Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-10-12
2002-01-15
Rose, Shep K. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
active
06339105
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a dosing regimen for the administration of the analgesic tramadol. The dosing regimen achieves the desired analgesic effect while reducing or delaying the on-set of the side effects generally associated with the administration of tramadol.
BACKGROUND OF THE INVENTION
Tramadol, the chemical name for which is 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol, is a synthetic, centrally-acting analgesic that is effective for the treatment of moderate to moderately-severe chronic pain. It has been marketed under the trade name Tramal™ since 1977 in the dosage forms of capsules, injections, suppositories and drops. The compound can be employed as the free base or its pharmaceutically acceptable salts, stereo isomers and solvates. It is generally supplied in the form of its hydrochloride salt and over 400 million doses of tramadol have been administered since its introduction in Germany.
Patients experiencing 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 chronic use of narcotics such as morphine and codeine for the treatment of 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. An alternative to this dilemma is tramadol, a non-narcotic, non-NSAID analgesic which is indicated for the management of moderate to moderately-severe pain.
After oral administration, tramadol is rapidly and almost completely absorbed and is extensively metabolized. The major metabolic pathways appear to be N- and O-demethylation and glucuronidation or sulfation in the liver. Only one metabolite, i.e. mono-O-desmethyltramadol, has been found to be pharmacologically active.
After a single 100 mg oral dose in healthy subjects, peak plasma concentrations of tramadol hydrochloride occurring two hours after administration are 308±78 ng/ml mean±standard deviation). Peak plasma concentrations of mono-O-desmethyl tramadol, the active metabolite of tramadol, are 55±20 ng/ml, occurring approximately three hours after administration. The terminal plasma elimination half-lives of tramadol hydrochloride and its active metabolite are 6.3±11.4 hours and 7.4±1.4 hours respectively. Tramadol is poorly bound to plasma proteins (20.2%) thus decreasing the potential for drug interactions with highly protein-bound agents.
The mode of action of tramadol is not completely understood, but in animal models at least two complementary mechanisms appear to be involved and they are 1) weak binding to the &mgr; opioid receptors and 2) weak inhibition of the reuptake of norepinephrine and serotonin. Tramadol is not chemically related to opiates, but its actions are similar to those of opioid (narcotic) analgesics. The opioid activity of tramadol results from the low-affinity binding of tramadol hydrochloride and the higher affinity binding of the metabolite to &mgr; receptors; however, its induced antinociception is only partially antagonized by the opiate antagonist naloxone in several animal tests. The inhibition of norepinephrine and serotonin reuptake, which has been demonstrated in vitro, is postulated to contribute independently to the overall analgesic profile of tramadol hydrochloride.
Tramadol is well tolerated, however, nuisance adverse events such as drowsiness, vomiting and dizziness can occur 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 tramadol hydrochloride are constipation, nausea, dizziness/vertigo, headache, somnolence, and vomiting. Taken together, the efficacy, safety, and pharmacokinetic profile of tramadol hydrochloride indicate that the drug may be useful in treating chronic pain.
An object of the present invention is to demonstrate that the frequency of nausea and vomiting, two of the most frequently reported adverse events and the events most commonly associated with discontinuation of treatment, as well other adverse events, can be reduced using a lower dosage titration scheme without diminishing the efficacy of the compound.
The present invention relates to a dosage regimen which consists of slowing the titration rate for tramadol which results in a reduction of the incidence of discontinuation due to side effects such as nausea and vomiting.
SUMMARY OF THE INVENTION
The present invention relates to a dosage regimen for tramadol which involves a slower titration rate than that currently prescribed. The slower rate of titration of tramadol therapy results in improved tolerability of the drug. The novel regimen results in a significant reduction in discontinuations due to a lower incidence or severity of side effects. As used hereinafter, the word tramadol is intended to include its pharmaceutically acceptable salts, stereo isomers and solvates thereof.
DETAILED DESCRIPTION OF THE INVENTION
Tramadol is indicated for the treatment of moderate to moderately-severe pain and its typical dosing regimen is 50-100 mg every 4 to 6 hours. About 200 mg/day is considered to be a normal initial dose. Clinical studies have shown tramadol to be an effective treatment for chronic joint pain. Tramadol is well tolerated, however, nuisance adverse events can occur during initiation of treatment with tramadol. These side effects may lead to early discontinuation of tramadol therapy.
Slow titration of a therapeutic agent is often used by practicing clinicians to minimize adverse events associated with centrally-acting agents such as antidepressants, analgesics and anticonvulsants. Although slow 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. It has now been discovered that initiating tramadol therapy using slow titration rates according to the regimen of this invention minimizes discontinuations due to adverse side effects associated with tramadol while maintaining its therapeutic effectiveness which results in a greater tolerance of the drug during therapy.
The regimen which is the basis of the present invention is a 1-28 day regimen. In practice, tramadol is administered over a ten-28 day period starting on day one in a pharmaceutical composition containing from about 10-50 mg of tramadol and the amount of drug is increased incrementally over the next 9-28 days until the target dose of about 200-400 mg/day is reached. Many patients find effective pain relief at 200 mg/day, however, some patients may require doses of up to 400 mg/day in order to achieve the desired relief. Generally, on days 1-3 of the regimen tramadol, in the form of the free base or its pharmaceutically acceptable salt, is administered at a dose of about 10-50 mg. On days 4-6 of the regimen tramadol is administered at a dose in the range of about 20-100 mg. On days 7-9 tramadol is administered at a dose in the range of about 30-150 mg and on days 10-28 and thereafter at a dose of about 40-400 mg. At the end of the period the therapy is continued at the target dose which may be anywhere from 200 to about 400 mg of tramadol.
In a preferred embodiment of the invention tramadol is administered in a regimen which comprises administering tramadol at the rate of about 25 mg of tramadol on days 1-3; 50 mg of tramadol on days 4-6; 75 mg of tramadol on days 7-9; 100 mg of tramadol on days 10-12; 150 mg of tramadol on days 13-15; and 200 mg of tramadol on days 16-28 and thereafter.
In another preferred embodiment of the invention tramadol is administered in a regimen which comprises administering tramadol at the rate of 50 mg of tramadol on days 1-3; 100 mg of tramadol on days 4-6; 150 mg of tramadol on days 7-9; and 200 mg of tra
Kamin Marc
Olson William
Ortho-McNeil Pharmaceutical , Inc.
Palo Ralph R.
Rose Shep K.
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