`
`Exhibit 1005
`
`U.S. Patent No. 5,872,145 (“Plachetka ‘145”)
`US. Patent No. 5,872,145 (“Plachetka ‘145”)
`
`Exhibit 1005
`
`

`

`United States Patent [19]
`Plachetka
`
`[54] FORMULATION OF 5-HT AGONIST AND
`NSAID FOR TREATMENT OF MIGRAINE
`[75] Inventor: John R. Plachetka, Chapel Hill, NC.
`[73] Assignee: Pozen, Inc., Chapel Hill, NC.
`[21] Appl. No.: 907,826
`[22]
`Filed:
`Aug. 14, 1997
`Related US. Application Data
`Provisional application No. 60/024,129 Aug. 16, 1996.
`Int. Cl.6 ...................... .. A61K 31/405; A61K 31/19;
`A61K 31/16
`[52] US. Cl. ........................ .. 514/415; 514/569; 514/570;
`514/629
`[58] Field of Search ................................... .. 514/415, 569,
`514/629, 570
`
`[60]
`[51]
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`5/1977 Zor et al. .
`4,024,279
`3/1989 Dowle et al. .
`4,816,470
`5,360,925 11/1994 Chabrier De Lassauniere et al.
`
`560/
`169
`2/1995 McDonald et al. ................... .. 514/456
`5,387,604
`5/1996 Friedman ................................ .. 607/89
`5,514,168
`2/1997 Ogletree .
`5,605,917
`3/1997 Wythes .
`5,607,960
`4/1997 Crenshaw et al. .
`5,618,816
`FOREIGN PATENT DOCUMENTS
`2162522 8/1985 United Kingdom.
`OTHER PUBLICATIONS
`Anderson, “Double—blind study of naproXen vs placebo in
`the treatment of acute migraine.” (1989); Cephalalgia, vol.
`9, 29—32.
`Baumel, “Migraine: A pharmacological revieW With neWer
`options and delivery modalities,” (1994), Neurology, vol.
`44Supp3, S13—S17.
`Boureau, “Comparison of subcutaneous sumatriptan With
`usual acute treatments for migraine. French Sumatriptan
`Group.” (1995) Eur NeuroL, vol. 35(5), 264—269.
`Bousser, Efficacy of subcutaneous sumatriptanin the acute
`treatment of early—morning migraine: a placebo—controlled
`trial. Early—Morning Sumatriptan Study Group (1993) J
`Intern Med, vol. 234(2), 211—216.
`
`US005872145A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,872,145
`Feb. 16, 1999
`
`Cady, “Treatment of Acute Migraine With Subcutaneous
`Sumatriptan.” (1991) JAIVIA, vol. 265,No. 21, 2831—2835.
`Cady, “Efficacy of subcutaneous sumatriptan in repreated
`episodes of migraine” (1993) Neurology, vol. 43,
`1363—1368.
`CentonZe, “Evaluation of the efficacy of oral sumatriptan in
`the management of migraine attacks. Clinical Results”
`(1995) La Clinica Teraputica, vol. 146(11), 721—728
`(Article in the Italian language, Citation to English language
`abstract only at 727).
`Dechant, “Sumatriptan A revieW of its Pharmacodynamic
`Properties, and Therapeutic Ef?cacy in the Acute Treatment
`of Migraine and Cluster Headache” (1992) Drugs, vol. 43(5)
`776—798.
`Klapper, “Toward a Standard Drug Formulary for the Treat
`ment of Headache” (1995) Headache, Apr., 1995, 225—227.
`Oral Sumatriptan Group, “Sumatriptan—An Oral Dose—de
`?ning Study” (1991) Eur NeuroL, vol. 31, 300—305.
`Thomson, “A Study to Compare Oral Sumatriptan With Oral
`Aspirin plus Oral Metoclopramide in the Acute Treatment of
`Migraine” (1992) Eur NeuroL, vol. 32, 177—184.
`Todd, “NaproXen A reappraisal of its Pharmacology, and
`Therapeutic Use in Rheumatic Diseases and pain States”
`(1990) Drugs, vol. 40(1), 91—137.
`Tokola, “Effects of migraine attack and metoclopramide on
`the absorption of tolfenamic acid” (1984) Br. J Clin. Phar
`mac, vol. 17, 67—75.
`Tokola, “Tolfenamic acid, metoclopramide, caffeine and
`their combinations in the treatment of migraine attacks”
`(1984) Cephalalgia, vol. 4, 253—263.
`
`Primary Examiner—William R. A. Jarvis
`Attorney, Agent, or Firm—Lorusso & Loud
`[57]
`ABSTRACT
`This invention comprises a method of treating migraine in a
`human comprising co-timely administering of a therapeuti
`cally effective amount of a 5-HT agonist coordinated With a
`therapeutically effective amount of an analgesic, particularly
`a long-acting NSAID in doses beloW those ordinarily con
`sidered as minimum effective doses as to both 5-HT agonist
`and long-acting NSAID. Dosage forms are also included
`herein.
`
`61 Claims, N0 Drawings
`
`

`

`10
`
`15
`
`20
`
`25
`
`30
`
`1
`FORMULATION OF 5-HT AGONIST AND
`NSAID FOR TREATMENT OF MIGRAINE
`RELATED APPLICATIONS
`This application claims priority from Provisional Appli
`cation 60/024,129 ?led Aug. 16, 1996.
`FILED OF THE INVENTION
`This invention comprises a method of treating migraine in
`a human comprising co-timely administering of a therapeu
`tically effective amount of a 5-HT agonist coordinated With
`a therapeutically effective amount of an analgesic, particu
`larly a long-acting NSAID, and in some instances, doses
`beloW those ordinarily considered as minimum effective
`doses as to one or both 5-HT agonist and long-acting
`NSAID. Dosage forms are also included herein.
`This invention also comprises a unit dosage form com
`prising a co-timely delivered therapeutically effective
`amount of a 5HT agonist coordinated and a therapeutically
`effective amount of an NSAID or non-NSAID analgesic.
`Particularly noted is the NSAID ibuprofen. The invention
`further comprises such unit dosage form Wherein the NSAID
`is a long-acting NSAID. In some embodiments of the unit
`dosage form the 5HT agonist is sumatriptan, optionally in an
`amount of from about 1 to about 300 mg, and further
`Wherein the amount is about 1 to about 10 mg (particularly
`adapted to parenteral administration). A long-acting NSAID
`useful in the unit dosage form is naproxen, or pharmaceu
`tically acceptable salt thereof such as naproxen sodium.
`Such unit dosage form usefully contains naproxen, or phar
`maceutically acceptable salt thereof in an amount of from
`about 100 mg to about 1500 mg, and particularly in an
`amount of from about 200 to about 600 mg. A unit dosage
`form of sumatriptan and naproxen is speci?cally noted. Such
`unit dosage form usefully comprises from about 5 to about
`100 mg. sumatriptan, and from about 200 to about 600 mg
`naproxen.
`BACKGROUND OF THE INVENTION
`The compound 5 -hydroxytryptamine (5 -HT or 5HT), also
`knoWn as serotonin or enteramine, is a knoWn vasoactive
`agent and endogenous neurotransmitter acting on receptors
`both Within and outside the central nervous system and on
`blood vessels. Drugs acting on these receptors are knoWn as
`5-HT agonists or antagonists. These 5-HT receptors have
`been further classi?ed into several receptor sub-classes,
`some of Which themselves contain sub-types, and are
`designated, for example, 5-HT1, 5-HT1-like, 5-HT1B,
`5-HT1D, 5-HT2, 5-HT3, and so on.
`5-HT1-like agonists and agonists at other 5-HT1 sites
`comprise a knoWn subclass of therapeutics With a variety of
`uses, notably including migraine therapy. Representative
`members of this class of compounds include sumatriptan
`succinate (distributed under the name ImitrexTM by
`GlaxoWellcome). Sumatriptan and related 5-HT agonist
`heterocyclic compounds are described in US. Pat. No.
`4,816,470 to DoWle et al., the teachings of Which are
`incorporated by reference. Note is made of ergot alkaloids
`Which have 5-HT receptor activity, and these drugs are
`distinct from sumatriptan and its analogs in their chemical
`structure. In addition, ergots exhibit additional pharmaco
`logical properties distinct from sumatriptan. Ergot alkaloids
`and related compounds such as dihydroergotamine mesylate
`(DHE 45) are identi?ed With 5-HT agonist receptor activi
`ties and have been used in migraine therapy. Without being
`
`5,872,145
`2
`bound by any particular theory, it is believed that the ef?cacy
`of ergots in relieving migraine arises, in part, from pharma
`cological activity distinct from the recogniZed 5-HT1 ago
`nist property. Particular reference is made to ergotamine
`tartrate, ergonovine maleate, and ergoloid mesylates (i.e.
`dihydroergocornine, dihydroergocristine, dihydroergocryp
`tine (dihydro-ot-ergocryptine and dihydro-[3-ergocryptine),
`and dihydroergotamine mesylate.
`Some of these agents are not reliably effective treatments
`for migraine. HoWever, some agents are useful in the treat
`ment of migraine, but after an initial therapeutic effect in
`some patients, migraine symptoms are seen again Within
`about 1—24 hours after the initial relief. That is, after a
`dosage of a therapeutic agent has been administered to a
`subject in an amount to effectively treat a migraine, and
`migraine palliation has been observed, migraine symptoms
`occur again from as soon as about 1—8 hours after ?rst relief
`to about 12 to 24 hours later. It Will be appreciated that
`individual migraineurs display individualiZed symptoms and
`timing for this phenomenon as Will treatment With particular
`therapeutic agents.
`In some forms of migraine, certain patients have found
`total or partial relief With the use of analgesics such as
`acetaminophen and phenacetin and other non-steroidal non
`opiate analgesics not generally classi?ed as anti
`in?ammatory. While, these agents, When taken alone, are
`rarely effective in providing complete and rapid relief of all
`the symptoms of migraine, especially When the symptoms of
`the attack already include nausea or vomiting, in combina
`tion therapy of the present invention their effectiveness is
`surprisingly increased.
`As outlined by K. M. A. Welch (New Eng. J Med,
`19931329; 1476—1483), the initial dosages of the analgesics
`useful for the treatment of migraine are: aspirin, 500—650
`mg; acetaminophen, 500 mg; naproxen sodium, 750—825
`mg; tolfenamic acid, 200—400 mg; and, ibuprofen 200 mg.
`After oral dosing, peak plasma concentrations in subjects
`not experiencing a migraine attack usually occur at or about
`1 hour for aspirin and acetaminophen, and betWeen 1—2
`hours for naproxen sodium, tolfenamic acid, and ibuprofen.
`The headache, Which occurs under the circumstances
`described above, has been variously and interchangeably
`termed a “rebound,” “relapse,” “recurrent,” or “secondary”
`headache. The terms not Withstanding, it is presently
`unknoWn as to Whether this later headache is a continuation
`of the physiological chain of events that caused original
`headache, or a neW headache due to other or repeated but
`unrelated underlying pathology. It is also possible that the
`folloW on headache is a response to therapeutic agents Which
`initially Were successful in treating the initial migraine
`symptoms. The terms “rebound”, “relapse,” “recurrent” and
`“secondary” (as de?ned beloW) are considered synonymous
`as used herein Without inferring a mechanism or cause of the
`headache described above.
`It has been reported that of the 50 to 70% of patients Who
`experience migraine symptom relief Within 2 hours from
`initial dosing With a 5-HT agonist, 30—50% experience
`migraine symptoms again Within the next 1—24 hours. In
`vieW of the extreme discomfort and long duration of pain
`that characteriZes migraine headaches, a therapy that
`reduces or avoids rebound migraine is of substantial impor
`tance.
`Note is made of certain studies illuminating aspects of
`migraine therapy and of observed recurrent headache after
`treatment With a 5-HT agonist, the teachings of Which are
`incorporated by reference.
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`

`

`10
`
`15
`
`20
`
`25
`
`5,872,145
`3
`4
`1. Sumatriptan-A reappraisal of its pharmacology and
`This invention is directed to both the method of treating
`therapeutic ef?cacy in the acute treatment of migraine
`migraine as noted and to the speci?c dosage form, Which is,
`optionally a quick dissolve tablet, trochee, capsule, caplet,
`and cluster headache. Plosker G L et al.; Drugs
`dragee, or loZenge. Particular quick dissolve formulations
`1994:47:622—655
`include the 5-HT agonist sumatriptan and the NSAID
`2. Subcutaneous Sumatriptan in a clinical setting: The ?rst
`naproXen, and further Wherein the unit dosage form com
`100 consecutive patients With acute migraine in a
`prises from about 5 to about 100 mg. sumatriptan, and from
`tertiary care center. Sheftell F D et al.; Headache
`about 200 to about 600 mg naproXen.
`1994:34:67—72
`The method of this invention also includes administering
`3. Migraine and cluster headache—their management
`a therapeutically effective amount of NSAID as measured
`With sumatriptan: a critical revieW of the current clini
`subject blood levels is reached by at least about 1 hour after
`cal experience. Wilkinson M et al.; Cephalalgia
`5-HT agonist administration and maintained for at least
`1995;15:337—357
`about 12 hours after 5-HT agonist administration.
`4. Treatment of the migraine attack. Silberstein S D;
`In yet another embodiment, the invention includes a
`Current Opinion in Neurology 1994;7:258—263
`method of treating migraine in a human comprising a
`5. Drug therapy of migraine. Welch K M A; New Eng. J
`combination drug therapy of co-timely administration in the
`Med; 1993;329: 1476—1483
`treatment of rebound headache by providing a rebound
`6. Recent advances in the acute management of migraine
`headache preventing therapeutically effective amount of a
`and cluster headaches. Kumar K L; J Gen Int Med
`5 -HT agonist coordinated With a rebound headache prevent
`1994;9:339—348
`ing therapeutically effective amount of a long-acting NSAID
`SUMMARY OF THE INVENTION
`or other analgesic or combination of NSAID and other
`analgesic.
`This invention comprises a method of treating migraine in
`In an additional embodiment, the method of this invention
`a human comprising co-timely administering of a therapeu
`comprising 5-HT agonist administration and long-acting
`tically effective amount of a 5-HT agonist coordinated With
`NSAID administration, Wherein at least one of said thera
`a therapeutically effective amount of an NSAID or non
`peutically effective amounts of either 5-HT agonist or the
`NSAID analgesic, and particularly a long-acting NSAID. In
`dose of NSAID or non-NSAID analgesic is sub-therapeutic
`some embodiments, an additional NSAID or non-NSAID
`(sub-MED) When used alone (a sub-minimal effective dose
`analgesic is also employed in co-timely coordinated admin
`(MED) amount). Either the 5-HT agonist or the NSAID/
`istration. Particular note is made of ibuprofen or aspirin,
`non-NSAID analgesic is used in sub-MED amount or
`each With quick onset. Particular note is further made of the
`NSAID in sub-MED amount or both. While this does not
`non-NSAID analgesic acetaminophen. Particular attention is
`eXclude multiple 5-HT agonists and NSAIDs being used in
`draWn to the method of this invention Wherein the 5-HT
`treatment of a single subject, it is contemplated that particu
`agonist is sumatriptan. In some embodiments of this method
`lar embodiments Will consist of a single 5-HT agonist, and
`sumatriptan administered in an amount of from about 0.01
`a single long-acting NSAID, Wherein one or both drugs are
`and further from about 1 to about 300 mg, and, optionally,
`administered in sub-MED amounts.
`administration is oral, intranasal, rectal, sub-lingual,
`The invention further includes a method of treating
`injected, inhaled or buccal. In particular embodiments
`migraine in a human comprising co-timely administering of
`Wherein administering of sumatriptan is parenteral, the
`a therapeutically effective amount of a 5-HT agonist coor
`administered amount is about 1 to about 10 mg. For sub
`cutaneous sumatriptan, injecting so as to establish a peak
`dinated With a therapeutically effective amount of a non
`NSAID analgesic such as acetaminophen. In some embodi
`blood level of from about 1 to about 150 ng/ml is
`ments co-timely administering of a therapeutically effective
`contemplated, With speci?c reference to a peak blood level
`amount of a 5 -HT agonist coordinated With a therapeutically
`from about 10 to about 90 ng/ml, and more speci?cally from
`about 10 to about 70 ng/ml. Pharmacologically and phar
`effective amount of a quick onset analgesic such as
`ibuprofen, aspirin or acetaminophen is useful.
`macokinetically comparable blood levels are particularly
`noted embodiments for other 5-HT agonists.
`DETAILED DESCRIPTION OF THE
`In the claimed method, naproXen, or pharmaceutically
`INVENTION
`acceptable salt thereof is a useful NSAID, and particularly
`naproXen sodium, and further When the 5-HT agonist is
`It has noW been discovered that a combination therapy of
`a 5-HT agonist, including drugs structurally similar to 5-HT
`sumatriptan. In this method naproXen or pharmaceutically
`agonists like sumatriptan or like members of the ergot family
`acceptable salt thereof is administered to a human in an
`of compounds, combined With a long acting nonsteroidal
`amount of from about 100 mg to about 1500 mg, With
`anti-in?ammatory drug (NSAID) substantially reduces or
`particular reference to from about 100 mg to about 1500 mg,
`eliminates the relapse phenomenon in a signi?cant portion
`and more particularly from about 200 to about 600 mg.
`Pharmacologically and pharmacokinetically comparable
`of migraineurs that otherWise experience relapse and that the
`combination of the tWo agents results in an enhanced
`doses are particularly noted embodiments for other NSAIDs
`therapeutic effect alloWing for greater and/or longer lasting
`and non-NSAID analgesics.
`ef?cacy and/or loWer doses than can be obtained With the
`In further embodiments of the method of coadministering
`conventional doses of either individual agent. NaproXen
`sumatriptan With naproXen or pharmaceutically acceptable
`sodium is one such long acting NSAID and sumatriptan is
`salt thereof (e.g., naproXen sodium) is establishing a blood
`one such 5-HT agonist.
`plasma level of from about 10 to about 150 mcg/ml of blood,
`and optionally from about 30 to about 80 mcg/ml.
`This invention Will best be understood With reference to
`the folloWing de?nitions:
`In particular embodiments of the claimed method an 5 -HT
`A. “Long acting” in relation to NSAIDs shall mean a
`agonist and an NSAID or non-NSAID analgesic are admin
`pharmacokinetic half-life of at least about 4—6 hours
`istered simultaneously, either as separate formulations or
`combined in a unit dosage form.
`and preferably about 8—14 hours and a duration of
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`

`

`10
`
`15
`
`20
`
`25
`
`5,872,145
`6
`5
`Ergonovine maleate is administrable by injection at about
`action equal to or exceeding about 6—8 hours. Particular
`0.2 mg/ml, and oral tablets of about the same strength are
`reference is made to ?urbiprofen With a half-life of
`also administrable.
`about 6 hours; ketoprofen With a half-life of about 2 to
`Ergoloid mesylates (i.e. dihydroergocornine,
`4 hours; naproxen and naproxen sodium With half-lives
`dihydroergocristine, dihydroergocryptine (dihydro-ot
`of about 12 to 15 hours and about 12 to 13 hours
`ergocryptine and dihydro-[3-ergocryptine) are usefully pro
`respectively; oxaproZin With a half-life of about 42 to
`vided in tablets of from about 0.2 to 2.5 mg With particular
`50 hours; etodolac With a half-life of about 7 hours;
`reference to about 0.5 to about 1.0 mg tablets. Such tablets
`indomethacin With a half-life of about 4 to 6 hours;
`contain about 0.167 mg of each of dihydroergocornine,
`ketorolac With a half-life of up to about 8—9 hours;
`dihydroergocristine, and dihydroergocryptine (dihydro-ot
`nabumetone With a half-life of about 22 to 30 hours;
`ergocryptine and dihydro-[3-ergocryptine). Liquid suspen
`mefenamic acid With a half-life of up to about 4 hours;
`sions and liquid ?lled capsules of about 1 mg/ml are also
`and piroxicam With a half-life of about 4 to 6 hours.
`useful.
`B. “Therapeutically effective amount” as to a drug
`Concerning NSAID dosages, as there is considerable
`dosage, shall mean that dosage that provides the spe
`variability as to the presenting condition of subjects, the
`ci?c pharmacological response for Which the drug is
`skilled practitioner is expected to adjust dosages in such
`administered in a signi?cant number of subjects in need
`regard. Nevertheless it is noted that indomethacin is par
`of such treatment. It is emphasiZed that migraine head
`ticularly useful When contained in tablets of from about 25
`ache is not Well understood and the etiologies of
`to 75 mg, in suppositories of about 50 mg, and in oral
`particular migraine attacks vary, as does the response to
`suspensions of about 25 mg/5 ml. Atypical daily oral dosage
`particular drugs. Thus reference to “speci?c pharma
`of indomethacin is three 25 mg doses taken at intervals
`cological response for Which the drug is administered
`during one day amounting to 75 mg total, though daily doses
`in a signi?cant number of subjects in need of such
`of up to about 150 mg are also useful in some subjects.
`treatment” is a recognition that a “therapeutically effec
`Sustained release dosage forms of indomethacin are also
`tive amount,” administered to a particular subject in a
`available and provide longer lasting blood levels than con
`particular instance Will not abort migraine onset or
`ventional tablets. In particular, a 25 mg sustained release
`relieve an actual migraine headache, even though such
`dosage is deemed a “therapeutically effective amount”
`dosage form can be used as an alternative to 25 mg three
`times daily or 75 mg tWice daily can be substituted for 50 mg
`by those skilled in the art. It is to be further understood
`three times daily.
`that drug dosages are, in particular instances, measured
`Ibuprofen is conveniently provided in tablets or caplets of
`as oral dosages, or parenteral or inhaled dosages or With
`50, 100, 200, 300, 400, 600, and 800 mg and as a suspension
`reference to drug levels as measured in blood.
`of 100 mg/5 ml. Daily doses should not exceed 3200 mg and
`For 5-HT agonists and NSAIDs and non-NSAID
`doses should be individualiZed. In addition, 200 mg—800 mg
`analgesics, and particularly as to those already in the
`may be particularly useful When given 3—4 times daily.
`marketplace, a therapeutically effective amount shall par
`Flurbiprofen is particularly useful When contained in
`ticularly include (but not be limited to) that dosage that has
`tablets of from about 50 to 100 mg. Daily doses of about 100
`been determined as safe and effective for any indication.
`Nevertheless, in particular applications this does not exclude
`to 500 mg, and particularly about 200 to 300 mg total are
`substantially lesser (or greater) dosages than established
`useful.
`Ketoprofen is particularly useful When contained in cap
`minimum (or maximum) dosages for Which a particular
`sules of from about 25 to 75 mg. Daily doses of about 100
`5 -HT agonist or NSAID could be used to effectively treat an
`episode of migraine.
`to 500 mg, and particularly about 100 to 300 mg are useful,
`Particular reference is made to the folloWing dosages of
`as is about 25 to about 50 mg every six to eight hours.
`Naproxen is particularly useful When contained in tablets
`5-HT agonists and NSAIDs, any of Which are usefully
`combined into single dosage forms. Concerning dosages, as
`of from about 250 to about 500 mg, and in oral suspensions
`of about 125 mg/5 ml. For naproxen sodium, tablets of about
`there is considerable variability as to the presenting condi
`tion of subjects, the skilled practitioner is expected to adjust
`275 or about 550 mg are particularly useful. Initial doses of
`dosages in such regard.
`about 100 to 1250 mg, and particularly 350 to 800 mg are
`Sumatriptan is usefully provided as oral tablets of 25 mg,
`also useful With particular note of doses of about 550 mg.
`OxaproZin is notable for having a pharmacokinetic half
`50 mg and 100 mg and as a parenteral dosage form con
`taining about 6 mg/ml and about 6 mg/0.5 ml for subcuta
`life of 42—50 hours and a bioavailability of 95%. It is
`usefully provided as caplets of 600 mg. Daily doses of 1200
`neous administration. Oral dosages of about 1—300 mg are
`mg have been found to be particularly useful and daily doses
`also useful With particular reference to doses of about
`10—100 mg. Peak serum levels of approximately 1—300
`should not exceed 1800 mg or 26 mg/kg. The loWest
`effective dose should alWays be used.
`ng/ml are produced With doses in these ranges. Subcutane
`Etodolac is usefully provided in capsules of 200 mg and
`ous injections of about 1 to 8 mg of sumatriptan are useful,
`With particular reference to about 3 to 6 mg doses. Injections
`300 mg and tablets of 400 mg. Useful doses for acute pain
`produce peak serum levels of approximately 1 to 150 ng/ml.
`are 200—400 mg every 6—8 hours not to exceed 1200 mg/day.
`Other dosage forms of sumatriptan include, but are not
`Patients <60kg are advised not to exceed doses of 20 mg/kg
`limited to, suppositories, aerosols for inhalation or intranasal
`Doses for other uses are also limited to 1200 mg per day in
`divided doses, particularly 2, 3, or 4 times daily.
`administration, and nose drops, and all are contemplated in
`the practice of this invention.
`Ketorolac is usefully provided in tablets of 10 mg and as
`a sterile parenteral preparation for injection in 15 mg/ml and
`Ergotamine tartrate in oral doses of about 1 to 5 mg With
`30 mg/ml dosage forms. Oral doses of up to 40 mg With
`particular reference to about 1—2 mg are useful, as are doses
`particular reference to 10—30 mg per day and parenteral
`of about 1—2 mg at 30 minute intervals, up to about 6 to 8
`mg in one day. Oral inhalation of sequential doses of about
`doses up to 120—150 mg per day have been useful in the
`amelioration of pain.
`0.1 to 0.5 mg at intervals of about 5 minutes are noted, With
`Nabumetone is usefully provided in tablets of 500 mg and
`particular reference to doses of about 0.36 mg. Suppositories
`750 mg. Daily doses of up to 1500—2000 mg/day after an
`of 0.1 to 5 mg With particular reference to about 2 mg are
`useful.
`initial dose of 1000 mg are of particular use.
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`

`

`10
`
`15
`
`20
`
`25
`
`5,872,145
`8
`7
`Mefenamic acid is particularly useful When contained in
`E. “5-HT agonist” is to be broadly understood to include
`5-HT agonists of all types, including but not limited to
`capsules of from about 250 mg. For acute pain such as
`5-HT1-like agonists, 5-HT1B, and 5-HT 1D agonists.
`migraine, an initial dosage of about 100 to 1000 mg and
`particularly about 500 mg is useful, though other dosages are
`Particular reference is made to sumatriptan succinate
`required for speci?c subjects.
`and related 5-HT agonist heterocyclic compounds
`Meclofenamate sodium is usefully provided as capsules
`described in US. Pat. No. 4,816,470 to DoWle et al.;
`ergot alkaloids and related compounds such as dihy
`of 50 mg and 100 mg. Daily doses up to 400 mg are useful
`droergotamine mesylate (DHE 45), ergotamine tartrate,
`and in particular doses of 50—100 mg every 4—6 hours are
`ergonovine maleate, ergoloid mesylates (i.e.
`useful for pain relief.
`dihydroergocornine, dihydroergocristine, dihydroer
`Piroxicam is particularly useful When contained in tablets
`gocryptine (dihydro-ot-ergocryptine and dihydro-[3
`of from about 10 to 20 mg. It is noted that, as steady state
`plasma concentrations are not reached until about 7 to 12
`ergocryptine); P?Zer CP-93129 as described in Euro
`days of dosing, prophylactic use of piroxicam is a speci?c
`pean Patent Application 379314 (the teachings of
`avenue of therapy to establish or a plasma concentration of
`Which are incorporated herein by reference), and
`greater than about 5 to 6 pig/ml. In such situation, coordi
`Allelix ALX 1323; Merck L 741604; SmithklineBee
`nation and co-timely administration of an 5-HT agonist is
`cham SB 220453; and Almirall LAS31416, Zolmitrip
`achieved by the administration of the 5-HT agonist approxi
`tan GlaxoWellcome licensed to Zeneca; and naratriptan
`mately at the onset of a migraine.
`to GlaxoWellcome. In addition, other pharmacologi
`Useful dosages of other analgesics to combine With 5-HT
`cally related compounds are contemplated as Within the
`agonists include aspirin (particularly about 325—1000 mg
`ambit of this invention.
`and 500—650 mg), phenacetin, and acetaminophen
`F. “Relapse headache” variously and interchangeably
`(particularly about 325—1000 mg). The rapid absorption of
`termed a “rebound, relapse, recurrent or secondary”
`acetaminophen in about 30 to 60 minutes and the plasma
`headache shall mean headaches experienced most nota
`half-life of about 2 hours are noted. In the practice of this
`bly by that portion of the migraineur population that,
`invention, the combination of 5-HT agonist With one or
`While experiencing initial relief (or avoidance of
`more NSAIDs or other analgesics (non-NSAID analgesics)
`is particularly contemplated. In particular pharmaceutical
`migraine in the case of treated precursor symptoms)
`applications such as those subjects Who do not usually
`upon administration of a 5-HT agonist, experience
`experience rebound headache, the rapid relief aspect of a
`return of migraine or migraine symptoms Within the
`next about 1 to 24 hours. As noted above, this group
`short onset analgesic directs the use of a dosage of a 5-HT
`comprises perhaps 40% of those subjects that experi
`agonist With such analgesics as acetaminophen or ibuprofen
`ence returns of migraine or migraine symptoms, Whom
`or both. Other combinations such as a 5-HT agonist,
`initially respond to 5-HT agonist therapy. Although it is
`acetaminophen and naproxen sodium, or 5-HT agonist,
`ibuprofen and naproxen sodium are contemplated.
`presently unknoWn if this is a continuation of the
`original headache, a neW headache either due to the
`C. “Co-timely” as to drug administration shall mean
`ongoing underlying pathology or perhaps related to the
`administration of a second drug for migraine relief
`administration of the therapeutic agents used initially to
`While a ?rst drug for migraine relief is present in a
`treat the migraine symptoms, these terms Will be con
`therapeutically effective amount. It is to be understood
`that in some instances this Will require sequential
`sidered synonymous as used herein Without inferring a
`mechanism or cause of the secondary headaches
`administration. In some instances, multiple routes of
`described above.
`administration Will be employed such as intravenous or
`“Rebound moderated” as to sumatriptan shall mean that at
`subcutaneous injection of an 5 -HT agonist, While a long
`least about 20% of that 40% Will not experience recurrence
`acting NSAID is taken orally from prior to or subse
`of migraine Within the 24 hours subsequent to “initial
`quent to such 5-HT agonist injection.
`migraine relief” as de?ned beloW, Which translates into an
`D. “Coordinated” in the practice of the present invention
`8% overall improvement in the response of an entire group.
`combining 5-HT agonist and NSAID administration
`As to ergots, rebound moderated shall mean a statistically
`shall mean administration of an NSAID such that
`signi?cant improvement in return of migraine or migraine
`effective plasma levels of the NSAID Will be present in
`symptoms.
`a subject from about one hour to about 12—24 hours
`G. “Initial migraine relief” shall be understood to be the
`after the onset of migraine or onset of precursor symp
`reduction or abolition of migraine symptoms from ?rst
`toms of a migraine. In some embodiments this Will be
`onset of either a migraine attack or the precursor indicia
`about 1 to 12 hours after a 5-HT agonist has been
`administered. The coordination time is clearly related
`of a migraine headache such as the aura and visual
`“scotoma” in about a 24 hour period.
`to the route of NSAID administration. That is, for
`H. “Unit dosage form” shall mean single drug adminis
`example, i.m. routes Will generally have shorter lead
`tration entity. By Way of example, a single tablet,
`times to peak plasma level than oral routes. With oral
`capsule, dragee, or trochee, suppository, or syringe
`NSAID formulations, it is noted that the time to peak
`plasma levels for particular NSAIDs is as folloWs:
`combining both an 5-HT agonist and an NSAID Would
`?urbiprofen peaks in about 1 to 2 hours; ketoprofen
`be a unit dosage form. Administration of a unit dosage
`form Will result in blood levels of the NSAID required
`peaks in about one-half to 2 hours; naproxen and
`to produce a therapeutic effect Within about the ?rst
`naproxen sodium peak at about 2 to 4 hours and 1 to 2
`hours respectively; oxaproZin peaks at about 3 to 5
`hour after dosing and Will still be present at least about
`8—12 hours after initial dosing, and in particular
`hours; etodolac peaks at about 1 to 2 hours; indometha
`cin peaks at about 1 to 4 hours; ketorolac peaks at about
`instances, for as long as about 24 hours after dosing.
`Blood levels of the 5-HT agonist normally associated
`one-half to 1 hour; nabumetone peaks at about 2.5 to 4
`hours; mefenamic peaks at about 2 to 4 hours; meclofe
`With a therapeutic effect Will be present Within the ?rst
`namat