U.S. patent application number 12/106695 was filed with the patent office on 2009-01-08 for titration of tapentadol.
This patent application is currently assigned to Gruenenthal GmbH. Invention is credited to Claudia LANGE, Ferdinand Rombout.
Application Number | 20090012180 12/106695 |
Document ID | / |
Family ID | 38123877 |
Filed Date | 2009-01-08 |
United States Patent
Application |
20090012180 |
Kind Code |
A1 |
LANGE; Claudia ; et
al. |
January 8, 2009 |
Titration of Tapentadol
Abstract
The use of tapentadol for the manufacture of a medicament
comprising at least one administration unit A containing dose a of
tapentadol and at least one administration unit B containing dose b
of tapentadol, where dose a<dose b, for the treatment of
pain.
Inventors: |
LANGE; Claudia;
(Duesseldorf, DE) ; Rombout; Ferdinand;
(NL-Klimmen, NL) |
Correspondence
Address: |
CROWELL & MORING LLP;INTELLECTUAL PROPERTY GROUP
P.O. BOX 14300
WASHINGTON
DC
20044-4300
US
|
Assignee: |
Gruenenthal GmbH
Aachen
DE
|
Family ID: |
38123877 |
Appl. No.: |
12/106695 |
Filed: |
April 21, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60907939 |
Apr 23, 2007 |
|
|
|
Current U.S.
Class: |
514/649 |
Current CPC
Class: |
A61K 31/137 20130101;
A61P 25/04 20180101; A61K 9/0053 20130101 |
Class at
Publication: |
514/649 |
International
Class: |
A61K 31/137 20060101
A61K031/137; A61P 25/00 20060101 A61P025/00 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 23, 2007 |
EP |
07 008 218.5 |
Claims
1. Use of tapentadol for the manufacture of a medicament comprising
at least one administration unit A containing dose a of tapentadol
and at least one administration unit B containing dose b of
tapentadol, where dose a<dose b, for the treatment of pain.
2. The use according to claim 1, where dose a is within the range
of from 10 to 90 wt.-% of dose b.
3. The use according to claim 1, where the medicament further
comprises at least one administration unit C containing dose c of
tapentadol, where dose b<dose c.
4. The use according to claim 3, where dose a is within the range
of from 10 to 65 wt.-% of dose c and where dose b is within the
range of from 35 to 90 wt.-% of dose c.
5. The use according to claim 1, where the medicament further
comprises at least one administration unit D containing dose d of
tapentadol, where dose c<dose d.
6. The use according to claim 5, where dose a is within the range
of from 10 to 55 wt.-% of dose d, where dose b is within the range
of from 35 to 75 wt.-% of dose d, and where dose c is within the
range of from 60 to 95 wt.-% of dose d.
7. The use according to claim 5, where the medicament further
comprises at least one administration unit E containing dose e of
tapentadol, where dose d<dose e.
8. The use according to claim 7, where dose a is within the range
of from 10 to 30 wt.-% of dose e, where dose b is within the range
of from 30 to 50 wt.-% of dose e, where dose c is within the range
of from 50 to 70 wt.-% of dose e, and where dose d is within the
range of from 70 to 90 wt.-% of dose e.
9. The use according to claim 1, where dose a, dose b, optional
dose c, optional dose d and optional dose e are each independently
within the range of from 10 to 275 mg.
10. The use according to claim 1, where the medicament is in the
form of a packaging containing one or more administration units A,
one or more administration units B, optionally one or more
administration units C, optionally one or more administration units
D and optionally one or more administration units E.
11. The use according to claim 1, where administration unit A
comprises n.sub.A dosage forms, administration unit B comprises
n.sub.B dosage forms, optional administration unit C comprises
n.sub.C dosage forms, optional administration unit D comprises
n.sub.D dosage forms and optional administration unit E comprises
n.sub.E dosage forms, where n.sub.A=n.sub.B or n.sub.A<n.sub.B
or n.sub.A>n.sub.B.
12. The use according to claim 11, wherein
n.sub.A.ltoreq.n.sub.B.ltoreq.optional n.sub.C.ltoreq.optional
n.sub.D.ltoreq.optional n.sub.E.
13. The use according to claim 11, wherein all dosage forms are
identical and n.sub.A.ltoreq.n.sub.B<optional
n.sub.C<optional n.sub.D<optional n.sub.E.
14. The use according to claim 11, wherein n.sub.A, n.sub.B,
optional n.sub.C, optional n.sub.D and optional n.sub.E are
independently of one another 1, 2, 3, 4 or 5.
15. The use according to claim 1, wherein administration unit A,
administration unit B, optional administration unit C, optional
administration unit D and optional administration unit E are
adapted to be administered sequentially.
16. The use according to claim 15, where administration unit A,
administration unit B, optional administration unit C, optional
administration unit D and optional administration unit E are
adapted to be administered in alphabetical order.
17. The use according to claim 1, wherein administration unit A,
administration unit B, optional administration unit C, optional
administration unit D and optional administration unit E are each
adapted to be administered once daily (sid), twice daily (bid) or
thrice daily (tid).
18. The use according to claim 1, wherein dose a is below the
pharmaceutically effective pain treating dose of tapentadol.
19. The use according to claim 1, wherein administration unit A,
administration unit B, optional administration unit C, optional
administration unit D and optional administration unit E each are
solid.
20. The use according to claim 1, wherein the medicament comprises
(i) a plurality of administration units A containing dose a of
tapentadol that are adapted to be administered during a first
administration interval of at least 2 days, (ii) a plurality of
administration units B containing dose b of tapentadol that are
adapted to be administered during a second administration interval
of at least 2 days following the first administration interval,
(iii) optionally, a plurality of administration units C containing
dose c of tapentadol that are adapted to be administered during a
third administration interval of at least 2 days following the
second administration interval, (iv) optionally, a plurality of
administration units D containing dose d of tapentadol that are
adapted to be administered during a fourth administration interval
of at least 2 days following the third administration interval, and
(v) optionally, a plurality of administration units E containing
dose e of tapentadol that are adapted to be administered during a
fifth administration interval of at least 2 days following the
fourth administration interval.
21. The use according to claim 20, where the medicament comprises
(i) a plurality of administration units A containing dose a of
tapentadol that are adapted to be orally administered twice daily
(bid) during a first administration interval of at least a
consecutive days, (ii) a plurality of administration units B
containing dose b of tapentadol that are adapted to be orally
administered twice daily (bid) during a second administration
interval of at least .beta. consecutive days following the first
administration interval, (iii) optionally, a plurality of
administration units C containing dose c of tapentadol that are
adapted to be orally administered twice daily (bid) during a third
administration interval of at least .OMEGA. consecutive days
following the second administration interval, (iv) optionally, a
plurality of administration units D containing dose d of tapentadol
that are adapted to be orally administered twice daily (bid) during
a fourth administration interval of at least .delta. consecutive
days following the third administration interval, and (v)
optionally, a plurality of administration units E containing dose e
of tapentadol that are adapted to be orally administered twice
daily (bid) during a fifth administration interval of at least a
consecutive days following the fourth administration interval;
where a, b, c, d, e and .alpha., .beta., .OMEGA., .delta.,
.epsilon. satisfy requirement P, Q, R, or S: TABLE-US-00004
[mg]/[days] P Q R S (a/.alpha.) (25 .+-. 5%/.gtoreq.2) (50 .+-.
5%/.gtoreq.2) (100 .+-. (100 .+-. 5%/.gtoreq.2) 5%/.gtoreq.2)
(b/.beta.) (50 .+-. 5%/.gtoreq.2) (100 .+-. 5%/.gtoreq.2) (150 .+-.
(150 .+-. 5%/.gtoreq.2) 5%/.gtoreq.2) (c/.chi.) (100 .+-.
5%/.gtoreq.2) (150 .+-. 5%/.gtoreq.0) (250 .+-. (200 .+-.
5%/.gtoreq.0) 5%/.gtoreq.0) (d/.delta.) (150 .+-. 5%/.gtoreq.0)
(200 .+-. 5%/.gtoreq.0) (250 .+-. 5%/.gtoreq.0) (e/.epsilon.) (200
.+-. 5%/.gtoreq.0) (250 .+-. 5%/.gtoreq.0)
22. The use according to claim 1, wherein the pain is neuropathic
pain, malignant pain or chronic pain.
23. A kit comprising at least one administration unit A, at least
one administration unit B, optionally at least one administration
unit C, optionally at least one administration unit D and
optionally at least one administration unit E, as defined in claim
1.
24. A pharmaceutical oral dosage form containing tapentadol, which
comprises a notch, that divides the dosage form into at least two
portions and mechanically weakens the dosage form so that it may be
manually broken at the notch along a predetermined site of
fracture, which contains 40 to 260 mg of tapentadol so that, after
being broken at the notch along the predetermined site of fracture,
each portion contains about 20 to about 130 mg of tapentadol.
25. The dosage form according to claim 24, wherein the notch is
linear or assumes the shape of a cross.
26. A method of treating pain in a subject in need thereof, said
method comprising administering said subject dose a of tapentadol
during a first administration interval and dose b of tapentadol
during a second administration interval following the first
administration interval, where dose a<dose b.
27. The method according to claim 26, where dose a and dose b of
tapentadol are administered orally.
28. The method according to claim 26, wherein dose a and dose b of
tapentadol are administered once daily (sid), twice daily (bid) or
thrice daily (tid).
29. The method according to claim 26, wherein dose a is within the
range of from 10 to 90 wt.-% of dose b.
30. The method according to claim 26, further comprising orally
administering dose c of tapentadol once daily (sid), twice daily
(bid) or thrice daily (tid) during a third administration interval
following the second administration interval, where dose b<dose
C.
31. The method according to claim 30, where dose a is within the
range of from 10 to 65 wt.-% of dose c and where dose b is within
the range of from 35 to 90 wt.-% of dose c.
32. The method according to claim 30, further comprising orally
administering dose d of tapentadol once daily (sid), twice daily
(bid) or thrice daily (tid) during a fourth administration interval
following the third administration interval, where dose c<dose
d.
33. The method according to claim 32, where dose a is within the
range of from 10 to 55 wt.-% of dose d, where dose b is within the
range of from 35 to 75 wt.-% of dose d, and where dose c is within
the range of from 60 to 95 wt.-% of dose d.
34. The method according to claim 32, further comprising orally
administering dose e of tapentadol once daily (sid), twice daily
(bid) or thrice daily (tid) during a fifth administration interval
following the fourth administration interval, where dose d<dose
e.
35. The method according to claim 34, where dose a is within the
range of from 10 to 30 wt.-% of dose e, where dose b is within the
range of from 30 to 50 wt.-% of dose e, where dose c is within the
range of from 50 to 70 wt.-% of dose e, and where dose d is within
the range of from 70 to 90 wt.-% of dose e.
36. The method according to claim 26, wherein dose a, dose b,
optional dose c, optional dose d and optional dose e are
independently selected so that the daily dose of tapentadol is
always within the range of from 20 to 550 mg.
37. The method according to claim 26, comprising orally
administering (i) dose a of tapentadol twice daily (bid) during a
first administration interval of at least a consecutive days, (ii)
dose b of tapentadol twice daily (bid) during a second
administration interval of at least .beta. consecutive days
following the first administration interval, (iii) optionally, dose
c of tapentadol twice daily (bid) during a third administration
interval of at least .OMEGA. consecutive days following the second
administration interval, (iv) optionally, dose d of tapentadol
twice daily (bid) during a fourth administration interval of at
least .delta. consecutive days following the third administration
interval, and (v) optionally, dose e of tapentadol twice daily
(bid) during a fifth administration interval of at least s
consecutive days following the fourth administration interval;
where a, b, c, d, e and .alpha., .beta., .OMEGA., .delta.,
.epsilon. satisfy requirement P, Q, R, or S: TABLE-US-00005
[mg]/[days] P Q R S (a/.alpha.) (25 .+-. 5%/.gtoreq.2) (50 .+-.
5%/.gtoreq.2) (100 .+-. (100 .+-. 5%/.gtoreq.2) 5%/.gtoreq.2)
(b/.beta.) (50 .+-. 5%/.gtoreq.2) (100 .+-. 5%/.gtoreq.2) (150 .+-.
(150 .+-. 5%/.gtoreq.2) 5%/.gtoreq.2) (c/.chi.) (100 .+-.
5%/.gtoreq.2) (150 .+-. 5%/.gtoreq.0) (250 .+-. (200 .+-.
5%/.gtoreq.0) 5%/.gtoreq.0) (d/.delta.) (150 .+-. 5%/.gtoreq.0)
(200 .+-. 5%/.gtoreq.0) (250 .+-. 5%/.gtoreq.0) (e/.epsilon.) (200
.+-. 5%/.gtoreq.0) (250 .+-. 5%/.gtoreq.0)
38. The method according to claim 26, wherein tapentadol is
administered in a regimen including at least 30 consecutive
days.
39. The method according to claim 38, wherein at the end of the
regimen the administration of tapentadol is terminated without drug
tapering.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from U.S. provisional
patent application No. 60/907,939, filed Apr. 23, 2007.
FIELD OF THE INVENTION
[0002] The present invention relates to a dosing regimen for the
administration of the analgesic tapentadol, preferably as a
prolonged release dosage form. The dosing regimen achieves the
desired analgesic effect while reducing or delaying the onset of
side effects.
BACKGROUND OF THE INVENTION
[0003] Tapentadol (CG5503), the chemical name for which is
(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, is
a synthetic, centrally-acting analgesic that is effective for the
treatment of moderate to moderately-severe acute or chronic pain.
The compound can be employed as the free base or its
pharmaceutically acceptable salts and solvates. Preparation of the
free base is known from EP-A 693 475.
[0004] Patients experiencing acute or chronic pain require an
analgesic therapeutic regimen that is both effective and well
tolerated. The two traditional categories of analgesics, i.e.
opioids and nonsteroidal anti-inflammatory drugs (NSAIDs), are both
effective but are associated with potentially serious side effects.
Concerns regarding tolerance and dependence minimize the use of
narcotics such as morphine and codeine for the treatment of acute
or chronic pain. Patients on chronic NSAID therapy risk severe
gastrointestinal symptoms, including ulceration and bleeding which
have been estimated to result in up to 20,000 deaths each year.
[0005] An alternative to this dilemma is tapentadol, a non-NSAID
analgesic which is indicated for the management of moderate to
severe pain.
[0006] Tapentadol is an investigational, centrally acting analgesic
with a dual mode of action consisting of p-opioid receptor (MOR)
agonism and norepinephrine (NE) reuptake inhibition. The efficacy,
safety, and pharmacokinetic profile of tapentadol indicate that the
drug may be useful in treating acute as well as chronic pain.
[0007] The activity of tapentadol is independent of metabolic
activation and resides in a single enantiomer which readily crosses
the blood-brain barrier; hence, tapentadol displays a rapid onset
of action after administration. The biotransformation of tapentadol
by metabolic enzymes results in deactivation, i.e., tapentadol has
no active metabolites, and the main metabolic pathway for
elimination is phase II glucuronidation. Phase I biotransformations
such as hydroxylation and N-demethylation play only a minor role in
the metabolic fate of tapentadol. Owing to the minor involvement of
phase I metabolic pathways, tapentadol has a low potential for
drug-drug interactions and interindividual variability (cf.
Tzschentke T. M. et al. Tapentadol Hydrochloride. Drugs of the
Future 2006, 31, 1053-1061; Evans W. E., Relling, M. V.
Pharmacogenomics: Translating Functional Genomics into Rational
Therapies. Science 1999, 286, 487-491).
[0008] Tapentadol is well tolerated, however, nuisance adverse
events such as somnolence can occur, e.g., during the initiation of
treatment, which may lead to early discontinuation of the
treatment. The most frequently reported adverse events observed in
clinical trials of tapentadol are associated with the central
nervous system (e.g. somnolence, dizziness/vertigo, headache) and
the gastrointestinal tract (e.g. constipation, nausea, vomiting)
(cf. Weber H. et al. Journal of Pain 2006, 7, S3; Kleinert R. et
al. Journal of Pain 2006, 7, 44).
[0009] The occurrence of somnolence is of particular concern,
because drug-induced somnolence may have a negative effect on
activities of daily living and impair the physical functioning of
chronic pain patients. "Quality of Life" may suffer thereby.
[0010] Various concepts to decrease the occurrence of adverse side
effects are known in the prior art. For example, eating and
drinking habits, drug formulations, and/or the route of
administration can be changed. Further, a second drug can be
co-administered simultaneously with, before or after the drug of
interest in order to suppress its adverse side-effects. However,
these actions can impair patient compliance by, for example,
forcing the patient to change his habitual life style. Further,
changing the mode of administration, e.g. from oral to rectal, is
conceived by many patients as uncomfortable and unhygienic. The
resulting decreased patient compliance can result in termination of
a required drug therapy.
SUMMARY OF THE INVENTION
[0011] It is an object of the present invention to improve the
tolerability of tapentadol in the treatment of pain, preferably of
chronic pain, particularly to reduce the frequency of somnolence;
one of the most frequently reported adverse events, as well other
adverse events, without diminishing the efficacy of the compound
and the patient compliance.
[0012] These and other objects have been achieved by the invention
as described and claimed hereinafter.
[0013] The present invention relates to the use of tapentadol for
the manufacture of a medicament comprising [0014] at least one
administration unit A containing dose a of tapentadol and [0015] at
least one administration unit B containing dose b of
tapentadol,
[0016] where dose a<dose b,
for the treatment of pain.
[0017] Preferably, tapentadol is used for the manufacture of a
medicament, where dose a of tapentadol is administered during a
first administration interval and dose b of tapentadol is
administered during a second administration interval following said
first administration interval, where dose a<dose b, for the
treatment of pain.
[0018] It has been surprisingly found that the tolerability of
tapentadol may be improved by initiating the treatment at a
comparatively low dose of tapentadol and successively increasing
the dose according to a titration regimen.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIGS. 1, 2, 3 and 4 show preferred embodiments of the
medicament according to the invention in form of blister
packages.
[0020] FIGS. 5 and 6 show the effect of titration of tapentadol
prolonged release (PR) on the occurrence of somnolence observed in
clinical trials (examples E-1 and E-2 vs. comparative examples C-1
and C-2).
[0021] FIG. 7 schematically illustrates a preferred titration
regimen for tapentadol prolonged release (PR).
[0022] FIG. 8 shows the effect of titration of oxycodone controlled
release (CR) on the occurrence of somnolence observed in clinical
trials (example E-1 vs. comparative example C-1).
[0023] FIGS. 9 A/B show a mathematical analysis of the distribution
of serum concentrations of tapentadol (ng/ml) after administration
in comparative clinical trials (comparative examples C-1 and
C-2).
[0024] FIGS. 10 A/B show a mathematical analysis of the
distribution of serum concentrations of tapentadol (ng/ml) after
administration in the clinical trials according to the invention
(examples E-1 and E-2).
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0025] As used hereinafter, the word "tapentadol" is intended to
include
(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, its
pharmaceutically acceptable salts and solvates thereof. Suitable
pharmaceutically acceptable salts include salts of inorganic acids,
such as hydrochloric acid (tapentadol HCl), hydrobromic acid and
sulfuric acid, and salts of organic acids, such as methane sulfonic
acid, fumaric acid, maleic acid, acetic acid, oxalic acid, succinic
acid, malic acid, tartaric acid, mandelic acid, lactic acid, citric
acid, glutamic acid, acetylsalicylic acid, nicotinic acid,
aminobenoic acid, .alpha.-liponic acid, hippuric acid and
asparaginic acid. The preferred salt is the hydrochloride salt.
[0026] For the purpose of the specification, doses of tapentadol
relate to the free base. Thus, when a pharmaceutically acceptable
salt is used instead, its dose has to be adapted to the equivalent
dose of the free base. For example, a dose of "200 mg" means an
amount of 200 mg of the free base or any equivalent amount of a
pharmaceutically acceptable salt or solvate corresponding to 200 mg
of the free base (e.g. about 233 mg of the hydrochloride). If not
expressly stated otherwise, doses are "per administration", not
"per day".
Use of Tapentadol for the Manufacture of a Medicament for Treating
Pain
[0027] Tapentadol is indicated for the treatment of moderate to
severe acute and chronic pain. Clinical studies have shown
tapentadol prolonged release (PR) to be an effective treatment for
chronic joint pain (osteoarthritis of the hip or knee) and low back
pain. There is also indication that tapentadol prolonged release
(PR) is useful for the treatment of chronic cancer pain and chronic
painful diabetic peripheral neuropathy (DPN). Further, clinical
studies revealed that tapentadol immediate release (IR) is useful
in the treatment of acute dental pain, acute pain after
bunionectomy and acute pain after abdominal surgery. Further,
ongoing studies are concerned with acute pain after hip
replacement, acute pain after abdominal hysterectomy (visceral
pain) and acute pain in patients waiting for joint replacement.
[0028] Tapentadol is well tolerated, however, nuisance adverse
events can occur during initiation of treatment with tapentadol.
These side effects may lead to early discontinuation of tapentadol
therapy.
[0029] Titration of a therapeutic agent is sometimes used by
practicing clinicians to minimize adverse events associated with
centrally-acting agents such as antidepressants and
anticonvulsants. Although titration may minimize the adverse side
effects associated with a particular agent, it may also delay the
onset of the effect of the agent as well.
[0030] For example, the slow titration of the drug tramadol has
been reported to reduce the frequency of certain adverse effects
such as dizziness, nausea and vomiting (Ruoff G. E., Slowing the
Initial Titration Rate of Tramadol Improves Tolerability.
Pharmacotherapy 1999, 19, 88-93). However, this study also showed
that the frequency of somnolence was not significantly reduced by
the slow titration of tramadol. This specific pharmacological
behavior of tramadol is likely based on its unique properties,
particularly its racemic nature, its activating metabolic pathway
and number of active metabolites, the change of the relative
contribution of the individual metabolites to the overall efficacy
of the drug over time, its 5-HT reuptake inhibiting mechanism of
action, and the like. The results of Ruoff et al. support the
notion that it remains unpredictable whether adverse events in
general might be affected by titration of drugs, let alone whether
a particular adverse event might be affected.
[0031] It has now been discovered that initiating tapentadol
therapy according to a titration regimen minimizes adverse side
effects associated with tapentadol, particularly somnolence, while
maintaining its therapeutic effectiveness which results in a
greater tolerability of the drug during therapy.
[0032] It has been surprisingly found that particularly adverse
events that are associated with the central nervous system, such as
somnolence, can be minimized by titration according to the
invention. As far as adverse events associated with the
gastrointestinal tract are concerned, titration of tapentadol
according the present invention is also advantageous.
[0033] Furthermore, it has been surprisingly found that at the end
of a long term dosing regimen, the occurrence of mild-moderate
withdrawal symptoms following drug discontinuation are
significantly fewer compared to other opioids, such as oxycodone.
Thus, there is little indication of the need for drug tapering
(downward titration) at the end of the overall dosing regimen.
[0034] A first aspect of the invention relates to the use of
tapentadol for the manufacture of a medicament comprising:
[0035] at least one administration unit A containing dose a of
tapentadol and
[0036] at least one administration unit B containing dose b of
tapentadol, where dose a<dose b,
[0037] for the treatment of pain, preferably of chronic pain.
[0038] As used herein, an "administration unit" may be composed of
a single dosage form or of a group of dosage forms. In other words,
administration unit X comprises n.sub.X dosage forms, where n.sub.X
is an integer .gtoreq.1.
[0039] When n.sub.X=1, administration unit X comprises a single
dosage form. When n.sub.X>1, administration unit X comprises a
group of dosage forms which are adapted and intended to be
administered simultaneously. In this context, "simultaneously" does
not mean exactly at the same time, but approximately at the same
time, e.g., within a period of up to five minutes, preferably up to
one minute. For example, an administration unit containing 200 mg
of tapentadol may be either a single dosage form (n.sub.X=1)
containing the entire amount of tapentadol (200 mg) or a group of
dosage forms (n.sub.X>1), e.g., two dosage forms (n.sub.X=2)
each containing 100 mg of tapentadol; or, e.g., three dosage forms
(n.sub.X=3) two of which contain 50 mg of tapentadol each and one
of which contains 100 mg of tapentadol; or, e.g., four dosage forms
(n.sub.X=4) each containing 50 mg of tapentadol.
[0040] Thus, administration of dose x of tapentadol may be achieved
either by administering administration unit X composed of a single
dosage form containing dose x of tapentadol or by administering
administration unit X composed of a group of n.sub.X dosage forms
(with n.sub.X>1), the entirety of said group of n.sub.X dosage
forms containing dose x of tapentadol, which group of n.sub.X
dosage forms is adapted and intended to be administered
simultaneously.
[0041] Preferably, the invention relates to the use of tapentadol
for the manufacture of a medicament comprising [0042] at least one
administration unit A, that is composed of n.sub.A dosage forms the
entirety of which contains dose a of tapentadol, and [0043] at
least one administration unit B that is composed of n.sub.B dosage
forms the entirety of which contains dose b of tapentadol, [0044]
where [0045] dose a<dose b, and [0046] n.sub.A and n.sub.B are
independently of one another an integer .gtoreq.1, for the
treatment of pain. Preferably n.sub.A=n.sub.B, n.sub.A>n.sub.B
or n.sub.A<n.sub.B
[0047] Preferably, administration unit A and administration unit B
are solid.
[0048] In one preferred embodiment, tapentadol is used for the
manufacture of a medicament, where dose a of tapentadol is
administered during a first administration interval of at least one
day and dose b of tapentadol is administered during a second
administration interval of at least one day following said first
administration interval, where dose a<dose b, for the treatment
of pain, preferably of chronic pain.
[0049] Preferably, dose a is within the range of from 10 to 90 wt-%
of dose b, more preferably from 20 to 80 wt.-%, still more
preferably from 45 to 70 wt.-%.
[0050] In one preferred embodiment dose a is below the
pharmaceutically effective pain treating dose of tapentadol. The
pharmaceutically effective pain treating dose of tapentadol may
vary individually and can be determined by routine experimentation
for a given subject. Usually, the minimum pharmaceutically
effective pain treating dose will be above 50 mg twice daily (bid).
Preferably, effective pain treatment is to be regarded as at least
5% decrease in pain in an individual, more preferably at least 10%,
still more preferably at least 15% and most preferably at least 20%
decrease in pain in an individual, taking into account that low
serum concentrations of tapentadol suffice to show an effect in
individuals that are relatively sensitive and higher serum
concentrations of tapentadol are needed to show an effect in
persons that are relatively unsensitive. Preliminary clinical
trials revealed that a significant pain treating effect is seen at
serum concentrations in the range of from about 5 ng/ml
(approximately -2 mm visual analog scale (VAS) in a population
mean) to about 300 ng/ml (approximately -15 mm visual analog scale
(VAS) in a population mean).
[0051] Preferably, the ratio of dose a:dose b ([mg]:[mg]) is
selected from the group consisting of [0052] (25.+-.5%):(50.+-.5%),
(25.+-.5%):(75.+-.5%), (25.+-.5%):(100.+-.5%),
(25.+-.5%):(125.+-.5%), (25.+-.5%):(150.+-.5%),
(25.+-.5%):(175.+-.5%), (25.+-.5%):(200.+-.5%),
(25.+-.5%):(225.+-.5%), (25.+-.5%):(250.+-.5%); [0053]
(50.+-.5%):(75.+-.5%), (50.+-.5%):(100.+-.5%),
(50.+-.5%):(125.+-.5%), (50.+-.5%):(150.+-.5%),
(50.+-.5%):(175.+-.5%), (50.+-.5%):(200.+-.5%),
(50.+-.5%):(225.+-.5%), (50.+-.5%):(250.+-.5%); [0054]
(75.+-.5%):(100.+-.5%), (75.+-.5%):(125.+-.5%),
(75.+-.5%):(150.+-.5%), (75.+-.5%):(175.+-.5%),
(75.+-.5%):(200.+-.5%), (75.+-.5%):(225.+-.5%),
(75.+-.5%):(250.+-.5%); [0055] (100.+-.5%):(125.+-.5%),
(100.+-.5%):(150.+-.5%), (100.+-.5%):(175.+-.5%),
(100.+-.5%):(200.+-.5%), (100.+-.5%):(225.+-.5%),
(100.+-.5%):(250.+-.5%); [0056] (125.+-.5%):(150.+-.5%),
(125.+-.5%):(175.+-.5%), (125.+-.5%):(200.+-.5%),
(125.+-.5%):(225.+-.5%), (125.+-.5%):(250.+-.5%); [0057]
(150.+-.5%):(175.+-.5%), (150.+-.5%):(200.+-.5%),
(150.+-.5%):(225.+-.5%), (150.+-.5%):(250.+-.5%); [0058]
(175.+-.5%):(200.+-.5%), (175.+-.5%):(225.+-.5%),
(175.+-.5%):(250.+-.5%); [0059] (200.+-.5%):(225.+-.5%),
(200.+-.5%):(250.+-.5%); and [0060] (225.+-.5%):(250.+-.5%).
[0061] In a preferred embodiment, under in vitro conditions,
administration unit A releases 50% of dose a in a shorter or in a
longer time interval than administration unit B releases 50% of
dose b. The skilled person is fully aware of suitable in vitro
conditions, e.g., release may be investigated according to the
European Pharmacopoeia, paddle method, 100 Upm, artificial gastric
juice.
[0062] In one preferred embodiment administration unit A and
administration unit B are adapted to be administered via different
routes, which preferably are independently selected from the group
consisting of orally, buccally, sublingually, transmucosally,
intralumbally, intraperitoneally, transdermally, intraveneously,
intramusculously, intragluteally, intracutaneously and
subcutaneously. Most preferably, however, administration unit A and
administration unit B are adapted to be administered via the same
route, preferably orally.
[0063] In another preferred embodiment, the medicament further
comprises at least one administration unit C containing dose c of
tapentadol, where dose b<dose c. Preferably, dose a is within
the range of from 10 to 65 wt.-% of dose c, more preferably from 20
to 55 wt.-%, and dose b is within the range of from 35 to 90 wt.-%
of dose c, more preferably from 45 to 80 wt.-%.
[0064] In yet another preferred embodiment, tapentadol is used for
the manufacture of a medicament, where dose a of tapentadol is
administered during a first administration interval of at least one
day, dose b of tapentadol is administered during a second
administration interval of at least one day following said first
administration interval, and dose c of tapentadol is administered
during a third administration interval of at least one day
following said second administration interval, where dose a<dose
b<dose c, for the treatment of pain, preferably of chronic
pain.
[0065] Preferably, the ratio of dose a:dose b:dose c
([mg]:[mg]:[mg]) is selected from the group consisting of [0066]
(25.+-.5%):(50.+-.5%):(75.+-.5%),
(25.+-.5%):(50.+-.5%):(100.+-.5%),
(25.+-.5%):(50.+-.5%):(125.+-.5%),
(25.+-.5%):(50.+-.5%):(150.+-.5%),
(25.+-.5%):(50.+-.5%):(175.+-.5%),
(25.+-.5%):(50.+-.5%):(200.+-.5%),
(25.+-.5%):(50.+-.5%):(225.+-.5%),
(25.+-.5%):(50.+-.5%):(250.+-.5%);
(25.+-.5%):(75.+-.5%):(100.+-.5%),
(25.+-.5%):(75.+-.5%):(125.+-.5%),
(25.+-.5%):(75.+-.5%):(150.+-.5%),
(25.+-.5%):(75.+-.5%):(175.+-.5%),
(25.+-.5%):(75.+-.5%):(200.+-.5%),
(25.+-.5%):(75.+-.5%):(225.+-.5%),
(25.+-.5%):(75.+-.5%):(250.+-.5%);
(25.+-.5%):(100.+-.5%):(125.+-.5%),
(25.+-.5%):(100.+-.5%):(150.+-.5%),
(25.+-.5%):(100.+-.5%):(175.+-.5%),
(25.+-.5%):(100.+-.5%):(200.+-.5%),
(25.+-.5%):(100.+-.5%):(225.+-.5%),
(25.+-.5%):(100.+-.5%):(250.+-.5%);
(25.+-.5%):(125.+-.5%):(150.+-.5%),
(25.+-.5%):(125.+-.5%):(175.+-.5%),
(25.+-.5%):(125.+-.5%):(200.+-.5%),
(25.+-.5%):(125.+-.5%):(225.+-.5%),
(25.+-.5%):(125.+-.5%):(250.+-.5%);
(25.+-.5%):(150.+-.5%):(175.+-.5%),
(25.+-.5%):(150.+-.5%):(200.+-.5%),
(25.+-.5%):(150.+-.5%):(225.+-.5%),
(25.+-.5%):(150.+-.5%):(250.+-.5%);
(25.+-.5%):(175.+-.5%):(200.+-.5%),
(25.+-.5%):(175.+-.5%):(225.+-.5%),
(25.+-.5%):(175.+-.5%):(250.+-.5%);
(25.+-.5%):(200.+-.5%):(225.+-.5%),
(25.+-.5%):(200.+-.5%):(250.+-.5%);
(25.+-.5%):(225.+-.5%):(250.+-.5%); [0067]
(50.+-.5%):(75.+-.5%):(100.+-.5%),
(50.+-.5%):(75.+-.5%):(125.+-.5%),
(50.+-.5%):(75.+-.5%):(150.+-.5%),
(50.+-.5%):(75.+-.5%):(175.+-.5%),
(50.+-.5%):(75.+-.5%):(200.+-.5%),
(50.+-.5%):(75.+-.5%):(225.+-.5%),
(50.+-.5%):(75.+-.5%):(250.+-.5%);
(50.+-.5%):(100.+-.5%):(125.+-.5%),
(50.+-.5%):(100.+-.5%):(150.+-.5%),
(50.+-.5%):(100.+-.5%):(175.+-.5%),
(50.+-.5%):(100.+-.5%):(200.+-.5%),
(50.+-.5%):(100.+-.5%):(225.+-.5%),
(50.+-.5%):(100.+-.5%):(250.+-.5%);
(50.+-.5%):(125.+-.5%):(150.+-.5%),
(50.+-.5%):(125.+-.5%):(175.+-.5%),
(50.+-.5%):(125.+-.5%):(200.+-.5%),
(50.+-.5%):(125.+-.5%):(225.+-.5%),
(50.+-.5%):(125.+-.5%):(250.+-.5%);
(50.+-.5%):(150.+-.5%):(175.+-.5%);
(50.+-.5%):(150.+-.5%):(200.+-.5%),
(50.+-.5%):(150.+-.5%):(225.+-.5%),
(50.+-.5%):(150.+-.5%):(250.+-.5%);
(50.+-.5%):(175.+-.5%):(200.+-.5%),
(50.+-.5%):(175.+-.5%):(225.+-.5%),
(50.+-.5%):(175.+-.5%):(250.+-.5%);
(50.+-.5%):(200.+-.5%):(225.+-.5%),
(50.+-.5%):(200.+-.5%):(250.+-.5%);
(50.+-.5%):(225.+-.5%):(250.+-.5%); [0068]
(75.+-.5%):(100.+-.5%):(125.+-.5%),
(75.+-.5%):(100.+-.5%):(150.+-.5%),
(75.+-.5%):(100.+-.5%):(175.+-.5%),
(75.+-.5%):(100.+-.5%):(200.+-.5%),
(75.+-.5%):(100.+-.5%):(225.+-.5%),
(75.+-.5%):(100.+-.5%):(250.+-.5%);
(75.+-.5%):(125.+-.5%):(150.+-.5%),
(75.+-.5%):(125.+-.5%):(175.+-.5%),
(75.+-.5%):(125.+-.5%):(200.+-.5%),
(75.+-.5%):(125.+-.5%):(225.+-.5%),
(75.+-.5%):(125.+-.5%):(250.+-.5%);
(75.+-.5%):(150.+-.5%):(175.+-.5%),
(75.+-.5%):(150.+-.5%):(200.+-.5%),
(75.+-.5%):(150.+-.5%):(225.+-.5%),
(75.+-.5%):(150.+-.5%):(250.+-.5%);
(75.+-.5%):(175.+-.5%):(200.+-.5%),
(75.+-.5%):(175.+-.5%):(225.+-.5%),
(75.+-.5%):(175.+-.5%):(250.+-.5%);
(75.+-.5%):(200.+-.5%):(225.+-.5%),
(75.+-.5%):(200.+-.5%):(250.+-.5%);
(75.+-.5%):(225.+-.5%):(250.+-.5%); [0069]
(100.+-.5%):(125.+-.5%):(150.+-.5%),
(100.+-.5%):(125.+-.5%):(175.+-.5%),
(100.+-.5%):(125.+-.5%):(200.+-.5%),
(100.+-.5%):(125.+-.5%):(225.+-.5%),
(100.+-.5%):(125.+-.5%):(250.+-.5%);
(100.+-.5%):(150.+-.5%):(175.+-.5%),
(100.+-.5%):(150.+-.5%):(200.+-.5%),
(100.+-.5%):(150.+-.5%):(225.+-.5%),
(100.+-.5%):(150.+-.5%):(250.+-.5%);
(100.+-.5%):(175.+-.5%):(200.+-.5%),
(100.+-.5%):(175.+-.5%):(225.+-.5%),
(100.+-.5%):(175.+-.5%):(250.+-.5%);
(100.+-.5%):(200.+-.5%):(225.+-.5%),
(100.+-.5%):(200.+-.5%):(250.+-.5%);
(100.+-.5%):(225.+-.5%):(250.+-.5%); [0070]
(125.+-.5%):(150.+-.5%):(175.+-.5%),
(125.+-.5%):(150.+-.5%):(200.+-.5%),
(125.+-.5%):(150.+-.5%):(225.+-.5%),
(125.+-.5%):(150.+-.5%):(250.+-.5%);
(125.+-.5%):(175.+-.5%):(200.+-.5%),
(125.+-.5%):(175.+-.5%):(225.+-.5%),
(125.+-.5%):(175.+-.5%):(250.+-.5%);
(125.+-.5%):(200.+-.5%):(225.+-.5%),
(125.+-.5%):(200.+-.5%):(250.+-.5%);
(125.+-.5%):(225.+-.5%):(250.+-.5%); [0071]
(150.+-.5%):(175.+-.5%):(200.+-.5%),
(150.+-.5%):(175.+-.5%):(225.+-.5%),
(150.+-.5%):(175.+-.5%):(250.+-.5%);
(150.+-.5%):(200.+-.5%):(225.+-.5%),
(150.+-.5%):(200.+-.5%):(250.+-.5%);
(150.+-.5%):(225.+-.5%):(250.+-.5%); [0072]
(175.+-.5%):(200.+-.5%):(225.+-.5%),
(175.+-.5%):(200.+-.5%):(250.+-.5%);
(175.+-.5%):(225.+-.5%):(250.+-.5%); and [0073]
(200.+-.5%):(225.+-.5%):(250.+-.5%).
[0074] In a preferred embodiment, the medicament further comprises
at least one administration unit D containing dose d of tapentadol,
where dose c<dose d.
[0075] In a preferred embodiment, tapentadol is used for the
manufacture of a medicament, where dose a of tapentadol is
administered during a first administration interval of at least one
day, dose b of tapentadol is administered during a second
administration interval of at least one day following said first
administration interval, dose c of tapentadol is administered
during a third administration interval of at least one day
following said second administration interval, and dose d of
tapentadol is administered during a fourth administration interval
of at least one day following said third administration interval,
where dose a<dose b<dose c<dose d, for the treatment of
pain, preferably of chronic pain. Preferably, dose a is within the
range of from 10 to 55 wt.-% of dose d, more preferably 15 to 50
wt.-%, dose b is within the range of from 35 to 75 wt.-% of dose d,
more preferably 40 to 70 wt.-%, and dose c is within the range of
from 60 to 95 wt.-% of dose d, more preferably 65 to 90 wt.-%.
[0076] Still more preferably, the medicament further comprises at
least one administration unit E containing dose e of tapentadol,
where dose d<dose e.
[0077] In a preferred embodiment, tapentadol is used for the
manufacture of a medicament, where dose a of tapentadol is
administered during a first administration interval of at least one
day, dose b of tapentadol is administered during a second
administration interval of at least one day following said first
administration interval, dose c of tapentadol is administered
during a third administration interval of at least one day
following said second administration interval, dose d of tapentadol
is administered during a fourth administration interval of at least
one day following said third administration interval, and dose e of
tapentadol is administered during a fifth administration interval
of at least one day following said fourth administration interval,
where dose a<dose b<dose c<dose d<dose e, for the
treatment of pain.
[0078] Preferably, dose a is within the range of from 10 to 30
wt.-% of dose e, more preferably 15 to 25 wt.-%, dose b is within
the range of from 30 to 50 wt.-% of dose e, more preferably 35 to
45 wt.-%, dose c is within the range of from 50 to 70 wt.-% of dose
e, more preferably 55 to 65 wt.-%, and dose d is within the range
of from 70 to 90 wt.-% of dose e, more preferably 75 to 85
wt.-%.
[0079] Preferably, the daily dose of tapentadol is within the range
of from 20 to 550 mg, more preferably 30 to 530 mg and most
preferably 40 to 520 mg.
[0080] In a preferred embodiment, administration unit A,
administration unit B, optional administration unit C, optional
administration unit D and optional administration unit E are
adapted to be administered once daily (sid) each, and dose a, dose
b, optional dose c, optional dose d and optional dose e are each
independently within the range of from 20 to 550 mg, more
preferably 30 to 530 mg and most preferably 40 to 520 mg.
[0081] In another preferred embodiment, administration unit A,
administration unit B, optional administration unit C, optional
administration unit D and optional administration unit E are
adapted to be administered twice daily (bid) each, and dose a, dose
b, optional dose c, optional dose d and optional dose e are each
independently within the range of from 10 to 275 mg, more
preferably 15 to 265 mg and most preferably 20 to 260 mg.
[0082] In still another preferred embodiment, administration unit
A, administration unit B, optional administration unit C, optional
administration unit D and optional administration unit E are
adapted to be administered thrice daily (tid) each, and dose a,
dose b, optional dose c, optional dose d and optional dose e are
each independently within the range of from 6 to 180 mg, more
preferably 10 to 175 mg and most preferably 13 to 170 mg.
[0083] In a preferred embodiment of the medicament according to the
invention, administration unit A comprises n.sub.A dosage forms,
administration unit B comprises n.sub.B dosage forms, optional
administration unit C comprises n.sub.C dosage forms, optional
administration unit D comprises n.sub.D dosage forms and optional
administration unit E comprises n.sub.E dosage forms, where
n.sub.A=n.sub.B or n.sub.A<n.sub.B or n.sub.A>n.sub.B. The
n.sub.X dosage forms belonging to administration unit X are to be
administered simultaneously, i.e. approximately at the same time.
Preferably, n.sub.A<n.sub.B.ltoreq.optional
n.sub.C.ltoreq.optional n.sub.D.gtoreq.optional n.sub.E.
[0084] The medicament according to the invention is adapted to
administer tapentadol by initiating the treatment at a
comparatively low dose of tapentadol (dose a), preferably at a dose
of 25 mg.+-.5%, 50 mg.+-.5%, 75 mg.+-.5% or 100 mg.+-.5%, more
preferably below the pharmaceutically effective pain treating dose
of tapentadol, and successively increasing the dose according to a
titration regimen (dose b, optional dose c, optional dose d and
optional dose e).
[0085] Usually, initial dose a is administered not only once, but
several times for several days, preferably twice daily (bid),
during a certain period of time (first administration interval),
e.g., during three days. Thus, for example, initial dose a is
administered [0086] on the first day of said first administration
interval by means of two administration units A (e.g., one
administration unit A is administered in the morning and one
administration unit A is administered in the evening of said first
day), [0087] on the second day of said first administration
interval by means of two further administration units A (e.g., one
administration unit A is administered in the morning and one
administration unit A is administered in the evening of said second
day) and [0088] on the third day of said first administration
interval by means of two further administration units A (e.g., one
administration unit A is administered in the morning and one
administration unit A is administered in the evening of said third
day). Thus, a total of six administration units A, each containing
dose a of tapentadol, is needed in order to administer tapentadol
during this exemplified first administration interval.
[0089] Thereafter, following the first administration interval, the
increase of the dose of tapentadol according to the titration
regimen may be realized by administering dose b, e.g., also during
a period of three days (second administration interval), e.g.,
twice daily (bid). Thus, for example, consecutive dose b is
administered [0090] on the first day of said second administration
interval by means of two administration units B (e.g., one
administration unit B is administered in the morning and one
administration unit B is administered in the evening of said first
day), [0091] on the second day of said second administration
interval by means of two administration units B (e.g., one
administration unit B is administered in the morning and one
administration unit B is administered in the evening of said second
day) and [0092] on the third day of said second administration
interval by means of two administration units B (e.g., one
administration unit B is administered in the morning and one
administration unit B is administered in the evening of said third
day). Thus, a total of six administration units B, each containing
dose b of tapentadol, is needed in order to administer tapentadol
during this exemplified second administration interval.
[0093] Thereafter, following the second administration interval,
the further increase of the dose of tapentadol according to the
titration regimen may optionally be realized by administering doses
c, d and e of tapentadol, i.e. by administering administration
units C, D and E during a third, fourth and fifth administration
interval, respectively.
[0094] Patients may be allowed 1, 2 or more doses of tapentadol,
e.g. 25 mg, at least 6 hours apart, as supplemental analgesia.
[0095] As administration unit X may comprise n.sub.X dosage forms,
two cases may be distinguished: [0096] when n.sub.X=1, every
administration of administration unit X is performed by
administering a single dosage form containing dose x of tapentadol
at the respective point in time during the titration regimen;
[0097] when n.sub.X>1, every administration of administration
unit X is performed by simultaneously administering a plurality of
dosage forms, namely n.sub.X dosage forms, at the respective point
in time during the titration regimen, wherein each of the n.sub.X
dosage forms contains tapentadol in an amount below dose x but the
entirety of all n.sub.X dosage forms contains dose x of tapentadol.
The n.sub.X dosage forms of administration unit X can be identical
or different.
[0098] When n.sub.X>1, the dosage forms belonging to
administration unit X may be identical or different and may be
provided in the same package or in different packages. For example,
if dose x of administration unit X is 250 mg and n.sub.X is 2, the
first dosage form may contain 100 mg of tapentadol and the second
dosage form may contain 150 mg of tapentadol, or the first dosage
form may contain 200 mg of tapentadol and the second dosage form
may contain 50 mg of tapentadol, so that the entirety of the 2
dosage forms of administration unit X contains the required dose x
of 250 mg of tapentadol. The skilled person recognizes that the
n.sub.X dosage forms may be provided in the same package or in
different packages. For example, a first dosage form containing 200
mg of tapentadol may be taken from a first package and a second
dosage form containing 50 mg of tapentadol may be taken from a
second package and both dosage forms may be combined in order to
form an administration unit containing a dose of 250 mg of
tapentadol.
[0099] This embodiment is further illustrated in FIG. 1. For
example, administration of an administration unit containing a dose
of 150 mg of tapentadol may be realized by administering [0100]
three dosage forms each containing 50 mg of tapentadol (to the
left); [0101] one dosage form containing 50 mg of tapentadol (to
the left) and one dosage form containing 100 mg of tapentadol (in
the middle); or [0102] a single dosage form containing 150 mg of
tapentadol (to the right). Preferably, n.sub.A, n.sub.B, optional
n.sub.C, optional n.sub.D and optional n.sub.E are independently of
one another 1, 2, 3, 4 or 5.
[0103] In one preferred embodiment, all dosage forms contained in
the medicament according to the invention are different and/or
n.sub.A=n.sub.B=optional n.sub.C=optional n.sub.D=optional
n.sub.E=1.
[0104] In another preferred embodiment, all dosage forms contained
in the medicament according to the invention are identical, i.e.
contain the same amount of tapentadol, and
n.sub.A<n.sub.B<optional n.sub.C<optional
n.sub.D<optional n.sub.E, more preferably n.sub.A=1, n.sub.B=2,
optional n.sub.C=3, optional n.sub.D=4, and optional n.sub.E=5.
Preferably, dose a/n.sub.A=dose b/n.sub.B=optional dose
c/n.sub.C=optional dose d/n.sub.D=optional dose e/n.sub.E.
[0105] Preferably, the medicament according to the invention is
provided in form of a packaging containing one or more
administration units A, one or more administration units B,
optionally one or more administration units C, optionally one or
more administration units D and optionally one or more
administration units E.
[0106] For example, the medicament according to the invention may
be provided in form of a blister packaging containing 36 identical
dosage forms each containing, e.g., 50 mg.+-.5% of tapentadol. When
dose a amounts to, e.g., 50 mg.+-.5% of tapentadol, administration
units A each comprise a single dosage form (n.sub.A=1). For
example, six of the dosage forms in the blister packaging may be
marked as administration units A and/or may be locally separated
from the other dosage forms in the blister packaging. When dose b
amounts to, e.g., 100 mg.+-.5% of tapentadol, administration units
B each comprise two dosage forms (n.sub.B=2). For example, twelve
of the dosage forms in the blister packaging may be divided into
six groups each group comprising two dosage forms. Every group may
be marked as administration unit B and/or may be locally separated
from the other dosage forms in the blister packaging. When dose c
amounts to, e.g., 150 mg.+-.5% of tapentadol, administration units
C each comprise three dosage forms (n.sub.C=3). For example,
eighteen of the dosage forms in the blister packaging may be
divided into six groups each group comprising three dosage forms.
Every group may be marked as administration unit C and/or may be
locally separated from the other dosage forms in the blister
packaging. This embodiment of the medicament according to the
invention is further illustrated in FIGS. 2 and 3.
[0107] Alternatively, the medicament according to the invention may
be provided in form of a blister packaging containing, e.g., 18
administration units each consisting of a single dosage form
(n.sub.x=1). These administration units may be divided into three
groups each comprising 6 dosage forms. For example, six of the
dosage forms in the blister packaging may each contain dose a,
e.g., 50 mg.+-.5% of tapentadol, and may be marked as
administration units A and/or may be locally separated from the
other dosage forms in the blister packaging. Another six of the
dosage forms in the blister packaging may each contain dose b,
e.g., 100 mg.+-.5% of tapentadol, and may be marked as
administration unit B and/or may be locally separated from the
other dosage forms in the blister packaging. The remaining six of
the dosage forms in the blister packaging may each contain dose c,
e.g., 150 mg.+-.5% of tapentadol, and may be marked as
administration unit C and/or may be locally separated from the
other dosage forms in the blister packaging. This embodiment of the
medicament according to the invention is further illustrated in
FIG. 4.
[0108] Preferably, the medicament according to the invention
comprises a plurality of administration units A, a plurality of
administration units B, optionally a plurality of administration
units C, optionally a plurality of administration units D and
optionally a plurality of administration units E. Preferably, these
administration units are adapted to be administered sequentially,
preferably in alphabetical order. Preferably, the entirety of all
administration units A (each comprising n.sub.A dosage forms) is
adapted to be administered during a first administration interval
and the entirety of all administration units B (each comprising
n.sub.B dosage forms) is adapted to be administered during a second
administration interval following the first administration
interval, i.e. after the administration of the entirety of all
administration units A has been completed.
[0109] In a preferred embodiment of the present invention, the
medicament is provided in form of a packaging comprising a
plurality of administration units A, a plurality of administration
units B, optionally a plurality of administration units C,
optionally a plurality of administration units D and optionally a
plurality of administration units E, which are adapted to be
administered in sequential, alphabetical order, preferably twice
daily (bid), so that all administration units A are adapted to be
administered during a first administration interval, all
administration units B are adapted to be administered during a
second administration interval following the first administration
interval, optionally all administration units C are adapted to be
administered during a third administration interval following the
second administration interval, optionally all administration units
D are adapted to be administered during a fourth administration
interval following the third administration interval, and
optionally all administration units E are adapted to be
administered during a fifth administration interval following the
fourth administration interval.
[0110] Preferably, administration units A, administration units B,
optional administration units C, optional administration units D
and optional administration units E are each adapted to be
administered once daily (sid), twice daily (bid) or thrice daily
(tid), twice daily (bid) being particularly preferred.
[0111] According to one preferred embodiment of the present
invention, the medicament comprises: [0112] (i) a plurality of
administration units A as defined supra that are adapted to be
administered during a first administration interval of at least 2
days, preferably at least 3 days, preferably twice daily (bid),
[0113] (ii) a plurality of administration units B as defined supra
that are adapted to be administered during a second administration
interval of at least 2 days, preferably at least 3 days, more
preferably at least 11 days, following the first administration
interval, preferably twice daily (bid), [0114] (iii) optionally, a
plurality of administration units C as defined supra that are
adapted to be administered during a third administration interval
of at least 2 days, preferably at least 3 days, more preferably at
least 14 days, following the second administration interval,
preferably twice daily (bid), [0115] (iv) optionally, a plurality
of administration units D as defined supra that are adapted to be
administered during a fourth administration interval of at least 2
days, preferably at least 3 days, following the third
administration interval, preferably twice daily (bid), and [0116]
(v) optionally, a plurality of administration units E as defined
supra that are adapted to be administered during a fifth
administration interval of at least 2 days, preferably at least 3
days, following the fourth administration interval, preferably
twice daily (bid).
[0117] Particularly preferably, the medicament comprises [0118] (i)
a plurality of administration units A containing dose a of
tapentadol, that are adapted to be orally administered twice daily
(bid) during a first administration interval of at least a
consecutive days, [0119] (ii) a plurality of administration units B
containing dose b of tapentadol, that are adapted to be orally
administered twice daily (bid) during a second administration
interval of at least .beta. consecutive days following the first
administration interval, [0120] (iii) optionally, a plurality of
administration units C containing dose c of tapentadol, that are
adapted to be orally administered twice daily (bid) during a third
administration interval of at least .OMEGA. consecutive days
following the second administration interval, [0121] (iv)
optionally, a plurality of administration units D containing dose d
of tapentadol, that are adapted to be orally administered twice
daily (bid) during a fourth administration interval of at least
.delta. consecutive days following the third administration
interval, and [0122] (v) optionally, a plurality of administration
units E containing dose e of tapentadol, that are adapted to be
orally administered twice daily (bid) during a fifth administration
interval of at least .epsilon. consecutive days following the
fourth administration interval; where a, b, c, d, e and .alpha.,
.beta., .OMEGA., .epsilon. satisfy any requirement selected from
the group of requirements P.sub.1-9, Q.sub.1-9, R.sub.1-9 and
S.sub.1-9:
TABLE-US-00001 [0122] [mg] d P.sub.1 P.sub.2 P.sub.3 P.sub.4
P.sub.5 P.sub.6 P.sub.7 P.sub.8 P.sub.9 a = 25 .+-. 5% .alpha.
.gtoreq.2 .gtoreq.2 .gtoreq.2 .gtoreq.3 .gtoreq.3 .gtoreq.3
.gtoreq.4 .gtoreq.4 .gtoreq.4 b = 50 .+-. 5% .beta. .gtoreq.2
.gtoreq.2 .gtoreq.3 .gtoreq.3 .gtoreq.3 .gtoreq.4 .gtoreq.4
.gtoreq.4 .gtoreq.5 C = 100 .+-. 5% .chi. .gtoreq.2 .gtoreq.3
.gtoreq.3 .gtoreq.3 .gtoreq.4 .gtoreq.4 .gtoreq.4 .gtoreq.5
.gtoreq.5 D = 150 .+-. 5% .delta. 0/.gtoreq.2 0/.gtoreq.3
0/.gtoreq.3 0/.gtoreq.3 0/.gtoreq.4 0/.gtoreq.4 0/.gtoreq.4
0/.gtoreq.5 0/.gtoreq.5 E = 200 .+-. 5% .epsilon. 0/.gtoreq.2
0/.gtoreq.3 0/.gtoreq.3 0/.gtoreq.3 0/.gtoreq.4 0/.gtoreq.4
0/.gtoreq.4 0/.gtoreq.5 0/.gtoreq.5 [mg] d Q.sub.1 Q.sub.2 Q.sub.3
Q.sub.4 Q.sub.5 Q.sub.6 Q.sub.7 Q.sub.8 Q.sub.9 a = 50 .+-. 5%
.alpha. .gtoreq.2 .gtoreq.2 .gtoreq.3 .gtoreq.3 .gtoreq.4 .gtoreq.4
.gtoreq.5 .gtoreq.5 .gtoreq.6 B = 100 .+-. 5% .beta. .gtoreq.2
.gtoreq.2 .gtoreq.3 .gtoreq.4 .gtoreq.4 .gtoreq.5 .gtoreq.5
.gtoreq.6 .gtoreq.6 C = 150 .+-. 5% .chi. 0/.gtoreq.2 0/.gtoreq.2
0/.gtoreq.3 0/.gtoreq.4 0/.gtoreq.4 0/.gtoreq.5 0/.gtoreq.5
0/.gtoreq.6 0/.gtoreq.6 D = 200 .+-. 5% .delta. 0/.gtoreq.2
0/.gtoreq.2 0/.gtoreq.3 0/.gtoreq.4 0/.gtoreq.4 0/.gtoreq.5
0/.gtoreq.5 0/.gtoreq.6 0/.gtoreq.6 E = 250 .+-. 5% .epsilon.
0/.gtoreq.2 0/.gtoreq.2 0/.gtoreq.3 0/.gtoreq.4 0/.gtoreq.4
0/.gtoreq.5 0/.gtoreq.5 0/.gtoreq.6 0/.gtoreq.6 [mg] d R.sub.1
R.sub.2 R.sub.3 R.sub.4 R.sub.5 R.sub.6 R.sub.7 R.sub.8 R.sub.9 a =
50 .+-. 5% .alpha. .gtoreq.2 .gtoreq.2 .gtoreq.3 .gtoreq.3
.gtoreq.4 .gtoreq.4 .gtoreq.5 .gtoreq.5 .gtoreq.6 B = 100 .+-. 5%
.beta. .gtoreq.2 .gtoreq.3 .gtoreq.3 .gtoreq.4 .gtoreq.4 .gtoreq.5
.gtoreq.5 .gtoreq.6 .gtoreq.6 C = 200 .+-. 5% .chi. 0/.gtoreq.2
0/.gtoreq.3 0/.gtoreq.3 0/.gtoreq.4 0/.gtoreq.4 0/.gtoreq.5
0/.gtoreq.5 0/.gtoreq.6 0/.gtoreq.6 [mg] d S.sub.1 S.sub.2 S.sub.3
S.sub.4 S.sub.5 S.sub.6 S.sub.7 S.sub.8 S.sub.9 A = 100 .+-. 5%
.alpha. .gtoreq.2 .gtoreq.2 .gtoreq.3 .gtoreq.3 .gtoreq.4 .gtoreq.4
.gtoreq.5 .gtoreq.5 .gtoreq.6 B = 150 .+-. 5% .beta. .gtoreq.2
.gtoreq.3 .gtoreq.3 .gtoreq.4 .gtoreq.4 .gtoreq.5 .gtoreq.5
.gtoreq.6 .gtoreq.6 C = 200 .+-. 5% .chi. 0/.gtoreq.2 0/.gtoreq.3
0/.gtoreq.3 0/.gtoreq.4 0/.gtoreq.4 0/.gtoreq.5 0/.gtoreq.5
0/.gtoreq.6 0/.gtoreq.6 D = 250 .+-. 5% .delta. 0/.gtoreq.2
0/.gtoreq.3 0/.gtoreq.3 0/.gtoreq.4 0/.gtoreq.4 0/.gtoreq.5
0/.gtoreq.5 0/.gtoreq.6 0/.gtoreq.6
In the above tables, e.g., "0/.gtoreq.2" means that either the
respective dose is not administered, i.e. the titration regimen
does not encompass this step ("0"), or the respective dose is
administered during an administration interval of at least 2 days
(".gtoreq.2").
[0123] Preferably, tapentadol is used in the manufacture of a
medicament for the treatment of pain, wherein dose a of tapentadol
is administered twice daily (bid) for .alpha. days; then dose b of
tapentadol is administered twice daily (bid) for .beta. days; then,
optionally, dose c of tapentadol is administered twice daily (bid)
for .OMEGA. days; then, optionally, dose d of tapentadol is
administered twice daily for .delta. days; and then, optionally,
dose e of tapentadol twice daily for .epsilon. days is
administered; where a, b, c, d, e and .alpha., .beta., .OMEGA.,
.delta., .epsilon. satisfy any requirement selected from the group
of the above requirements P.sub.1-9, Q.sub.1-9, R.sub.1-9 and
S.sub.1-9.
[0124] The embodiments P.sub.1 to P.sub.9 are particularly useful
for the treatment of chronic pain, especially due to osteoarthritis
(hip or knee) or low back pain.
[0125] The embodiments Q.sub.1 to Q.sub.9 are particularly useful
for the treatment of chronic pain, especially due to osteoarthritis
(hip or knee), low back pain or painful diabetic peripheral
neuropathy (DPN).
[0126] The embodiments R.sub.1 to R.sub.9 are particularly useful
for the treatment of chronic pain, especially due to osteoarthritis
(hip or knee) or low back pain.
[0127] The embodiments S.sub.1 to S.sub.9 are particularly useful
for the treatment of chronic pain, especially chronic malignant
tumor-related pain.
[0128] Preferably, administration unit A, administration unit B,
optional administration unit C, optional administration unit D and
optional administration unit E and the dosage forms belonging to
said administration units, respectively, each [0129] are adapted to
be administered orally; and/or [0130] are solid and/or compressed
and/or film coated; and/or [0131] release tapentadol from a
sustained release matrix; and/or [0132] contain tapentadol in an
amount of from 0.001 to 99.999 wt.-%, more preferably 0.1 to 99.9
wt.-%, still more preferably 1.0 to 99.0 wt.-%, yet more preferably
2.5 to 80 wt.-%, most preferably 5.0 to 50 wt.-% and in particular
7.5 to 40 wt.-%, based on the total weight of the administration
unit; and/or [0133] contain a pharmaceutically acceptable carrier
and/or pharmaceutically acceptable excipients; and/or [0134] have a
total weight within the range of from 25 to 2,000 mg, more
preferably 50 to 1,800 mg, still more preferably 60 to 1,600 mg,
yet more preferably 70 to 1,400 mg, most preferably 80 to 1,200 mg
and most preferably 100 to 1,000 mg; and/or [0135] are selected
from the group consisting of tablets, capsules, pellets and
granules.
[0136] In another preferred embodiment of the medicament according
to the invention, dose a, dose b, optional dose c, optional dose d
and optional dose e are independently selected so that the mean
serum concentration of tapentadol is at least 0.1 ng/ml, more
preferably at least 1.0 ng/ml, still more preferably at least 2.0
ng/ml, most preferably at least 5.0 ng/ml and in particular at
least 10 ng/ml at any point in time during the administration
interval(s), except during an initial phase of up to one, two or
three days. More preferably, the mean serum concentration of
tapentadol is within the range of from 0.1 to 10,000 ng/ml, more
preferably 1.0 to 9,000 ng/ml, still more preferably 2.0 to 8,000
ng/ml, yet more preferably 3.0 to 5,000 ng/ml, most preferably 4.0
to 500 ng/ml and in particular 5.0 to 300 ng/ml at any point in
time during the administration interval(s), except during an
initial phase of up to one, two or three days.
[0137] According to a preferred embodiment of the invention, after
administration of the medicament twice daily (bid) for a duration
of at least 3 days following the regimen according to the
invention, the mean serum concentration of tapentadol is at least
15 ng/ml or at least 20 ng/ml, more preferably at least 25 ng/ml or
at least 30 ng/ml, still more preferably at least 35 ng/ml or at
least 40 ng/ml, most preferably at least 45 ng/ml or at least 50
ng/ml and particularly at least 55 ng/ml or at least 60 ng/ml. A
person skilled in the art knows how to measure the serum
concentration of tapentadol and its metabolites. In this context it
can be referred to e.g. T. M. Tschentke et al., Drugs of the
Future, 2006, 31(12), 1053.
[0138] In one preferred embodiment, tapentadol is used in the
manufacture of a medicament for the treatment of pain, by
administration of which medicament [0139] after 24 hours during a
preceding administration interval of at least 2 days, more
preferably at least 3 days, a mean serum concentration of
tapentadol of at most 27 ng/ml.+-.75% (.+-.67%, .+-.50%, .+-.40%,
.+-.30% or .+-.20%), more preferably at most 24 ng/ml.+-.75%
(.+-.67%, .+-.50%, .+-.40%, .+-.30% or .+-.20%), still more
preferably at most 20 ng/ml.+-.75% (.+-.67%, .+-.50%, .+-.40%,
.+-.30% or .+-.20%) is achieved, and [0140] after 24 hours during a
consecutive administration interval of at least 2 days, more
preferably at least 3 days, following said preceding administration
interval, a mean serum concentration of tapentadol of at least 27
ng/ml.+-.75% (.+-.67%, .+-.50%, .+-.40%, .+-.30% or .+-.20%), more
preferably at least 30 ng/ml.+-.75% (.+-.67%, .+-.50%, .+-.40%,
.+-.30% or .+-.20%), still more preferably at least 33 ng/ml.+-.75%
(.+-.67%, .+-.50%, .+-.40%, .+-.30% or .+-.20%) is achieved.
[0141] In another preferred embodiment, tapentadol is used in the
manufacture of a medicament for the treatment of pain, by
administration of which medicament [0142] after 24 hours during a
preceding administration interval of at least 2 days, more
preferably at least 3 days, a mean serum concentration of
tapentadol of at most 45 ng/ml.+-.75% (.+-.67%, .+-.50%, .+-.40%,
.+-.30% or .+-.20%), more preferably at most 41 ng/ml.+-.75%
(.+-.67%, .+-.50%, .+-.40%, .+-.30% or .+-.20%), still more
preferably at most 37 ng/ml.+-.75% (.+-.67%, 50%, .+-.40%, .+-.30%
or .+-.20%) is achieved, and [0143] after 24 hours during a
consecutive administration interval of at least 2 days, more
preferably at least 3 days, following said preceding administration
interval, a mean serum concentration of tapentadol of at least 45
ng/ml.+-.75% (.+-.67%, .+-.50%, .+-.40%, .+-.30% or .+-.20%), more
preferably at least 49 ng/ml.+-.75% (.+-.67%, .+-.50%, .+-.40%,
.+-.30% or .+-.20%), still more preferably at least 53 ng/ml.+-.75%
(.+-.67%, .+-.50%, .+-.40%, .+-.30% or .+-.20%) is achieved.
[0144] In still another preferred embodiment, tapentadol is used in
the manufacture of a medicament for the treatment of pain, by
administration of which medicament [0145] after 24 hours during a
preceding administration interval of at least 2 days, more
preferably at least 3 days, a mean serum concentration of
tapentadol of at most 62 ng/ml.+-.75% (.+-.67%, .+-.50%, .+-.40%,
.+-.30% or .+-.20%), more preferably at most 60 ng/ml.+-.75%
(.+-.67%, .+-.50%, .+-.40%, .+-.30% or .+-.20%), still more
preferably at most 57 ng/ml.+-.75% (.+-.67%, .+-.50%, .+-.40%,
.+-.30% or .+-.20%) is achieved, and [0146] after 24 hours during a
consecutive administration interval of at least 2 days, more
preferably at least 3 days, following said preceding administration
interval, a mean serum concentration of tapentadol of at least 62
ng/ml.+-.75% (.+-.67%, .+-.50%, .+-.40%, .+-.30% or 20%), more
preferably at least 64 ng/ml.+-.75% (.+-.67%, .+-.50%, .+-.40%,
.+-.30% or .+-.20%), still more preferably at least 67 ng/ml.+-.75%
(.+-.67%, .+-.50%, .+-.40%, .+-.30% or .+-.20%) is achieved.
[0147] Usually, about 24 hours are needed to achieve steady state
conditions within a given administration interval when increasing
(or decreasing) the dose of tapentadol from the dose administered
during the preceding administration interval to the dose
administered during the consecutive administration interval.
[0148] Preferably, tapentadol is used in the manufacture of a
medicament for the treatment of pain, wherein [0149] tapentadol is
administered, preferably twice daily (bid), during a first
administration interval of .alpha. days, after 24 hours providing a
mean serum concentration C.sub..alpha. of tapentadol; [0150] then
tapentadol is administered, preferably twice daily (bid), during a
second administration interval of .beta. days following said first
administration interval, after 24 hours providing a mean serum
concentration C.sub..beta. of tapentadol; [0151] then, optionally,
tapentadol is administered, preferably twice daily (bid), during a
third administration interval of .OMEGA. days following said second
administration interval, after 24 hours providing a mean serum
concentration C.sub..OMEGA. of tapentadol; [0152] then, optionally,
tapentadol is administered, preferably twice daily (bid), during a
fourth administration interval of .delta. days following said third
administration interval, after 24 hours providing a mean serum
concentration C.sub..delta. of tapentadol; and, [0153] then,
optionally, tapentadol is administered, preferably twice daily
(bid), during a fifth administration interval of .epsilon. days
following said fourth administration interval, after 24 hours
providing a mean serum concentration C.sub..epsilon. of tapentadol,
where .alpha., .beta., .OMEGA., .delta., .epsilon. and
C.sub..alpha., C.sub..beta., C.sub..OMEGA., C.sub..delta.,
C.sub..epsilon. satisfy any requirement selected from the group of
requirements T.sub.1-9, U.sub.1-9, V.sub.1-9 and W.sub.1-9:
TABLE-US-00002 [0153] [ng/ml] d T.sub.1 T.sub.2 T.sub.3 T.sub.4
T.sub.5 T.sub.6 T.sub.7 T.sub.8 T.sub.9 C.sub..alpha. = 9 .+-. 75%
.alpha. .gtoreq.2 .gtoreq.2 .gtoreq.2 .gtoreq.3 .gtoreq.3 .gtoreq.3
.gtoreq.4 .gtoreq.4 .gtoreq.4 C.sub..beta. = 18 .+-. 75% .beta.
.gtoreq.2 .gtoreq.2 .gtoreq.3 .gtoreq.3 .gtoreq.3 .gtoreq.4
.gtoreq.4 .gtoreq.4 .gtoreq.5 C.sub..chi. = 35 .+-. 75% .chi.
.gtoreq.2 .gtoreq.3 .gtoreq.3 .gtoreq.3 .gtoreq.4 .gtoreq.4
.gtoreq.4 .gtoreq.5 .gtoreq.5 C.sub..delta. = 55 .+-. 75% .delta.
0/.gtoreq.2 0/.gtoreq.3 0/.gtoreq.3 0/.gtoreq.3 0/.gtoreq.4
0/.gtoreq.4 0/.gtoreq.4 0/.gtoreq.5 0/.gtoreq.5 C.sub..epsilon. =
69 .+-. 75% .epsilon. 0/.gtoreq.2 0/.gtoreq.3 0/.gtoreq.3
0/.gtoreq.3 0/.gtoreq.4 0/.gtoreq.4 0/.gtoreq.4 0/.gtoreq.5
0/.gtoreq.5 [ng/ml] d U.sub.1 U.sub.2 U.sub.3 U.sub.4 U.sub.5
U.sub.6 U.sub.7 U.sub.8 U.sub.9 C.sub..alpha. = 18 .+-. 75% .alpha.
.gtoreq.2 .gtoreq.2 .gtoreq.3 .gtoreq.3 .gtoreq.4 .gtoreq.4
.gtoreq.5 .gtoreq.5 .gtoreq.6 C.sub..beta. = 35 .+-. 75% .beta.
.gtoreq.2 .gtoreq.2 .gtoreq.3 .gtoreq.4 .gtoreq.4 .gtoreq.5
.gtoreq.5 .gtoreq.6 .gtoreq.6 C.sub..chi. = 55 .+-. 75% .chi.
0/.gtoreq.2 0/.gtoreq.2 0/.gtoreq.3 0/.gtoreq.4 0/.gtoreq.4
0/.gtoreq.5 0/.gtoreq.5 0/.gtoreq.6 0/.gtoreq.6 C.sub..delta. = 69
.+-. 75% .delta. 0/.gtoreq.2 0/.gtoreq.2 0/.gtoreq.3 0/.gtoreq.4
0/.gtoreq.4 0/.gtoreq.5 0/.gtoreq.5 0/.gtoreq.6 0/.gtoreq.6
C.sub..epsilon. = 90 .+-. 75% .epsilon. 0/.gtoreq.2 0/.gtoreq.2
0/.gtoreq.3 0/.gtoreq.4 0/.gtoreq.4 0/.gtoreq.5 0/.gtoreq.5
0/.gtoreq.6 0/.gtoreq.6 [ng/ml] d V.sub.1 V.sub.2 V.sub.3 V.sub.4
V.sub.5 V.sub.6 V.sub.7 V.sub.8 V.sub.9 C.sub..alpha. = 18 .+-. 75%
.alpha. .gtoreq.2 .gtoreq.2 .gtoreq.3 .gtoreq.3 .gtoreq.4 .gtoreq.4
.gtoreq.5 .gtoreq.5 .gtoreq.6 C.sub..beta. = 35 .+-. 75% .beta.
.gtoreq.2 .gtoreq.3 .gtoreq.3 .gtoreq.4 .gtoreq.4 .gtoreq.5
.gtoreq.5 .gtoreq.6 .gtoreq.6 C.sub..chi. = 69 .+-. 75% .chi.
0/.gtoreq.2 0/.gtoreq.3 0/.gtoreq.3 0/.gtoreq.4 0/.gtoreq.4
0/.gtoreq.5 0/.gtoreq.5 0/.gtoreq.6 0/.gtoreq.6 [ng/ml] d W.sub.1
W.sub.2 W.sub.3 W.sub.4 W.sub.5 W.sub.6 W.sub.7 W.sub.8 W.sub.9
C.sub..alpha. = 35 .+-. 75% .alpha. .gtoreq.2 .gtoreq.2 .gtoreq.3
.gtoreq.3 .gtoreq.4 .gtoreq.4 .gtoreq.5 .gtoreq.5 .gtoreq.6
C.sub..beta. = 55 .+-. 75% .beta. .gtoreq.2 .gtoreq.3 .gtoreq.3
.gtoreq.4 .gtoreq.4 .gtoreq.5 .gtoreq.5 .gtoreq.6 .gtoreq.6
C.sub..chi. = 69 .+-. 75% .chi. 0/.gtoreq.2 0/.gtoreq.3 0/.gtoreq.3
0/.gtoreq.4 0/.gtoreq.4 0/.gtoreq.5 0/.gtoreq.5 0/.gtoreq.6
0/.gtoreq.6 C.sub..delta. = 90 .+-. 75% .delta. 0/.gtoreq.2
0/.gtoreq.3 0/.gtoreq.3 0/.gtoreq.4 0/.gtoreq.4 0/.gtoreq.5
0/.gtoreq.5 0/.gtoreq.6 0/.gtoreq.6
[0154] In further preferred embodiments, the margins of the serum
concentrations C.sub..alpha., C.sub..beta., C.sub..OMEGA.,
C.sub..delta., C.sub..epsilon. in the above tables, instead of
.+-.75%, are .+-.67%, more preferably .+-.50%, still more
preferably .+-.40% or .+-.35%, most preferably .+-.30% or .+-.25%
and in particular .+-.20%, .+-.15%, .+-.10% or .+-.5%.
[0155] When, for example, tapentadol is administered during a
second administration interval of .beta. days following a first
administration interval, after 24 hours providing a mean serum
concentration C.sub..beta. of tapentadol, this means that 24 hours
after having initiated the second administration interval, the mean
serum concentration has reached the value C.sub..beta.. Usually,
about 24 hours are needed to achieve steady state conditions within
a given administration interval when increasing (or decreasing) the
dose of tapentadol from the dose administered during the preceding
administration interval to the dose administered during the next
administration interval.
[0156] Further preferred embodiments of the medicament according to
the invention are described in connection with the further aspects
of the invention.
Pharmaceutical Excipients
[0157] Administration units A and B and the optionally present
administration units C, D and E of the medicament according to the
invention may each comprise 1 or more dosage forms, which in turn
may contain, besides tapentadol, additives and/or auxiliary
substances. Suitable additives and/or auxiliary substances in the
context of this invention include all those substances known to
persons skilled in the art for preparing galenical formulations.
The choice of these auxiliary substances and the amounts thereof to
be employed depend on whether the administration unit/dosage form
is to be administered orally, intravenously, intraperitoneally,
intradermally, intramuscularly, intranasally, buccally or locally.
Formulations in the form of tablets, chewable tablets, coated
tablets, capsules, granules, drops, juices or syrups are suitable
for oral administration, and solutions, suspensions, easily
reconstitutable dry formulations and sprays are suitable for
parenteral, topical and inhalatory administration. Suppositories
for use in the rectum are a further possibility. The use in a depot
in dissolved form, a carrier film or a patch, optionally with the
addition of agents which promote penetration through the skin, are
examples of suitable forms for percutaneous administration.
[0158] Examples of auxiliary substances and additives for the oral
administration units/dosage forms include disintegrating agents,
lubricants, binders, fillers, mold release agents, optionally
solvents, flavorings, sugars, in particular carrier agents,
diluents, dyestuffs, antioxidants etc. For suppositories, inter
alia, waxes and fatty acid esters can be used, and for compositions
for parental administration carrier substances, preservatives,
suspension auxiliaries etc. can be used.
[0159] The dosage forms comprise preferably 0.05 wt.-% to 99.5
wt.-% of tapentadol, more preferably 0.1 to 90 wt.-%, still more
preferably 0.5 to 80 wt.-%, most preferably 1.0 to 50 wt.-% and in
particular 5.0 to 20 wt.-%.
[0160] Auxiliary substances can be, for example: water, ethanol,
2-propanol, glycerol, ethylene glycol, propylene glycol,
polyethylene glycol, polypropylene glycol, glucose, fructose,
lactose, sucrose, dextrose, molasses, starch, modified starch,
gelatine, sorbitol, inositol, mannitol, microcrystalline cellulose,
methylcellulose, carboxymethyl cellulose, cellulose acetate,
shellac, cetyl alcohol, polyvinylpyrrolidone, paraffins, waxes,
naturally occurring and synthetic gums, gum acacia, alginates,
dextran, saturated and unsaturated fatty acids, stearic acid,
magnesium stearate, zinc stearate, glyceryl stearate, sodium lauryl
sulfate, edible oils, sesame oil, coconut oil, groundnut oil, soya
bean oil, lecithin, sodium lactate, polyoxyethylene and
polypropylene fatty acid esters, sorbitan fatty acid esters, sorbic
acid, benzoic acid, citric acid, ascorbic acid, tannic acid, sodium
chloride, potassium chloride, magnesium chloride, calcium chloride,
magnesium oxide, zinc oxide, silicon dioxide, titanium oxide,
titanium dioxide, magnesium sulfate, zinc sulfate, calcium sulfate,
potash, calcium phosphate, dicalcium phosphate, potassium bromide,
potassium iodide, talc, kaolin, pectin, crospovidone, agar and
bentonite.
[0161] The administration units/dosage forms according to the
invention may be controlled release, delayed release, prolonged
release/extended release, sustained release, repeat-action release,
etc. Prolonged release administration units/dosage forms are
preferred.
[0162] The administration units/dosage forms according to the
invention are prepared with the aid of means, devices, methods and
processes which are well-known in the prior art of pharmaceutical
formulation, such as are described, for example, in "Remington's
Pharmaceutical Sciences", ed. A. R. Gennaro, 17th ed., Mack
Publishing Company, Easton, Pa. (1985), in particular in part 8,
chapter 76 to 93.
[0163] Thus, e.g., for a solid formulation, such as a tablet,
tapentadol can be granulated with a pharmaceutical carrier, e.g.
conventional tablet constituents, such as maize starch, lactose,
sucrose, sorbitol, talc, magnesium stearate, dicalcium phosphate or
pharmaceutically acceptable gums, and pharmaceutical diluents, such
as e.g. water, in order to form a solid composition which comprises
tapentadol in homogeneous distribution. Homogeneous distribution is
understood here as meaning that tapentadol is uniformly distributed
over the entire composition, so that this can easily be divided
into unit dose forms, such as tablets, pills or capsules, having
the same activity. The solid composition is then divided into unit
dose forms. The administration units according to the invention can
also be coated or compounded in another manner in order to provide
a dose form with delayed release. Suitable coating compositions
are, inter alia, polymeric acids and mixtures of polymeric acids
with materials such as e.g. shellac, cetyl alcohol and/or cellulose
acetate.
[0164] Tapentadol can be released in a delayed or prolonged or
sustained manner from administration units/dosage forms which can
be used orally, rectally or percutaneously. Corresponding
formulations, in particular in the form of a "twice daily (bid)"
preparation which has to be taken only twice a day (bid), are
particularly preferred for the indication according to the
invention (cf. US-A-2005-58706).
[0165] Delayed or prolonged or sustained release of tapentadol may
be achieved by administration units/dosage forms which contain
tapentadol in a matrix, which contains e.g. 1 to 80% by weight, in
particular 5 to 80 by weight, of one or more hydrophilic or
hydrophobic polymers as pharmaceutically acceptable matrix forming
agents and which comprise cellulose ethers and/or cellulose esters
having a viscosity (determined using a Pharm. Eu. capillary
viscosimeter) of 3,000 to 150,000 mPa s in a 2% by weight aqueous
solution at 20.degree. C. as pharmaceutically acceptable matrix
forming agents. Preferred pharmaceutically acceptable matrix
forming agents include polyethylene oxide having a molecular mass
of more than 0.5 mio g/mol, cellulose ethers and/or cellulose
esters having a viscosity between 10,000, in particular 50,000 mPa
s, and 150,000 mPa s in a 2% by weight aqueous solution at
20.degree. C. Particularly suitable pharmaceutically acceptable
matrix forming agents may be selected from the group consisting of
hydroxypropylmethyl celluloses (HPMC), hydroxyethyl celluloses,
hydroxypropyl celluloses (HPC), methyl celluloses, ethyl celluloses
and carboxymethyl celluloses and are selected, in particular, from
the group consisting of HPMCs, hydroxyethyl celluloses and HPCs.
HPMCs having a viscosity of approximately 100,000 mPa s, measured
in a 2% by weight aqueous solution at 20.degree. C. are most
preferred.
[0166] The administration units/dosage forms according to the
invention can exist both as a simple tablet and as a coated tablet,
for example as a film tablet or dragee. The tablets are typically
round and biconvex, but oblong tablet shapes which allow the tablet
to be divided are also possible. Granules, spheroids, pellets or
microcapsules which are poured into sachets or capsules or may be
compressed to disintegrating tablets are also possible within the
scope of the invention.
[0167] Instead of a slow release matrix, it is also possible to use
a normal release matrix with a coating which retards release of the
active ingredient. For example, tapentadol can be contained in a
conventional matrix of microcrystalline cellulose and optionally
further pharmaceutical auxiliaries such as binders, fillers,
glidants, lubricants and flow regulators, which are covered or
coated with a material controlling the slow release of tapentadol
in an aqueous medium. Suitable coating agents include, for example,
water-insoluble waxes and polymers such as polymethacrylates
(Eudragit or the like) or water-insoluble celluloses, in particular
ethyl cellulose. The coating material can optionally also contain
water-soluble polymers such as polyvinyl pyrrolidone, water-soluble
celluloses such as hydroxypropylmethyl cellulose or hydroxypropyl
cellulose, other water-soluble agents such as Polysorbate 80 or
hydrophilic pore-forming agents such as polyethylene glycol,
lactose or mannitol.
[0168] As an alternative or a supplement to the possibilities of a
slow release matrix in the delayed release or prolonged release or
sustained release dosage forms or of a normal release matrix with a
coating which retards the release of tapentadol, an osmotically
driven release system can also be used to achieve a slow release.
Embodiments and examples of the actual production of osmotically
driven release systems can be found in U.S. Pat. No. 4,765,989,
U.S. Pat. No. 4,783,337, and U.S. Pat. No. 4,612,008.
Kit
[0169] A further aspect of the invention relates to a kit
comprising at least one administration unit A, at least one
administration unit B, optionally at least one administration unit
C, optionally at least one administration unit D and optionally at
least one administration unit E, as defined above. The kit
according to the invention preferably comprises a packaging
containing a plurality of administration units A each comprising
n.sub.A dosage forms, a plurality of administration units B each
comprising n.sub.B dosage forms, optionally a plurality of
administration units C each comprising n.sub.C dosage forms,
optionally a plurality of administration units D each comprising
n.sub.D dosage forms, and optionally a plurality of administration
units E each comprising n.sub.D dosage forms, where n.sub.A,
n.sub.B, optional n.sub.C, optional n.sub.D and optional n.sub.E
are preferably independently of one another 1, 2, 3, 4 or 5.
[0170] Preferably, the n.sub.X dosage form(s) belonging to a
particular administration unit X are grouped and/or marked and/or
locally separated from the other administration units and dosage
forms, respectively, that are contained in the packaging (cf. FIGS.
2 and 3).
[0171] In one preferred embodiment, all dosage forms contained in
the kit according to the invention are identical, i.e. contain the
same amount of tapentadol, and n.sub.A<n.sub.B<optional
n.sub.C<optional n.sub.D<optional n.sub.E, more preferably
n.sub.A=1, n.sub.B=2, optional n.sub.C=3, optional n.sub.D=4, and
optional n.sub.E=5. Preferably, dose a/n.sub.A=dose
b/n.sub.B=optional dose c/n.sub.C=optional dose d/n.sub.D=optional
dose e/n.sub.E.
[0172] In another preferred embodiment, the dosage forms that
belong to administration unit(s) A differ from the dosage forms
that belong to administration unit(s) B, which in turn differ from
the dosage forms that belong to administration unit(s) C, and so
on. Preferably, n.sub.A=n.sub.B=optional n.sub.C=optional
n.sub.D=optional n.sub.E=1 or 2 (cf. FIG. 4).
[0173] Preferably, the kit according to the invention comprises a
plurality of administration units and dosage forms, respectively,
suitable for administering dose a of tapentadol twice daily (bid)
for .alpha. days, then dose b of tapentadol twice daily (bid) for
.beta. days, then optionally dose c of tapentadol twice daily (bid)
for .OMEGA. days, then optionally dose d of tapentadol twice daily
for .delta. days, and then optionally dose e of tapentadol twice
daily for .epsilon. days, where a, b, c, d, e and .alpha., .beta.,
.OMEGA., .delta., .epsilon. satisfy any requirement selected from
the group of the above requirements P.sub.1-9, Q.sub.1-9, R.sub.1-9
and S.sub.1-9.
[0174] Further preferred embodiments of the kit according to the
invention are described in connection with the further aspects of
the invention.
Dosage Form Having a Predetermined Site of Fracture
[0175] Still another aspect of the invention relates to a
pharmaceutical oral dosage form containing tapentadol, which
comprises a notch that divides the dosage form into at least two
portions and mechanically weakens the dosage form so that it may be
manually broken at the notch along a predetermined site of fracture
(breaking notch). The dosage form is preferably adapted to be
administered twice daily (bid) and tapentadol is embedded in a
retard matrix. The matrix ensures that delayed release of
tapentadol from the dosage form is not diminished when breaking the
administration unit at the notch. The notch may be linear or assume
the shape of a cross. When the notch is linear, the dosage form may
be broken into two halves, which preferably have about the same
shape, size and content of tapentadol. When the notch assumes the
shape of a cross, the dosage form may be broken into two halves and
each have in turn may be broken into two quarts, which preferably
have about the same shape, size and content of tapentadol.
Preferably, the dosage form contains 40 to 260 mg of tapentadol.
Preferably, after being broken at the notch along the predetermined
site of fracture, each halve contains about 20 to about 130 mg of
tapentadol and each quart contains about 10 to about 65 mg of
tapentadol respectively.
[0176] The dosage form according to the invention may be used to
realize a titration regimen. For example, if tapentadol is to be
administered twice daily (bid) during the first administration
interval at a dose of 100 mg.+-.5% and during the second
administration interval at a dose of 200 mg.+-.5%, the dosage form
according to the invention may contain a total of 200 mg.+-.5% of
tapentadol. For administration during the first administration
interval, each dosage form is manually broken and only a halve
containing about 100 mg.+-.5% of tapentadol is administered. After
the first administration interval, the dosage form is not broken
anymore, but administered as such.
[0177] The individual fragments of the dosage form according to the
invention that are obtained when the dosage form is broken along
the notch preferably each contain a dose of tapentadol that
corresponds to any of doses a, doses b, doses c, doses d, and doses
e, respectively, as defined supra.
Method of Treating Pain
[0178] A further aspect of the invention relates to a method of
treating pain which comprises administering to one in need thereof
tapentadol according to a titration regimen, preferably by means of
the medicament according to the invention. Preferably, in the
regimen tapentadol is administered once daily (sid), twice daily
(bid), or thrice daily (tid), twice daily (bid) being particularly
preferred.
[0179] As far as the doses are concerned, each regimen may be
divided into a titration phase and a continuous phase. For the
purpose of the specification "titration" means that after a certain
administration interval, the dose of tapentadol is increased (or
decreased) until the optimal dose is reached.
[0180] The regimen may be static (forced) or dynamic. Preferably,
the regimen is dynamic, i.e. the dose is successively increased
until the optimal, pharmaceutically effective dose for the
individual subject has been reached. The optimal dose may vary
individually and also depends upon the type and degree of pain to
be treated. Preferably, the optimal dose is defined as the dose
providing a meaningful improvement of pain with acceptable side
effects in the patient's perception (maximum therapeutic benefit).
The regimen results in a lower incidence or severity of side
effects, such as somnolence.
[0181] Preferably, the subject monitors the achievement of
amelioration of pain and the occurrence of side effects caused by
the current dose of tapentadol. Depending upon the assessment of
the desired pain reduction on the one hand and the adverse events
on the other hand, the subject decides whether the dose of
tapentadol is [0182] further increased (next titration step
upwards), [0183] maintained at the current level (no further
titration step) or [0184] decreased (next titration step
downwards).
[0185] Preferably, during the titration phase tapentadol is
administered twice daily (bid) at a constant first (initial) dose
for a first administration interval. After said first
administration interval, tapentadol is administered twice daily
(bid) at a constant second dose for a second administration
interval, with the proviso that the second dose is higher than the
first dose.
[0186] After said second administration interval, the titration
phase may be terminated, i.e. administration of tapentadol may be
continued twice daily (bid) at said constant second dose, thereby
initiating the continuous phase. Under these circumstances, the
titration phase is terminated by the fact that the dose of
tapentadol that was administered during the second administration
interval is no further increased (or decreased). Alternatively,
after said second administration interval, the titration phase may
continue, i.e. tapentadol is administered twice daily (bid) at a
constant third dose for a third administration interval, with the
proviso that the third dose is higher than the second dose.
[0187] After said third administration interval, the titration
phase may be terminated, i.e. administration of tapentadol may be
continued twice daily (bid) at said constant third dose, thereby
initiating the continuous phase. Alternatively, after said third
administration interval, the titration phase may continue, i.e.
tapentadol is administered twice daily (bid) at a constant fourth
dose for a fourth administration interval. At this stage the dose
may be either further increased or decreased, depending on the
individual needs of the subject.
[0188] Preferably, the titration phase encompasses at least 2
administration intervals, preferably 3, 4 or 5 administration
intervals, at which different doses of tapentadol are administered,
preferably twice daily (bid), resulting in biphasic, triphasic,
tetraphasic and pentaphasic regimens, respectively.
[0189] Preferably, the titration phase of the dosing regimen
comprises at least 1, 2, 3, 4, 5, 6 or 7 days, more preferably at
least 14 days, still more preferably 7 to 28 days, most preferably
14 to 28 days and in particular 14 to 21 days.
[0190] In one preferred embodiment, the dosing regimen is biphasic
(two consecutive administration intervals), comprises 1, 2, 3, 4,
5, 6 or 7 to 28 days, more preferably 7 to 21 days and most
preferably 7 to 14 days, the dose of tapentadol at the first
administration interval is within the range of from 50 mg.+-.5% to
100 mg.+-.5%, preferably twice daily (bid), and the dose of
tapentadol at the second administration interval is within the
range of from 100 mg.+-.5% to 150 mg.+-.5%, preferably twice daily
(bid). Preferably, the second administration interval commences 2
to 11, more preferably 3 to 7 days after initiation of
administration of tapentadol.
[0191] In another preferred embodiment, the dosing regimen is
triphasic (three consecutive administration intervals), comprises
1, 2, 3, 4, 5, 6 or 7 to 28 days, more preferably 7 to 21 days and
most preferably 7 to 14 days, the dose of tapentadol at the first
administration interval is within the range of from 25 mg.+-.5% to
100 mg.+-.5%, preferably twice daily (bid), the dose of tapentadol
at the second administration interval is within the range of from
50 mg.+-.5% to 150 mg.+-.5%, preferably twice daily (bid), and the
dose of tapentadol at the third administration interval is within
the range of from 100 mg.+-.5% to 200 mg.+-.5%, preferably twice
daily (bid). Preferably, the second administration interval
commences 2 to 11, more preferably 3 to 7 days after initiation of
administration of tapentadol and the third administration interval
commences 5 to 22, more preferably 6 to 14 days after initiation of
administration of tapentadol.
[0192] In still another preferred embodiment, the dosing regimen is
tetraphasic (four consecutive administration intervals), comprises
1, 2, 3, 4, 5, 6 or 7 to 28 days, more preferably 7 to 21 days and
most preferably 14 to 21 days, the dose of tapentadol at the first
administration interval is within the range of from 25 mg.+-.5% to
100 mg.+-.5%, preferably twice daily (bid), the dose of tapentadol
at the second administration interval is within the range of from
50 mg.+-.5% to 150 mg.+-.5%, preferably twice daily (bid), the dose
of tapentadol at the third administration interval is within the
range of from 100 mg.+-.5% to 200 mg.+-.5%, preferably twice daily
(bid), and the dose of tapentadol at the fourth administration
interval is within the range of from 150 mg.+-.5% to 250 mg.+-.5%,
preferably twice daily (bid). Preferably, the second administration
interval commences 2 to 11, more preferably 3 to 7 days after
initiation of administration of tapentadol, the third
administration interval commences 5 to 16, more preferably 6 to 14
days after initiation of administration of tapentadol and the
fourth administration interval commences 8 to 22, more preferably 9
to 14 days after initiation of administration of tapentadol.
[0193] In yet another preferred embodiment, the dosing regimen is
pentaphasic (five consecutive administration intervals), comprises
1, 2, 3, 4, 5, 6 or 7 to 28 days, more preferably 7 to 21 days and
most preferably 14 to 21 days, the dose of tapentadol at the first
administration interval is within the range of from 25 mg.+-.5% to
50 mg.+-.5%, preferably twice daily (bid), the dose of tapentadol
at the second administration interval is within the range of from
50 mg.+-.5% to 100 mg.+-.5%, preferably twice daily (bid), the dose
of tapentadol at the third administration interval is within the
range of from 100 mg.+-.5% to 150 mg.+-.5%, preferably twice daily
(bid), the dose of tapentadol at the fourth administration interval
is within the range of from 150 mg.+-.5% to 200 mg.+-.5%,
preferably twice daily (bid), and the dose of tapentadol at the
fifth administration interval is within the range of from 200
mg.+-.5% to 250 mg.+-.5%, preferably twice daily (bid) Preferably,
the second administration interval commences 2 to 11, more
preferably 3 to 7 days after initiation of administration of
tapentadol, the third administration interval commences 5 to 16,
more preferably 6 to 14 days after initiation of administration of
tapentadol, the fourth administration interval commences 8 to 22,
more preferably 9 to 14 days after initiation of administration of
tapentadol, and the fifth administration interval commences 11 to
27, more preferably 12 to 17 days after initiation of
administration of tapentadol.
[0194] The individual doses that are to be administered may be
administered by a single administration unit containing the entire
dose or by a plurality of administration units each containing a
portion of said entire dose. For example, a dose of 100 mg
tapentadol may be administered either by a tablet containing 100 mg
or by two tablets each containing 50 mg.
[0195] The method for treating pain, preferably of chronic pain,
according to the invention follows a titration regimen. Preferably,
the method comprises administering to one in need thereof [0196]
dose a of tapentadol, preferably once daily (sid), twice daily
(bid) or thrice daily (tid), during a first administration interval
and [0197] dose b of tapentadol, preferably once daily (sid), twice
daily (bid) or thrice daily (tid), [0198] during a second
administration interval following the first administration
interval, where dose a<dose b.
[0199] Preferably, the first administration interval and the second
administration interval last independently of one another at least
1 day, more preferably at least 2 days and in particular at least 3
days.
[0200] Preferably, tapentadol is administered orally. Preferably,
tapentadol is administered twice daily (bid). Preferably, dose a is
within the range of from 10 to 90 wt.-% of dose b, more preferably
from 20 to 80 wt.-%, still more preferably from 45 to 70 wt.-%.
[0201] In one preferred embodiment, the method according to the
invention further comprises orally administering dose c of
tapentadol once daily (sid), twice daily (bid) or thrice daily
(tid) during a third administration interval following the second
administration interval, where dose b<dose c. Preferably, dose a
is within the range of from 10 to 65 wt.-% of dose c, more
preferably from 20 to 55 wt.-%, and dose b is within the range of
from 35 to 90 wt.-% of dose c, more preferably from 45 to 80
wt.-%.
[0202] In a further preferred embodiment, the method according to
the invention further comprises orally administering dose d of
tapentadol once daily (sid), twice daily (bid) or thrice daily
(tid) during a fourth administration interval following the third
administration interval, where dose c<dose d (or where dose
c>dose d). Preferably, dose a is within the range of from 10 to
55 wt.-% of dose d, more preferably 15 to 50 wt.-%, dose b is
within the range of from 35 to 75 wt.-% of dose d, more preferably
40 to 70 wt.-%, and dose c is within the range of from 60 to 95
wt.-% of dose d, more preferably 65 to 90 wt.-%.
[0203] In a still further preferred embodiment, the method
according to the invention further comprises orally administering
dose e of tapentadol once daily (sid), twice daily (bid) or thrice
daily (tid) during a fifth administration interval following the
fourth administration interval, where dose d<dose e (where dose
d>dose e). Preferably, dose a is within the range of from 10 to
30 wt.-% of dose e, more preferably 15 to 25 wt.-%, dose b is
within the range of from 30 to 50 wt.-% of dose e, more preferably
35 to 45 wt.-%, dose c is within the range of from 50 to 70 wt.-%
of dose e, more preferably 55 to 65 wt.-%, and dose d is within the
range of from 70 to 90 wt.-% of dose e, more preferably 75 to 85
wt.-%.
[0204] Preferably, the first administration interval, second
administration interval, optional third administration interval,
optional fourth administration interval and optional fifth
administration interval comprise independently of one another 1 to
21 days, more preferably 2 to 14 days.
[0205] Preferably, the method according to the invention comprises
administering [0206] (i) dose a of tapentadol once daily (sid),
twice daily (bid) or thrice daily (tid) during a first
administration interval of at least 2 days, preferably at least 3
days, [0207] (ii) dose b of tapentadol once daily (sid), twice
daily (bid) or thrice daily (tid) during a second administration
interval of at least 2 days, preferably at least 3 days, following
the first administration interval, [0208] (iii) optionally, dose c
of tapentadol once daily (sid), twice daily (bid) or thrice daily
(tid) during a third administration interval of at least 2 days,
preferably at least 3 days, following the second administration
interval, [0209] (iv) optionally, dose d of tapentadol once daily
(sid), twice daily (bid) or thrice daily (tid) during a fourth
administration interval of at least 2 days, preferably at least 3
days, following the third administration interval, and [0210] (v)
optionally, dose e of tapentadol once daily (sid), twice daily
(bid) or thrice daily (tid) during a fifth administration interval
of at least 2 days, preferably at least 3 days, following the
fourth administration interval.
[0211] Preferably, the number of administrations per day is
harmonized, i.e. when during the first administration interval
tapentadol is administered twice daily (bid), during the second
administration interval tapentadol is preferably also administered
twice daily (bid), i.e. neither once daily (sid) nor thrice daily
(tid).
[0212] In one preferred embodiment of the method according to the
invention, dose a, dose b, optional dose c, optional dose d and
optional dose e are independently selected so that the daily dose
of tapentadol on every day of every administration interval is
within the range of from 20 to 550 mg, more preferably 30 to 530 mg
and most preferably 40 to 510 mg.
[0213] Particularly preferably, the method according to the
invention comprises orally administering [0214] (i) dose a of
tapentadol twice daily (bid) during a first administration interval
of at least a consecutive days, [0215] (ii) dose b of tapentadol
twice daily (bid) during a second administration interval of at
least .beta. consecutive days following the first administration
interval, [0216] (iii) optionally, dose c of tapentadol twice daily
(bid) during a third administration interval of at least .OMEGA.
consecutive days following the second administration interval,
[0217] (iv) optionally, dose d of tapentadol twice daily (bid)
during a fourth administration interval of at least .OMEGA.
consecutive days following the third administration interval, and
[0218] (v) optionally, dose e of tapentadol twice daily (bid)
during a fifth administration interval of at least .epsilon.
consecutive days following the fourth administration interval;
where a, b, c, d, e and .alpha., .beta., .OMEGA., .delta.,
.epsilon. satisfy any requirement selected from the group of
requirements P.sub.1-9, Q.sub.1-9, R.sub.1-9 and S.sub.1-9 as
described supra.
[0219] In a particularly preferred embodiment, subjects initiate
treatment with tapentadol, orally administered twice daily (bid),
at a dose of 50 mg.+-.5%. After 3 days the dose is increased to 100
mg.+-.5%. This is the minimum dose to be continued with. To the
discretion of the subject, upward titration may then occur at a
minimum of 3-day intervals (6 consecutive doses) in increments of
50 mg.+-.5%. The maximum dose allowed is preferably 250 mg.+-.5%.
To the discretion of the subject, downward titration (preferably
not below the minimum dose) is also permitted using the same
decrements without a time restriction.
[0220] In still another particularly preferred embodiment subjects
initiate treatment with tapentadol, orally administered twice daily
(bid), at a dose of 50 mg.+-.5%. After 3 days the dose is increased
to 100 mg.+-.5%. This is the minimum dose to be continued with. The
subject remains on the 100 mg.+-.5% dose for the next 4 days.
Thereafter, to the discretion of the subject, upward titration may
occur at a minimum of 3-day intervals (6 consecutive doses) in
increments of 50 mg.+-.5%. The maximum dose allowed is preferably
250 mg.+-.5%. To the discretion of the subject, downward titration
(preferably not below the minimum dose) is also permitted using the
same decrements without a time restriction.
[0221] The two foregoing embodiments are particularly useful for
the treatment of chronic pain, especially due to osteoarthritis
(hip or knee), low back pain, painful diabetic peripheral
neuropathy (DPN) and malignant pain.
[0222] In another particularly preferred embodiment subjects
initiate treatment with tapentadol, orally administered twice daily
(bid), at a dose of 100 mg.+-.5%. This is the minimum dose to be
continued with. To the discretion of the subject, upward titration
may then occur at a minimum of 3-day intervals (6 consecutive
doses) in increments of 50 mg.+-.5%. The maximum dose allowed is
preferably 250 mg.+-.5%. To the discretion of the subject, downward
titration (preferably not below the minimum dose) is also permitted
using the same decrements without a time restriction. This
embodiment is particularly useful for the treatment of chronic
pain, especially chronic malignant tumor-related pain.
[0223] Preferably, the usual initial dose is 50 mg of tapentadol
prolonged release (PR) twice daily (bid). Patients are individually
titrated to the optimal individual dose, which is defined as the
dose providing a meaningful improvement of pain with acceptable
side effects in the patient's perception (maximum therapeutic
benefit). Upward titration may occur at intervals in increments of
50 mg tapentadol prolonged release (PR) twice daily (bid). Downward
titration should use the same decrements. The dose used should be
the lowest dose that provides pain relief. Tapentadol may be
administered with or without food.
[0224] Preferably, the usual initial dose is 50 mg of tapentadol
prolonged release (PR) twice daily (bid). Patients are individually
titrated to the optimal individual dose, which is defined as the
dose providing a meaningful improvement of pain with acceptable
side effects in the patient's perception (maximum therapeutic
benefit). Upward titration may occur at a minimum of 3-day
intervals (6 consecutive doses) in increments of 50 mg tapentadol
prolonged release (PR) twice daily (bid). Downward titration using
the same decrements can be performed without a time restriction.
The dose used should be the lowest dose that provides pain relief.
The maximum dose is 250 mg tapentadol prolonged release (PR) twice
daily (bid). Tapentadol may be administered with or without
food.
[0225] In another preferred embodiment of the method according to
the invention, dose a, dose b, optional dose c, optional dose d and
optional dose e are independently selected so that the mean serum
concentration of tapentadol is within the range of from 0.1 to
10,000 ng/ml, more preferably 1.0 to 9,000 ng/ml, still more
preferably 2.0 to 8,000 ng/ml, most preferably 3.0 to 1,000 ng/ml
and in particular 5.0 to 300 ng/ml at any point in time, except the
initial phase of one, two or three days.
[0226] In a preferred embodiment of the method according to the
invention, [0227] tapentadol is administered, preferably twice
daily (bid), during a first administration interval of .alpha.
days, after 24 hours providing a mean serum concentration Ca of
tapentadol; [0228] then tapentadol is administered, preferably
twice daily (bid), during a second administration interval of 3
days following said first administration interval, after 24 hours
providing a mean serum concentration C.beta. of tapentadol; then,
optionally, tapentadol is administered, preferably twice daily
(bid), during a third administration interval of .OMEGA. days
following said second administration interval, after 24 hours
providing a mean serum concentration C.sub.X of tapentadol; [0229]
then, optionally, tapentadol is administered, preferably twice
daily (bid), during a fourth administration interval of 8 days
following said third administration interval, after 24 hours
providing a mean serum concentration C.sub.8 of tapentadol; and,
[0230] then, optionally, tapentadol is administered, preferably
twice daily (bid), during a fifth administration interval of
.epsilon. days following said fourth administration interval, after
24 hours providing a mean serum concentration C.sub..epsilon. of
tapentadol, where .alpha., .beta., .OMEGA., .delta., .epsilon. and
C.sub..alpha., C.sub..beta., C.sub..OMEGA., C.sub..delta.,
C.sub..epsilon. satisfy any requirement selected from the group of
requirements T.sub.1-9, U.sub.1-9, V.sub.1-9 and W.sub.1-9:
TABLE-US-00003 [0230] [ng/ml] d T.sub.1 T.sub.2 T.sub.3 T.sub.4
T.sub.5 T.sub.6 T.sub.7 T.sub.8 T.sub.9 C.sub..alpha. = 9 .+-. 75%
.alpha. .gtoreq.2 .gtoreq.2 .gtoreq.2 .gtoreq.3 .gtoreq.3 .gtoreq.3
.gtoreq.4 .gtoreq.4 .gtoreq.4 C.sub..beta. = 18 .+-. 75% .beta.
.gtoreq.2 .gtoreq.2 .gtoreq.3 .gtoreq.3 .gtoreq.3 .gtoreq.4
.gtoreq.4 .gtoreq.4 .gtoreq.5 C.sub..chi. = 35 .+-. 75% .chi.
.gtoreq.2 .gtoreq.3 .gtoreq.3 .gtoreq.3 .gtoreq.4 .gtoreq.4
.gtoreq.4 .gtoreq.5 .gtoreq.5 C.sub..delta. = 55 .+-. 75% .delta.
0/.gtoreq.2 0/.gtoreq.3 0/.gtoreq.3 0/.gtoreq.3 0/.gtoreq.4
0/.gtoreq.4 0/.gtoreq.4 0/.gtoreq.5 0/.gtoreq.5 C.sub..epsilon. =
69 .+-. 75% .epsilon. 0/.gtoreq.2 0/.gtoreq.3 0/.gtoreq.3
0/.gtoreq.3 0/.gtoreq.4 0/.gtoreq.4 0/.gtoreq.4 0/.gtoreq.5
0/.gtoreq.5 [ng/ml] d U.sub.1 U.sub.2 U.sub.3 U.sub.4 U.sub.5
U.sub.6 U.sub.7 U.sub.8 U.sub.9 C.sub..alpha. = 18 .+-. 75% .alpha.
.gtoreq.2 .gtoreq.2 .gtoreq.3 .gtoreq.3 .gtoreq.4 .gtoreq.4
.gtoreq.5 .gtoreq.5 .gtoreq.6 C.sub..beta. = 35 .+-. 75% .beta.
.gtoreq.2 .gtoreq.2 .gtoreq.3 .gtoreq.4 .gtoreq.4 .gtoreq.5
.gtoreq.5 .gtoreq.6 .gtoreq.6 C.sub..chi. = 55 .+-. 75% .chi.
0/.gtoreq.2 0/.gtoreq.2 0/.gtoreq.3 0/.gtoreq.4 0/.gtoreq.4
0/.gtoreq.5 0/.gtoreq.5 0/.gtoreq.6 0/.gtoreq.6 C.sub..delta. = 69
.+-. 75% .delta. 0/.gtoreq.2 0/.gtoreq.2 0/.gtoreq.3 0/.gtoreq.4
0/.gtoreq.4 0/.gtoreq.5 0/.gtoreq.5 0/.gtoreq.6 0/.gtoreq.6
C.sub..epsilon. = 90 .+-. 75% .epsilon. 0/.gtoreq.2 0/.gtoreq.2
0/.gtoreq.3 0/.gtoreq.4 0/.gtoreq.4 0/.gtoreq.5 0/.gtoreq.5
0/.gtoreq.6 0/.gtoreq.6 [ng/ml] d V.sub.1 V.sub.2 V.sub.3 V.sub.4
V.sub.5 V.sub.6 V.sub.7 V.sub.8 V.sub.9 C.sub..alpha. = 18 .+-. 75%
.alpha. .gtoreq.2 .gtoreq.2 .gtoreq.3 .gtoreq.3 .gtoreq.4 .gtoreq.4
.gtoreq.5 .gtoreq.5 .gtoreq.6 C.sub..beta. = 35 .+-. 75% .beta.
.gtoreq.2 .gtoreq.3 .gtoreq.3 .gtoreq.4 .gtoreq.4 .gtoreq.5
.gtoreq.5 .gtoreq.6 .gtoreq.6 C.sub..chi. = 69 .+-. 75% .chi.
0/.gtoreq.2 0/.gtoreq.3 0/.gtoreq.3 0/.gtoreq.4 0/.gtoreq.4
0/.gtoreq.5 0/.gtoreq.5 0/.gtoreq.6 0/.gtoreq.6 [ng/ml] d W.sub.1
W.sub.2 W.sub.3 W.sub.4 W.sub.5 W.sub.6 W.sub.7 W.sub.8 W.sub.9
C.sub..alpha. = 35 .+-. 75% .alpha. .gtoreq.2 .gtoreq.2 .gtoreq.3
.gtoreq.3 .gtoreq.4 .gtoreq.4 .gtoreq.5 .gtoreq.5 .gtoreq.6
C.sub..beta. = 55 .+-. 75% .beta. .gtoreq.2 .gtoreq.3 .gtoreq.3
.gtoreq.4 .gtoreq.4 .gtoreq.5 .gtoreq.5 .gtoreq.6 .gtoreq.6
C.sub..chi. = 69 .+-. 75% .chi. 0/.gtoreq.2 0/.gtoreq.3 0/.gtoreq.3
0/.gtoreq.4 0/.gtoreq.4 0/.gtoreq.5 0/.gtoreq.5 0/.gtoreq.6
0/.gtoreq.6 C.sub..delta. = 90 .+-. 75% .delta. 0/.gtoreq.2
0/.gtoreq.3 0/.gtoreq.3 0/.gtoreq.4 0/.gtoreq.4 0/.gtoreq.5
0/.gtoreq.5 0/.gtoreq.6 0/.gtoreq.6
[0231] In further preferred embodiments, the margins of the serum
concentrations C.sub..alpha., C.sub..beta., C.sub..OMEGA.,
C.sub..delta., C.sub..epsilon. in the above tables, instead of
.+-.75%, are .+-.67%, more preferably .+-.50%, still more
preferably .+-.40% or .+-.35%, most preferably .+-.30% or .+-.25%
and in particular .+-.20%, .+-.15%, .+-.10% or .+-.5%. Usually,
about 24 hours are needed to achieve steady state conditions within
a given administration interval when increasing (or decreasing) the
dose of tapentadol from the dose administered during the preceding
administration interval to the dose administered during the next
administration interval.
[0232] As already mentioned above, the overall dosing regimen
typically comprises a titration phase followed by a continuous
phase. In a preferred embodiment, the overall dosing regimen
(titration phase+continuous phase) includes at least 10 consecutive
days, more preferably at least 20 consecutive days, still more
preferably at least 30 consecutive days, yet more preferably at
least 50 consecutive days, most preferably at least 70 consecutive
days and in particular at least 90 consecutive days.
[0233] In one preferred embodiment the overall administration is
terminated after the titration phase and the subsequent continuous
phase have been completed, i.e., after the continuous phase
preferably no second titration phase (e.g., downward titration,
drug tapering) is supplemented. In other words, at the end of the
overall dosing regimen the administration of tapentadol is
preferably terminated at once, i.e. from the full dose (last
regular dose) at the continuous phase down to zero without any
intermediate doses.
[0234] It has been surprisingly found that for tapentadol at the
end of a long term dosing regimen, the occurrence of mild-moderate
withdrawal symptoms following drug discontinuation are
significantly fewer compared to other opioids, such as oxycodone.
Thus, there is little indication of the need for drug tapering
(downward titration) at the end of the overall dosing regimen.
[0235] Further preferred embodiments of the method according to the
invention are described in connection with the further aspects of
the invention.
[0236] The titration of tapentadol is effective in reducing
discontinuations due to adverse effects while maintaining the
analgesic properties of the compound. This is particularly true in
the case of patients who previously had difficulty tolerating an
analgesic because of side effects such as somnolence. This result
is based on the cumulative proportion of patients who discontinued
use of the agent due to adverse side effects.
EXAMPLES
[0237] The following examples describe the invention in greater
detail and are intended to illustrate the invention but not to
limit its scope.
A) Comparative Example C-1
Without Titration
Design:
[0238] A randomized, double-blind, multiple dose, parallel-group
study assessing the efficacy and safety of 3 dosages of tapentadol
prolonged release (bid) (25 mg, 50 mg and 100 mg) compared to
oxycodone prolonged release (bid) 20 mg and placebo over 28 days in
patients with hip and/or kneejoint osteoarthritis.
Subjects:
[0239] 40-75 years old, male and female patients.
[0240] 375 patients, randomized to placebo, standard opioid,
tapentadol.
Treatment Regimen:
[0241] Day 1 only evening dose
Day 2-Day 28 bid
[0242] Day 29 only morning dose.
B) Comparative Example C-2
Without Titration
Design:
[0243] A randomized, double-blind, multiple dose, parallel-group
study assessing the efficacy and safety of tapentadol prolonged
release 25, 50 and 100 mg compared to placebo and tramadol
prolonged release 100 mg in patients with chronic low back
pain.
Subjects:
[0244] Male and female patients 18-75 years old with a history of
low back pain of at least 6 months, requiring regular treatment on
at least 60 out of last 90 days.
[0245] 430 patients, randomized to placebo, tramadol 100 mg
prolonged release, 3 dosages tapentadol.
Treatment Regimen:
[0246] Daily bid for 28 days
C) Example E-1
Forced Titration
Static Regimen
Design:
[0247] A randomized, double-blind, parallel-group study assessing
the efficacy and safety of two titration regimen of tapentadol
prolonged release (25 mg, 50 mg, 100 mg and 100 mg, 150 mg, 200 mg
of free base of tapentadol) given orally twice daily (bid) compared
to placebo and oxycodone controlled release (10 mg, 10 mg, 20 mg)
in patients with chronic pain due to osteoarthritis of the
knee.
Subjects:
[0248] Male and female patients .gtoreq.40 years old with a
diagnosis of osteoarthritis of the knee
Treatment Regimen:
[0249] Patients started with the lowest dose of the titration phase
for the first 3 days and up-titrated to the intermediate dose on
day 4. Subjects were maintained at the intermediate dose for the
next 11 days. After these 11 days patients started the maintenance
phase and received the highest dose of each regimen for the
remaining 14 days. Subjects who were unable to tolerate the highest
dose after having received that dose for at least 3 days were
allowed to down titrate to the intermediate dose. Down titration
was permitted only once during the fixed-dose maintenance
phase.
D) Example E-2
Forced Titration
Static Regimen
Design:
[0250] A randomized, double-blind, parallel-group study that
compares the efficacy and safety of two titration regimens of
tapentadol prolonged release (25 mg-50 mg-100 mg and 100 mg-150
mg-200 mg) given orally twice daily (bid) and tramadol prolonged
release (100 mg-150 mg-200 mg) p.o. bid to placebo in patients with
moderate to severe chronic pain due to chronic low back pain.
Subjects:
[0251] Male and female patients .gtoreq.18 years old with a
diagnosis of low back pain of at least 3 months.
Treatment Regimen:
[0252] Patients took the first dose and continued on the lowest
dose in their treatment regimen for 3 days (i.e. 6 doses). After
the sixth dose, patients titrated to the intermediate dose in their
treatment regimen and continued on this intermediate dose for 11
days (i.e. 22 doses). Up-titration was mandatory. Patients who were
unable to tolerate study medication were removed from the study.
After the twenty second dose, patients titrated to the final dose
in their treatment regimen and continued on this final dose for 14
days.
E) Using Modeling & Simulation (M&S) to Estimate the
Influence of Dose Titration with Tapentadol on the Occurrence of
Somnolence
[0253] PK/PD modeling and simulation were used to investigate if
dose titration would bring a benefit for the development of adverse
events. The estimation of advantage of dose titration was based on
somnolence as an indicator for typical opioid related adverse
events. It was also one of the adverse events most commonly
occurring and therefore enabling a modeling and simulation with
enough reliability.
[0254] Concentration measurements were taken from comparative
examples C-1 and C-2, both without dose titration. Examples E-1 and
E-2 in the same indications were used to get PK/PD information
under dose titration. In all studies adverse events were noted.
[0255] A population PK model was build over all studies using
NONMEM V level 1.1 and a population PK/PD model was build for
somnolence for studies of examples E-1 and E-2. Simulations were
performed using Trial Simulator 2.1, taking into account the PK/PD
model for somnolence established for the data from the studies of
examples E-1 and E-2 and the population PK model without covariates
for all 4 studies.
Results PK/PD Somnolence:
[0256] FIG. 5 (Tapentadol--observations of somnolence versus
concentration with a 2 degree polynomial fitting) and FIG. 6
(Tapentadol--observations of somnolence versus concentration with a
6 degree polynomial fitting) clearly show that despite the dosages
and concentrations being clearly lower in the studies of
comparative examples C-1 and C-2, adverse events occurred typically
at a much lower concentration compared to the studies of examples
E-1 and E-2 in which dose titration was used.
[0257] From FIG. 6 it can be seen that in the range of
concentrations where enough somnolence was present the curves for
the studies with and without dose titration run almost in parallel
but shifted to lower concentrations if no titration was applied.
The downward bend at the end of the polynomial regression is caused
by a lack of high concentrations, a phenomenon normally seen with a
high degree polynomial.
[0258] Due to the similarity of the curves and the lower number of
data points in the studies of comparative examples C-1 and C-2 no
model was build for this PK/PD relationship. Instead, the numbers
found for examples E1 and E2 were adapted so the results of
simulating the comparative examples C-1 and C-2 would resemble the
curve in FIGS. 5 and 6.
[0259] The following equations, obtained by modeling was used to
establish the probability for somnolence for the dose
titration:
Logit=-3.4+0.000445*Concentration 0.74
[0260] For fixed dose the following equation was derived from the
equation above based on FIGS. 5 and 6:
Logit=-3.4+0.0009*Concentration 1.74
[0261] FIG. 7 shows a schematic illustration of the titration
regimen used for tapentadol in the clinical studies.
Results PK/PD Simulations:
[0262] The population PK model together with the relationship
between concentrations and somnolence was used to simulate 2000
patients, 1000 patients with dose titration (1 week 58 mg, 1 week
116 mg, 2 weeks 233 mg tapentadol HCl) and 1000 patients without
dose titration (4 weeks at 233 mg). It was simulated what the
probability in both designs would be when the subject was asked
whether he had somnolence three times a day for seven days during
the 4.sup.th week of treatment. Drop outs were not taken into
account in the simulation procedures.
[0263] Result clearly indicate that the number of somnolence
episodes was much lower in the group that was having dose
titration. Overall the number of somnolence episodes in the last
week of treatment was 15.5% in the group with dose titration versus
33.2% in the group with fixed dose. Mean of the concentrations on
each of the times the question for somnolence was asked reached
were almost identical in the two dose groups. When just looking at
the last concentration at the last visit the incidence of
somnolence was 7.6% in the dose titration group versus 12.9% in the
fixed dose group.
[0264] In the studies which did not use titration somnolence
occurred in 4.3% of patients at a total daily dose of 172 mg
tapentadol base (pooled data from both studies). However, in the
studies using forced titration somnolence occurred in 6% of
patients at a total daily dose of 200 mg, and in 12% of patients at
a total daily dose of 400 mg tapentadol base (pooled data).
F) Comparison
Titration of Oxycodone
[0265] FIG. 8 (oxycodone--observations of somnolence versus
concentration with a linear fitting) indicates that when
administering oxycodone according to the titration regimen of
example E-1, there is no comparable effect on the suppression of
somnolence.
G) Serum Concentrations of Tapentadol
[0266] FIGS. 9 A/B show a mathematical analysis of the distribution
of concentrations of tapentadol (ng/ml) after administration in the
comparative clinical trials (comparative examples C-1 and C-2).
[0267] FIGS. 10 A/B show a mathematical analysis of the
distribution of concentrations of tapentadol (ng/ml) after
administration in the clinical trials according to the invention
(examples E-1 and E-2).
H) Example E-3
End of Administration Regimen
[0268] The symptoms of opioid withdrawal following long-term
treatment (90 days) with tapentadol immediate release (IR) compared
with oxycodone IR were evaluated in a randomized, double-blind,
active-control, parallel group, flexible dose, multicenter phase
III trial of patients with chronic low back pain of chronic pain
from osteoarthritis of the knee or hip. Patients (N=849) were
randomly assigned in a 4:1 ratio to a flexible dose of
tapentadol
[0269] IR (50 or 100 mg/dose; maximum 600 mg/day) or oxycodone IR
(10 or 15 mg/dose; maximum 90 mg/day) every 4 to 6 hours. Symptoms
of withdrawal following opioid discontinuation were examined using
the Clinical Opioid Withdrawal Score (COWS) and the Subjective
Opioid Withdrawal Score (SOWS) questionnaires. Based on the COWS
assessment 2 to 4 days after study medication ceased, patients
reporting mild-to-moderate withdrawal symptoms were significantly
less in the tapentadol IR group (17%) than the oxycodone IR group
(29%; nominal P<0.05 using Cochran-Mantel-Haenszel test). The
mean total SOWS score, 2 to 4 days after last study drug intake,
was lower for the tapentadol IR group (6.9) than the oxycodone IR
group (8.7). The corresponding P value (analysis of variance model)
revealed no significant difference between the treatment groups. In
addition, 5 or more days after last study drug intake, the mean
total SOWS score was 6.3 for the tapentadol IR group and 7.0 for
the oxycodone IR group (no significant difference). These findings
suggest that although there is a possibility of withdrawal, there
is little indication of the need for drug tapering.
[0270] The foregoing description and examples have been set forth
merely to illustrate the invention and are not intended to be
limiting. Since modifications of the described embodiments
incorporating the spirit and substance of the invention may occur
to persons skilled in the art, the invention should be construed
broadly to include all variations within the scope of the appended
claims and equivalents thereof.
* * * * *