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TITLE OF THE INVENTION
METHODS OF CONVERTING A PATIENT'S TREATMENT REGIMEN FROM
INTRAVENOUS ADMINISTRATION OF AN OPIOID TO ORAL, CO-
ADMINISTRATION OF MORPHINE AND OXYCODONE USING A DOSING
ALGORITHM TO PROVIDE ANALGESIA
CROSS REFERENCE TO RELATED APPLICATION
This application claims priority to U.S. Patent Application Serial No,
12/881,677,
filed on September 14, 2010 and issued as U.S. Patent No. 7,723,453 on April
12, 2011; to
US. Patent Application Serial No, 12/881,728, filed on September 14, 2010 and
issued as
U.S. Patent No. 8,0.12,990 on Septetnber 6, 2011; and to
Patent Application Serial No.
13/185,016, filed On July 18, 2011: *hid) are all incorporated herein by
reference.
FIELD OF THE INVENTION
The present invention relates to: treatment of pain in patients. In certain
aspect% the
present invention is directed to a method of converting :a patient's pain
treatment regimen
from intravenous (IV) administration Of an opioid to an orally administered
combination of
morphine and oxycbdone in a weight ratio of about 3:2. This method may include
the use, of
a dosing algorithm for determining an appropriate dosage of the morphine and
Oxycodone
combination.
BACKGROUND OF THE INVENTION
Patients who experience significant pain as the result of, for Uample, a
Serious
traumatic injury, a surgical procedure, or chronic illness (e.g., cancer),
require relief through
strong prescription medication, Opiate drugs are a class Of pain-relieving
prescription
medications frequently used in the treatment of a variety of acute and
chronic, moderate: to
severe, pain. Examples include natural opiates Such as morphine, eedeine, and
thebaine:
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semi-synthetic opioids such as hydromorphone, hydrocodone, oxycodone,
oxymorphone,
diacetylmorphine (heroin), nicomorphine, dipropanoylmorphine, benzylmorphine,
ethylmorphine, buprenorphine and morphine glucuronides (including the 3- and 6-
glucuronide); and fiilly synthetic opioids such as alfentanil, fentanyl,
remifentanil, sufentanil,
tTefentanil, pethidine, methadone, tramadol and dextropropoxyphene.
The World Health Organization's guidelines recommend that two strong ()plaids
should not be co-administered, presumably because it is generally thought that
all opioids
exert their analgesic effects through the same receptor mechanisms in the
central nervous
system (CNS). See World Health Organization, Cancer Pain Relief and Palliative
Care,
Geneva: WHO 1990. Studies have shown, however, that the antinociceptive (also
termed
analgesic) effects of structurally related morphine and oxycodone are
differentially
antagonized by naloxonazine (a selective g-opiold receptor antagonist) and nor-
BN1 (a K-
selective opioid antagonist), respectively, indicating that they produce
antinociception
through different opioid receptor mechanisms. See Ross et al., Pain 1997, 73,
151-57. The
opioid receptor is believed to have four receptor subtypes named 1.t-opioid
receptor (MOR),
a-opioid receptor (SOR), K-opioid receptor (KOR) and 8-opioid receptor (DOR).
The
biochemical and cellular effects of morphine are mediated through the IvIOR,
found in high
density within the CNS.
it has been found that co-administration to rats of sub-antinociceptive (also
termed
sub-analgesic) doses of morphine with sub-antinociceptive doses of oxycodone
results in
synergistic levels of antinociception. See Ross et al, Pain 2000, 84, 421-28.
Animals that
received the sub-antinociceptive doses of morphine with sub-antinociceptive
doses of
oxycodone were similar to placebo-injected control animals With respect to CNS
side effects.
See Oat 424-25. Animals that received equipotent doses of either opioid alone
were more
sedated as compared to the control animals. See idat 425-26.
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Synergistic analgesic effects of orally co-administering morphine and
oxycodone at a
3:2 ratio have been demonstrated in patients (see, e.g., U.S. Patent No.
6,310,072 and U.S.
Publication Nos. 2005/0053659, 2007/0031489, 2009/0291975 and U.S. application
Serial
No. 12/567,209). However, efficacy of treating pain by co-administering
morphine and
oxycodone is dependent, at least in part, on the quantity that is
administered. For example,
administration of a dosage of morphine and oxycodone will not produce
analgesia if the
quantity administered is too low. The quantity of morphine and oxycodone
administered may
also play a role in the occurrence of side effects that are common to opioids,
such as nausea,
vomiting, drowsiness, dizziness, mental clouding, dysphoria, pruritus,
constipation, increased
biliaty tract pressure, urinary retention, hypotension, respiratory depression
and bladder
dysfunction. Moreover, the onset of tolerance to the therapeutic effects of
the drugs, as well
as the initiation of physical dependence, may occur with daily administration
of oploids; the
extent of such tolerance or physical dependence is dependent in part on the
quantity of
opioids administered. Therefore, it is important to determine an effective
oral dosing
regimen for co-administering morphine and oxycodone in order to effectively
and safely treat
pain.
The determination of the appropriate quantity of morphine and oxycodone to
administer is especially important for patients recovering from a serious
traumatic injury or a
surgical procedure. These patients are often treated for pain initially by IV
administration of
an opioid drug such as morphine. Once these patients leave the hospital or
surgical center
and are no longer under medical supervision, they mast receive the opioid
drugs by a
different route (e.g., orally) since repeated =1V dosing is no longer
practical. In the past,
doctors have often estimated the necessary oral dose of some drugs following
IV
administration, but such practice often results in either over-medication,
which can lead to
adverse side effects, or under-medication, which can result in ineffective
pain management.
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A lso, physicians often consult equianalgesic tables before opioid rotation or
conversion to
determine a new safe starting dose appropriate for adequate pain control.
Unfortunately,
there are wide and clinically important differences in published opioid
equianalgesic ratios.
See Shaheen et aL, J. Pain Symptom. Manag., 38:3 (2009) 409-16. Thus, there is
a need for a
method of converting doses of intravenously administered opioids to an oral
opioid dose that
effectively manages the patient's pain and at the same time reduces or
eliminates the
problems associated with over- or under-medication. in particular, there is a
need for a
method of converting doses of intravenously administered opioid to orally co-
administered
morphine-oxycodone combination in a weight ratio of about 3:2
I O.
SUMMARY OF THE INVENTION
The present invention provides a method of treating pain in patients. In
particular, the
method addresses the need to convert the treatment regimen of patients who
were receiving
IV administration of an opioid in the hospital or surgical center, to oral
doses of opioids, such
as when IV dosing is no longer practical or appropriate to administer.
One aspect of the present invention is directed to a method of converting a
treatment
for pain comprising IV administration of an opioid to a treatment for pain
comprising oral co-
administration of an immediate release morphine-oxycodone combination (i.e.,
morphine, or
a pharmaceutically acceptable salt thereof, and oxycodone, or a
pharmaceutically acceptable
salt thereof) in a weight ratio of about 3:2, in a human patient in need of
analgesia, such that
the method may comprise determining a four-hour average oral morphine
equivalent dose of
the opioid administered intravenously to the human patient, and orally co-
administering to
the human patient a first dose of an immediate release morphine-oxycodone
combination in
accordance to a dosing algorithm. Applying a dosing algorithm according to
some
embodiments of the invention, if the four-hour average oral morphine
equivalent dose is
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between about 0 mg and about 30 mg, then the first dose of the morphine-
oxycodone
combination is no greater than about 12 mg of morphine, or a pharmaceutically
acceptable
salt thereof, and about 8 mg of oxycodone, or a pharmaceutically acceptable
salt thereof. If
the four-hour average oral morphine equivalent dose is greater than about 30
mg and less
than or equal to about 40 mg, then the first dose of the morphine-oxycodone
combination is
about 18 mg of morphine, or a pharmaceutically acceptable salt thereof, and
about 12 mg of
oxycodone, or a pharmaceutically acceptable salt thereof Further, if the four-
hour average
oral morphine equivalent dose is greater than about 40 mg and less than or
equal to about 120
mg, then the first dose of the morphine-oxycodone combination is about 24 mg
of morphine,
or a pharmaceutically acceptable salt thereof, and about 16 mg of oxycodone,
or a
pharmaceutically acceptable salt thereof.
In some embodiments, if the four-hour average oral morphine equivalent dose is
between about 0 mg and about 30 mg, then the first dose of the morphine-
oxycodone
combination is about 12 mg of morphine, or a pharmaceutically acceptable salt
thereof, and
about 8 mg of oxycodone, or a pharmaceutically acceptable salt thereof
In certain embodiments, if the four-hour average oral morphine equivalent dose
is
between about 0 mg an.d about 10 mg, then the first dose of the morphine-
oxycodone
combination is about 3 mg of morphine, or a pharmaceutically acceptable salt
thereof, and
about 2 mg of oxycodone, or a pharmaceutically acceptable salt thereof. If the
four-hour
average oral morphine equivalent dose is greater than about 10 mg and less
than or equal to
about 15 mg, then the first dose of the morphine-oxycodone combination is
about 6 mg of
morphine, or a pharmaceutically acceptable salt thereof, and about 4 mg of
oxycodone, or a
pharmaceutically acceptable salt thereof. If the four-hour average oral
morphine equivalent
dose is greater than about 15 mg and less than or equal to about 20 mg, then
the first dose of
the morphine-oxycodone combination is about 9 mg of morphine, or a
pharmaceutically
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acceptable salt thereof, and about 6 mg of oxyCodone,:or a pharmaceutically
acceptable salt
thereof. If the four-hour average oral morphine equivalent dose is greater
than about 20 mg
and less than or equal to about 30 mg, then the first dose of the morphine-
oxycodone
Oonibination is about 12:MR of morphine, or a pharmaceutically acceptable salt
thereof, and
about 8 mg of oXycodone, or a pharmaceutically acceptable salt thereof,
Applying a dosing algorithm according to Ow embodiments of the invention, if
the
four-hour average Oral morphine equivalent dose is between about 0 mg and
about 30 mg,
then the first dose of the=rnOrphine-oxycodone Combination is about 12 mg of
morphine, or a
pharmaceutically acceptable salt thereof, and about $: mg of oxycodone, or a
pharmaceutically acceptable salt thereof If the four-hour average oral
morphine equivalent
dose is greater than about 30 mg and less than Or equal to about 40 mg, then
the first dose of
the morphinc-oxycOdone tothbination is about 18 mg of morphine, or a
pharmaceutically
acceptabie salt thereof, and about 12 rag of oXyebdone, or a pharmaceutically
acceptable salt
thereof. Further, if the four-hour average oral morphine equivalent dose is
greater than about
40 rug and less than or equal to about 120 mg, then the first dose of the
morphine-oxyeodone
combination is about 24 Mg of morphine, or a pharmaceutically acceptable salt
thereof, and
about 16 mg of oxStodone, or a pharmaceutically aceeptable salt thereof.
In some embodiments, the four-hour average prat morphine equivalent dose is
determined by Equation (1):
t 4-Hour Average n
:I Oral Morphine x4 __________________________________ xbxs (1)
Equivalent Dose h 4
wherein m = total amount (mg) of oral morphine eqUivalents of the opioid used
during IV
administration (including bolus and PCA);n =oral morphine equivalents (trig)
of the opioid
used during the first four hours of IV administration; h total time (hour)
that the oral
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morphine equivalents of the opioid waS administered intravenously; b clinical
bieequiValency factor; and s ¨ safety factor.
In some embodiments, .for the various opioids administered intraVenously, the
bioequivalency factor is between about I and about 15. In other embodiments,
the clinical
bioequivaleney factor is about 2. in some embodiments, the safety factor is
between about
0.50 and about 1Ø In other embodiments, the safety factor is about 0.75.
In certain embodiments, the present invention is directed to:a:method of
converting a
t-catment for pain comprising IV administration of an .oploid to a treatment
for pain
comprising: oral co-administration of an immediate release morphine-oxycodone
combination
in a weight ratio of about 3:2,in a human patient in need of analgesia, such
that the method
may-comprise determining a one-hour average oral morphine equivalent doseOf
the opioid
administered intravenously to the human patient, and orally cO-adininisteriniz
to the human
patient a first dose of an immediate release morphine-oxycodone combination in
accordance
to a dosingalgorithm. The dosing algorithm used after determining a one-hour
average oral
morphine equivalent dose is generally the same as the dosing algorithm used
after
determining a four-hour averageOral morphine equivalent dose; the difference
isthat each
first dose of the morphine,,oxycodone combination corresponds to a range of
averageoral
morphine equivalentdose that is ono-fourth of the range of the four-hour oral
morphine
equivalent dose. Therefore, if Me one-hour average oral morphine equivalent
(1680$.
between about 0 mg. and about 7.5.mg, -then the first dose of the morphinO-
Oxypodone
combination is no greater than about 12 mg of morphine, ora pharmaceutically
acceptable
salt thereof; and about 8 mg of oxycodoneõ or a pharmaceutically acceptable
salt thereof If
the ono-hour average oral morphine equivalent dose is greater than .about 7.5
mg and less
than or equal to about 10 mg, then the first :dose of the morphine-oxyceidone
combination is
about 18 mgof morphine, or a pharmaceutically acceptable salt thereof, and
aboutl2ing Of
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oxycodone, or a pharmaceutically acceptable salt thereof. Further, if the one-
hour average
oral morphine equivalent doSe is greater than about 10 mg and less than or
equal to about 30
mg, then the first dose of the morphine-oxycodone combination is about 24 mg
of morphine,
Or a pharmaceutically acceptable salt thereof, and about 16 mg olokyeodone, or
a
pharmaceutically acceptable salt therea
In some embodiments, if the one-hotir average oral morphine equivalent doSe iS
between about 0 mg and about 7.5 mg, then the first dose of the morphine-
OxyCOdOne
combination is about 12 mg of morphine, or a pharMacetitically acceptable salt
thered and
about 8 mg of oxycodone, or a pharmaceutically acceptable salt thereof.
In certain embodiments, if the one-hour average oral morphine equivalent dose
is
between :OW 0 mg and about 2.5 Mg, then the first dose of the morphine-
oxycodone
combination is about 3 mg of morphine, or a pharrnaceutically acceptable salt
thereof; and
about 2 mg of Oxycodone, or a pharmaceutically acceptable salt thereof. If the
one-hour
average oral morphine equivalent dose is greater than abotit 15 mg and less
than Or equal to
about 3.75 mg, then the first dose of the morphine-oxycodone combination is
about 6 Mg of
morphine, Or :a pharmaceutically acceptable salt thereof, and about 4 mg Of
oxycodone, or a
pharmaceutically acceptable salt thereof. If the one-hour average oral
morphine equivalent
dose is greater than about 3.75 mg and less than or equal to about 5 ing, then
the first dose of
the morphine-okycodone combination is about 9 mg of morphine, or a
pharmaceutically
acceptable salt thereof, and about 6 Mg of oxyeedone, Or a pharmaceutically
acceptable salt
thereof. If the one-hour average oral morphine equivalent dose is greater than
about 5 mg
and less than or equal to about 7,5 mg, then the first dose of the morphine-
okycodone
combination is about 12 mg of morphine, or a pharmaceutically acceptable salt
thereof, and
about 8 mg of oxyoodone, or a pharmaceutically acceptable salt thereof.
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In some embodiments, the one-hour average oral morphine equivalent dose is
determined by Equation (2):
Hourly Average m
Oral Morphine xbx s (2)
Equivalent Dose) h ¨ 4
wherein m = total amount (mg) of oral morphine equivalents of the opioid used
during TV
administration (including bolus and PCA); n = oral morphine equivalents (mg)
of the opioid
used during the first four hours of IV administration; h = total time (hour)
that the oral
morphine equivalents of the opioid was administered intravenously; b =
clinical
bioequivaleney factor; and s = safety factor.
Another aspect of the present invention is directed to a method of converting
a
treatment for pain comprising TV administration of morphine, or a
pharmaceutically
acceptable salt thereof, to a treatment for pain comprising oral co-
administration of an
immediate release morphine-oxycodone combination (i.e., morphine, or a
pharmaceutically
I S acceptable salt thereof, and oxycodone, or a pharmaceutically
acceptable salt thereof) in a
weight ratio of about 3:2, in a human patient in need of analgesia, such that
the method may
comprise determining a net average hourly IV morphine dose, and orally co-
administering to
the human patient a first dose of an immediate release morphine-oxycodone
combination in
accordance to an algorithm. Applying a dosing algorithm according to some
embodiments of
the invention, if the net average hourly IV morphine dose is between about 0
mg and about 9
mg, then the first dose of the morphine-oxycodone combination is no greater
than about 12
mg of morphine, or a pharmaceutically acceptable salt thereof, and about 8 mg
of oxycodone,
or a pharmaceutically acceptable salt thereof. If the net average hourly IV
morphine dose is
greater than about 9 mg and less than or equal to about 14 mg, then the first
dose of the
morphine-oxycodone combination is about 18 mg of morphine, or a
pharmaceutically
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acceptable salt thereof, and about 12 mg of oxycodone, or a pharmaceutically
acceptable salt
thereof. Finally, if the net average hourly IV morphine dose is greater than
about 14 mg, then
the first dose of the morphine-oxycodone combination is about 24 mg of
morphine, or a
pharmaceutically acceptable salt thereof, and about 16 mg of oxycodone, or a
pharmaceutically acceptable salt thereof.
In some embodiments; if the net average hourly IV morphine dose is between
about 0
mg and about 9 mg, then the first dose of the morphine-oxycodone combination
is about 12
mg of morphine, or a pharmaceutically acceptable salt thereof, and about 8 mg
of oxycodone,
or a pharmaceutically acceptable salt thereof.
in some embodiments, if the net average hourly IV morphine dose is between
about 0
mg and about 3 mg, then the first dose of the morphine-oxycodone combination
is about 3
mg of morphine, or a pharmaceutically acceptable salt thereof, and about 2 mg
of oxycodone,
or a pharmaceutically acceptable salt thereof. If the net average hourly IV
morphine dose is
greater than about 3 mg and less than or equal to about 5 mg, then the first
dose of the
morphine-oxycodone combination is about 6 mg of morphine, or a
pharmaceutically
acceptable salt thereof, and about 4 mg of oxycodone, or a pharmaceutically
acceptable salt
thereof. if the net average hourly IV morphine dose is greater than about 5 mg
and less than
or equal to about 7 mg, then the first dose of the morphine-oxycodone
combination is about 9
nig of morphine, or a pharmaceutically acceptable salt thereof, and about 6 mg
of oxycodone,
or a pharmaceutically acceptable salt thereof. If the net average hourly IV
morphine dose is
greater than about 7 mg and less than or equal to about 9 mg, then the first
dose of the
morphine-oxycodone combination is about 12 mg of morphine, or a
pharmaceutically
acceptable salt thereof, and about 8 mg of oxycodone, or a pharmaceutically
acceptable salt
thereof.
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Applying a dosing algorithm according to certain embodiments of the present
invention, if the net average hourly IV morphine dose is between about 0 mg
and about 9 mg,
then the first dose of the morphine-oxycodone combination is about 12 mg of
morphine, or a
pharmaceutically acceptable salt thereof, and about 8 mg of oxycodone, or a
pharmaceutically acceptable salt thereof. If the net average hourly IV
morphine dose is
greater than about 9 mg and less than or equal to about 14 mg, then the first
dose of the
morphine-oxycodone combination is about 18 mg of morphine, or a
pharmaceutically
acceptable salt thereof, and about 12 mg of oxycodone, or a pharmaceutically
acceptable salt
thereof. If the net average hourly IV morphine dose is greater than about 14
mg, then the first
dose of the morphine-oxycodone combination is about 24 mg of morphine, or a
pharmaceutically acceptable salt thereof, and about 16 mg of oxycodone, or a
pharmaceutically acceptable salt thereof.
In one aspect of the present invention, the net average hourly IV morphine
dose may
be determined by (i) calculating a net amount of morphine (or a
pharmaceutically acceptable
salt thereof) administered intravenously to the human patient, wherein the net
amount is the
total amount of morphine administered intravenously to the human patient minus
the amount
of morphine administered intravenously to the human patient during the first
four hours of
administration; (ii) calculating a net time that morphine was administered
intravenously to the
human patient, wherein the net time is the total time that morphine was
administered
intravenously minus four hours; and (iii) dividing the net amount of morphine
administered
intravenously to the human patient by the net time that morphine was
administered
intravenously to the human patient.
In certain embodiments, the pharmaceutically acceptable salt may be a
hydrochloride,
hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, citrate, tartrate,
bitartrate, phosphate,
malate, maleate, napsylate, fumarate, succinate, acetate, tereplithalate,
pamoate or pectinate.
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In particular embodiments, the morphine-oxycodone combination comprises
morphine sulfate and oxycodone hydrochloride.
In some embodiments, the morphine-oxycodone combination may be in an immediate
release dosage form, sustained release dosage form, or controlled release
dosage form. In
particular embodiments, the morphine-oxycodone combination may be in an
immediate
release dosage form..
In some embodiments, the morphine,oxycodone combination may be co-administered
in a single dosage form, In other embodiments, the morphine-oxycodone
combination may
be co-administered in separate dosage forms,
1Ø In some em.bodiments, the IV opioid comprises morphine, codeine;
thebaineõ.
hydromorphone, hydrocodone, oxycodone, pvtporphone, diacetylmorphine (heroin),
'bicomorphine, dipropanoylmorphine, benzylmorphine, ethylmorphine,
buprenorphine and
morphine gincuronides (including the 3- and 6-glucuronide), alfentanil,
fentanyl,
remifentanii, sufentanil, trefentanil, pethidine, methadone, tramadol,
dextropropoxyphene, a
pharMaceutically acceptable salt thereof, or a combination thereof,
In certain embodiments, the IV opioid comprises morphine or oxycodone or a
pharmaceutically acceptable salt thereof
in certain embodiments, the method may further comprise orally co-
administering one
or more subsequent doses. of morphine-oxycodone combination 'about every four
tosix hours,
wherein the stibsequent doses comprise the same amount of morphine, or a
pharmaceutically
acceptable salt thereof, and oxycodone, or a pharmaceuticallyacceptable salt
thereof, as: the
first dose.
In various. embodiments, if the patient has inadequate pain relief, then .the
method
may further cOmprise orally co-administering one or more subsequent doses of
morphine-
Pxyeodonc combination about every four to six hours, under the following
conditions: if the
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first dose is about 3 mg of morphine, or a pharmaceutically acceptable salt
thereof, and about
2 mg of oxycodone, or a pharmaceutically acceptable salt thereof, then the
first subsequent
dose is about 6 mg of morphine, or a pharmaceutically acceptable salt thereof,
and about 4
mg of oxycodone, or a pharmaceutically acceptable salt thereof; if the first
dose is about 6 mg
of morphine, or a pharmaceutically acceptable salt thereof, and about 4 mg of
oxycodone, or
a pharmaceutically acceptable salt thereof, then the first subsequent dose is
about 9 mg of
morphine, or a pharmaceutically acceptable salt thereof, and about 6 mg of
oxycodone, or a
pharmaceutically acceptable salt thereof; if the first dose is about 9 mg of
morphine, or a
pharmaceutically acceptable salt thereof, and about 6 mg of oxycodone, or a
pharmaceutically acceptable salt thereof, then the first subsequent dose is
about 12 mg of
morphine, or a pharmaceutically acceptable salt thereof, and about 8 mg of
oxycodone, or a
pharmaceutically acceptable salt thereof; if the first dose is about 12 mg of
morphine, or a
pharmaceutically acceptable salt thereof, and about 8 mg of oxycodone, or a
pharmaceutically acceptable salt thereof, then the first subsequent dose is
about 18 mg of
morphine, or a pharmaceutically acceptable salt thereof', and about 12 mg of
oxycodone, or a
pharmaceutically acceptable salt thereof; and if the first dose is about 18 mg
of morphine, or
a pharmaceutically acceptable salt thereof, and about 12 mg of oxycodone, or a
pharmaceutically acceptable salt thereof, then the first subsequent dose is
about 24 mg of
morphine, or a pharmaceutically acceptable salt thereof, and about 16 mg of
oxycodone, or a
pharmaceutically acceptable salt thereof.
In certain embodiments, if the patient experiences, for example, adverse
effects with
the first dose, then the method may further comprise orally co-administering
one or more
subsequent doses of morphine, or a pharmaceutically acceptable salt thereof,
and oxycodone,
or a pharmaceutically acceptable salt thereof about every four to six hours,
under the
following conditions: if the first dose is about 24 mg of morphine, or a
pharmaceutically
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acceptable salt thereof, and about 16 mg of oxycodone, or a pharmaceutically
acceptable salt
thereof, then the first subsequent dose is about 18 mg of morphine, or a
pharmaceutically
acceptable salt thereof, and about 12 mg of oxycodone, or a pharmaceutically
acceptable salt
thereof; if the first dose is about 18 mg of morphine, or a pharmaceutically
acceptable salt
thereof, and about 12 mg of oxycodone, or a pharmaceutically acceptable salt
thereof, then
the first subsequent dose is about 12 mg of morphine, or a pharmaceutically
acceptable salt
thereof, and about 8 mg of oxycodone, or a pharmaceutically acceptable salt
thereof; if the
first dose is about 12 mg of morphine, or a pharmaceutically acceptable salt
thereof, and
about 8 mg of oxycodone, or a pharmaceutically acceptable salt thereof, then
the first
subsequent dose is about 9 mg of morphine, or a pharmaceutically acceptable
salt thereof,
and about 6 mg of oxycodone, or a pharmaceutically acceptable salt thereof; if
the first dose
is about 9 mg of morphine, or a pharmaceutically acceptable salt thereof, and
about 6 mg of
oxycodone, or a pharmaceutically acceptable salt thereof, then the first
subsequent dose is
about 6 mg of morphine, or a pharmaceutically acceptable salt thereof, and
about 4 mg of
oxycodone, or a pharmaceutically acceptable salt thereof; and if the first
dose is about 6 mg
of morphine, or a pharmaceutically acceptable salt thereof, and about 4 mg of
oxycodone, or
a pharmaceutically acceptable salt thereof, then the first subsequent dose is
about 3 mg of
morphine, or a pharmaceutically acceptable salt thereof, and about 2 mg of
oxycodone, or a
pharmaceutically acceptable salt thereof.
These and other objects, features and advantages of the present invention will
become
apparent after a review of the following detailed description.
DETAILED DESCRIPTION
The present invention relates to a method of converting a treatment for pain
comprising IV administration of an opioid, to a treatment for pain comprising
oral co-
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administration of a first dose of an immediate release morphine-oxycodone
combination.
The present invention also relates to a method or treating pain in patients
who had been
treated with IV administration of opioids, comprising converting the patients
to a treatment
comprising oral co-administration of a first dose of an immediate release
morphine-
oxycodone combination.
As used herein, "morphine" or "oxycodone" recited separately refers to the
free base
forms of morphine or oxycodone, respectively.
As used herein, "pharmaceutically acceptable salt" refers to a salt that is
toxicologically safe for human and animal administration.
As used herein, "morphine-oxycodone combination" refers to a combination of
morphine, or a pharmaceutically acceptable salt thereof, and oxycodone, or a
pharmaceutically acceptable salt thereof.
As used herein, "morphine equivalent dose" refers to a calculation of the
amount of
morphine that produces the same analgesic effects as a particular amount of
another plaid
for given route(s) of dose administration. For example, the oral morphine
equivalent dose of
1 mg of oral oxycodone is 1.5 mg of oral morphine; in other words, 1 mg of
oxycodone
administered orally will provide the same analgesic effect as 1.5 mg of
morphine
administered orally.
As used herein, "administration concurrently or co-administration" refers to
the
administration of a single composition containing both morphine and oxycodone,
or
pharmaceutically acceptable salts thereof, or to the administration of each
opioid agonist as a
separate composition within a short enough period of time such that the
effective result is
equivalent to that obtained when both such opioid agonists are administered as
a single
composition.
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As used herein in the context of a number, or a range of numbers, "about" will
be
understood to embrace somewhat larger or smaller values than the indicated
value to account:
for, aS examples, experimental errors inherent in the measurement and.
Variability between.
different .methodologies for measuring the value, as Will be apparent to one
skilled in the art,
Methods of Converting Patients from IV Administration of Opioids
Embodiments of the present invention relate to a method of converting a
treatment for
pain oomprising.TV administration fan opioid to a treatment for pain
comprising Orate0-
administration of a first dose of immediate release morphine and oxyeOdone, or
pharmaceutically acceptable salts thereof, in patients in need ofanalgeSia.
In certain embodiments, the IV administration of opioids May be by PCA. In
.spnW
embodiments, the opioid administered intravenously may be any-eOmpOund, such
as a drag,
that binds to opioid receptors. Examples of an opioid include, but are not
limited to,.
morphine, oxyeodone, cOdeine, hydrocadone, diamorphine, fentanY.1, alfentanyl,
13 buprenorphine, hydromorphone, methadone, and oxymorphone.
A dosing algorithm may be used to determine the first oral immediate.release
dose of
the morphine-oxycodonc combination. In some embodiments, afour-hour average
oral
morphine.equivalent dose may be initially calculated based on the conditions
of the IV
administration of opioids, after which the first dose of the morphine-
Oxycodone combination
za is determined,
The four-hour average oral morphine equivalent dose _may be determined using
Equation (I):
44Iour Average \ m n
-- ,. 13:xs
Oral Morphine: < (1)
4 )
Equivalent DOW h¨
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wherein m = total amount (mg) of oral morphine equivalents of the opioid used
during IV
administration (including bolus and PCA); n - oral morphine equivalents (mg)
of the opioid
used during the first four hours of IV administration; h i- total time (hour)
that the oral
morphine equivalents of the opioid was administered under IV administration; b
= clinical
bioequivalency factor; and s = safety factor.
In some embodiments, a one-hour average oral morphine equivalent dose may be
initially calculated based on the conditions of the IV administration of
opioids, after which
the first dose of the morphine-oxycodone combination is determined.
The one-hour average oral morphine equivalent dose may be determined using
Equation (2):
Hourly Average m
( ( ¨ n '\
Oral Morphine 1 _
) xbxs (2)
Equivalent Dose/ b ¨ 4)
wherein in = total amount (mg) of oral morphine equivalents of the opioid used
during IV
administration (including bolus and PCA); n = oral morphine equivalents (mg)
of the opioid
used during the first four hours of IV administration; h = total time (hour)
that the oral
morphine equivalents of the opioid was administered under IV administration; b
= clinical
bioequivalency factor; and s = safety factor.
The term, "net amount of oral morphine equivalents administered," may he used
to
describe the oral morphine equivalents used during IV administration, minus
the oral
morphine equivalents used during first four hours of IV administration (in -
n). The term,
"net time administered," may be used to describe the total hours that the oral
morphine
equivalents was administered IV less four hours (h - 4). "Net average hourly
intravenous
dosing" is therefore the net amount of oral morphine equivalents administered
divided by the
net time administered.
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In Equations 1 and 2, the calculation of (m n) and (h 4) essentially exempts
front.
the ultimate determination the opioid given during the first four hours of
intravenous
administration. The first four hours are exempt because the amount of an
opioid
administered intravenously immediately following surgery or trauma is not
generally
indicative of analgesia required by the patient. During these initial hours
the patient is likely
under the influence of the analgesia used during surgery and/or would have
little mobility that
may not necessitate the need for a heightened level of analgesia that is often
required
throughout later stages of recovery.
A factor of four is used in Equation Ito convert the 00 average hourly IV
dosing ((m
¨ n) ¨ 4)) into a four-hour average since oral dosing of the morphine-
oxycodone
combination will be about every four to gix. hours. .In the absence Oa factor
of four as shown
in -Equation 2, the net average hourly -1V dosing is converted into a one-hour
average,
The clinical bioequivalency factor considers the differences in the
bioavailability
between IV and oral routes of opioid administration and the conversion of non-
morphine
opioid analgesics to a Morphine equivalent dose In certainembodiments, the
clinical
bioequivalency facto fiir various opidids may vary between about 1 and about
15. The range
also accounts for inter-patient variability, including the variability between
opioid nave and
opioid tolerant patients. In some embodiments, the clinical bioequivalency
factor tor various
opioids May Vary between about 1 and about .10, For IV morphine., or a
pharmaceutically
acceptable salt thereof, the clinical bioequivaleneTWOr may Vary between about
I and
about 5. In certain embodiments, the clinical bioequivaleney factor for
morphine, or a
pharmaceutically acceptable salt thereof, may be about 2. In some embodiments,
the clinical
bioequivaleney factor for oXycOdone, or a pharmaceutically acceptable salt
thereof, may he
between about 1.5 and 7.5. In other embodiments, the clinical bioequivalency
factor for
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oxycoclone, or a pharmaceutically acceptable salt thereof, may be between
about 3 and about
5.
The safety factor allows for a lesser amount of oral morph ine-oxycodone
combination
to be administered to minimize the chance of overdosing or occurrence of
adverse events
upon administration of the first dose. The safety factor may range from about
0.25 to about
1Ø In certain embodiments, the Safety factor may be about 0.50. In some
embodiments, the
safety factor may be about 0.75.
In certain embodiments, when the four-hour average oral morphine equivalent
dose
may be known or calculated as described above, the first dose of an immediate
release
morphine-oxycodone combination can be determined using the dosing algorithm
shown in
Table 1.
Table 1: Algorithm for the Conversion of Four-Hour Average Oral Morphine
Equivalents to
a First Dose of an Immediate Release Morphine-Oxycodone Combination
Administered
Orally.
Four-Hour Average Oral First Dose Of
Morphine Equivalent Dose Morphine-Oxycodone Combination
0 - 30 mg No greater than 12 mg / 8 mg
>30 - 910 mg 18 mg/12 mg
>40 - <120 mg
1 24 mg / 16 mg
.................................................................. 1
According to the dosing algorithm of Table 1, if the four-hour average oral
morphine
equivalent dose is between about 0 mg and about 30 mg, the corresponding first
dose of
morphine-oxycodone combination may be no greater than about 12 mg /8 mg; if
the four-
hour average oral morphine equivalent dose is greater than about 30 mg and
less than or
equal to about 40 mg, the corresponding first dose of morphine-oxycodone
combination may
be about 18 mg / 12 mg; if the four-hour average oral morphine equivalent dose
is greater
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than about 40 mg and less than or equal to about 120 mg the corresponding
first dose of
morphine-oxycodorte combination may be about 24 mg / 16 mg.
Etisome embodiments in which the four-hour average oral morphine equivalent
dose
is between about 0-mg and about 30 mg, the first dose of an
immediateTelease.morphine-
oXyeodone combination administered orally can be determined using the dosing
algorithm
Shown in Table 2.
Table 2.: Algorithm for the Conversion of Four-Hour Average Oral Morphine
Equivalents to
a First Dose. of an Immediate Release Morphine-ONycodone Combination
Administered.
1 Four-Hour Average Oral First Dose of
Morphine Equivalent Dose Morphine-Oxycodone Combination
0 -- 10 mg 3 mg / 2 mg
>10 mg .6 mg / 4 mg
>1.5 ¨ <20 mg 9 mg / 61-11
>20--30mg 1.2 mg / 8 mg
According to the dosing algorithm of Tablel, if the four-hour average oral
morphine
equivalent dose is between about 0 mg and about 10.mg, the corresponding first
dose of
morphine-oxycodone combination may be about 3 mg / 2 big; if the four-hour
average oral
morphine equivalent dose..iS greater than about TO ing and less than or equal
to about 15 mg,
the Corresponding first dose of morphine-oxyoodone combination may be about
/ 4 mg;
if the four-hour average oral morphine equivalent dose is greater than about
15. trig and less.
than or equal to about 20 mg, the corresponding first dose of
rnorphine.o0oodone
combination. may be about 9 mg / 6 mg; if the four-hour average oral morphine
equivalent
20. dose is greater than about 20 mg and less than or equal to about 30
mg, the corresponding
first dose of morphine-okytodone combination maybe about 12 mg / 8 mg,
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In some embodiments, when the four-hontaverage oral morphine equivalent dose
may be known or calculated as described above, the first dose of an immediate
release
morphine,oxyeodone combination administered orally can be. also determined
using the
dosing algorithm shown in Table 3.
Table 1.Algorithm for the Conversion of Four-Hour Average Oral Morphine
Equivalent.
Dose to. a :First Dose of an Immediate Release Morphine-Oxycod.one Combination
Administered Orally.
Four-flour Average Oral First Rose of
Morphine Equivalent Dose Morphine-Oxycodone Combination
0 ¨ 30 mg 12 mg / 8 mg
>30 --- <40111Q 18 mg / 12 rng
>40.¨ .'120 mg 24 mg / '16 mg
According to the dosing algorithm of Table 3, if the four-hour average oral
morphine
equivalent dose is between about 0 mg and about 30 mg, the corresponding first
dose of
mprphine-oxycodone combination, maybe about 12 mg / 8 mg; if the bur-hour
average oral
morphine equivalent.dose is greater than about 30 mg and less than or equal to
about 40 mg,,
the corresponding first dose of morphine-oxycodone combination may be about 18
mg" 12
M2; if the four-houraverage oral morphine equ.ivalent dose is greater than
about 40 mg and
less than or equal to about 120 mg, the corresponding first dose of morphine-
ox.ycodone
combination.may be about 24 mg / 16 mg.
In certain embodiment, when the one-hour average, oral morphine equivalent
dose
may be known Or calculated as described above, the first dose-ofari immediate
release
morphiae-oXyrodone combination can be determined by divieling.the four-hour
average oral
morphine equivalent dose ranges of the dosing algorithm in Table 1 by four,
resulting in the
dosing.algorithrt shown in Table 4.
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Table 4; Algorithm for the Conversion of One-Hour Average Oral Morphine
Equivalents to:a
First 'Dose of an immediate Release Morphine-OxycbdOne Combination
Administered
Orally.
' One-Hour Average Oral First Dose of
Morphine Equivalent Dose Morphine-0.xycodone Combination.
0 7,5 mg No greater than 12 -111Q 8 mg
>75 1O mg 18 mg / 12 mg
>10 --- 530 mg 24 Mg / 16 mg
According to the dosing algorithm. of Table 4, if the one-hour average oral
morphine
equivalent dose is between about 0 mg and about 7.5 mg, the corresponding
first dose
morphine-o;s(yeodone combination may be no greater than about 12 mg / l rag;
if the one-
hour average oral morphine equivalent dose: is greater than about 7.5 mg and
less than or
la equal to about 10 rug, the corresponding -first close of morphine-
oxypodoneeombination may
be about 18 mg /12 mg; if the one-hour average oral morphine equivalent dose
is greater
than about 10 mg and less than or equal to about 30 mg, the corresponding
first dose of
morphine-oxycodone combination may .be about 24 mg /
In some embodiments in which the one-hour overage oral morphine equivalent
dosels
between about 0 mg and about 7.5_4.1g, the first dose of an immediate release
morphine-
aqcodone combination can he determined by dividing the four-hour average oral
morphine
equivalent dose ranges of the dosing algorithm in Table 2 by four, resulting
in the dosing
algorithm shown in Table 5,
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Table 5: Algorithm for the Conversion of One-Hour Average Oral Morphine
Equivalents to a
First Dose of an Immediate Release Morphine-Oxycodone Combination Administered
Orally.
One-Hour Average Oral First Dose of
Morphine Equivalent Dose Morphine-Oveodone Combination
0 ¨ 2.5 rng 3 rng/2mg
>2.5 ¨ <3.75 mg 6 mg/4 mg
>3.75 ¨ 55 mg 9 mg / 6 mg
>5 ¨ 57.5 mg 12 mg/ 8 mg
According to the dosing algorithm of Table 5, if the one-hour average oral
morphine
equivalent dose is between about 0 mg and about 2.5 mg, the corresponding
first dose of
morphine-oxycodone combination may be about 3 mg /2 mg; if the one-hour
average oral
morphine equivalent dose is greater than about 2.5 mg and less than or equal
to about 3.75
mg, the corresponding first dose of morphine-oxycodone combination may be
about 6 mg / 4
mg; if the one-hour average oral morphine equivalent dose is greater than
about 3.75 mg and
less than or equal to about 5 mg, the corresponding first dose of morphine-
oxycodone
combination may be about 9 mg/ 6 mg; if the one-hour average oral morphine
equivalent
dose is greater than about 5 mg and less than or equal to about 7.5 mg, the
corresponding first
dose of morphine-oxycodone combination may be about 12 mg /8 mg.
In some embodiments, when the one-hour average oral morphine equivalent dose
may
be known or calculated as described above, the first dose of an immediate
release morphine-
oxycodone combination can be determined by dividing the four-hour average oral
morphine
equivalent dose ranges of the dosing algorithm in Table 3 by lour, resulting
in the dosing
algorithm shown in Table 6.
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Table 6.. Algorithm for the Conversion of One-Hour Ayerage Oral Morphine
Equivalent Dose
to a First Dose of an Immediate Release Morphine-Oxycodone Combination
Administered
Orally.
, One-Hour Average Oral First Dose of
Morphine Equivalent Dose Morphine-Oxycodone=Cornbination
--- 7.5 mg 12 mg 8 mg
>75-.I0mg 1.8 mg / 12 mg
>10 mg 24 mg / 16 mg
. .
According to the dosing algorithm of Table 3, if the one-hour average oral
morphine
equivalent doseis between about 0 mg and about 7.5 mg, the corresponding first
dose of
morphine-oxycodone combination may be about 12 mg / 8 mg; if the one-hour
average oral
morphine equivalent dose is greater than about 7.5 mg and less than or equal
to about H) mg,
the corresponding first dose of morphine-oxycodone combination may be about 18
mg / 12
.mg; if the one-houraverageoral morphine equivalent dose is greater than about
10 mg and
less than orequal to about 30 mg, tbtcorresponding first dose of rnorphine-
oxycodone.
combination may be about 24 mg / 16 mg
In certain embodiments, when the net average hourly intravenous dosing may be
known or calculated as:described above, the first dose of an immediate release
morphine-
oxycodone combination administered orally can be determined using the dosing
algorithm
shown in Table 7..
20.
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Table Algorithm for the conversion Of Net Average Hourly intravenous .1)Osing
to a First
Dose of an Immediate Release Morphine-Oxycodone Combination Administered
Orally.
.Net Average Hourly- First Dose of
Intravenous Dosin __________________ Morphine-Oxycodone Combination
0 - 9 mg No greater than 12 mg / 8 mg
>9 - <14 mg 18 mg / 12 mg
>14 mg
24 mg / 16 mg
According to the closing algorithm of Table 7, if the net average hourly
intravenous
dosing is between about 0 mg and about 9 mg, the corresponding first dose of
morphine-
oxycodone combination may be no greater than about 12 mg / 8 ingt if the net
average hourly
intravenous dosing is greater than about 9 mg and less than or equal to about
14 mg, the
corresponding first dose of morphine-oxycodone combination may be about 18 mg
/ .12 mg.
If the net.average hourly intravenous morphine administered is greater than
about 14 mg, the
corresponding first dose of morphine-oxycodone combination may be about 24 mg
of
morphine and about 16 mg of oxyzod one.
En some..embodiments in. which the net average hourly intravenous dosing is
between
about 0 mg and about 9 mg, :the first dose of an immediate release dose of a
morphine-
oXycodone combination administered orally can be determined using the dosing
algorithm
shown in Table .8.
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`Table 8: Algorithm for the Conversion of Net Average Hourly Intravenous
Dosing to a First
Dose of an Immediate Release Morphine-Oxycodone Combination Administered
Orally.
Net Average Hourly First Dose of
Intravenous Dosing Morphine-Oxycodone Combination
0 --- 3 mg 3 mg / 2 mg
>3 ¨ rng 6 mg / 4 ing
=>5¨<img 9 nig/ 6 rng
>7--9 mg 12 mg /8 mg
According to the dosing algorithm of Table 8, if the net average hourly
intravenous
dosing is between about Oing. and about 3 mg, the corresponding -first dose.
of morphine-
oxycodone combination May be about 3 mg / 2.mg; if the net average hourly
intravenous
dosing is greater than about 3 mg and less than or equal to about 5 mg, the
corresponding first
dose of morphine-Oxycodone combination may be about .6..Mg./ 4:mg; if the net
average
1 0 .hOuriy intravenous dosing is greater than about 5 mg and less than or
equal to about 7 mg, the
in some embodiments,. when the net average hourly intravenous dosing is
knowtor
calculated as described above, the first dose of an immediate releasentorphine-
oXycodone
.combination administered orally can be determined using the dosing algorithm
shown in
Table 9,
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Table 9: Algorithm for the. Conversion of Net. Average Hourly Intravenous
Dosing to a FirSt
Dose.of an Immediate Release Morphine-Oxycodone Combination Administered
Orally.
Net Average Hourly ' First Dose of
intravenous Dosing Morphine-Oxycodone Combination
0 ¨ 9 mg 12 mg / 8 mg
>9 ¨ 5,14 mg 18 mg / 12 mg
>14 .ing 241ng / 1 15 nig
According to the dosing algorithm of Table 9, if the net average hourly
intravenous
dosing is between about 0 mg and. about 9.mg.õ the corresponding first dose of
morphine-
oxycodone Combination may be about 12 mg / 8 mg; if the net average hourly
intravenous
dosing is greater than about 9 mg and less than or equal to about 14 mgõ the
corresponding
first dose of morphine-oxycodone combination may be about 18 mg 112 mg. If the
net
average hourly intravenous morphine administered is greater than about 14 mg,
the
corresponding first dose. of morphine-oxycodone combination may be about 24 mg
of
morphine and about 16 mg of oxycodone.
After the treatment regimen is converted, the morphine-oxycodone combination
may
be administered to the patients every 2 to 10 hours, or every 3 to 8 hours, or
every 4 to 6
hours. Alternatively, the morphine-oxycodone combination may be administered
at the
discretion of the physician applying the method and prescribing the
combination. For opioid
tolerant patients, the physielan should take into consideration the patient's
prior.o0ioid dose.
and PCA dose of morphine and dose the subject accordingly.
After the first oral immediate release dose of the morphine,oxycodone
combination,
one or more subsequent doses may be administered about everyfour to Six hours
apart. In
certain embodiments, the one or more subsequent doses may comprise the same
amount of
morphine, or a pharmaceutically acceptable salt thereof and oxycodone or
pharmaceutically
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acteptable salt thereof as the first dose. In the event the patient requires
greater analgesia
than what resulted from the first dose of Morphine and oxycodone, the one or
More
subsequeadoses can be increased compared to the first dose (up-titration).
Thus, in certain
embodiments, the subsequent doses of morphine-ox.ycodone combination may: be
co-
:5 administered about every four to six hours apart as follows::
(i) if the first dose is about 3 mg Ofinorphine, or a pharmaceutically
acceptable
salt thereof, and about 2 mg of oxycodone, or a pharmaceutically acceptable
salt thereof, then the _first subsequent dosetnay be about 6 mg of morphine,
or
a pharmaceutically acceptable salt thereof, and about 4 trni of oxycodone, or
a
pharmaceutically acceptable salt thereof;
(ii) if the first dose is about 6 trig of morphine, or a Pharmaceutically
acceptable
salt thereof, and about 4 mg of oxyCodone, or a pharmaceutically acceptable
salt thereOf, then the first subsequent dose may be aboat 9 <nig of MOrphine,
or
a pharmaceutically acceptable salt thereof, and about 6 mg of oXycodone, or a
pharmaceutically acceptable salt thereof;
(iii) if the first dose is about 9 mg of morphine, Or a
.pharmaceuticallyacceptable
salt thereof, and about 6 mg of oXYcodoneõ Or a pharmaceutically acceptable
salt thereof, then the first subsequent dose may be about 12. mg of morphine,
or a pharmaceutically acceptable salt thereof, and about 8. mg of oxyOodone,
or
a pharmaceutically acceptable: salt thereof;
(iv) if the first dose is about 12 mg of morphine, Or a pharmaceutically
acceptable
salt thereof, and about 8 mg ofoxycodone,. or a pharmaceutically acceptable
salt thereof, then the first subsequent dose. may be about 18 mg of-morphine,
or a pharmaceutically acceptable salt thereof, and about 12 mg of oxycodone,
or a pharmaceutically acceptable salt thereof; and
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(v) if the first dose is about 18 mg of morphine, Or a
pharmaceutically acceptable
salt thereof, and about 12 mg ofoXycodoneõ or a pharmaceutically acceptable
salt thereof, then the first subsequent dose May be about24 mg of morphine,
or a pharmaccUtically acceptable salt thereof, and about 16 mg of oxycodone,
Or a pharmaceutically acceptable salt thereof,
In the event that the patient requires lower doses than the first administered
oral
immediate dose .Ofmorphine and oxycodone to maintain analgesia or because of
adverse
effects, the one Or more subsequent doses may be decreased compared to the
first dose
(down-titration). Thus, in some embodiments, subsequent doses of morphine and
oxycodone
are co-administered about every li-mr to six hours apart as follows:
(i) if the first .dose is about 24 mg of morphine, or a pharmaceutically
acceptable
salt thereof, and about 16 mg of oxycOdone, or a pharmaceutically acceptable
salt therecif, then the first subsequent dose may be about IS mg ofrnorphine,
or a pharmaceutically acceptable salt thereof, and about 1210g.of oxyeodone,
Or a pharmaceutically acceptable salt thereof;
(ii) if the first dose is about 18 mg of morphine, or a pharmaceutically
acceptable
salt thereof, and about 12 mg Of oxycodone, or a pharmaceutically acceptable
'salt thereof, then the first subsequent dose may be about 12 mg of morphine,
or a pharmaceutically acceptable salt thereof, and about 8 mg of oxycodone, or
a pharmaceutically acceptable salt thereof
(iii) if the first dose is ahOut 12 mg of morphine, or a pharrnaceutically
acceptable
salt. thereof, and about 8 mg of 010-Cadmic, or a pharmaceatically :acceptable
salt thereof, then the first subsequent dose may be about 9 mg of morphine, or
a pharmaceutically acceptable salt thereof, and about 6 mg Of oxycodone, Or :a
25. pharmaceutically acceptable salt thereof;
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(iv) if the first dose is about 9 mg of morphine, or a pharmaceutically
acceptable
salt thereof, and about 6 mg of oxycodone, or a pharmaceutically acceptable
salt thereof, then the first subsequent dose may be about 6 mg of morphine, or
a pharmaceutically acceptable salt thereof, and about 4 mg of oxycodone, or a
pharmaceutically acceptable salt thereof; and
(v) if the first dose is about 6 mg of morphine, or a pharmaceutically
acceptable
salt thereof, and about 4 mg of oxycodone, or a pharmaceutically acceptable
salt thereof, then the first subsequent dose may be about 3 mg of morphine, or
a pharmaceutically acceptable salt thereof, and about 2 mg of oxycodone, or a
pharmaceutically acceptable salt thereof.
Patients who no longer require analgesia may terminate the administration of
the
medication. However, depending on the dose that is being administered, if a
patient is taking
the dose on a regular basis (usually at least three to four times per day) for
seven days,
termination of the medication may lead to withdrawal and the symptoms may
include
anxiety, muscle aches, abdominal cramping, diarrhea, nausea and vomiting. A
dosing
algorithm to reduce or prevent withdrawal symptoms associated with termination
of the
morphine-oxycodone combination may be found in Table 10.
Table 10: Dosing Algorithm for Termination of an Administration of Morphine-
Oxycodone.
Current Combination of Oral
Down-Titration*
Morphine and Oxycodone Dose
About 3 mg /2 mg Can stop
administration
About 6 mg /4 mg Can stop
administration
Down-titrate to about 6 mg /4 mg for about 1 -
About 12 mg / 8 mg
2 days, then stop administration
About 18 mg / 12 mg
Down-titrate to about 12 mg / 8 mg for about 2
days, then to about 6 mg / 4 mg for about 1 - 2
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days, then stop administration
Down-titrate to about 12 mg / 8 mg for about 2
About 24 mg / 16 mg
days, then to about 6 mg /4 mg for about 1 - 2
days, then stop administration
* If a patient experiences any signs or symptoms of withdrawal, then the
dose should be increased to the prior dose and the down-titration should be
tapered more slowly.
Morphine-Oxycodone Combination
As described above, the morphine-oxycodone combination may comprise morphine
or a pharmaceutically acceptable salt thereof, and oxycodone or a
pharmaceutically
acceptable salt thereof. The salt may be selected from a group including, but
not limited to,
hydrochlorides, hydrobromides, hydroiodides, sulfates, bisulfates, nitrates,
citrates, tartrates,
bitartrates, phosphates, nalates, maleates, napsylates, fumarates, succinates,
acetates,
terephthalates, pamoates and pectinates. In some embodiments, the
pharmaceutically
acceptable salt of morphine may be a hydrochloride; a sulfate or a tartrate
salt, and the
pharmaceutically acceptable salt of oxycodone may be a hydrochloride, a
terephthalate or a
pectinate salt. In particular embodiments, the morphine-oxycodone combination
comprises
morphine sulfate and oxycodone hydrochloride.
The morphine-oxycodone combination may comprise morphine, or a
pharmaceutically acceptable salt thereof, in a different pharmaceutical
composition from
oxycodone, or a pharmaceutically acceptable salt thereof. In particular
embodiments,
morphine sulfate and oxycodone hydrochloride are in the same pharmaceutical
composition.
A suitable combination product of morphine and oxycodone, or pharmaceutically
acceptable salts thereof, is disclosed in co-pending U.S. Patent Application
Serial Nos.
11/544,187, 12/469,438, and 12/567,209.
The pharmaceutical compositions for oral administration may be administered in
immediate release dosage forms. Immediate release dosage forms such as solid
or liquid
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dosage forms include, by way of example and not limitation, tablets, troches,
capsules,
dispersions, suspensions, solutions, syrups, and the like. Pharmaceutical
compositions may
be presented as discrete units such as capsules, sachets or tablets, each
containing a.
predetermined amount of each of the morphine and oxycodone, or
pharmaceutically
acceptable salts thereof, as a powder or granules or as a solution:or a
suspension in an
aqueous liquid, a non-aqueous liquid., an oil-in-water liquid emuisiontor.a
water-in-oil liquid
emulsion. Such compositions may be prepared by any of the methods of pharmacy
hut all
methods include the step of bringing together each of the opioids with a
pharmaceutically
acceptable carrier. In general, the compositions may be prepared by unifortnly
and intimately
adMiXing the morphine and oxyc,odone, or pharmaceutically acceptable Salts
thereof, with
liquid carriers or finely divided solid carriers or both, and then, if
necessary, shaping the
product into the desired presentation. As used herein the language
"pharmaceutically
acceptable carrier" is: intended to include any and all solvents, dispersion
mediktoatings,
antibaeterial and antifungal agents, iSotonic and absorption delaying agents,
and the like,
compatible with pharmaceutical administration. The use of such media and
Agents together
with pharrnacentiCallyactive substances. is well knoWn in the art. These
carriers include, by
Way of example and not limitation, sugars, starches, cellulose and its
derivatives, malt,.
gelatin, talc, calcium sulfate, .Vegetable oilS,. synthetic oils, polyols,
alginic acid, phosphate
buffered solutions,. emuisifierS, isotonic saline, and pyrogen-free water ;
Supplementary
active, compounds can also be incorporated into the compositions.
Oral compositions generally may include an inert diluent Of an edible Carrier.
Suitable oral compositions may be, e.g., enclosed in gelatin capsules or
compressed into
tablets, troches, or capsules.. For the purpose of oral therapeutic
administration, the active
compound may be incorporated with exelpients and used in the form of tablets,
troches, or
capsules. Pharmaceutically compatible binding agents, and/or adjuvant
materials may be:
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included as part of the composition. The tablets, pills, capsules, troches and
the like may
contain any of the following ingredients, or compounds of a similar nature: a
binder such as
micmcrystalline cellulose, gum tTagacanth or gelatin; an excipient such as
starch or lactose, a
disintegrating agent such as alginic acid, Primogel, or corn starch; a
lubricant such as
magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a
sweetening
agent such as sucrose or saccharin; or a flavoring agent such as peppermint,
methyl salicylate,
or orange flavoring.
It is especially advantageous to formulate oral compositions in dosage unit
form for
ease of administration and uniformity of dosage. The term "dosage unit form"
as used herein
refers to physically discrete units suited as unitary dosages for the patient
to be treated; each
unit containing a predetermined quantity of active compound calculated to
produce the
desired therapeutic effect in association with the required pharmaceutical
carrier. The
specification for the dosage unit forms of the invention are dictated by and
directly dependent
on the unique characteristics of the active compound and the particular
therapeutic effect to
be achieved, and the limitations inherent in the art of compounding such an
active compound
for the treatment of individuals.
The pharmaceutical compositions for oral administration may also be
administered in
controlled release dosage forms. For example, controlled release dosage forms
as described
hereinafter may be administered every 12- or 24-hours comprising,
respectively, about 3 or 6
times the amount of the immediate-release dosage form. In this regard, it is
well known that
the change from immediate-release dosages to controlled-release dosages of
morphine and
oxycodone, or pharmaceutically acceptable salts thereof, may be a simple
milligram to
milligram conversion that results in the same total "around-the-clock" dose of
the morphine
and oxycodone, or pharmaceutically acceptable salts thereof. See Chemy and
Portenoy,
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"Practical Issues in the Management of Cancer Pain," in Textbook of cancer
Pain, Third
Edition, Eds. Wall and Meizack, Churchill Livingstone, 1994, 1453.
Controlled-release of the morphine and oxycodone, or pharmaceutically
acceptable
salts thereof, may be affected by incorporating the morphine and oxycodone, or
pharmaceutically acceptable salts thereof, into, by way of example and not
limitation,
hydrophobic polymers, including acrylic resins, waxes, higher aliphatic
alcohols, polylactic
and polyglycolic acids and certain cellulose derivatives, such as
hydroxypropylmethyl
cellulose. In addition, the controlled release may be affected by using other
polymer
matrices, liposomes and/or microspheres. The controlled release formulation of
morphine
and oxycodone, or pharmaceutically acceptable salts thereof, may be released
at a slower rate
and over a longer period of time. For example, in some embodiments, the
controlled release
formulation of morphine and oxycodone, or pharmaceutically acceptable salts
thereof, may
release effective amounts of a mixture of morphine and oxycodone, or
pharmaceutically
acceptable salts thereof, over 12 hours. In other embodiments, the controlled
release
thrmulation may release effective amounts of morphine and oxycodone, or
pharmaceutically
acceptable salts thereof, over 4 hours or over 8 hours. In still other
embodiments, the
controlled release formulation may release effective amounts of morphine and
oxycodone, or
pharmaceutically acceptable salts thereof, Over IS. 18, 24 or 30 hours.
In some embodiments of the invention, the dose of the morphine component, or a
pharmaceutically acceptable salt thereof, in the pharmaceutical compositions
in accordance
with the present invention, or methods of the present invention, for opioid-
neve human
adults through oral administration and in immediate release form may be about
3 mg or more;
about 6 mg or more; about 12 mg or more; about 18 mg or more; or about 24 mg
or more,
every four hours. For non-opioid-nalve human adults through oral
administration in
immediate release form, the dose of the morphine component may be higher.
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In some embodiments of the invention, the analgesid dose of the oxycodone
component, or a pharmaceutically acceptable salt thereof in the pharmaceutical
compositions
in accordance with the present invention, or methods of the present invention,
for opioid
neve human adults through oral administration and in immediate release form
may he 2 nig
or more; 4 mg or more; 8 nig or more; 12 mg or more; or 16 mg or more, eery
font hots:,
For non-opioid-naIve human adults through oral administration in immediate
release form,
the dose of the oxycodone component may be higher.,
The concentration of morphine and oxycodone in the blOod stream will depend on
the
amount of compound administered in the composition as well as the route of
administration
and the specific formulation used. For ekample, it IS Well known in the art
that administratiOn
of morphine and oxycodone by IV injection 'typically results in a significant
concentratiOn of:
each compound in the blood stream almost immediately after administration
(without delay),
whereas formulations adapted for oral administration of morphine and oxycodone
will
typically: achieve effective concentrations in the bloodstream later than IV
administration and
at different concentrations depending on oral availability :Oldie:Compounds.
Further, the
routes of administration of the compounds May further result in different
inactivation and
excretion rates of morphine and oxycodone when administered in a corabination.
Therefore,
it will be apparent to one of skill in the art that the absolute and relative
amounts of morphine
and axyeodone, or pharmaceutically acceptable salts thereof administered to
patients: Via oral
administration to achieve efficacy with a lower incidence of adverse side
effects may differ
from the amounts of drugs required for 1V administration or other routes Of
administration.
Table 11 provides pharmacokinetic data for healthy subjects that were orally
co-administered
a single dose of inorphine and oxycOdone in dosage strengths of about 3 mg / 2
mg and about
12 mg.! 8 mg. Values for the observed maximum plasma concentration (Cõ,),
total area
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under the plasma concentration-time curve (AUC0.,) and the time to maximum
plasma
concentration (Tintuawere determined.
Table 1.1. Pharmacokinetic Data for Oral CO-Administration of Morphine and
.Oxycodone in
a Ratio olabout 3:2 by. Weight.*
Analyte Dose C.max .AUC TraaN
(mg) (rtglmL) (ng=hitn:L/mg) (h)
'Morphine .3 (n=18) 3.9 4.24 . 0.5.0
(p.-18) 16.1 4.55 0.54
Qxycodone 2 (n-18) 4.9 .962 1.0
8 (n-18) L 17,8 9.62 1.0
* Pharmacokinetic analyses were performed using WinNonlie
Professional, Version
5.2. Standard noneompartmental analyses were conductedtor computation of
metrics of exposure (Cm,õ, AUC).
** Dose. Adjusted.
Plasma levels of morphine and oxyeodone each appeared to increase linearly in
a
dose-proportionate manner after single-dose administration of
themorphine:oxycodone
combination (within .the 3 M2 / 2 mg to 12 mg / 8 mg dose range). All dose-
normalized, log-
transformed parameters (cin._ and ALIC0,..) were within the 80-125 %
bioequivalenee criteria
limits; .a demonstration of the dose proportionality b.etweenthe 3 mg / 2 mg
and 12 mg / KIng
dose strengths. These data provide conclusive evidence of dose proportionality
between the
two dosage strengths.
Method of Treating Patients
The present invention also relates to a.method for the treatment of pain in a
human
patient in need of analgesia by oral co-administration of an immediate release
morphine-
oxyeodone combination in a weightratio of about 3:2:. In some embodiments such
method
includes the use of a dosing algorithm to determine the first oral dose of the
immediate
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release morphine-oxycodone combination following administration of IV opioid
(e.g.,
morphine or a pharmaceutically acceptable salt thereof) to the patient. The
dosing algorithm
used in these methods may be a dosing algorithm described above.
For example, if the net average hourly intravenous dosing may be known or
calculated, a dosing algorithm may be applied such that if the net average
hourly intravenous
dosing is between about 0 mg and about 9 mg, the corresponding first dose of
morphine-
oxycodone combination may be about 12 mg / 8 mg; if the net average hourly
intravenous
dosing is greater than about 9 mg and less than or equal to about 14 mg, the
corresponding
first dose of morphine-oxycodone combination may be about 18 mg / 12 mg. lithe
net
average hourly intravenous morphine administered is greater than about 14 mg,
the
corresponding first dose of morphine-oxycodone combination may be about 24 mg
of
morphine and about 16 mg of oxycodone.
The present invention will be understood more readily by reference to the
following
examples, which are provided by way of illustration and are not intended to be
limiting of the
invention.
EXAMPLES
Example I
A patient undergoes surgery that is completed at 12:30 PM, whereby IV PCA
morphine is started at 1:00 PM. At 7:00 AM the next morning IV PCA
administration of
morphine is stopped and the patient is converted to oral MOXDUOI', which is a
combination
of morphine sulfate and oxycodone hydrochloride in the ratio of approximately
3:2 by weight
in a form for oral administration for immediate release. Therefore, from the
beginning of the
IV PCA morphine administration to the end is a total time of 18 hours of IV
PCA morphine
dosing available for the calculation of the algorithm. During the first tbur
hours of that total
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time of IV PC.A morphine dosing, the patient receives 9 mg of morphine. The
patient
receives a total amount of 129 mg of morphine during the total time of IV PCA
morphine
administration. Therefore, the net amount of morphine administered by IV PCA
is calculated
by subtracting 9 mg (the amount of IV PCA morphine administered during the
first four
hours of IV PCA) from the total amount of 129 mg, thereby giving a net amount
of morphine
administered by IV PCA of 120 mg (129 mg - 9 mg). The net time of IV PCA
morphine
administration is calculated as the total time of 18 hours minus the first
four hours, for a net
time of IV PCA morphine administration of 14 hours (18 hours - 4 hours). The
net average
hourly IV PCA morphine administration is calculated by dividing the net amount
of IV PCA
morphine administration (120 mg) by the net time of IV PCA morphine
administration (14
hours), which in this case is 120 mg divided by 14 hours, which gives an net
average hourly
IV morphine dosing of about 9 mg (120 mW.14 hours). With reference to Table 7
above for a
net average hourly IV morphine dosing of about 9 mg per hour, the patient is
converted to a
corresponding first oral dose of MOX.DLIU* of 12 mg of morphine sulfate and 8
mg of
oxycodone hydrochloride in an immediate release dosage form.
Example 2
A patient undergoes surgery that is completed at 2:00 PM, whereby IV PCA
morphine
is started at 2:30 PM. At 7:30 AM the next morning IV PCA administration of
morphine is
stopped and the patient is converted to oral MOXDI..01', which is a
combination of morphine
sulfate and oxycodone hydrochloride in the ratio of approximately 3:2 by
weight in a form
for immediate release. Therefore, from the beginning of the IV PCA morphine
administration to the end is a total time of 17 hours of IV PCA morphine
dosing available for
the calculation of the algorithm. During the first four hours of that total
time of IV .PCA
morphine dosing, the patient receives 9 mg of morphine IV PCA and a nurse
gives 2 mg IV
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morphine through the PCA pump for a total of 1 1 mg of IV morphine during the
first four
hours. The patient receives a total amount of 60 mg of morphine during the
total time of IV
PCA morphine administration. Therefore, the net amount of morphine
administered by IV
PCA is calculated by subtracting from the total amount of 60 mg the amount of
IV -PCA
morphine administered during the fist four hours of IV PCA, which is 11 mg,
thereby giving
a net amount of morphine administered IV PCA o149 mg (60 mg - 11 mg). The net
time of
IV PCA morphine administration is calculated as the total time of 17 hours
minus the first
four hours, for a net time of IV PCA morphine administration of 13 hours (17
hours - 4
hours). The net average hourly IV PCA morphine administration is calculated by
dividing
the net amount of IV PCA morphine administration (49 mg) by the net time of IV
PCA
morphine administration (11 hours), which in this case gives an net average
hourly
intravenous morphine dosing of about 4.5 mg (49 mg 111 hours). With reference
to Table 9
above for a net average hourly intravenous morphine dosing of about 4.5 mg,
the patient is
therefore converted to a first dose of oral MOXDUO at a dose of 12 mg of
morphine sulfate
and 8 mg of oxycodone hydrochloride in immediate release form.
Example 3
An open-label, multicenter, multiple-dose pilot study of flexible doses of
oral
MOXDUO in a 3:2 ratio of morphine sulfate to oxycodone hydrochloride,
compared to
PERCOCET (1-2 tablets of 5 mg/325 mg oxycodone/acetaminophen) for the
management
of acute, moderate to severe postoperative pain following unilateral total
knee arthroplasty or
total hip arthroplasty was conducted. One objective of the study was to
evaluate the
adequacy of an algorithm for conversion of IV PCA morphine to oral morphine-
equivalent
doses of MOXDUO administered every 4 to 6 hours over a 48-hour treatment
period. Any
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adverevents, including Treatment-Emergent Adverse Events (TEAE).or Serious
Adverse
Events (SAE), including signs of abuse potential were also assessed.
Testing Protocol
Immediate post-operative analgesia consisted of PCA IV morphine..
Subjects'were
connected to a PCA pump within 120 minutes after clOstut Of surgery. Morphine
doses (0.5-
2.0 mg/dose) were administered by PCA pump with a 5-minute lockout periodand a
maximum dose of 10 mg morphine per hour. If the analgesia was insufficient,
the one-hour
limit may be increaSed to ¨15 mg morphine per hour at the discretion of the
doetbr. During
the course of IV PCA morphine, including prior to the initial dose of self-
administered IV
PCA morphine, the nursing staff may administer Via the PCA puniga :Single
bolus dose of up
to 5 mg of morphine, if necessary.
Eligibility for enrollment of subjects in the study required the
administration of an
average oral morphine equivalent dose of < 120 mg IV morpinne.by PCA pump
(including
morphine administered as a bolus by nursing staff and all self-administered
morphine) over a
peried of at least 8 hours (interval between first dose and final dose via
pump). Following
surgery, subjects were. disconnected from the PCA. pump between 5:00 AM ¨ 7:00
AM on the
morning following surgery to obtain an IV morphine baseline to be used with.
an algorithm to
determine the starting dose for administration of oral MOXIDUQ,..
20. Calculation of total dose of morphine (mg) used during the total period
of IV
morphine PCA includes the sum of any morphine administered as a bolus by
nursing staff
and all self-administered morphine, 1140XDUO4b Study medication was
administered q. 4-6 h
(not to exceed 6 doses in 24 hours) and the last dose was administered 42
hours eter the first
dose,.
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The primary efficacy endpoint was the mean Sum of Pain Intensity Difference
scores
during the 48-hour treatment period (SPID48). A subject who had at least 30%
decrease in
pain intensity compared to baseline or had a good to excellent outcome on a
global
assessment of study medication scale at 24 or 48 hours was considered a
responder. All
adverse events were described by onset, duration, resolution, relationship,
and intensity (mild,
moderate, severe). The algorithm tbr conversion of IV morphine PCA to oral
MOXDU0' is
shown above in Table 3. The doses OM inistered to the subjects throaghout the
study are
provided below in Table 12.
Table 12. lvIOXIDUW) Doses Administered to Subjects Following w PCA Morphine,
Patient Calculate 4-h First First Subsequent I Other Subsequent Final
Dose
Ave Oral .IVIE1 Dose Dose Doses (mg:nag)
(mg/hr) ' (tugang) (mg:rng) (mg:nig)
.... I ------- 21 12:8 18:12 18:12 I 18:12
18:1
7-
1
2416 ni
2 : 18;12
18:12
3 o
., 12:8 ______ 64 6:4 6:4
4 31 18:12 No change 24:16 _________________ 24:16
5 _________ 13 12:8 L No change No change
12:8
6 t----- 4 12:8 No change No e chano
,7., 12:8
'7 26 12:8 No change 18:12 18:12
8: 11 12:8 ¨ 18:12 12:8 12:8
9 _) ,,
------------------------- 12:8 __ No change No change 12:8
10 29 .... 12:8 ... No change No change 12:8
2416
11 24 12:8 18:12 NA2
18:12
12 27 128 18:17 24:16 24:16
H
24:16
18:12
13 13 12;8 18;12 12:8 24:16
, 18;12
_____________________________________________________ 24:16
---- 14 7 12:8 No change No change 12:8
L.
'ME = morphine equivalents
.2Subject inadvertently administered PERCOCE14 instead of:MIOXDUO at 5th
dose,
(Notably, the algorithm of 'I'able 6 for conversion of IV morphine PCA to
N1OXDUO could
have also beehtised, Wherein calculation of the one-hour average oral morphine
equivalent
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dose for each patient would equal the four-hour average oral morphine
equivalent dose,
divided by four; the First Dose, First Subsequent Dose, Other Subsequent
Doses, and Final
Dose resulting from using the Table 6 algorithm would be the same as resulting
from using
the Table 3 algorithm, which is shown in Table 12.)
The second dose (first subsequent dose) of MOXDUO received by the subjects (4-
6
hours after the first dose) was more indicative of the amount of analgesia
required as the
subjects became mobile and typically experienced more pain. Of the 14
subjects, 8 subjects
did not require an upward dose titration for the second dose. in fact, 1 of
the 14 subjects
down-titrated at the first subsequent dose and completed the study at the
lower dose level.
During the remainder of the 48-hour study period, 6 subjects required an
increased dose and
completed the study at the higher dose level compared to the first
administered dose.
Efficacy Results
Both MOXDUO and PERCOCET treatment groups had a similar proportion of
responders (77 % and 79 %, respectively). The efficacy endpoint of the SPI048
did not show
a significant difference in values between MOXDUO (mean value of 148) and
PERCOCET (mean value of 140); however, the power to detect statistical
significant
differences between treatments was low with these sample sizes, Nonetheless,
scores on
individual domains of the Brief Pain Inventory-Short Form (BPI-SF) showed a
significantly
greater improvement of BPI-SF scores for MOXDUO for pain interfering with
general
activity than the PERCOCET treatment group at 48 hours/early termination.
Safety Results
The dosing algorithm for converting IV PCA morphine to the first dose of oral
MOXDUO was both conservative and safe. None of the subjects administered
MOXDUO
discontinued due to an adverse event, although one subject in the PERCOCEI4'
treatment
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group discontinued because of a possibly related TEAE of stomach irritation.
The overall
incidence of nausea, pruritus, constipation, and dizziness was higher during
the IV PCA
morphine use than during the same time period after first dose of study
medication. Eleven
(25 %) subjects had moderate-or severe nausea while on IV PCA morphine. No
moderate
-
severe vomiting, nausea, or dizziness was reported by subjects in the MOXDUO
treatment
(g)
group, although in the PERCOCET- treatment group, moderate to severe nausea
and
vomiting were experienced by 4 (27 %) and 3 (20 %). of subjects, respectively.
Ondansetron
was administered during the study treatment to 6 subjects in both the
IVIOXDU0and
PERCOCEt-4. treatment groups. "Woozy" was the only potential abuse liability
symptom
that was reported and occurred in one subject in the PERCOCET treatment
group.
Conclusion
The analgesic efficacy of MOXDUO16 and PERCOCET4) :treatment groups were
similar in terms of proportion of responders and median SPID4s. In addition,
values for the
Sum of Pain ReSponSe and Pain Intensity Difference (SPRID), mean distance
walked on Day
2 of rehabilitation, and time to remedication were similar for both treatment
groups (data not
shown). The MOXIDLIO''' dosing treatment group had a significantly lower BPI-
SF score for
pain interfering with general activity than the PERCOCET treatment group at
48 hours/early
termination. For example, patients being administered MOXIX.10 had a mean%
improvement in BPI from baseline to end of treatment for general activity,
walking ability,
and ability to sleep of 54 %, 35 %, and 31 %, respectively. Patients that were
administered
PERCOCET bad BPI scores of 19 %, 7%, and 15 %, respectiVely, for the %IMO
categOrieS.
NO related SAEs, severe TEAES, or AEs leading, to discontinuation occurred in
the
1\40XDIVI):treatment group. In the PERCOCET treatment group, 'I subject had a
severe
TEAE of dry mouth, and I subject discontinued due to an adverse ow pfstomaeh
irritation,.
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The incidence of moderate to severe nausea and vomiting was higher in the
PERCOCEe
treatment group compared with the equi-analgesic MOXDUO dosing treatment
group,
which had no such events.
The dosing algorithms of the instant invention allows for the determination of
a
simple and convenient starting dose of MOXDUO for patients being administered
IV
opioids, such as morphine. The titration algorithms also allow for the ease of
upward and
downward titration of MOXDUOID, if required. The algorithms used in the
present invention
provide surprising and unexpected results since patients being administered
MOXDUCr'
reached a level of analgesia within the first administered dose, or the first
subsequent dose of
MOXDU0e. 'these results are in contrast to patients that may require up to 48-
hours of dose
titrations to obtain analgesia. See S. Mercadante, Eur, .1, Pain 11(2007) 823-
30 (In
conclusion dose titration with oral opioids, particularly with short-onset
drugs such as
morphine, may provide adequate pain relief in about 48 hr in most patients").
* * * *
It should be understood, of course, that the foregoing relates only to certain
disclosed
embodiments of the present invention and that numerous modifications or
alterations may be
made therein without departing from the spirit and scope of the invention as
set forth in the
appended claims.
44
