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Titration of Tapentadol

a technology of tapentadol and dosing regimen, which is applied in the direction of biocide, nervous disorder, drug composition, etc., can solve the problems of 20,000 deaths each year, affecting the safety of chronic nsaid therapy, and potentially serious side effects, so as to reduce the frequency of somnolence, improve the tolerability of tapentadol, and reduce the effect of drug efficacy

Inactive Publication Date: 2009-01-08
GRUNENTHAL GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[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.
[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.

Problems solved by technology

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.
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.
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 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.
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.

Method used

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  • Titration of Tapentadol
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  • Titration of Tapentadol

Examples

Experimental program
Comparison scheme
Effect test

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.

example e-1

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 ≧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...

example e-3

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 ox...

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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.

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 ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/137A61P25/00
CPCA61K31/137A61P25/04A61K9/0053
Inventor LANGE, CLAUDIAROMBOUT, FERDINAND
Owner GRUNENTHAL GMBH
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