid side effects and adverse reaction which could
necessitate
the need for basic laboratory work, x-rays, ECGs, diagnostic tests,
intravenous and
parenteral drug therapy and even hospitalization to treat severe
complications.
The following exemplifies some specific forms of patient incentive information
of
15 the present invention.
1. "The reward for your efforts may mean freedom from your (Specific disease
or
condition.)"
2. "Stick with it!"
3. "You are now in control."
4. "You are one-third of the way through your therapy!"
5. "Keep up the good work!"
6. "Each day of treatment helps bring freedom from your (Specific disease or
condition.)
7. "You are one-half of the way through your therapy!"
8. "Each day of treatment helps bring freedom from your symptoms."
9. "Congratulations! You are halfway through your drug therapy. Just one more
week (or
number of days, etc.) to go!"
10. "Now you are two-thirds of the way through your therapy."
1 I . "Just think -- freedom from your (disease or condition) can be on the
horizon."
I2. "Just think -- freedom from your symptoms can be on the horizon."
13. "Aren't you glad that you've made the effort to take your medicine
according to the
instructions?"
14. "Each dose of therapy counts."
15. "Freedom from your (disease or condition) can be within your reach."
16. "Freedom from your symptoms can be within your reach."
CA 02272099 1999-OS-17
WO 98!22072 PCT/US97120577
16
17. "Don't slack off now -- stick with your scheduled doses through tomorrow --
and take a
bow!"
18. "You did it!"
19. "Congratulations?"
20. "Take all of your medicine today and you can look forward to a future free
of your
(disease or condition.)"
21. "Take ail of your medicine today and you can look forward to a future free
of your
symptoms."
22. "Take charge of your future!"
The calendar of the present invention comprises separate pages corresponding
to
each day of treatment for the peroral complex drug regimen. Preferably, the
calendar is
provided so that after the patient takes the daily dosage of the drug regimen,
the patient can
either tear off a page of the calendar or can cross out that particular page.
The calendar can
be taken to the patient's next visit to their prescriber to confirm the level
of the patient's
compliance with the complex drug regimen. The calendar is preferably attached
to the
inside lid of the compliance package.
Preferably the compliance package comprises a number of reminder cards or
adhesive stickers equal to the number of daily doses to be administered by the
patient.
Preferably the compliance package reminder aid is one or more adhesive
stickers.
Preferably each reminder aid (adhesive stickers or reminder card) is provided
in a
form to allow the patient to place the sticker or card at a location that the
patient will be, at
the time a dose of the complex drug regimen is due to be taken by the patient.
For
example, the reminder sticker or card can be placed on the patient's
refrigerator, television,
alarm clock, computer screen, bathroom minor, medicine cabinet, desk, dining
table,
nightstand, coffee pot, toothbrush, etc.
The written instruction on the adhesive sticker or reminder card comprises one
or
more of the following: the drug trade name, generic name, a statement such as
"Don't
Forget To Take Your Medication," "Take Your Next Dose at ," etc.
Also, preferably the blister cards are separated, at approximately one-fourth
to
three-fourths of the way between the start and the finish of the complex drug
regimen, by a
card comprising patient information and patient incentive information. This
card
preferably contains a statement on the importance of completing the full
course of drug
therapy to avoid disease or symptom reoccurrence. Preferably in compliance
packing for
the treatment of H. pylori infections of the gastrointestinal tract, this card
is located
approximately between day 3 and day 4 (blister card 3 and 4), day 4 and S
(blister card 4
and 5), day 5 and 6 (blister card 5 and 6), day b and 7 (blister card 6 and
7), or day 7 and 8
CA 02272099 1999-OS-17
WO 98122072 PCTIUS97/20577
17
(blister card 7 and 8). This is because symptoms generally subside with
antimicrobial
therapy early in the course of treatment.
Preferably for the treatment of H. pylori infections, the card is located
between
blister card 7 and 8 and comprises a congratulatory statement for finishing
approximately
half of the full course of the complex drug regimen. Preferably for H. pylori
infections,
this card comprises the statement:
"Freedom from ulcers is on the horizon! Congratulations. You've finished
the first 7 days of your 14-day treatment. You may feel better, but be sure
to keep taking your medicine. You need all 14 days of medicine to kill the
germs that cause the ulcer. if you stop now, some germs may not be dead
and your ulcer could return. So keep up the good work! Don't stop until
all your medicine is gone."
The following are non-limiting examples of the package of this invention.
Example 1
A pharmaceutical package for aiding or increasing patient compliance for the
administration of a peroral complex pharmaceutical drug regimen, comprising:
(a) at least one blister card,
wherein each blister card comprises the total daily dose of the perorai
complex drug
regimen to be administered by the patient; wherein the blister card is divided
into sections
separating each complex drug regimen dose; wherein each dose section comprises
an
indicia denoting the time of day in which the dose is to be administered;
(b) a patient information booklet comprising dosing information, side effect
information, information describing the disease being treated, and patient
incentive
information; and
(c) a daily calendar comprising dosing information, side effect information,
information describing the disease being treated, and patient incentive
information;
wherein the complex drug regimen comprises varying the dosage level or the
dosage
interval for a single therapeutic agent, the simultaneous administration of
more than one
therapeutic agent, the concurrent administration of more than one therapeutic
agent.
Example 2
CA 02272099 1999-OS-17
WO 98/22072 PCTIUS97/20577
18
A pharmaceutical package for aiding or increasing patient compliance for the
administration of a peroral complex pharmaceutical drug regimen, comprising:
(a) at least one blister card,
wherein each blister card comprises the total daily dose of the peroral
complex drug
regimen to be administered by the patient; wherein the blister card is divided
into sections
separating each complex drug regimen dose; wherein each dose section comprises
an
indicia denoting the time of day in which the dose is to be administered;
(b) a patient information booklet comprising dosing information, side effect
information, information describing the disease being treated, and patient
incentive
information;
(c) a daily calendar comprising dosing information, side effect information,
information describing the disease being treated, and patient incentive
information; and
(d) a reminder aid selected from the group consisting of:
I ) one or more reminder cards comprising information to remind the patient
when to take a dose of the complex drug regimen;
2) one or more adhesive stickers comprising information to remind the
patient when to take a dose of the complex drug regimen;
3) a case of the size to contain a single blister card, the case comprising an
alarm which can be set by the patient to sound at the time that the next dose
is
to be administered; and
4) combinations thereof.
Examule 3
A pharmaceutical compliance package, comprising:
(a) a series of 14 blister cards,
wherein each blister card comprises 4 doses of the peroral complex drug
regimen to be
administered by the patient; wherein the blister card is divided into 4
perforated sections
separating each dose; wherein each dose section comprises a "Breakfast,"
"Lunch,"
"Dinner," and "Bedtime" indicia denoting the time in which the dose is to be
administered;
wherein each dose comprises a bismuth salt, tetracycline and metronidazole,
preferably
each dose comprises two bismuth subsalicylate tablets with 102 mg of
salicylate, one 500
mg tetracycline HC1 capsule, and one 250 mg metronidazole tablet; wherein each
blister
card has only one medication per blister cavity; and wherein preferably the
blister cards are
separated between the 7th and 8th blister card, by a card containing a
statement on the
importance of completing the -full course of drug therapy to avoid
disease/symptom
CA 02272099 1999-OS-17
WO 98122072 PCT/US97/20577
19
reoccurrence and a congratulatory statement to the patient for finishing half
of the complex
drug regimen;
(b) a patient information booklet comprising dosing information, side effect
information, information describing the disease being treated, and patient
incentive
information;
(c) a daily calendar comprising dosing information, side effect information,
information describing the disease being treated, and patient incentive
information;
and
(d) a reminder aid comprising 4 reminder cards or 4 adhesive stickers, to be
placed at the location that the patient will be at the time of each scheduled
dose,
comprising information to remind the patient when to take a dose of the
complex
drug regimen.
