Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

• the present invention relates to treatment of pain in patients.
• the present invention is directed to a method of converting a patient's pain treatment regimen from intravenous (IV) administration of an opioid to an orally administered combination of morphine and oxycodone in a weight ratio of about 3 :2,
• IV intravenous
• This method may include the use of a dosing algorithm for determining an appropriate dosage of the morphine and oxycodone combination.
• Opiate drugs are a class of pain-relieving prescription medications frequently used in the treatment of a variety of acute and chronic, moderate to severe, pain.
• Examples include natural opiates such as morphine, codeine, and thebaine; semi-synthetic opioids such as hydromorphone, hydrocodone, oxycodone, oxyrnorphone, diacetylrnorphine (heroin), nicom.orphine, dipropanoylmorphine, benzy (morph ne, ethylmorphine, buprenorphine and morphine glucuronid.es (including the 3- and 6- glucuronide); and fully synthetic opioids such as alfentanil, fentanyi, reniifentanil, sufentanil, trefentanil, pethidine, methadone, tramadol and dextropropoxyphene.
• semi-synthetic opioids such as hydromorphone, hydrocodone, oxycodone, oxyrnorphone, diacetylrnorphine (heroin), nicom.orphine, diprop
• the opioid receptor is believed to have four receptor subtypes named ⁇ -opioid receptor (MOR), ⁇ -opioid receptor (SOU), -opioid receptor ( O ) and ⁇ -opioid receptor (DOR),
• MOR ⁇ -opioid receptor
• SOU ⁇ -opioid receptor
• O -opioid receptor
• DOR ⁇ -opioid receptor
• the quantity of morphine and oxycodone administered may also play a role in the occurrence of side effects that are common to opioids, such as nausea, vomiting, drowsiness, dizziness, mental clouding, dysphoria, pruritus, constipation, increased biliary- tract pressure, urinary retention, hypotension, respiratory depression and bladder dysfunction.
• side effects such as nausea, vomiting, drowsiness, dizziness, mental clouding, dysphoria, pruritus, constipation, increased biliary- tract pressure, urinary retention, hypotension, respiratory depression and bladder dysfunction.
• the onset of tolerance to the therapeutic effects of the drugs, as well as the initiation of physical dependence may occur with daily administration of opioids; the extent of such tolerance or physical dependence is dependent in part on the quantity of opioids administered. Therefore, it is important to determine an effective oral dosing regimen for co-administering morphine and oxycodone in order to effectively and safely treat pain.
• the determination of the appropriate quantity of morphine and oxycodone to administer is especially important for patients recovering from a serious traumatic injury or a surgical procedure. These patients are often treated for pain initially by IV administration of an opioid drug such as morphine. Once these patients leave the hospital or surgical center and are no longer under medical supervision, they must receive the opioid drugs by a different route (e.g., orally) since repeated IV dosing is no longer practical, in the past, doctors have often estimated the necessary oral dose of some drugs following IV
• the present invention pro vides a method of treating pain in patients.
• the method addresses the need to convert the treatnient regimen of patients who were receiving IV administration of an opioid in the hospital or surgical center, to oral doses of opioids, such as when IV dosing is no longer practical or appropriate to administer.
• One aspect of the present invention is directed to a method of converting a treatment for pain comprising IV administration of an opioid to a treatment for pain comprising oral coadministration of an immediate release morphine-oxycodone combination (i.e., morphine, or a pharmaceutically acceptable salt thereof, and oxycodone, or a pharmaceutically acceptable salt thereof) in a weight ratio of about 3 :2, in a human patient in need of analgesia, such that the method may comprise determining a four-hour average oral morphine equivalent dose of the opioid administered intravenously to the human patient, and orally co-administering to the human patient a first dose of an immediate release morphine-oxycodone combination in accordance to a dosing algorithm.
• an immediate release morphine-oxycodone combination i.e., morphine, or a pharmaceutically acceptable salt thereof, and oxycodone, or a pharmaceutically acceptable salt thereof
• the four-hour average oral morphine equivalent dose is between about 0 mg and about 30 rag
• the first dose of the morphine-oxycodone combinat ion is no greater than about 12 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 8 mg of oxycodone, or a pharmaceutically acceptable salt thereof
• the first dose of the morphine-oxycodone combination is about 18 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 12 rag of oxycodone, or a pharmaceutically acceptable salt thereof.
• the first dose of the morphine-oxycodone combination is about 24 mg of morphine, or a pharmaceutically acceptable salt thereof and about 16 mg of oxycodone, or a pharmaceutically acceptable salt thereof.
• the first dose of the morphine-oxycodone combination is about 12 mg of morphine, or a pharmaceutically acceptable salt thereof and about 8 mg of oxycodone, or a pharmaceutically .acceptable salt thereof.
• the first dose of the morphine-oxycodone combination is about 3 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 2 mg of oxycodone, or a pharmaceutically acceptable salt thereof. If the four-hour average oral morphine equivalent dose is greater than about 10 mg and less than or equal to about 15 mg, then the first dose of the morphine-oxycodone combination is about 6 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 4 mg of oxycodone, or a pharmaceutically acceptable salt thereof.
• the first dose of the morphine-oxycodone combination is about 9 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 6 mg of oxycodone, or a pharmaceutically acceptable salt thereof, if the four-hour average oral morphine equivalent dose is greater than about 20 mg and less than or equal to about 30 nig, then the first dose of the morphine-oxycodone combination is about 12 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 8 mg of oxycodone, or a pharmaceutically acceptable salt thereof
• the four-hour average oral morphine equivalent dose is between about 0 rag and about 30 mg
• the first dose of the morphine-oxycodone combination is about 12 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 8 mg of oxycodone, or a
• the four-hour average oral morphine equivalent dose is greater than about 30 mg and less than or equal to about 40 mg, then the first dose of the morphine-oxycodone combination is about 18 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 12 mg of oxycodone, or a pharmaceutically acceptable salt thereof. Further, if the four-hour average oral morphine equivalent dose is greater than about 40 mg and less than or equal to about 120 mg, then the first dose of the morphine-oxycodone combination is about 24 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 16 mg of oxycodone, or a pharmaceutically acceptable salt thereof,
• the four-hour average oral morphine equivalent dose is determined fay Equation (1):
• bioequivaJency factor bioequivaJency factor
• s safety factor
• the clinical bioequivalency factor is between about 1 and about 15, in other embodiments, the clinical bioequivaJency factor is about 2. in some embodiments, the safety factor is between about 0.50 and about 1.0. in other embodiments, the safety factor is about 0.75.
• the present invention is directed to a method of converting a treatment for pain comprising IV administration of an opioid to a treatment for pain comprising oral co-administration of an immediate release morphine-oxycodone combination in a weight ratio of about 3:2. in a human patient in need of analgesia, such that the method may comprise determining a one-hour average oral morphine equivalent dose of the opioid administered intravenously to the human patient, and orally co-administering to the human patient a first dose of an immediate release morphine-oxycodone combination in accordance to a dosing algorithm.
• the dosing algorithm used after determining a one-hour average oral morphine equivalent dose is generally the same as the dosing algorithm used after determining a four-hour average oral morphine equivalent dose; the difference is that each first dose of the morphine-oxycodone combination corresponds to a range of average oral morphine equivalent dose that is one-fourth of the range of the four-hour oral morphine equivalent dose. Therefore, if the one-hour average oral morphine equivalent dose is between about 0 rng and about 7.5 mg, then the first dose of the morphine-oxycodone combination is no greater than about 12 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 8 mg of oxycodone, or a pharmaceutically acceptable salt thereof.
• the first dose of the morphine-oxycodone combinatio is about 18 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 12 mg of oxycodone, or a pharmaceutically acceptable salt thereof. Further, if the one-hour average oral morphine equivalent dose is greater than about 10 mg and less than or equal to about 30 mg, then the first dose of the morphine-oxyeodone combination is about 24 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 16 mg of oxycodone, or a pharmaceutically acceptable salt thereof. .
• the first dose of the morphine-oxycodone combination is about 12 mg of morphine, or a pharmaceutically acceptable salt thereof and about 8 mg of oxycodone, or a pharmaceutically acceptable salt thereof
• the first dose of the morphine-oxyeodone combination is about 3 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 2 mg of oxycodone, or a pharmaceutical ly acceptable salt thereof
• the one-hour average oral morphine equivalent dose is greater than about 2.5 mg and less than or equal to about 3.75 mg, then the first dose of the morphine-oxyeodone combination is about 6 mg of morphine, or a pharmaceutically acceptable sal thereof, and about 4 mg of oxycodone, or a pharmaceutically acceptable salt thereof.
• the one-hour average oral ' morphine equivalent dose is greater than about 3.75 rng and less than or equal to about 5 mg, then the first dose of the morphine-oxyeodone combination is about 9 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 6 mg of oxycodone, or a pharmaceutically acceptable salt thereof. If the one-hour average oral morphine equivalent dose is greater than about 5 mg and less than or equal to about 7.5 mg, then the first dose of the morphine-oxyeodone combination is about 12 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 8 mg of oxycodone, or a pharmaceutically acceptable salt thereof. In some embodiments, the one-hour average oral morphine equivalent dose is determined by Equation (2):
• m total amount (mg) of oral morphine equi valents of the opioid used during IV administration (including bolus and PCA);
• n oral morphine equivalents (mg) of the opioid used during the first four hours of IV administration;
• h :: total time (hour) that the oral morphine equivalents of the opioid was administered intravenously;
• Another aspect of the present invention is directed to a method of converting a treatment for pain comprising IV administration of morphine, or a pharmaceutically acceptable salt thereof, to a treatment for pain comprising oral co-administration of an immediate release morphine-oxycodone combination (i.e., morphine, or a pharmaceutically acceptable salt thereof, and oxycodone, or a pharmaceutically acceptable, salt thereof) in a weight ratio of about 3 :2, in a human patient in need of analgesia, such that the method may comprise determining a net average hourly IV morphine dose, and orally co-administering to the human patient a first dose of an immediate release morphine-oxycodone combination in accordance to an algorithm.
• an immediate release morphine-oxycodone combination i.e., morphine, or a pharmaceutically acceptable salt thereof, and oxycodone, or a pharmaceutically acceptable, salt thereof
• the net average hourly IV morphine dose is between about 0 mg and about 9 mg, then ihe first dose of the morphine-oxycodone combination is no greater than about 12 mg of morphine, or a pharmaceutically acceptable salt thereof and about 8 mg of oxycodone, or a pharmaceutically acceptable salt thereof. If the net average hourly IV morphine dose is greater than about 9 mg and less than or equal to about 14 mg, then the fi rst dose of the morphine-oxycodone combination is about 18 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 12 mg of oxycodone, or a pharmaceutically acceptable salt thereof.
• the first dose of the morphine-oxycodone combination is about 24 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 16 mg of oxycodone, or a
• the first dose of the morphine-oxycodone combination is about 12 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 8 rag of oxycodone, or a pharmaceutically acceptable salt thereof,
• the first dose of the morphine-oxycodone combination is about 3 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 2 mg of oxycodone, or a pharmaceutically acceptable salt thereof.
• the first dose of the morphine-oxycodone combination is about 6 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 4 mg of oxycodone, or a pharmaceutically acceptable salt thereof, if the net average hourly IV morphine dose is greater than about 5 mg and less than or equal to about 7 mg, then the first dose of the morphine-oxycodone combination is about 9 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 6 mg of oxycodone, or a pharmaoeuticaiiy acceptable salt thereof If the net average hourly IV morphine dose is greater than about 7 mg and less than or equal to about 9 mg, then the first dose of the morphine-oxycodone combination is about 12 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 8 mg of oxycodone, or a pharmaceutically acceptable salt thereof, Applying a dosing algorithm according
• the first dose of the morphine-oxycodone combination is about 1.8 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 12 mg of oxycodone, or a pharmaceutically acceptable salt thereof, if the net average hourly IV morphine dose is greater than about 14 mg, then the first dose of the morphine-oxycodone combination is about 24 mg of morphine, or a
• tire net average hourly IV morphine dose may ⁇ be determined by (i) calculating a net amount of morphine (or a pharmaceutically acceptable salt thereof) administered intravenously to the human patient, wherein the net amount is the total amount of morphine ad inistered intravenously to the human patient minus the amount of morphine administered intravenous iy to the human patient during the first four hours of administration; (ii) calculating a net time that morphine was administered intravenously to the human patient, wherein the net time is the total time that morphine was administered intravenously minus four hours; and (iii) dividing the net amount of morphine administered intravenously to the human patient by the net time that morphine was administered intravenously io the human patient.
• the pharmaceutically acceptable salt may be a hydrochloride, hydrobromide, hydroiodide, sulfate, bisuifaie, nitrate, citrate, tartrate, bitartrate, phosphate, malate, maleate, napsylate, fumarate, succinate, acetate, terephthaiate, pamoate or pectinate.
• the morphine-oxycodone combination comprises morphine sulfate and oxycodone hydrochloride.
• the morphine-oxycodone combination may be in an immediate release dosage form, sustained release dosage form, or controlled release dosage form.
• the morphine-oxycodone combination may be in an immediate release dosage form.
• the morphine-oxycodone combination may be co-administered in a single dosage form, in other embodiments, the morphine-oxycodone combination may be co-administered in separate dosage forms,
• the IV opioid comprises morphine, codeine, thebaine, hydromorphone, hydrocodone, oxycodone, oxymorphone, diacetylmorphine (heroin), nicomorphine, dipropanoylmorphine, benzylmorphine, ethylmorphine, buprenorphine and morphine glucuronides (including the 3- and 6-gIiicuronide), alfentanil, fentanyl, remifentanil, sufentanil, trefenta l, pethidine, methadone, tramadol, dextropropoxyphene, a pharmaceutically acceptable salt thereof, or a combination thereof
• the IV opioid comprises morphine or oxycodone or a pharmaceutically acceptable salt thereof.
• the method may further comprise orally co-administering one or more subsequent doses of ⁇ - ⁇ ;> ⁇ combination about every four to six hours, wherein the subsequent doses comprise the same amount of morphine, or a pharmaceutically acceptable salt thereof, and oxycodone, or a pharmaceutically acceptable salt thereof, as the first dose.
• the method may further comprise orally co-administering one or more subsequent doses of morphine- oxycodone combination about every four to six hours, under the following conditions: if the first dose is about 3 mg of morphine, or a pharmaceutically acceptable salt thereof and about 2 rag of oxycodone, or a pharmaceutically acceptable salt thereof, then the first subsequent dose is about 6 mg of morphine, or a pharmaceutically acceptable salt thereof and.
• the first dose is about 6 mg of morphine, or a pharmaceutically acceptable salt thereof and about 4 mg of oxycodone, or a pharmaceutically acceptable salt thereof, then the first subsequent dose is about 9 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 6 mg of oxycodone, or a pharmaceutically acceptable salt thereof; if the first dose is about 9 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 6 mg of oxycodone, or a
• the first subsequent dose is about 12 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 8 rag of oxycodone, or a pharmaceutically acceptable salt thereof; if the first dose is about 12 rag of morphine, or a pharmaceutically acceptable salt thereof, and about 8 mg of oxycodone, or a
• the first subsequent dose is about 1 8 mg of morphine, or a pharmaceutical ly accepiabie salt thereof, and about 12 mg of oxycodone, or a pharmaceutically acceptable salt thereof; and if the .first dose is about 18 mg of morphine, or a pharmaceuticalfy acceptable salt thereof, and about 12 mg of oxycodone, or a
• the first subsequent dose is about 24 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 16 rng of oxycodone, or a pharmaceutically acceptable salt thereof.
• the method may further comprise orally co-administering one or more subsequent doses of morphine, or a pharmaceutically acceptable salt thereof, and oxycodone, or a pharmaceutically acceptable salt thereof about ever four to six hours, under the following conditions: if the first dose is about 24 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 16 mg of oxycodone, or a pharmaceutical iy acceptable salt thereof, then the first subsequent dose is about 18 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 12 rng of oxycodone, or a pharmaceutically acceptable salt thereof; if the first dose is about 18 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 12 mg of oxycodone, or a pharmaceutically acceptable salt thereof, then the first subsequent dose is about 12 mg of morphine, or a pharmaceutically accepiable salt thereof and about 8 mg of oxycodone, or
• the present in vention relates to a method of converting a treatment for pain comprising IV administration of an opioi d , to a treatment for pain comprising oral co- administraiioa of a first dose of an immediate release morphine-oxycodone combination, '
• the present invention also relates to a method of treating pairs in patients who had been treated with IV administration of opioids, comprising converting the patients to a treatment comprising oral co-administration of a first dose of an immedi ate release morphine- oxycodone combination.
• morphine or “oxycodone” recited separately refers to the free base forms of morphine or oxycodone, respectively.
• pharmaceutically acceptable salt refers to a salt that is
• morphine-oxycodone combination refers to a combination of morphine, or a pharmaceutically acceptable salt thereof, and oxycodone, or a
• morphine equivalent dose refers to a calculation of the amount of morphine that produces the same analgesic effects as a particular amount of another opioid for given route(s) of dose administration.
• oral morphine equivalent dose of 1 mg of oral oxycodone is 1.5 mg of oral morphine; in other words, 1 mg of oxycodone administered orally will provide the same analgesic effect as 1 ,5 mg. of morphine
• administration concurrently or co-administration refers to the administration of a single composition containing both morphine and oxycodone, or pharmaceutically acceptable salts thereof, or to the administration of each opioid agonist as a. separate composition wi thin a short enough period of time such that the effective result is equivalent to that obtained when both such opioid agonists are adm nostired as a single composition.
• “about” will be understood to embrace somewhat larger or smaller values than the indicated value to account for, as examples, experimental errors inherent in the measurement and variability between different methodologies for measuring the value, as will be apparent to one skilled in the art,
• Embodiments of the present invention relate to a method of converting a treatment for pain comprising IV administration of an opioid to a treatment for pain comprising oral coadministration of a first dose of immediate release morphine and oxycodone, or
• the IV administration of opioids may be by PCA.
• the opioid administered intravenously may be any compound, such as a dr g, that binds to opioid receptors.
• Examples of an opioid include, but are not limited to, morphine, oxycodone, codeine, hydrocodone, diamorphine, fentanyl, alfentanyl,
• buprenorphine hydromorphone, methadone, and oxymorphone.
• a dosing algorithm may be used to determine the first oral immediate release dose of the morphine-oxyeodone combination, in some embodiments, a four-hour average oral morphine equivalent dose may be initially calculated based on the conditions of the IV administration of opioids, after which the fsrst dose of the morphine-oxyeodone combination is determined.
• the four-hour average oral morphine equivalent, dose may be determined using Equation (1):
• a one-hour average oral morphme equivalent dose may be mitially calculated based on the condiiions of the IV administration of opioids, after which the first dose of the morphine-oxycodone combination is determined.
• the one-hour average oral morphine equivalent dose may be determined using Equation (2 :
• m - total amount (mg) of oral morphine equivalents of the opioid used during IV administration including bolus and PCA
• n oral morphine equivalents (mg) of the opioid used during the first four hours of IV administration
• h total time (hour) that the oral morphine equivalents of the opioid was admi ni stered under IV administration
• b clinical bioequivalency factor
• s safety factor
• the terra "net amount of oral morphine equivalents administered.” may be used to describe the oral morphine equivalents used during IV administration, minus the oral morphine equivalents used during first four hours of IV administration (m - n).
• the term, "net time administered,” may be used to describe the total hours that the oral morphine equivalents was administered I less four hours (h - 4).
• "Net average hourly intravenous dosing” is therefore the net amount of oral morphine equivalents administered divided by the net time administered. in Equations 1 and 2, the calculation of (m - n) and (h - 4) essentially exempts from the ultimate determination the opioid given during the first four hours of intravenous administration. The first four hours are exempt because the amount of an opioid
• Equation 1 A factor of four is used in Equation 1 to convert the net average hourly IV dosing ( ⁇ rn - n) / (h - 4)) into a four-hour average since oral dosing of the morphine-oxycodone combination will be about every four to six. hours. In the absence of a factor of four as shown in Equation 2, the net average hourly IV dosing is converted into a one-hour average.
• the clinical bioequivalency factor considers the differences in the bioavailability between I V and oral routes of opioid administration and the conversion of non-morphine opioid analgesics to a morphine equivalent dose.
• the clinical bioequivalency factor for various opioids may vary between about 1 and about 15. The range also accounts for inter-patient variability, including the variability between opioid naive and opioid tolerant patients.
• the clinical bioequivalency factor for various opioids may vary between about ] and about 10
• the clinical bioequivalency factor may vary between about 1 and about 5.
• the clinical bioequivalency factor for morphine, or a pharmaceutically acceptable salt thereof may be about 2.
• the clinical bioequivalency factor for oxycodone, or a pharmaceutically acceptable salt thereof may be between about 1.5 and 7,5. In other embodiments, the clinical bioequivalency factor for oxycodone, or a pharmaceutically acceptable salt thereof, may be between about 3 and about 5.
• the safety iactor allows for a lesser amount of oral morphtne-oxycodone combination to be administered to minimize the chance of overdosing or occurrence of adverse events upon administration of the first dose.
• the safety factor may range from about 0,25 to about 1.0. in certain embodiments, the safety factor may be about 0,50. In some embodiments, the safety factor may be about 0.75,
• the first dose of an immediate release morphine-oxycodone combination can be determined using the dosing algorithm, shown in Table 1 ,
• the corresponding first dose of morphine-oxycodone combination may be no greater than about 12 mg / 8 mg; if the four- hour average oral morphine equivalent dose is greater than about 30 mg and less than or equal to about 4.0 rag, the corresponding first dose of morphine-oxycodone combination ma be about 18 mg / 12 mg; if the four-hour average oral morphine equivalent dose is greater than about 40 mg and less than or equal to about 120 mg, the corresponding first dose of morphine-oxycodone combination may be about 24 mg / 16 mg.
• the four-hour average oral morphine equivalent dose is between about 0 mg and about 30 mg ?
• the first dose of an immediate release morphineoxycodone combination administered orally can be determined using the dosing algorithm shown in Table 2.
• Table 2 Algorithm for the Conversion of Four-Hour Average Orai Morphine Equivalents to a First Dose of an Immediate Release Morphine-Oxycodone Combi nation Administered Orally.
• the corresponding first dose of morphine-oxycodone combination may be about 3 mg / 2 mg; if the four-hour average orai morphine equivalent dose is greater than about 10 mg and less than or equal to about 15 mg, the corresponding first dose of morphine-oxycodone combination may be about 6 mg 4 mg; if the four-hour average oral morphine equivalent dose is greater than about 15 mg and less than or equal to about 20 mg, the corresponding first dose of morphine-oxycodone
• the combination may be about 9 mg / 6 mg; if the four-hour average oral morphine equivalent dose is greater than about 20 mg and less than or equal to about 30 mg, the corresponding first dose of morphine-oxycodone combination may be about 12 mg / 8 mg.
• the first dose of an immediate release morphine-oxycodone combination administered orally can be also determined using the dosing algorithm shown in Table 3. Table 3. Algorithm for the Conversion of Four-Hour Average Oral Morphine Equivalent Dose to a First Dose of an immediate Release Morphine-Oxycodone Combination
• the corresponding first dose of morphine-oxycodone combination may be about 12 rag / 8 mg; if the four-hour average oral morphine equivalent dose is greater than about 30 mg and less than or equal to about 40 mg, the corresponding first dose of morphine-oxycodone combination may be about 18 mg / 12 mg; if the four-hour average oral morphine equivalent dose is greater than about 40 mg and less than or equal to about 120 mg. the corresponding first dose of morphine-oxycodone combination may be about 24 rag / 16 mg.
• the first dose of an immediate release morphine-oxycodone combination can be determined by dividing the four-hour average oral morphine equivalent dose ranges of the dosing algorithm in Table 1 by four, resulting in the dosing algorithm shown in Table 4.
• Table 4 Algorithm for the Conversion of One-Hour Average Oral Morphine Equivalents to a First Dose of an Immediate Release Morphine-Oxycodone Combination Administered Orally.
• the corresponding first dose of morphine-Qxycodone combination may be no greater than about 12 mg / 8 mg; if the one- hour average oral morphine equivalent dose is greater than about 7,5 mg and less than or equal to about 10 mg, the corresponding first dose of morphine-oxycodone combination may be about 1 8 mg / 12 mg; if the one-hour average oral morphine equivalent dose is greater than about 10 mg and less than or equal to about 30 mg, the corresponding first dose of morphine-oxycodone combination may be about 24 mg / 16 mg.
• the first dose of an immediate release morphine- oxycodone combination can be determined by dividing the four-hour average oral morphine equivalent dose ranges of the dosing algorithm in Table 2 by four, resulting in the dosing algorithm shown in Table 5.
• Table 5 Algorithm for the Conversion of One-Hour A verage Oral Morphine Equivalents to a First Dose of an Immediate Release Morphine-Oxycodone Combination Administered Orally.
• the corresponding first dose of morphine-oxycodone combination may be about 3 mg / 2 mg; if the one-hour average oral morphine equivalent dose is greater than about 2.5 mg and less than or equal to about 3.75 mg, the corresponding first dose of morphine-oxycodone combination may be about 6 mg / 4 mg; if the one-hour average oral morphine equivalent dose is greater than about 3.75 mg and less than or equal to about 5 mg, the corresponding first dose of morphine-oxycodone combination may be about 9 mg / 6 rag; if the one-hour average oral m orphine equivalent dose is greater than about 5 mg and less than or equal to about 7.5 mg, the corresponding first dose of morphine-oxycodone combination may be about 12 mg / 8 mg.
• the one-hour average oral morphine equivalent dose when the one-hour average oral morphine equivalent dose may be known or calculated as described above, the . first dose of an immediate release morphine- oxycodone combination can be detennined by dividing the four-hour average oral morphine equivalent dose ranges of the dosing algorithm in Table 3 by four, resulting in the dosing algorithm shown in ' Table 6. Tabic 6. Algorithm for the Conversion of One-Hour Average Oral Morphine Equivalent Dose to a First Dose of an ' Immediate Release Morphine-Oxycodone Combination Administered Orally.
• the corresponding first dose of morphine-oxycodone combination may be about 12 mg / 8 mg; if the one-hour average oral morphine equivalent dose is greater than about 7.5 mg arid less than or equal to about 10 mg, the corresponding first dose of morphine-oxycodone combination may be about 18 mg / 12 mg; if the one-hour average oral morphine equivalent dose is greater than about 10 mg and less thai) or equal to about 30 mg, the corresponding first dose of morphine-oxycodone combination may be about 24 mg / 16 mg.
• the first dose of an immediate release morphine- oxycodone combination administered orally can be determined using the dosing algorithm shown in Table 7.
• Table 7 Algorithm for the Conversion of Net Average Hourly Intravenous Dosing to a First Dose of an immediate Release Morphine-Oxycodone Combination Administered Orally.
• the corresponding first dose of morphine- oxycodone combination may be no greater than about 12 mg / 8 mg; if the net average hourly intravenous dosing is greater than about 9 mg and less than or equal to about 14 mg, the corresponding first dose of morphine-oxycodone combination may be about 1 8 mg / 12 mg. If the net average hourly intravenous morphine administered is greater than about 14 mg, the corresponding first dose of rnorphine-oxycodone combination may be about 24 mg of morphine and about 16 mg of oxycodone.
• the first dose of an immediate release dose of a morphine- oxycodone combination administered orally can be determined using the dosing algorithm shown in Table 8.
• Table 8 Algorithm for the Conversion of Net Average Hourly intravenous Dosing to a First Dose of an Immediate Release Morphine-Oxycodone Combination Administered Orally.
• the corresponding first dose of morphine- oxycodone combination may be about 3 rag / 2 mg; if the net average hourly intravenous dosing is greater than about 3 mg and less than or equal to about 5 mg, the corresponding first dose of morphine-oxycodone combination may be about 6 mg / 4 mg; if the net average hourly intravenous dosing is greater than about 5 mg and less than or equal to about 7 mg, the corresponding first dose of morphine-oxycodone combination may be about -9 mg / 6 mg; if the net average hourly intravenous dosing is greater than about 7 mg and less than or equal to about 9 mg, the corresponding first dose of morphine-oxycodone combination may be about 12 mg / 8 mg.
• the first dose of an immediate release morphine-oxycodone combination administered orally can be determined using the dosing algorithm shown, in Table 9.
• Table 9 Algorithm for the Conversion of Net Average Hourly intravenous Dosing to a First Dose of an Immediate Release Morphine-Oxyeodone Combination Administered Orally,
• the corresponding first dose oftnorphine- oxycodone combination ma be about 12 mg / 8 mg; if the net average hourly intravenous dosing is greater than about 9 mg and. less than or equal to about 14 mg, the corresponding first dose of morphine-oxycodone combination ma be about 18 mg / 12 mg. if the net- average hourly intravenous morphine administered is greater than about. 14 mg, the corresponding first dose of morphine-oxycodone combination may be about 24 mg of morphine and about 16 nig of oxycodone.
• the morphine-oxycodone combination may be administered to the patients every 2 to 10 hours, or every 3 to 8 hours, or every 4 to 6 hours.
• the morphine-oxycodone combination may be administered at the discretion of the physician applying the method and prescribing the combination, For opioid tolerant patients, the physician should take into consideration the patient's prior opioid dose and PC A dose of morphine and dose the subject accordingly.
• one or more subsequent doses may be administered abou every four to si hours apart, in certain embodiments. Die one or more subsequent doses may comprise the same amount of morphine or a pharmaceutically acceptable salt thereof and oxycodone or pharmaceutically acceptable salt thereof as the first dose, In the event the patient requires greater analgesia than what resulted from the first dose of morphine and oxycodone, the one or more subsequent doses can be increased compared to the first dose (up-titration). Thus, in certain embodiments, ihe subsequent doses of morphine-oxycodone combination may be co- administered about every four to six hours apart as follows:
• the first subsequent dose may be about 6 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 4 mg of oxycodone, or a pharmaceutically acceptable salt thereof;
• the first subsequent dose may be about 9 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 6 mg of oxycodone, or a pharmaceutically acceptable salt thereof;
• the first subsequent dose ma be about. 12 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 8 mg of oxycodone, or a pharmaceutically acceptable salt thereof;
• the first subsequent dose may be about 18 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 12 mg of oxycodone, or a pharmaceutically acceptable salt thereof; and (v) if the first dose is about 1 8 mg of morphine, or a pharmaceutically acceptable salt thereof and about 12 mg of oxycodone, or a pharmaceutically acceptable salt thereof, then the first subsequent dose may be about 24 mg of morphine, or a pharmaceutically acceptable salt thereof and about 16 mg of oxycodone, or a pharmaeeuticaliy acceptable salt thereof,
• the one or more subsequent doses may be decreased compared to the first dose
• subsequent doses of morphine and oxycodone are co-administered about every four to six hours apart as follows:
• the first subsequent dose may be about 18 mg of morphine, or a pharmaeeuticaliy acceptable salt thereof, and about 12 mg of oxycodone, or a pharmaceutically acceptable salt thereof;
• the first subsequent dose may be about 12 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 8 mg of oxycodone, or a pharmaceutically acceptable salt thereof;
• the first subsequent dose may be about 9 mg of morphine, or a pharmaceutically acceptable salt thereof and about 6 mg of oxycodone, or a pharmaceutically acceptable salt thereof;
• the first subsequent dose may be about 6 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 4 mg of oxycodone, or a pharmaceutically acceptable salt thereof;
• the first subsequent dose may be about 3 mg of morphine, or a pharmaceutically acceptable salt thereof, and about 2 mg of oxycodone, or a pharmaceuticall acceptable salt thereof.
• Patients who no longer require analgesia may terminate the administration of the medication. However, depending on the dose that is being administered, if a patient is taking the dose on a regular basis (usually at least three to four times per day) for seven days, termination of the medication may lead to withdrawal and the symptoms may include anxiety, muscle aches, abdominal cramping, diarrhea, nausea and vomiting, A dosing algorithm, to reduce o prevent withdrawal symptoms associated with termination of the morphine-oxyeodone combination may be found in Table 10.
• the morphine-oxycodone combination may comprise morphine or a pharmaceutically acceptable salt thereof, and oxycodone or a pharmaceutically
• the salt may be selected from a group including, but not limited to, hydrochlorides, hydrobromldes, hydroiodides, sulfates, bisulfates, nitrates, citrates, tartrates, bitartrates, phosphates, malates, maleates, napsylates, fumarates, succinates, acetates, terephthalates, pamoates and pectinates.
• the pharmaceutically acceptable salt of morphine may be a hydrochloride, a sulfate or a tartrate salt
• the pharmaceutically acceptable salt of oxycodone may be a hydrochloride, a terephthalate or a pectinate salt.
• the morphine-oxycodone combination comprises morphine sulfate and oxycodone hydrochloride.
• the morphine-oxycodone combination may comprise morphine, or a
• morphine sulfate and oxycodone hydrochloride are in the same pharmaceutical composition.
• compositions for oral administration may be administered in immediate release dosage forms.
• Immediate release dosage forms such as solid or liquid dosage forms include, by way of example and not limitation, tablets, troches, capsules, dispersions, suspensions, solutions, syrups, and the like.
• Pharmaceutical compositions may be presented as discrete units such as capsules, sachets or tablets, each containing a predetermined amount of each of the morphine and oxycodone, or pharmaceutically acceptable sails thereof, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
• compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing together each of the opioids with a pharmaceutically acceptable carrier.
• the compositions may be prepared by uniformly and intimately admixing the morphine and oxycodone, or pharmaceutically acceptable salts thereof, with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
• pharmaceutically acceptable carrier is intended to include any and all solvents, dispersio media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents together with pharmaceutically active substances is well known in the art.
• These carriers include, by way of example and not limitation, sugars, starches, cellulose and its deri vatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers, Isotonic saline, and pyrogen-free water. Supplementary active compounds can also be incorporated into the compositions.
• Oral compositions generally may include an inert diluent or an edible carrier.
• Suitable oral compositions may be, e.g., enclosed in gelaiin capsules or compressed into tablets, troches, or capsules.
• the active compound may be incorporated with excipients and used in the form of tablets, troches, or capsules.
• Pharmaceutically compatible binding agents, and/or adjuvant materials may be included as part of the composition.
• the tablets, pills, capsules, troches and the like may contain any of the following ingredients, or compounds of a similar nature: a binder such as macrocrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
• a binder such as macrocrystalline cellulose, gum tragacanth or gelatin
• an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
• a lubricant such as magnesium stearate or Sterotes
• a glidant such as colloidal silicon dioxide
• dosage unit form refers to physically discrete units suited as unitary dosages for the patient to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
• the specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.
• controlled release dosage forms as described hereinafter may be administered every 12- or 24-hours comprising, respectively, about 3 or 6 times the amount of the immediate-release dosage form, in this regard, it is well known that the change from immediate-release dosages to controlled-release dosages of morphine and oxycodone, or pharmaceutically acceptable salts thereof may be a simple milligram to milligram conversion that results in the same total "around-the-clock" dose of the morphine and oxycodone, or pharmaceutically acceptable salts thereof. See Cherny and Porienoy, "Practical Issues in the Management of Cancer Pain " in Textbook of Cancer Pain, Third Edition, Eds. Wall and Meizaek, Churchill Livingstone, 1994, 1453.
• Controlled-release of the morphine and oxycodone, or pharmaceutically acceptable salts thereof, may be affected by incorporating the morphine and oxycodone, or
• controlled release may be affected by using other polymer matrices, liposomes and/or microspheres.
• the controlled re!e-ase formulation of morphine and oxycodone, or pharmaceutically acceptable salts thereof may be released at a slower rate and over a longer period of time,
• the controlled release formulation of morphine and oxycodone, or pharmaceutically acceptable salts thereof may release effective amounts of a .
• the controlled release formulation may release effective amounts of morphine and oxycodone, or pharmaceutically acceptable salts thereof, over 4 hours or over 8 hours. In still other embodiments, the controlled release formulation may release, effective amounts of morphine and oxycodone, or pharmaceutically acceptable salts thereof, over 15, 1 8, 24 or 30 hours.
• the dose of the morphine component, or a pharmaceutical ly acceptable salt thereof, in the pharmaceutical compositions in accordance with the present invention, or methods of the present invention, for opioid-narve human adults through oral administration and in immediate release form may be about 3 mg or more; about 6 mg or more; about 12 mg or more; about 1 8 mg or more; or about 24 mg or more, every four hours.
• the dose of the morphine component may be higher.
• the analgesic dose of the oxycodone component, or a pharmaceuticalfy acceptable salt thereof, in the pharmaceutical compositions in accordance with the present invention, or methods of the present invention, for opioid- naive human adults through oral administration and in immediate release form may be 2 mg or more; 4 mg or more; 8 mg or more; 12 mg or more; or 16 mg or more, every four hours,
• the dose of the oxycodone component may be higher.
• the concentration of morphine and oxycodone in the blood stream will depend on the amount of compound administered in the composition as well as the route of administration and the specific formulation used. For example, it is well known in the art thai administration of morphine and oxycodone by IV injectio typically results in a significant concentration of each compound in the blood stream almost immediately afte administration (without delay), whereas formulations adapted for oral administration of morphine and oxycodone will typicaiiy achieve effective concentrations in the blood stream later than IV administration and at differen concentrations depending on oral availability of the compounds. Further, the routes of administration of the compounds may further result in different inactivation and excretion rates of morphine and oxycodone when administered in a combination.
• Table 3 1 provides pharmacokinetic data for healthy subjects that were orally co-administered a single dose of morphine and oxycodone in dosage strengths of about 3 mg / 2 mg and about 12 mg / 8 mg. Values for the observed maximum plasma concentration (C m8X ), total area under the plasma concentration-time curve (AUCo- ⁇ ) and the time to maximum plasma concentration (T max ) were determined.
• Plasma levels of morphine and oxycodone each appeared to increase linearly in a dose-proportionate manner after single-dose administration of the morphine:oxycodone combination (within the 3 mg / 2 mg to 12 mg / 8 mg dose range).
• All dose-normalized, log- transformed parameters (C Intel iax and AUCo- ⁇ ) were within the 80-125 % bioequi alence criteria limits, a demonstration of the dose proportionality between the 3 mg / 2 mg and 12 mg / 8 mg dose strengths. These data provide conclusive evidence of dose proportionality between the two dosage strengths.
• the present invention also relates to a method for the treatment of pain in a human patient in need of analgesia by oral co-administration of an immediate release morphine- oxycodone combination in a weight ratio of about 3:2.
• such method includes the use of a dosing algorithm to determine the first oral dose of the immediate release morphine-oxycodone combination following administration of IV opioid (e.g., morphine or a pharmaceutically acceptable salt thereof) to the patient.
• IV opioid e.g., morphine or a pharmaceutically acceptable salt thereof
• the dosing algorithm used in these methods may be a dosing algorithm described above.
• a dosing, algorithm may be applied such that if the net average hourly intravenous dosing is between about 0 rag and about 9 mg, the corresponding first dose of morphme- oxycodone combination may be about 12 mg / 8 mg; if the net average hourly intravenous dosing is greater than about 9 mg and less than or equal to about 14 mg, the corresponding first dose of inorphirie-oxycodone combination may be about 1 mg / 12 rag. If the net average hourly intravenous morphine administered is greater than about 14 mg, the corresponding first dose of morphine-oxycodone combination may be about 24 mg of morphine and about 16 mg of oxycodone.
• the patient receives a total amount of 129 mg of morphine during the total time of IV PCA morphine administration. Therefore, the net amount of morphine administered by IV PCA is calculated by subtracting 9 mg (the amount of TV PCA morphine administered during the first four hours of IV PCA) from the total amount of 129 mg, thereby giving a net amount of morphine administered by IV PCA of 120 mg (129 mg - 9 mg).
• the net time of IV PCA morphine administration is calculated as the total time of 18 hours minus the first four hours, for a net time of V PCA morphine administration of 14 hours (18 hours - 4 hours).
• the net average hourly IV PCA morphine administration is calculated by dividing the net amount of IV PCA morphine administration ( 120 mg) by the net time of IV PCA morphine administration (14 hours), which in this case is 120 mg divided by 1.4 hours, which gives an net average hourly I V morphine dosing of about 9 mg (120 mg/14 hours).
• the patient is converted to a corresponding first oral dose of MOXDUO ® of 12 rag of morphine sulfate and 8 mg of oxycodone hydrochloride in an immediate release dosage form.
• IV PCA morphine dosing is a total time of 17 hours of IV PCA morphine dosing available for the calculation of the algorithm.
• the patient receives 9 mg of morphine IV PCA and a nurse gives 2 mg IV morphine through the PCA pump for a total of I i mg of V morphine during the first four hours.
• the patient receives a iota! amount of 60 rng of morphine during the total time of IV PCA morphine administration. Therefore, the net amount of morphine administered by IV PCA is calculated by subtracting from the total amount of 60 mg the amount of iV PCA morphine administered during the fist four hours of IV PCA.
• the net time of IV PCA morphine administration is calculated as the total time of 17 hours minus the first four hours, for a net time of IV PCA morphine administration of 13 hours ( 17 hours - 4 hours).
• the net average hourly IV PCA morphine administration is calculated by dividing the net amount of IV PCA morphine administratio (49 mg) by the net time of IV PCA morphine administration ( i l hours), which in this case gives an net average hourly intravenous morphine dosing of about 4.5 mg (49 nig / 1 1 hours).
• the patient is therefore converted to a first dose of oral MOXDUO ® at a dose of 12 mg of morphine sulfate and 8 mg of oxycodone hydrochloride in . immediate release form.
• immediate post-operative analgesia consisted of PCA IV morphine.
• Subjects were connected to a PCA pump within 120 minutes after closure of surgery.
• Morphine doses (0.5- 2,0 mg/dose) were administered b PCA pump with a 5-minute lockout period and a maximum dose of 10 mg morphine per hour, if the analgesia was insufficient, the one-hour limit may be increased to ⁇ ] 5 m morphine per hour at the discretion of the doctor.
• the nursing staff may administer via the PCA pump a single bolus dose of up to 5 mg of morphine, if necessary.
• Eligibility for enrollment of subjects in the study required the administration of an average oral morphine equivalent dose of ⁇ 120 rag IV morphine by PCA pump (including morphine administered as a bolus by nursing staff and ail self-administered morphine) over a period of at leas 8 hours (interval between first dose and final dose via pump). Following surgery, subjects were disconnected from the PCA. pump between 5:00 AM - 7:00 AM on the morning following surgery to obtain an IV morphine baseline to be used with an algorithm to determine the starting dose for administration of oral MOXDUO 1 *,
• Calculation of total dose of morphine (mg) used during the total period of IV morphine PCA includes the sum of any morphine administered as a bolus by nursing staff and all self-administered morphine.
• MOXDUO* study medication was administered q. 4-6 h (not to exceed 6 doses in 24 hours) and the last dose was administered 42 hours after the first dose.
• the primary efficacy endpoint was the mean Sum of Pain intensity Difference scores during the 48-hour treatment period (SPID 48 ). A subject who had at least 30% decrease in pain intensity compared to baseline or had a good to excellent outcome on a global assessment of study medication scale at 24 or 48 hours was considered a responder.
• 8 subjects did not require an upward dose titration for the second dose.
• I of the 14 subjects down-titrated at the first subsequent dose and completed the study at the lower dose level.
• 6 subjects required an increased dose and completed the study at the higher dose level compared to the first administered dose.
• BPI-SF Brief Pain inventory-Short Form
• the dosing algorithm for converting IV PCA morphine to the first dose of oral MOXDUO ⁇ was both conservative and safe. None of the subjects administered MOXDUO* discontinued due to an adverse event, although one subject in the PERCOCET* treatment group discontinued because of a possibly related TEAE of stomach irritation. The overall incidence of nausea, pruritus, constipation, and dizziness was higher during the IV PC A morphine use than during the same time period after first dose of study medication. Eleven (25 % ⁇ subjects had moderate or severe nausea while on IV PCA morphine.
• MOXDUO* and PE COCET® treatment groups were similar in terms of proportion of responders and median SPID ⁇ .
• values for the Sum of Pain Response and Pain Intensity Difference (SPRID), mean distance walked on Day 2 of rehabilitation, and time to remedication were similar for both treatment groups (data not shown).
• the MOXDUO* dosing treatment group had a significantly lower BPI-SF score for pain interfering with general activity than the PERCOCET* treatment group at 48 hours/early termination.
• patients being administered MOXDUO* "' had a mean % improvement in BP! from baseline to end of treatment for general activity, walking ability, and ability to sleep of 54 %, 35 %, and 31 %, respectively.
• Patients that were administered PERCOCET® had BP! scores of 19 %, 17%, and 15 %, respectively, for the same categories. No related SAEs, severe TEAEs, or AEs leading to discontinuation occurred in the
• MOXDUO ® treatment group n the PERCOCET* treatment group. 1 subject had. a severe TEAE of dry mouth, and 1 subject discontinued due to an adverse event -of stomach irritation. The incidence of moderate to severe nausea and vomiting was higher in the PERCOCET ⁇ treatment group compared with the equi-analgesic MOX O! JO " dosing treatment group, w ich had no such events.
• the dosing algorithms of the instant invention allows for the determination of a simple and convenient starting dose of MOXDUO* for patients being administered IV opioids, such as morphine.
• the titration algorithms also allow for the ease of upward and downward titration ofMOXDUO ® if required.
• the algorithms used in the present invention provide surprising and unexpected results since patients being administered MOXDUO* reached a level of analgesia within the first administered dose, or the first subsequent dose of MOXDUO 3 ⁇ 4 , These results are in contrast to patients that may require up to 48 -hours of dose titrations to obtain analgesia, See S. Mercadante, Eur.

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