IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Utility Patent Application (Provisional)
`Utility Patent Application (Provisional)
`
`USE OF ZOLEDRONIC ACID AND RELATED COMPOUNDS FOR THE TREATMENT OF PAIN
`USE OF ZOLEDRONIC ACID AND RELATED COMPOUNDS FOR THE TREATMENT OF PAIN
`
`Inventor: Herriot Tabuteau
`Inventor: Herriot Tabuteau
`
`BACKGROUND OF THE INVENTION
`BACKGROUND OF THE INVENTION
`
`Complex regional pain syndrome type I (CRPS-I)„ also known as reflex sympathetic dystrophy
`Complex regional pain syndrome type I (CRPS-I)„ also known as reflex sympathetic dystrophy
`
`(RSD), and complex regional pain syndrome type II (CRPS-H), also known as causalgia, are debilitating
`(RSD), and complex regional pain syndrome type II (CRPS-H), also known as causalgia, are debilitating
`
`pain syndromes. They are characterized by severe pain in a limb accompanied by allodynia„
`pain syndromes. They are characterized by severe pain in a limb accompanied by allodynia„
`
`hyperalgesia, edema, changes in skin blood flow and abnormal sudomotor activity.
`hyperalgesia, edema, changes in skin blood flow and abnormal sudomotor activity.
`
`These disorders are often difficult to treat and there exists a need for additional therapeutic
`These disorders are often difficult to treat and there exists a need for additional therapeutic
`
`options.
`options.
`
`DESCRIPTION OF THE INVENTION
`DESCRIPTION OF THE INVENTION
`
`Disclosed are pharmaceutical compositions and methods for the treatment of any type of pain
`Disclosed are pharmaceutical compositions and methods for the treatment of any type of pain
`
`including, but not limited to, postoperative pain, cancer pain, arthritic pain, lumbosacral pain,
`including, but not limited to, postoperative pain, cancer pain, arthritic pain, lumbosacral pain,
`
`musculoskeletal pain, neuropathic pain, chronic pain, etc.
`musculoskeletal pain, neuropathic pain, chronic pain, etc.
`
`Disclosed are pharmaceutical compositions and methods for the treatment of complex regional
`Disclosed are pharmaceutical compositions and methods for the treatment of complex regional
`
`pain syndrome type I and type II (CRPS-I and CRPS-II).
`pain syndrome type I and type II (CRPS-I and CRPS-II).
`
`One embodiment is a pharmaceutical composition comprising pamidronate, neridronate,
`One embodiment is a pharmaceutical composition comprising pamidronate, neridronate,
`
`olpadronate, alendronate, incadronate, ibandronate, risedronate, zoledronate or another
`olpadronate, alendronate, incadronate, ibandronate, risedronate, zoledronate or another
`
`bisphosphonate compound for the treatment of pain.
`bisphosphonate compound for the treatment of pain.
`
`Page 1 of 47
`Page 1 of 47
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`Grun. Exh. 1036
`PGR for U.S. Patent No. 9,867,839
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`1
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`Grün. Exh. 1027
`PGR for U.S. Patent No. 10,052,338
`
`

`

`Another embodiment is a pharmaceutical composition comprising pamidronate, neridronate,
`Another embodiment is a pharmaceutical composition comprising pamidronate, neridronate,
`
`olpadronate, alendronate, incadronate, ibandronate, risedronate, zoledronate or another
`olpadronate, alendronate, incadronate, ibandronate, risedronate, zoledronate or another
`
`bisphosphonate compound for the treatment of CRPS-I and CRPS- I.
`bisphosphonate compound for the treatment of CRPS-I and CRPS- I.
`
`The terms pamidronate, neridronate, olpadronate, alendronate, incadronate, ibandronate,
`The terms pamidronate, neridronate, olpadronate, alendronate, incadronate, ibandronate,
`
`risedronate, zoledronate, or another bisphosphonate compound, as used in this application refer to
`risedronate, zoledronate, or another bisphosphonate compound, as used in this application refer to
`
`these compounds or their pharmaceutically acceptable salts, and any of their polymorphic forms.
`these compounds or their pharmaceutically acceptable salts, and any of their polymorphic forms.
`
`Other names for pamidronate, neridronate, olpadronate, alendronate, incadronate,
`Other names for pamidronate, neridronate, olpadronate, alendronate, incadronate,
`
`ibandronate, risedronate, and zoledronate may include but are not limited to pamidronic acid,
`ibandronate, risedronate, and zoledronate may include but are not limited to pamidronic acid,
`
`neridronic acid, olpadronic acid, alendronic acid, incadronic acid, ibandronic acid, risedronic acid, and
`neridronic acid, olpadronic acid, alendronic acid, incadronic acid, ibandronic acid, risedronic acid, and
`
`zoledronic acid, respectively,
`zoledronic acid, respectively,
`
`Another embodiment is a method for the treatment of treatment of pain comprising
`Another embodiment is a method for the treatment of treatment of pain comprising
`
`administering to an individual pamidronate, neridronate, olpadronate, alendronate, incadronate,
`administering to an individual pamidronate, neridronate, olpadronate, alendronate, incadronate,
`
`ibandronate, risedronate, zoledronate or another bisphosphonate compound.
`ibandronate, risedronate, zoledronate or another bisphosphonate compound.
`
`Yet another embodiment is a method for the treatment of treatment of CRPS-I and CRPS-II
`Yet another embodiment is a method for the treatment of treatment of CRPS-I and CRPS-II
`
`comprising administering to an individual pamidronate, neridronate, olpadronate, alendronate,
`comprising administering to an individual pamidronate, neridronate, olpadronate, alendronate,
`
`incadronate, ibandronate, risedronate, zoledronate or another bisphosphonate compound.
`incadronate, ibandronate, risedronate, zoledronate or another bisphosphonate compound.
`
`Any suitable route of administration may be employed for providing an individual with an
`Any suitable route of administration may be employed for providing an individual with an
`
`effective dosage of the parnidronate, neridronate, olpadronate, alendronate, incadronate, ibandronate,
`effective dosage of the parnidronate, neridronate, olpadronate, alendronate, incadronate, ibandronate,
`
`risedronate, zoledronate or another bisphosphonate compound. For example, oral, rectal, parenteral,
`risedronate, zoledronate or another bisphosphonate compound. For example, oral, rectal, parenteral,
`
`transdermal, sublingual, subcutaneous, intrathecal, intramuscular and the like may be employed as
`transdermal, sublingual, subcutaneous, intrathecal, intramuscular and the like may be employed as
`
`appropriate.
`appropriate.
`
`Dosage forms for the pamidronate, neridronate, olpadronate, alendronate, incadronate,
`Dosage forms for the pamidronate, neridronate, olpadronate, alendronate, incadronate,
`
`ibandronate, risedronate , zoledronate or another bisphosphonate compound in the present
`ibandronate, risedronate , zoledronate or another bisphosphonate compound in the present
`
`embodiments include but are not limited to tablets, coated tablets, cachets, capsules, caplets, troches,
`embodiments include but are not limited to tablets, coated tablets, cachets, capsules, caplets, troches,
`
`dispersions, sustained release formulations, suspensions, solutions, patches and the like.
`dispersions, sustained release formulations, suspensions, solutions, patches and the like.
`
`In addition to the common dosage forms set forth above, the parnidronate, neridronate,
`In addition to the common dosage forms set forth above, the parnidronate, neridronate,
`
`olpadronate,alendronate, incadronate, ibandronate, risedronate; zoledronate or another
`olpadronate,alendronate, incadronate, ibandronate, risedronate; zoledronate or another
`
`Page 2 of 47
`Page 2 of 47
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`
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`bisphosphonate compound may also be administered by controlled release or sustained release means bisphosphonate compound may also be administered by controlled release or sustained release means
`
`
`
`and/or delivery devices. and/or delivery devices.
`
`
`
`The effective amount of pamidronate, neridronate, olpadronate, alendronate, incadronate, The effective amount of pamidronate, neridronate, olpadronate, alendronate, incadronate,
`
`
`
`ibandronate, risedronate zoledronate or another bisphosphonate compound in the treatment of pain, ibandronate, risedronate zoledronate or another bisphosphonate compound in the treatment of pain,
`
`
`
`CRPS-I and CRPS-II will vary depending on various factors known to the treating physicians, such as the CRPS-I and CRPS-II will vary depending on various factors known to the treating physicians, such as the
`
`
`
`severity of the condition to be treated, route of administration, formulation and dosage forms, physical severity of the condition to be treated, route of administration, formulation and dosage forms, physical
`
`
`
`characters of the pamidronate, neridronate, olpadronate, alendronate, incadronate, ibandronate, characters of the pamidronate, neridronate, olpadronate, alendronate, incadronate, ibandronate,
`
`
`
`risedronate , zoledronate or another bisphosphonate compound used, and age, weight and response of risedronate , zoledronate or another bisphosphonate compound used, and age, weight and response of
`
`
`
`the individual patients. the individual patients.
`
`
`
`In some embodiments the daily oral dose of pamidronate is about 10 mg to about 1,000 mg„ In some embodiments the daily oral dose of pamidronate is about 10 mg to about 1,000 mg„
`
`
`
`about 50 mg to about 500 mg, about 100 mg to about 500 mg, or about 150 ITT to about 300 mg. In about 50 mg to about 500 mg, about 100 mg to about 500 mg, or about 150 ITT to about 300 mg. In
`
`
`
`some embodiments the parenteral dose of pamidronate is about 5 mg to about 500 mg, about 5 mg to some embodiments the parenteral dose of pamidronate is about 5 mg to about 500 mg, about 5 mg to
`
`
`
`about 200 mg, or about 10 mg to about 150 mg. about 200 mg, or about 10 mg to about 150 mg.
`
`
`
`In some embodiments the daily oral dose of neridronate is about 10 mg to about 1,000 mg, In some embodiments the daily oral dose of neridronate is about 10 mg to about 1,000 mg,
`
`
`
`about 50 mg to about 500 mg, about 100 mg to about 500 mg, or about 150 mg to about 300 mg. In about 50 mg to about 500 mg, about 100 mg to about 500 mg, or about 150 mg to about 300 mg. In
`
`
`
`some embodiments the parenteral dose of neridronate is about 5 mg to about 500 mg, about 5 mg to some embodiments the parenteral dose of neridronate is about 5 mg to about 500 mg, about 5 mg to
`
`
`
`about 200 mg, or about 10 mg to about 150 mg. about 200 mg, or about 10 mg to about 150 mg.
`
`
`
`In some embodiments the daily oral dose of olpadronate is about 0.5 mg to about 400 mg, In some embodiments the daily oral dose of olpadronate is about 0.5 mg to about 400 mg,
`
`
`
`about 1 mg to about 300 mg, about 5 mg to about 100 mg, or about 2 ITT to about 50 mg. In some about 1 mg to about 300 mg, about 5 mg to about 100 mg, or about 2 ITT to about 50 mg. In some
`
`
`
`embodiments the parenteral dose of olpadronate is about 1 mg to about 100 mg, about 1 mg to about embodiments the parenteral dose of olpadronate is about 1 mg to about 100 mg, about 1 mg to about
`
`
`
`40 mg, or about 2 mg to about 30 ITT, 40 mg, or about 2 mg to about 30 ITT,
`
`
`
`In some embodiments the daily oral dose of alendronate is about 0.5 mg to about 400 mg, In some embodiments the daily oral dose of alendronate is about 0.5 mg to about 400 mg,
`
`
`
`about 1 mg to about 200 mg, about 5 mg to about 100 mg, or about 2 mg to about 50 mg. In some about 1 mg to about 200 mg, about 5 mg to about 100 mg, or about 2 mg to about 50 mg. In some
`
`
`
`embodiments the parenteral dose of alendronate is about 1 mg to about 100 mg, about 1 mg to about embodiments the parenteral dose of alendronate is about 1 mg to about 100 mg, about 1 mg to about
`
`
`
`40 mg, or about 2 mg to about 30 mg. 40 mg, or about 2 mg to about 30 mg.
`
`
`
`In some embodiments the daily oral dose of incadronate is about 0.5 mg to about 400 mg, about In some embodiments the daily oral dose of incadronate is about 0.5 mg to about 400 mg, about
`
`
`
`1 mg to about 300 ITT, about 5 mg to about 100 ITT, or about 2 mg to about 50 mg. In some 1 mg to about 300 ITT, about 5 mg to about 100 ITT, or about 2 mg to about 50 mg. In some
`
`
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`embodiments the parenteral dose of incaclronate is about 1 mg to about 100 mg, about 1 mg to about
`embodiments the parenteral dose of incaclronate is about 1 mg to about 100 mg, about 1 mg to about
`
`40 mg, or about 2 mg to about 30 mg.
`40 mg, or about 2 mg to about 30 mg.
`
`In some embodiments the daily oral dose of ibandronate is about 0.25 mg to about 100 mg,
`In some embodiments the daily oral dose of ibandronate is about 0.25 mg to about 100 mg,
`
`about 0.5 mg to about 50 mg, about 2.5 mg to about 50 mg, or about 1 mg to about 25 mg. In some
`about 0.5 mg to about 50 mg, about 2.5 mg to about 50 mg, or about 1 mg to about 25 mg. In some
`
`embodiments the parenteral dose of ibandronate is about 0.5 mg to about 50 mg, about 0.5 mg to
`embodiments the parenteral dose of ibandronate is about 0.5 mg to about 50 mg, about 0.5 mg to
`
`about 20 mg, or about 1 mg to about 15 mg.
`about 20 mg, or about 1 mg to about 15 mg.
`
`In some embodiments the daily oral dose of risedronate is about 0.2.5 mg to about 100 mg,
`In some embodiments the daily oral dose of risedronate is about 0.2.5 mg to about 100 mg,
`
`about 0.5 mg to about 50 mg, about 2.5 mg to about 50 mg, or about 1 mg to about 25 mg. In some
`about 0.5 mg to about 50 mg, about 2.5 mg to about 50 mg, or about 1 mg to about 25 mg. In some
`
`embodiments the parenteral dose of risedronate is about 0.25 mg to about 25 mg, about 0,2.5 mg to
`embodiments the parenteral dose of risedronate is about 0.25 mg to about 25 mg, about 0,2.5 mg to
`
`about 10 mg, or about 0.5 mg to about 7,5 mg,
`about 10 mg, or about 0.5 mg to about 7,5 mg,
`
`In some embodiments the daily oral dose of zoledronate is about 0.005 mg to about 20 mg,
`In some embodiments the daily oral dose of zoledronate is about 0.005 mg to about 20 mg,
`
`about 0.1 mg to about 10 mg, about 0.5 mg to about 10 mg, or about 0.2 mg to about 5 mg. In some
`about 0.1 mg to about 10 mg, about 0.5 mg to about 10 mg, or about 0.2 mg to about 5 mg. In some
`
`embodiments the parenteral dose of zoledronate is about 0.25 mg to about 25 mg, about 0.25 mg to
`embodiments the parenteral dose of zoledronate is about 0.25 mg to about 25 mg, about 0.25 mg to
`
`about 10 mg, or about 0.5 mg to about 7.5 mg.
`about 10 mg, or about 0.5 mg to about 7.5 mg.
`
`Some embodiments include orally administering zoledronic acid in a form such as the disodium
`Some embodiments include orally administering zoledronic acid in a form such as the disodium
`
`salt. Any suitable amount of zoledronic acid or disodium salt of zoledronic acid may be used, such as
`salt. Any suitable amount of zoledronic acid or disodium salt of zoledronic acid may be used, such as
`
`about 10 mg to about 500 mg, about 20 mg to about 200 mg, about 50 mg to about 150 mg, about 50
`about 10 mg to about 500 mg, about 20 mg to about 200 mg, about 50 mg to about 150 mg, about 50
`
`mg, about 100 mg, or about 150 mg. In some embodiments, the oral zoledronic acid is administered
`mg, about 100 mg, or about 150 mg. In some embodiments, the oral zoledronic acid is administered
`
`daily, weekly, monthly, once a year, or twice a year. The oral zoledronic acid, or disodium salt thereof,
`daily, weekly, monthly, once a year, or twice a year. The oral zoledronic acid, or disodium salt thereof,
`
`may be administered in combination with about 0.1 mg to about 10 mg of zoledronic acid, or a salt
`may be administered in combination with about 0.1 mg to about 10 mg of zoledronic acid, or a salt
`
`thereof, administered intravenously. In some embodiments, about 50 mg, about 100 mg, or about 150
`thereof, administered intravenously. In some embodiments, about 50 mg, about 100 mg, or about 150
`
`mg of the disodium salt of zoledronic acid is administered orally in combination with 1 mg intravenous
`mg of the disodium salt of zoledronic acid is administered orally in combination with 1 mg intravenous
`
`zoledronic acid.
`zoledronic acid.
`
`Some oral dosage forms comprising zoledronic acid or a salt thereof may have enteric coatings.
`Some oral dosage forms comprising zoledronic acid or a salt thereof may have enteric coatings.
`
`In some embodiments, the pamidronate„ neridronate, olpadronate, alendronate, incadronate,
`In some embodiments, the pamidronate„ neridronate, olpadronate, alendronate, incadronate,
`
`ibandronate, risedronate , zoledronate or another bisphosphonate compound can be given weekly,
`ibandronate, risedronate , zoledronate or another bisphosphonate compound can be given weekly,
`
`monthly, every two or three months, once a year or twice a year.
`monthly, every two or three months, once a year or twice a year.
`
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`In some embodiments the weekly oral dose of pamidronate is about 70 mg to about 7,000 mg,
`In some embodiments the weekly oral dose of pamidronate is about 70 mg to about 7,000 mg,
`
`about 350 ITT to about 3,500 mg, about 700 mg to about 3„500 mg, or about 1,000 mg to about 2,000
`about 350 ITT to about 3,500 mg, about 700 mg to about 3„500 mg, or about 1,000 mg to about 2,000
`
`mg. In some embodiments the monthly oral dose of pamidronate is about 300 rng to about 30,000 mg,
`mg. In some embodiments the monthly oral dose of pamidronate is about 300 rng to about 30,000 mg,
`
`about 1„500 mg to about 15,000 mg, about 3,000 mg to about 15,000 mg, or' about 4,000 mg to about
`about 1„500 mg to about 15,000 mg, about 3,000 mg to about 15,000 mg, or' about 4,000 mg to about
`
`8,000 mg,
`8,000 mg,
`
`In some embodiments the weekly oral dose of neridronate is about 70 rng to about 7,000 mg,
`In some embodiments the weekly oral dose of neridronate is about 70 rng to about 7,000 mg,
`
`about 350 mg to about 3,500 mg, about 700 mg to about 3,500 mg, or about 1,000 mg to about 2,000
`about 350 mg to about 3,500 mg, about 700 mg to about 3,500 mg, or about 1,000 mg to about 2,000
`
`mg, In some embodiments the monthly oral dose of neridronate is about 300 mg to about 30,000 mg,
`mg, In some embodiments the monthly oral dose of neridronate is about 300 mg to about 30,000 mg,
`
`about 1,500 mg to about 15,000 mg, about 3,000 mg to about 15,000 mg, or about 4,000 mg to about
`about 1,500 mg to about 15,000 mg, about 3,000 mg to about 15,000 mg, or about 4,000 mg to about
`
`8,000 mg.
`8,000 mg.
`
`In some embodiments the weekly oral dose of olpadronate is about 3.5 rng to about 2:„800 mg,
`In some embodiments the weekly oral dose of olpadronate is about 3.5 rng to about 2:„800 mg,
`
`about 7 mg to about 2,100 mg, about 35 mg to about 700 mg, or about 15 mg to about 350 mg. In some
`about 7 mg to about 2,100 mg, about 35 mg to about 700 mg, or about 15 mg to about 350 mg. In some
`
`embodiments the monthly oral dose of olpadronate is about 15 mg to about 11,000 mg, about 30 mg to
`embodiments the monthly oral dose of olpadronate is about 15 mg to about 11,000 mg, about 30 mg to
`
`about 8,500 mg, about 150 mg to about 2,800 rng, or about 60 nig to about 1,500 mg.
`about 8,500 mg, about 150 mg to about 2,800 rng, or about 60 nig to about 1,500 mg.
`
`In some embodiments the weekly oral dose of alendronate is about 3.5 mg to about 2,800 mg,
`In some embodiments the weekly oral dose of alendronate is about 3.5 mg to about 2,800 mg,
`
`about 7 mg to about 2,100 mg, about 35 mg to about 700 mg, or about 15 mg to about 350 mg, In some
`about 7 mg to about 2,100 mg, about 35 mg to about 700 mg, or about 15 mg to about 350 mg, In some
`
`embodiments the monthly oral dose of alendronate is about 15 mg to about 11,000 mg, about 30 mg to
`embodiments the monthly oral dose of alendronate is about 15 mg to about 11,000 mg, about 30 mg to
`
`about 8,500 mg, about 150 mg to about 2,800 mg, or about 60 mg to about 1,500 mg.
`about 8,500 mg, about 150 mg to about 2,800 mg, or about 60 mg to about 1,500 mg.
`
`In some embodiments the weekly oral dose of incadronate is about 3,5 mg to about 2,800 rng,
`In some embodiments the weekly oral dose of incadronate is about 3,5 mg to about 2,800 rng,
`
`about 7 mg to about 2„100 mg, about 35 nig to about 700 mg, or about 15 mg to about 350 mg. In some
`about 7 mg to about 2„100 mg, about 35 nig to about 700 mg, or about 15 mg to about 350 mg. In some
`
`embodiments the monthly oral dose of incadronate is about 15 mg to about 11,000 mg, about 30 mg to
`embodiments the monthly oral dose of incadronate is about 15 mg to about 11,000 mg, about 30 mg to
`
`about 8„500 mg, about 150 nig to about 2,800 mg, or about 60 mg to about 1,500 rng,
`about 8„500 mg, about 150 nig to about 2,800 mg, or about 60 mg to about 1,500 rng,
`
`In some embodiments the weekly oral dose of ibandronate is about 1.75 mg to about 700 mg,
`In some embodiments the weekly oral dose of ibandronate is about 1.75 mg to about 700 mg,
`
`about 3.5 mg to about 350 mg, about 18 mg to about 350 mg, or about 7 rng to about 175 mg. In some
`about 3.5 mg to about 350 mg, about 18 mg to about 350 mg, or about 7 rng to about 175 mg. In some
`
`embodiments the monthly oral dose of ibandronate is about 7 mg to about 2,800 mg, about 15 mg to
`embodiments the monthly oral dose of ibandronate is about 7 mg to about 2,800 mg, about 15 mg to
`
`about 1,500 mg, about 70 mg to about 1,500 mg, or about 30 mg to about 700 mg.
`about 1,500 mg, about 70 mg to about 1,500 mg, or about 30 mg to about 700 mg.
`
`In some embodiments the weekly oral dose of risedronate is about :1..75 mg to about 700 rng,
`In some embodiments the weekly oral dose of risedronate is about :1..75 mg to about 700 rng,
`
`about 3.5 rng to about 350 mg, about 18 mg to about 350 mg, or about 7 mg to about 175 rng, In some
`about 3.5 rng to about 350 mg, about 18 mg to about 350 mg, or about 7 mg to about 175 rng, In some
`
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`embodiments the monthly oral dose of risedronate is about 7 mg to about 2,800 mg, about 15 mg to
`embodiments the monthly oral dose of risedronate is about 7 mg to about 2,800 mg, about 15 mg to
`
`about 1„500 mg,about 70 mg to about 1,500 mg, or about 30 mg to about 700 mg.
`about 1„500 mg,about 70 mg to about 1,500 mg, or about 30 mg to about 700 mg.
`
`In some embodiments the weekly oral dose of zoledronate is about 1 mg to about 500 mg,
`In some embodiments the weekly oral dose of zoledronate is about 1 mg to about 500 mg,
`
`about 10 mg to about 250 mg, about 20 mg to about 150 mg, or about 30 mg to about 100 mg. In some
`about 10 mg to about 250 mg, about 20 mg to about 150 mg, or about 30 mg to about 100 mg. In some
`
`embodiments the monthly oral dose of zoledronate is about 1 mg to about 1,000 mg, about 10 mg to
`embodiments the monthly oral dose of zoledronate is about 1 mg to about 1,000 mg, about 10 mg to
`
`about 600 mg, about 50 mg to about 500 mg, or about 100 mg to about 500 mg.
`about 600 mg, about 50 mg to about 500 mg, or about 100 mg to about 500 mg.
`
`The dose of pamidronate, neridronate, olpadronate, alendronate, incadronate, ibanclronate,
`The dose of pamidronate, neridronate, olpadronate, alendronate, incadronate, ibanclronate,
`
`risedronate, zoledronate or another bisphosphonate compound may be administered in a single or
`risedronate, zoledronate or another bisphosphonate compound may be administered in a single or
`
`divided dose.
`divided dose.
`
`Active substance:
`Active substance:
`
`Zoledronic acid
`Zoledronic acid
`
`International Nonproprietary Name
`International Nonproprietary Name
`
`Zoledronic acid, (disodium zoledronate tetrahydrate)
`Zoledronic acid, (disodium zoledronate tetrahydrate)
`
`(INN), (accompanied by its salt or
`(INN), (accompanied by its salt or
`
`hydrate form if relevant):
`hydrate form if relevant):
`
`Orphan indication:
`Orphan indication:
`
`Complex regional pain syndrome (CRPS)
`Complex regional pain syndrome (CRPS)
`
`Pharmaceutical form(s) and strength(s): Tablets or capsules
`Pharmaceutical form(s) and strength(s): Tablets or capsules
`
`Route(s) of administration:
`Route(s) of administration:
`
`Oral
`Oral
`
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`List of abbreviations
`List of abbreviations
`
`Abbreviation (cid:9)
`Abbreviation (cid:9)
`
`Definition
`Definition
`
`CGRP (cid:9)
`CGRP (cid:9)
`
`CIA (cid:9)
`CIA (cid:9)
`
`CRPS (cid:9)
`CRPS (cid:9)
`
`CRPS-I (cid:9)
`CRPS-I (cid:9)
`
`CRPS-II (cid:9)
`CRPS-II (cid:9)
`
`CT (cid:9)
`CT (cid:9)
`
`DMSO (cid:9)
`DMSO (cid:9)
`
`E.U. (cid:9)
`E.U. (cid:9)
`
`FDA (cid:9)
`FDA (cid:9)
`
`HLA (cid:9)
`HLA (cid:9)
`
`IASP (cid:9)
`IASP (cid:9)
`
`ICD (cid:9)
`ICD (cid:9)
`
`IV (cid:9)
`IV (cid:9)
`
`mg (cid:9)
`mg (cid:9)
`
`NGF (cid:9)
`NGF (cid:9)
`
`NHS (cid:9)
`NHS (cid:9)
`
`NRS (cid:9)
`NRS (cid:9)
`
`calcitonin-gene-related-peptide
`calcitonin-gene-related-peptide
`
`Central Intelligence Agency
`Central Intelligence Agency
`
`complex regional pain syndrome
`complex regional pain syndrome
`
`complex regional pain syndrome type I
`complex regional pain syndrome type I
`
`complex regional pain syndrome type II
`complex regional pain syndrome type II
`
`computed tomography
`computed tomography
`
`dimethyl sulfoxide
`dimethyl sulfoxide
`
`European Union
`European Union
`
`Food and Drug Administration
`Food and Drug Administration
`
`human leukocyte antigen
`human leukocyte antigen
`
`International Association for the Study of Pain
`International Association for the Study of Pain
`
`International Classification of Diseases
`International Classification of Diseases
`
`intravenous
`intravenous
`
`milligram
`milligram
`
`nerve growth factor
`nerve growth factor
`
`National Health Service
`National Health Service
`
`numerical rating scale
`numerical rating scale
`
`NSAID (cid:9)
`NSAID (cid:9)
`
`nonsteroidal anti-inflammatory drug
`nonsteroidal anti-inflammatory drug
`
`PT (cid:9)
`PT (cid:9)
`
`RCT (cid:9)
`RCT (cid:9)
`
`REP (cid:9)
`REP (cid:9)
`
`RSD (cid:9)
`RSD (cid:9)
`
`SCS (cid:9)
`SCS (cid:9)
`
`physical therapy
`physical therapy
`
`randomized controlled trial
`randomized controlled trial
`
`Rochester Epidemiology Project
`Rochester Epidemiology Project
`
`reflex sympathetic dystrophy
`reflex sympathetic dystrophy
`
`spinal cord stimulation
`spinal cord stimulation
`
`statis. sign. (cid:9)
`statis. sign. (cid:9)
`
`statistically significant
`statistically significant
`
`TNF (cid:9)
`TNF (cid:9)
`
`U.K. (cid:9)
`U.K. (cid:9)
`
`U.S. (cid:9)
`U.S. (cid:9)
`
`VAS (cid:9)
`VAS (cid:9)
`
`WHO (cid:9)
`WHO (cid:9)
`
`tumor necrosis factor
`tumor necrosis factor
`
`United Kingdom
`United Kingdom
`
`United States of America
`United States of America
`
`visual analog scale
`visual analog scale
`
`World Health Organization
`World Health Organization
`
`Page 7 of 47
`Page 7 of 47
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`
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`Sections A-E Sections A-E
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`A. Description of the condition A. Description of the condition
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`Al. Details of the condition Al. Details of the condition
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`
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`Summary of the Condition Summary of the Condition
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`
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`Complex regional pain syndrome (CRPS) is a disorder characterized by severe pain in a limb Complex regional pain syndrome (CRPS) is a disorder characterized by severe pain in a limb
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`
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`accompanied by autonomic, sensory, motor and trophic changes. The sensory changes, which include accompanied by autonomic, sensory, motor and trophic changes. The sensory changes, which include
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`
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`allodynia and hyperalgesia, are accompanied by movement disorders and joint stiffness. Radiographic allodynia and hyperalgesia, are accompanied by movement disorders and joint stiffness. Radiographic
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`
`
`examination often reveals patchy osteoporosis localized to the affected limb [1, 2, 4]. examination often reveals patchy osteoporosis localized to the affected limb [1, 2, 4].
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`The disorder impairs daily functioning and negatively impacts quality of life. For many patients, the pain The disorder impairs daily functioning and negatively impacts quality of life. For many patients, the pain
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`
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`and associated loss of function result in significant and sometimes permanent disability. Depression is a and associated loss of function result in significant and sometimes permanent disability. Depression is a
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`
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`common comorbidity [1, 2]. common comorbidity [1, 2].
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`
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`A distinction is made between CRPS type I (CRPS-I) in which a nerve lesion cannot be identified, and type A distinction is made between CRPS type I (CRPS-I) in which a nerve lesion cannot be identified, and type
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`
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`11 (CRPS-II) in which it can. Apart from this distinction, the clinical features of the two types are identical. 11 (CRPS-II) in which it can. Apart from this distinction, the clinical features of the two types are identical.
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`
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`CRPS-1 is formerly known as reflex sympathetic dystrophy (RSD). CRPS-II is formerly known as causalgia. CRPS-1 is formerly known as reflex sympathetic dystrophy (RSD). CRPS-II is formerly known as causalgia.
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`
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`CRPS-II accounts for a minority of cases comprising about 3% of observed cases in the population-based CRPS-II accounts for a minority of cases comprising about 3% of observed cases in the population-based
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`
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`survey of de Mos et al. [33]. survey of de Mos et al. [33].
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`
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`CRPS is often triggered after minor trauma, such as wrist fracture, surgery or needle stick, but can occur CRPS is often triggered after minor trauma, such as wrist fracture, surgery or needle stick, but can occur
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`spontaneously. It affects women 3-4 times as frequently as men and its prevalence increases with age spontaneously. It affects women 3-4 times as frequently as men and its prevalence increases with age
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`
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`[33, 34]. [33, 34].
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`
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`The pathophysiology of CRPS is multi-factorial and includes aberrant inflammatory mechanisms, The pathophysiology of CRPS is multi-factorial and includes aberrant inflammatory mechanisms,
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`
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`vasomotor dysfunction, and maladaptive neuroplasticity. vasomotor dysfunction, and maladaptive neuroplasticity.
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`Diagnosis of CRPS is made clinically using the International Association for the Study of Pain criteria or Diagnosis of CRPS is made clinically using the International Association for the Study of Pain criteria or
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`
`
`the Budapest criteria [4, 50]. the Budapest criteria [4, 50].
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`Terminology. CRPS is also referred to as reflex sympathetic dystrophy (RSD), causalgia, algodystrophy, Terminology. CRPS is also referred to as reflex sympathetic dystrophy (RSD), causalgia, algodystrophy,
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`and Sudeck's atrophy [5, 6]. and Sudeck's atrophy [5, 6].
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`Page 8 of 47 Page 8 of 47
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`ICD Classification ICD Classification
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`Table 1. 2012 ICD-10 Codes for CRPS [51] Table 1. 2012 ICD-10 Codes for CRPS [51]
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`G90.5 Complex regional pain syndrome I (CRPS I) G90.5 Complex regional pain syndrome I (CRPS I)
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`Reflex sympathetic dystrophy Reflex sympathetic dystrophy
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`
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`G90.50 Complex regional pain syndrome I, unspecified G90.50 Complex regional pain syndrome I, unspecified
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`
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`G90.51 Complex regional pain syndrome I of upper limb G90.51 Complex regional pain syndrome I of upper limb
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`G90.52 Complex regional pain syndrome I of lower limb G90.52 Complex regional pain syndrome I of lower limb
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`G90.59 Complex regional pain syndrome I of other specified site G90.59 Complex regional pain syndrome I of other specified site
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`G56.4 Causalgia of upper limb G56.4 Causalgia of upper limb
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`Complex regional pain syndrome II of upper limb Complex regional pain syndrome II of upper limb
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`
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`G56.40 Causalgia of unspecified upper limb G56.40 Causalgia of unspecified upper limb
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`G56.41 Causalgia of right upper limb G56.41 Causalgia of right upper limb
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`
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`G56.42 Causalgia of left upper limb G56.42 Causalgia of left upper limb
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`
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`G57.7 Causalgia of lower limb G57.7 Causalgia of lower limb
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`
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`Complex regional pain syndrome II of lower limb Complex regional pain syndrome II of lower limb
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`
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`G57.70 Causalgia of unspecified lower limb G57.70 Causalgia of unspecified lower limb
`
`
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`G57.71 Causalgia of right lower limb G57.71 Causalgia of right lower limb
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`
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`G57.72 Causalgia of left lower limb G57.72 Causalgia of left lower limb
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`CRPS is recognized and classified as a distinct syndrome under the International Classification of CRPS is recognized and classified as a distinct syndrome under the International Classification of
`
`
`
`Diseases (ICD), published by the World Health Organization. ICD is the standard diagnostic tool used to Diseases (ICD), published by the World Health Organization. ICD is the standard diagnostic tool used to
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`Page 9 of 47 Page 9 of 47
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`classify diseases and is in use in WHO Member States. The 2012 ICD, Tenth Revision (ICD-10) codes for
`classify diseases and is in use in WHO Member States. The 2012 ICD, Tenth Revision (ICD-10) codes for
`
`CRPS are listed above in Table 1 [51].
`CRPS are listed above in Table 1 [51].
`
`It is our intention to develop an oral formulation of zoledronic acid for the treat