US20140005217A1 - Nalmefene for reduction of alcohol consumption in specific target populations - Google Patents
Nalmefene for reduction of alcohol consumption in specific target populations Download PDFInfo
- Publication number
- US20140005217A1 US20140005217A1 US13/928,332 US201313928332A US2014005217A1 US 20140005217 A1 US20140005217 A1 US 20140005217A1 US 201313928332 A US201313928332 A US 201313928332A US 2014005217 A1 US2014005217 A1 US 2014005217A1
- Authority
- US
- United States
- Prior art keywords
- nalmefene
- patient
- alcohol
- longer
- day
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- WJBLNOPPDWQMCH-MBPVOVBZSA-N Nalmefene Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=C)O)CC1)O)CC1CC1 WJBLNOPPDWQMCH-MBPVOVBZSA-N 0.000 title claims abstract description 181
- 229960005297 nalmefene Drugs 0.000 title claims abstract description 179
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 title claims abstract description 176
- 230000009467 reduction Effects 0.000 title abstract description 34
- 208000007848 Alcoholism Diseases 0.000 claims abstract description 50
- 230000035622 drinking Effects 0.000 claims abstract description 47
- 201000007930 alcohol dependence Diseases 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims description 77
- 238000011282 treatment Methods 0.000 claims description 30
- 230000002829 reductive effect Effects 0.000 claims description 13
- 230000003466 anti-cipated effect Effects 0.000 claims description 11
- 238000009223 counseling Methods 0.000 claims description 11
- 208000025746 alcohol use disease Diseases 0.000 claims description 10
- 239000002775 capsule Substances 0.000 claims description 10
- 241000995051 Brenda Species 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- NSNHWTBQMQIDCF-UHFFFAOYSA-N dihydrate;hydrochloride Chemical compound O.O.Cl NSNHWTBQMQIDCF-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 4
- 235000019441 ethanol Nutrition 0.000 description 181
- 230000008859 change Effects 0.000 description 37
- 239000000902 placebo Substances 0.000 description 27
- 229940068196 placebo Drugs 0.000 description 27
- 239000003814 drug Substances 0.000 description 22
- 230000000694 effects Effects 0.000 description 18
- 238000012216 screening Methods 0.000 description 18
- 150000001875 compounds Chemical class 0.000 description 10
- 239000008194 pharmaceutical composition Substances 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- 208000024891 symptom Diseases 0.000 description 9
- 230000001154 acute effect Effects 0.000 description 6
- 238000003745 diagnosis Methods 0.000 description 6
- 230000036541 health Effects 0.000 description 6
- 229940005483 opioid analgesics Drugs 0.000 description 6
- 230000000306 recurrent effect Effects 0.000 description 6
- 206010062237 Renal impairment Diseases 0.000 description 5
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 5
- 238000001784 detoxification Methods 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 208000019423 liver disease Diseases 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 230000002085 persistent effect Effects 0.000 description 5
- 206010010904 Convulsion Diseases 0.000 description 4
- 206010012225 Delirium tremens Diseases 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 4
- 208000029650 alcohol withdrawal Diseases 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- 208000020016 psychiatric disease Diseases 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 3
- 206010053164 Alcohol withdrawal syndrome Diseases 0.000 description 3
- 208000004547 Hallucinations Diseases 0.000 description 3
- 208000026251 Opioid-Related disease Diseases 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 230000006735 deficit Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 239000000014 opioid analgesic Substances 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229940127450 Opioid Agonists Drugs 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 230000006399 behavior Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 235000019788 craving Nutrition 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 230000004590 drinking behavior Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229940126602 investigational medicinal product Drugs 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229960003086 naltrexone Drugs 0.000 description 2
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- 208000007232 portal hypertension Diseases 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- 239000004229 Alkannin Substances 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 239000004230 Fast Yellow AB Substances 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 239000004233 Indanthrene blue RS Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000004235 Orange GGN Substances 0.000 description 1
- 239000004237 Ponceau 6R Substances 0.000 description 1
- 239000004236 Ponceau SX Substances 0.000 description 1
- 101100244562 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) oprD gene Proteins 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 239000004231 Riboflavin-5-Sodium Phosphate Substances 0.000 description 1
- 206010048010 Withdrawal syndrome Diseases 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- 239000004234 Yellow 2G Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 235000019232 alkannin Nutrition 0.000 description 1
- 239000004191 allura red AC Substances 0.000 description 1
- 235000012741 allura red AC Nutrition 0.000 description 1
- 239000004178 amaranth Substances 0.000 description 1
- 235000012735 amaranth Nutrition 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000004176 azorubin Substances 0.000 description 1
- 235000012733 azorubine Nutrition 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 239000004161 brilliant blue FCF Substances 0.000 description 1
- 235000012745 brilliant blue FCF Nutrition 0.000 description 1
- 239000004106 carminic acid Substances 0.000 description 1
- 235000012730 carminic acid Nutrition 0.000 description 1
- 239000001679 citrus red 2 Substances 0.000 description 1
- 235000013986 citrus red 2 Nutrition 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000004148 curcumin Substances 0.000 description 1
- 235000013365 dairy product Nutrition 0.000 description 1
- 108700023159 delta Opioid Receptors Proteins 0.000 description 1
- 102000048124 delta Opioid Receptors Human genes 0.000 description 1
- 230000003001 depressive effect Effects 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 230000009429 distress Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 239000004174 erythrosine Substances 0.000 description 1
- 235000012732 erythrosine Nutrition 0.000 description 1
- 235000019233 fast yellow AB Nutrition 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 235000019239 indanthrene blue RS Nutrition 0.000 description 1
- 239000004179 indigotine Substances 0.000 description 1
- 235000012738 indigotine Nutrition 0.000 description 1
- 230000035987 intoxication Effects 0.000 description 1
- 231100000566 intoxication Toxicity 0.000 description 1
- 102000048260 kappa Opioid Receptors Human genes 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 102000051367 mu Opioid Receptors Human genes 0.000 description 1
- 235000019236 orange GGN Nutrition 0.000 description 1
- 239000004177 patent blue V Substances 0.000 description 1
- 235000012736 patent blue V Nutrition 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000004175 ponceau 4R Substances 0.000 description 1
- 235000012731 ponceau 4R Nutrition 0.000 description 1
- 235000019238 ponceau 6R Nutrition 0.000 description 1
- 235000019237 ponceau SX Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000004172 quinoline yellow Substances 0.000 description 1
- 235000012752 quinoline yellow Nutrition 0.000 description 1
- 239000004180 red 2G Substances 0.000 description 1
- 235000012739 red 2G Nutrition 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000002151 riboflavin Substances 0.000 description 1
- 235000019192 riboflavin Nutrition 0.000 description 1
- 235000019234 riboflavin-5-sodium phosphate Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 201000009032 substance abuse Diseases 0.000 description 1
- 239000004173 sunset yellow FCF Substances 0.000 description 1
- 235000012751 sunset yellow FCF Nutrition 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000004149 tartrazine Substances 0.000 description 1
- 235000012756 tartrazine Nutrition 0.000 description 1
- 235000019235 yellow 2G Nutrition 0.000 description 1
- 108020001588 κ-opioid receptors Proteins 0.000 description 1
- 108020001612 μ-opioid receptors Proteins 0.000 description 1
Images
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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- 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
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to nalmefene for use in the reduction of alcohol consumption in a patient with alcohol dependence who has a high drinking risk level.
- the present invention also relates to nalmefene for use in the reduction of alcohol consumption in a patient with alcohol dependence who maintains a high DRL after an observation period following initial assessment.
- Nalmefene 17-(cyclopropylmethyl)-4,5-alpha-epoxy-6-methylenemorphinan-3,14-diol] has the following general formula:
- Nalmefene is a known opioid system modulator, with a distinct ⁇ , ⁇ , and ⁇ receptor profile, which can inhibit pharmacological effects of both administered opioid agonists and endogenous agonists derived from the opioid system.
- the clinical usefulness of nalmefene comes from its ability to promptly and selectively reverse the effects of these opioid agonists.
- Nalmefene has primarily been developed for use in the management of alcohol dependence.
- a double-blind, placebo-controlled study has shown good effect of 20 to 80 mg daily oral dosing of nalmefene (Mason et al., Arch. Gen. Psychiatry , (1999), Vol. 56: 719-724): while another study reported no evidence of superiority of nalmetene over placebo in a study evaluating 5, 20 and 40 mg daily doses of nalmefene (Anton et al., J. Clin. Psychopharmacol ., (2004), Vol. 24(4): 421-428). A more recent study.
- Risk levels according to Table 1 can be assessed e.g. by calculating mean daily alcohol consumption in g/day over a month such as over 4 weeks. There is a need for a new treatment for use in reduction of alcohol consumption. Reduction of alcohol consumption is likely to provide benefits associated with decreased risk of health-related harm and decreased number of adverse social consequences.
- the present invention relates to a nalmefene for use in the reduction of alcohol consumption in a patient with alcohol dependence, wherein said use comprises the following steps:
- FIGS. 1-12 show the change from baseline in monthly Heavy Drinking days (HDDs) and Total Alcohol Consumption (TAC) (g/day) per study. Results are shown for the Total study population, Patients with a high DRL at baseline, Total study population excluding Early Reducers (ERs) and Patients with a high DRL at baseline and randomization
- HDDs Heavy Drinking days
- TAC Total Alcohol Consumption
- FIGS. 1 a - 12 a show the change from baseline in monthly HDDs.
- X-axis time (months);
- Y-axis change in HDD.
- FIGS. 1 b - 12 b show the change from baseline in monthly TAC (g/day.
- X-axis time (months);
- Y-axis change in TAC (g/day).
- FIG. 1 a Study 12014A, total study population, change in monthly HDD.
- FIG. 1 b Study 12014A, total study population, change in monthly TAC.
- FIG. 2 a Study 12014A, high DRL at baseline, change in monthly HDD.
- FIG. 2 b Study 12014A, high DRL at baseline, change in monthly TAC.
- FIG. 3 a Study 12014A, total study population excluding ERs, change in monthly HDD.
- FIG. 3 b Study 12014A, total study population excluding ERs, change in monthly TAC.
- FIG. 4 a Study 12014A, high DRL at baseline and randomization, change in monthly HDD.
- FIG. 4 b Study 12014A, high DRL at baseline and randomization, change in monthly TAC.
- FIG. 5 a Study 12023A, total study population, change in monthly HDD.
- FIG. 5 b Study 12023A, total study population, change in monthly TAC.
- FIG. 6 a Study 12023A, high DRL at baseline, change in monthly HDD.
- FIG. 6 b Study 12023A, high ORL at baseline, change in monthly TAC.
- FIG. 7 a Study 12023A, total study population excluding ERs, change in monthly HDD.
- FIG. 7 b Study 12023A, total study population excluding ERs, change in monthly TAC.
- FIG. 8 a Study 12023A, high ORL at baseline and randomization, change in monthly HDD.
- FIG. 8 b Study 12023A, high DRL at baseline and randomization, change in monthly TAC.
- FIG. 9 a Study 12013A, total study population, change in monthly HDD.
- FIG. 9 b Study 12013A, total study population, change in monthly TAC.
- FIG. 10 a Study 12013A, high DRL at baseline, change in monthly HDD.
- FIG. 10 b Study 12013A, high DRL at baseline, change in monthly TAC.
- FIG. 11 a Study 12013A, total study population excluding ERs, change in monthly HDD.
- FIG. 11 b Study 12013A, total study population excluding ERs, change in monthly TAC.
- FIG. 12 a Study 12013A, high DRL at baseline arid randomization, change in monthly HDD.
- FIG. 12 b Study 12013A, high DRL at baseline and randomization, change in monthly TAC.
- nalmefene is intended to include any forms of the compound, such as the free base and pharmaceutically acceptable salts.
- the free base and pharmaceutically acceptable salts include anhydrous forms and solvated forms such as hydrates.
- the anhydrous forms and the solvates include amorphous and crystalline forms.
- nalmefene is in the form of the hydrochloride.
- nalmefene is in the form of the hydrochloride dihydrate.
- HDD heavy drinking day
- nalmefene should be taken, preferably 1-2 hours prior to the anticipated time of drinking. If the patient has started drinking alcohol without taking nalmefene, the patient should take one dose as soon as possible after that.
- DRL pestking risk level
- Drinking Risk Levels according to Table 1 can be assessed e.g. by calculating mean daily alcohol consumption in g/day over a period such as 1 week or longer, such as 2 weeks or longer, such as 3 weeks or longer, such as 4 weeks or longer, such as 1 month or longer such as 2 months or longer, such as 3 months or longer, such as 4 months or longer, such as 5 months or longer, such as 6 months or longer, such as about 1 year.
- Assessment of DRL can be performed by specialists and/or physicians such as general practitioners and/or other health care providers based on patients estimates of their alcohol consumption.
- DRL was measured by assessment of mean daily alcohol consumption in g/day over a 4 week period up to the initial visit. After a 1-2 week observation period the drinking risk level was re-assessed by assessment of mean daily alcohol consumption in g/day over said 1-2 week observation period.
- high risk or “at least high risk” is intended to include the two groups defined as “high risk” and “very high risk” according to WHOs drinking risk levels listed in Table 1, i.e. patients having drinking risk level corresponding to a total alcohol consumption of >60 g/day of pure alcohol for men and >40 g/day for women.
- the present invention does not distinguish between patients with high and very high drinking risk levels, and when the terms “high drinking risk level” or “high DRL” are used in a claim or in an embodiment of the invention it is intended to include both the group defined as “high risk” and the group defined as “very high risk” according to VVHOs drinking risk levels listed in Table 1.
- ER head reducer
- ER the term “early reducer” abbreviated ER indicates a patient included in the three Lundbeck phase Ill studies (12014A, 12023A and 12013A) who had considerably reduced the alcohol consumption in the period between screening and randomisation. More specifically, patients defined as ERs have reduced their alcohol consumption from high or medium DRL to a level below medium drinking risk level i.e. said patients had an alcohol consumption of 0-40 g/day for men and 0-20 g/day for women estimated as the mean daily alcohol consumption in a 1-2 week period between screening and randomization.
- an “observation period in accordance with clinical practice” is an observation following initial assessment of the DRL. Said period is preferably 1-2 weeks most preferably about 2 weeks.
- the term “adult” indicates a person who is at least 16 years old such as at least 18 years old.
- the term “adolescent” indicates a person who is 12-18 years old such as 12-16 years old.
- the terms “motivational support” and “counseling focused on enhanced treatment adherence and reduced alcohol consumption” indicate psychological motivation-enhancing interventions and can be used interchangeably with the terms “psychosocial support” or “psychosocial intervention focused on treatment adherence and reducing alcohol consumption”.
- Said motivational support can be administered by a specialist and/or a physician such as a general practitioner and/or other health care providers.
- One example of such interventions is the BRENDA model, which is a time-limited, patient-centered clinical motivational intervention that complements the use of medication with focus on changing behavior and increasing medication adherence.
- the BRENDA model has been described by Starosta et al., J. Psychiatr. Pract . (2006), Vol.
- the term “initial motivational support” indicates such motivation-enhancing interventions provided to the patient prior to treatment with nalmefene.
- the term “ongoing motivational support” indicates such motivation-enhancing interventions provided to the patient concurrent to treatment with nalmefene e.g. on a recurrent basis.
- “Pharmaceutical composition” refers to a dose such as an oral dose form, such as a solid oral dose form, typically tablets or capsules. In a preferred embodiment, said dose form is suitable for as-needed dosing. Said pharmaceutical composition typically comprises a therapeutically effective amount of nalmefene and one or more pharmaceutically acceptable carrier. “Pharmaceutical compositions of the present invention” refers to all pharmaceutical compositions covered by the claims and description.
- a “unit dosage form” refers to a formulation unit of a pharmaceutical composition e.g. one tablet or capsule.
- “therapeutically effective amount” of a compound means the amount/dose of a compound or pharmaceutical composition that is sufficient to produce an effective response (i.e., a biological or medical response of a tissue, system, animal or human sought by a researcher, veterinarian, medical doctor or other clinician) upon administration to a patient.
- the “therapeutically effective amount” will vary depending on, inter alia, the disease and its severity, and on the age, weight, physical condition and responsiveness of the patient to be treated.
- the “therapeutically effective amount” may vary if the compound of the invention is combined with one or more compounds: In such a case the amount of a given compound might be lower, such as a sub-effective amount.
- a “therapeutically effective amount” of nalmefene is 18 mg.
- treatment refers to the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder.
- the term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound to alleviate the symptoms or complications, to delay the progression of the disease, disorder or condition, to alleviate or relieve the symptoms and complications, and/or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prevention is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications.
- alcohol dependence is a commonly known term for a skilled person and is defined in the revised 4 th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) ( Diagnostic and Statistical Manual of Mental Disorders, 4 th edition text revision, American Psychiatric Publishing, 2000), the entire contents of which are incorporated herein by reference.
- DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders
- the term “alcohol dependence” is defined as the presence of three or more of the seven areas of life impairment related to alcohol in the same 12month period.
- alcohol use disorder is defined in the 5 th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) (Diagnostic and Statistical Manual of Mental Disorders, 5 th edition, American Psychiatric Publishing, 2013), the entire contents of which are incorporated herein by reference.
- the term “alcohol use disorder” is defined as a problematic pattern of alcohol use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a 12-month period: 1) Alcohol is often taken in larger amounts or over a longer period than was intended. 2) There is a persistent desire or unsuccessful efforts to cut down or control alcohol use. 3) A great deal of time is spent in activities necessary to obtain alcohol, use alcohol, or recover from its effects.
- Alcohol use disorder is separated into the following three categories; Mild: Presence of 2-3 symptoms, Moderate: Presence of 4-5 symptoms, Severe: Presence of 6 or more symptoms.
- TLFB Timeline Follow-back
- memory aids such as a calendar
- patients provide retrospective estimates of the number of standard drinks for each day.
- TLFB was characterized by the following approach.
- a day was defined as a 24-hour period starting at 6.00 a.m. and ending at 6.00 a.m. the following morning.
- At the Screening Visit each patient was to provide a retrospective estimate of his/her daily drinking over the previous month (a month was defined as a period of 28 consecutive days).
- the patient was to provide information on his/her drinking since the previous visit.
- TLFB TLFB that was completed at the next visit was extended to cover the days that should have been recorded at the missing visit.
- Patients could use their personal calendars to help them recalling their drinking or they could use a calendar provided by the site for their personal use. Calendars were only to be used as a memory aid to support the patients' input to TLFB.
- the patients were asked to report their alcohol intake by standard units according to the national definition of a standard unit. The standard national units were defined in standard drink conversion cards distributed to the patients.
- Hepatic impairment can be assessed by the Child-Pugh scoring system, as defined in Child and Turcotte J G. Surgery and portal hypertension. In: The liver and portal hypertension . Edited by C G Child. Philadelphia: Saunders 1964:5064, the entire contents of which are incorporated herein by reference. Patients can be classified according to this system with e.g. “moderate or severe hepatic impairment”.
- Renal impairment can be assessed by measuring estimated global filtration rate (eGFR) as described in Stevens et al., N. Engl. Med . (2006) 354:2473-2483, the entire contents of which are incorporated herein by reference. Patients with “severe renal impairment” are classified by an eGFR ⁇ 30 ml/min Per. 1.73 m 2 .
- the patients' clinical status, social situation, and alcohol consumption pattern were evaluated.
- the drinking risk level was re-assessed by calculating mean daily alcohol consumption in g/day over the 1- to 2-week observation period, and treatment with nalmefene was initiated together with counseling with focus on motivating the patients to adhere to the treatment and to change their drinking behavior.
- HDDs monthly number of heavy drinking days
- TAC mean daily total alcohol consumption
- the present invention relates to nalmefene for use in the reduction of alcohol consumption in a patient with alcohol dependence who has a high drinking risk level i.e.
- the present invention relates to nalmefene for use in the reduction of alcohol consumption in a patient with alcohol dependence who has at a least high drinking risk level according to WHO criteria, such as a high or very high drinking risk level according to WHO criteria.
- the present invention relates to nalmefene for use in the reduction of alcohol consumption in a patient with alcohol dependence who maintains the level of alcohol consumption after an observation period in accordance with clinical practice, such as an observation period of 1-2 weeks.
- the invention relates to nalmefene for use in the reduction of alcohol consumption in a patient with alcohol dependence who maintains at least medium DRL after an observation period in accordance with clinical practice, such as an observation period of 1-2 weeks.
- the present invention relates to nalmefene for use in the reduction of alcohol consumption in a patient with alcohol dependence who have a high drinking risk level, i.e alcohol consumption >60 g/day of pure alcohol for men and >40 g/day for women, and who continue to have a high drinking risk level after an observation period in accordance with clinical practice.
- patients according to the invention have a diagnosis of alcohol dependence according to the DSM-IV-TR criteria. In one embodiment, patients according to the invention have a diagnosis of alcohol use disorder according to the DSM-V criteria. In a further embodiment, patients according to the invention have a diagnosis selected from one or more of mild, moderate and severe alcohol use disorder according to the DSM-V criteria. In one embodiment, said patients have mild alcohol use disorder. In one embodiment, said patients have moderate alcohol use disorder. In one embodiment, said patients have severe alcohol use disorder.
- the present invention relates to a method for conducting a clinical study for assessment of the efficacy of a treatment on the reduction of alcohol consumption, wherein the method comprises the following steps;
- said patients selected for screening according to step a) have a primary diagnosis of DSM-IV alcohol dependence or DSM-V alcohol use disorder.
- said patients excluded in step c) have reduced their alcohol consumption to a drinking risk level from high or medium DRL to below medium ORL or from high ORL to below high DRL.
- nalmefene or a pharmaceutically acceptable salt thereof may be administered in any suitable way, e.g. orally or parenterally, and it may be presented in any suitable form for such administration, e.g. in the form of tablets, capsules, powders, syrups or solutions or dispersions for injection.
- nalmefene is administered in the form of a solid pharmaceutical entity, suitably as a tablet or a capsule or in the form of a suspension, solution or dispersion for injection.
- nalmefene may be administered with a pharmaceutically acceptable carrier, such as an adjuvant and/or diluent.
- Tablets may thus be prepared by mixing the active ingredients with an ordinary carrier, such as an adjuvant and/or diluent, and subsequently compressing the mixture in a tabletting machine.
- an adjuvant and/or diluents include: corn starch, lactose, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvant or additive such as colorings, aroma, and preservatives may also be used provided that they are compatible with the active ingredients.
- the pharmaceutical compositions of the invention thus typically comprise a therapeutically effective amount of nalmefene and one or more pharmaceutically acceptable carrier.
- a suitable oral formulation of nalmefene is described in WO 2012/059103.
- Nalmefene may be administered as an oral dose form, such as a solid oral dose form, typically tablets or capsules, or as a liquid oral dose form. Nalmefene may be administered in an immediate release dosage form or a controlled or sustained release dosage form. Nalmefene may be conveniently administered orally in unit dosage forms, such as tablets or capsules, containing the active ingredient in an amount from about 1 to about 100 mg, such as from 5 to 50 mg. Typically, the pharmaceutical composition comprises from 10 mg to 20 mg, such as about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 Mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg or about 20 mg of nalmefene. In a preferred embodiment, the pharmaceutical composition comprises about 18 mg of nalmefene. In one embodiment, the unit dosage form comprises nalmefene in a therapeutically effective amount.
- nalmefene is taken as-needed, that is, on each day a patient perceives a risk of drinking alcohol, one dose of nalmefene should be taken, preferably 1-2 hours prior to anticipated time of drinking. In one embodiment, if the patient has started drinking alcohol without taking nalmefene, the patient should take one dose of nalmefene as soon as possible after that.
- nalmefene is in the form of the hydrochloride dihydrate.
- Nalmefene according to the present invention is intended to be used for dosing in humans which are adults or adolescents.
- nalmefene is intended to be used for dosing in humans 12 years or older, such as 14 years or older, such as 16 years or older, such as 18 years or older.
- the first embodiment is denoted E1
- the second embodiment is denoted E2 and so forth.
- DRL is assessed by calculating mean daily alcohol consumption in g/day over a period preceding assessment, wherein said period is 1 week or longer, such as 2 weeks or longer, such as 3 weeks or longer, such as 4 weeks or longer, such as 1 month or longer such as 2 months or longer, such as 3 months or longer, such as 4 months or longer, such as 5 months or longer, such as 6 months or longer such as about 1 year.
- Nalmefene for use in the reduction of alcohol consumption in a patient with alcohol dependence who maintains the level of alcohol consumption despite initial motivational support.
- E20 Nalmefene for use in reduction of alcohol consumption in a patient with alcohol dependence who has a DRL corresponding to consumption >60 g/day of pure alcohol for men and >40 g/day for women assessed by calculating mean daily alcohol consumption in g/day over a period preceding assessment; wherein said patient maintains a DRL corresponding to consumption >60 g/day of pure alcohol for men and >40 g/day for women after an observation period following initial assessment, assessed by calculating mean daily alcohol consumption in g/day over said observation period.
- E36 Nalmefene according to any of embodiments 1-35, wherein said patient is 12 years or older, such as 14 years or older, such as 16 years or older, such as 18 years or older.
- E45 Nalmefene according to any of embodiments 1-44, wherein said patient does not fall into one or more of the following categories: patients taking opioid analgesics, opioid-addicted patients without successful withdrawal, patients with acute symptoms of opioid withdrawal, patients for whom re cent use of opioids is suspected, patients with moderate or severe hepatic impairment, patients with moderate or severe renal impairment, patients with current or recent opioid addiction, patients with a recent history of acute alcohol withdrawal syndrome (including hallucinations, seizures, and delirium tremens).
- patients taking opioid analgesics opioid-addicted patients without successful withdrawal
- patients with acute symptoms of opioid withdrawal patients for whom re cent use of opioids is suspected
- patients with moderate or severe hepatic impairment patients with moderate or severe renal impairment
- patients with current or recent opioid addiction patients with a recent history of acute alcohol withdrawal syndrome (including hallucinations, seizures, and delirium tremens).
- a method for reduction of alcohol consumption in a patient with alcohol dependence who has a high DRL which method comprises the administration of a therapeutically effective amount of nalmefene to said patient.
- E48 The method according to any of embodiments 46-47, wherein said DRL is assessed by calculating mean daily alcohol consumption in g/day over a period preceding assessment, wherein said period is 1 week or longer, such as 2 weeks or longer, such as 3 weeks or longer, such as 4 weeks or longer, such as 1 month or longer such as 2 months or longer, such as 3 months or longer, such as 4 months or longer, such as 5 months or longer, such as 6 months or longer, such as about 1 year.
- said period is 1 week or longer, such as 2 weeks or longer, such as 3 weeks or longer, such as 4 weeks or longer, such as 1 month or longer such as 2 months or longer, such as 3 months or longer, such as 4 months or longer, such as 5 months or longer, such as 6 months or longer, such as about 1 year.
- E55 A method for reduction of alcohol consumption in a patient with alcohol dependence who maintains the level of alcohol consumption despite initial motivational support, which method comprises the administration of a therapeutically effective amount of nalmefene to said patient.
- E56 A method for reduction of alcohol consumption in a patient with alcohol dependence who maintains the level of alcohol consumption after an observation period in accordance with clinical practice such as an observation period of 1-2 weeks such as an observation period of about 2 weeks, which method comprises the administration of a therapeutically effective amount of nalmefene to said patient.
- E60 The method according to embodiment 59, wherein said patient has a DRL corresponding to consumption >60 g/day of pure alcohol for men and >40 g/day for women at initial assessment.
- E63 The method according to any of embodiments 59-62, wherein said high DRL at initial assessment is assessed by calculating mean daily alcohol consumption in g/day over a period preceding assessment, wherein said period is 1 week or longer, such as 2 weeks or longer such as 3 weeks or longer, such as 4 weeks or longer, such as 1 month or longer such as 2 months or longer, such as 3 months or longer, such as 4 months or longer, such as 5 months or longer, such as 6 months or longer, such as about 1 year.
- E65 A method for reduction of alcohol consumption in a patient with alcohol dependence who has a DRL corresponding to consumption >60 g/day of pure alcohol for men and >40 g/day for women assessed by calculating mean dairy alcohol consumption in g/day over a period preceding assessment, wherein said patient maintains a DRL corresponding to consumption >60 g/day of pure alcohol for men and >40 g/day for women after an observation following initial assessment, assessed by calculating mean daily alcohol consumption in g/day over said observation period, which method comprises the administration of a therapeutically effective amount of nalmefene to said patient.
- E66 The method according to embodiment 65, wherein said period preceding assessment is 1 week or longer, such as 2 weeks or longer, such as 3 weeks or longer, such as 4 weeks or longer, such as 1 month or longer such as 2 months or longer, such as 3 months or longer, such as 4 months or longer, such as 5 months or longer, such as 6 months or longer, such as about 1 year.
- E70 The method according to embodiment 69. wherein said observation period following initial assessment is 1-2 weeks, such as about 2 weeks.
- E71 The method according to any of embodiments 69-70, wherein the patient identified in step a) has a DRL corresponding to consumption >60 g/day of pure alcohol for men and >40 g/day for women.
- E81 The method according to any of embodiments 46-80, wherein said patient is 12 years or older, such as 14 years or older, such as 16 years or older, such as 18 years or older.
- E82 The method according to any of embodiments 46-81, wherein the amount of nalmefene is 10-20 mg such as 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg or 20 mg.
- E90 The method according to any of embodiments 46-89, wherein said patient does not fall into one or more of the following categories: patients taking opioid analgesics, opioid-addicted patients without successful withdrawal, patients with acute symptoms of opioid withdrawal, patients for whom recent use of opioids is suspected, patients with moderate or severe hepatic impairment, patients with moderate or severe renal impairment, patients with current or recent opioid addiction, patients with a recent history of acute alcohol withdrawal syndrome (including hallucinations, seizures, and delirium tremens).
- E93 The use according to any of embodiments 91-92, wherein said DRL is assessed by calculating mean daily alcohol consumption in g/day over a period preceding assessment, wherein said period is 1 week or longer, such as 2 weeks or longer, such as 3 weeks or longer, such as 4 weeks or longer, such as 1 month or longer such as 2 months or longer, such as 3 months or longer, such as 4 months or longer, such as 5 months or longer, such as 6 months or longer, such as about 1 year.
- said period is 1 week or longer, such as 2 weeks or longer, such as 3 weeks or longer, such as 4 weeks or longer, such as 1 month or longer such as 2 months or longer, such as 3 months or longer, such as 4 months or longer, such as 5 months or longer, such as 6 months or longer, such as about 1 year.
- nalmefene for the manufacture of a medicament for reduction of alcohol consumption in a patient who maintains the level of alcohol consumption after an observation period in accordance with clinical practice such as an observation period of 1-2 weeks, such as an observation period of about 2 weeks.
- nalmefene for the manufacture of a medicament for reduction of alcohol consumption in a patient with alcohol dependence who maintains at least medium DRL after an observation period following initial assessment such as an observation period of 1-2 weeks, such as an observation period of 2 weeks.
- E105 The use according to embodiment 104, wherein said patient has a DRL corresponding to consumption >60 g/day of pure alcohol for men and >40 g/day for women at initial assessment.
- E108 The use according to any of embodiments 104-107, wherein said high DRL at initial assessment is assessed by calculating mean daily alcohol consumption in g/day over a period preceding assessment, wherein said period is 1 week or longer, such as 2 weeks or longer, such as 3 weeks or longer, such as 4 weeks or longer, such as 1 month or longer such as 2 months or longer, such as 3 months or longer, such as 4 months or longer, such as 5 months or longer, such as 6 months or longer, such as about 1 year.
- said period is 1 week or longer, such as 2 weeks or longer, such as 3 weeks or longer, such as 4 weeks or longer, such as 1 month or longer such as 2 months or longer, such as 3 months or longer, such as 4 months or longer, such as 5 months or longer, such as 6 months or longer, such as about 1 year.
- nalmefene for the manufacture of a medicament for reduction of alcohol consumption in a patient with alcohol dependence who has a DRL corresponding to consumption >60 g/day of pure alcohol for men and >40 g/day for women assessed by calculating mean daily alcohol consumption in g/day over a preceding assessment, wherein said patient maintains a DRL corresponding to consumption >60 g/day of pure alcohol for men and >40 g/day for women after an observation period following initial assessment, assessed by calculating mean daily alcohol consumption in g/day over said observation period.
- E111 The use according to embodiment 110, wherein said period preceding assessment is 1 week or longer, such as 2 weeks or longer, such as 3 weeks or longer, such as 4 weeks or longer, such as 1 month or longer such as 2 months or longer, such as 3 months or longer, such as 4 months or longer, such as 5 months or longer, such as 6 months or longer, such as about 1 year.
- E125 The use according to any of embodiments 91-124, wherein said patient is an adult or an adolescent.
- E126 The use according to any of embodiments 91-125, wherein said patient is 12 years or older, such as 14 years or older, such as 16 years or older, such as 18 years or older.
- E127 The use according to any of embodiments 91-126, wherein said medicament comprises nalmefene in a dose of 10-20 mg such as 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg or 20 mg.
- E135. The use according to any of embodiments 91-134, wherein said patient does not fall into one or more of the following categories: patients taking opioid analgesics, opioid-addicted patients without successful withdrawal, patients with acute symptoms of opioid withdrawal, patients for whom recent use of opioids is suspected, patients with moderate or severe hepatic impairment, patients with moderate or severe renal impairment, patients with current or recent opioid addiction, patients with a recent history of acute alcohol withdrawal syndrome (including hallucinations, seizures, and delirium tremens).
- nalmefene The efficacy of nalmefene on the reduction of alcohol consumption in patients with alcohol dependence (DSM-IV) was evaluated in two efficacy studies (Study 12014A and Study 12023A). Both studies were randomised, double blind, two-parallel group, placebo controlled, and after 6 months of treatment, patients receiving nalmefene were re-randomised to receive either placebo or nalmefene in a 1 month run out period. The efficacy of nalmefene was also evaluated in a randomised, double blind, two parallel group, placebo controlled 1 year safety study (Study 12013A). The studies included 1941 patients, 1144 of whom were treated with nalmefene 18 mg in an as-needed dosing regimen.
- a 2-week screening period a 24-week double-blind treatment period
- a 4-week double-blind placebo-controlled run-out in each of the treatment arms
- a 4-week safety follow-up One to two weeks after the Screening Visit the patients were randomised 1:1 to 24 weeks of as-needed, double-blind treatment (Mainalmefene (18 mg) or placebo.
- MTP Main Treatment Period
- ROP double-blind Run-out Period
- TFB Timeline Follow-back
- the patients' clinical status, social situation, and alcohol consumption pattern were evaluated (based on patient reporting).
- the drinking risk level was re-assessed (i.e. the mean daily alcohol consumption over the 1-2 week assessment period was calculated), and treatment with nalmefene was initiated together with counseling with focus on motivating the patients to adhere to the treatment and to change their drinking behavior.
- a motivational and adherence enhancing intervention according to the BRENDA model, was administered to all the patients to support the patients in changing their behavior and to enhance adherence to treatment.
- the patients' alcohol intake was estimated based on national definitions of standard units (subsequently converted into grams of alcohol).
- a standard drink conversion card was distributed to each patient at the Screening Visit.
- Each patient was also provided with a calendar that he/she could use to support his/her input to the TLFB, or he/she could use a personal calendar, if preferred.
- baseline was defined as the month (that is, 4 weeks /28 consecutive days) preceding the Screening Visit.
- the investigational medicinal product (IMP) was taken as-needed.
- Each patient was instructed to take a maximum of one tablet on each day the patient perceived a risk of drinking alcohol, preferably 1 to 2 hours prior to the anticipated time of drinking. If the patient had started drinking alcohol without taking nalmefene, the patient as to take one tablet as soon as possible.
- the dates when nalmefene was taken/not taken were recorded using the TLFB method.
- the chosen comparator was placebo
- Table 5 summarizes the number of patients in the efficacy analysis for each patient group.
- a HDD was defined as a day with a consumption ⁇ 60 g alcohol for men and a ⁇ 40 g for women. Data obtained at month 6 are listed in Table 6 below.
- the change in HDD and TAC over time in patients treated with nalmefene or placebo is further-more reflected in FIGS. 1-12 .
- Table 6 indicates that in all three studies the difference between nalmefene and placebo measured in HDDs and TAC was more pronounced in the group of patients with High DRL at baseline than in the total study population.
- Table 6 also indicates that in all three studies the difference between nalmefene and placebo measured in HDDs and TAC was more pronounced in the group of patients excluding ERs than in the total study population.
- table 6 clearly indicates that in all three studies the difference between nalmefene and placebo measured in HDDs and TAC was more pronounced in the group of patients with High DRL at baseline and randomization than in the total study population.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Emergency Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Addiction (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Steroid Compounds (AREA)
- Medicinal Preparation (AREA)
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13/928,332 US20140005217A1 (en) | 2012-06-27 | 2013-06-26 | Nalmefene for reduction of alcohol consumption in specific target populations |
US15/093,097 US9642849B2 (en) | 2012-06-27 | 2016-04-07 | Nalmefene for reduction of alcohol consumption in specific target populations |
US15/466,024 US10034874B2 (en) | 2012-06-27 | 2017-03-22 | Nalmefene for reduction of alcohol consumption in specific target populations |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201261664804P | 2012-06-27 | 2012-06-27 | |
US201261721539P | 2012-11-02 | 2012-11-02 | |
US201261736740P | 2012-12-13 | 2012-12-13 | |
US201361788810P | 2013-03-15 | 2013-03-15 | |
US13/928,332 US20140005217A1 (en) | 2012-06-27 | 2013-06-26 | Nalmefene for reduction of alcohol consumption in specific target populations |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/093,097 Continuation US9642849B2 (en) | 2012-06-27 | 2016-04-07 | Nalmefene for reduction of alcohol consumption in specific target populations |
Publications (1)
Publication Number | Publication Date |
---|---|
US20140005217A1 true US20140005217A1 (en) | 2014-01-02 |
Family
ID=48703496
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/928,332 Abandoned US20140005217A1 (en) | 2012-06-27 | 2013-06-26 | Nalmefene for reduction of alcohol consumption in specific target populations |
US13/928,317 Abandoned US20140005216A1 (en) | 2012-06-27 | 2013-06-26 | Nalmefene for reduction of alcohol consumption in specific target populations |
US15/093,097 Active US9642849B2 (en) | 2012-06-27 | 2016-04-07 | Nalmefene for reduction of alcohol consumption in specific target populations |
US15/466,024 Active US10034874B2 (en) | 2012-06-27 | 2017-03-22 | Nalmefene for reduction of alcohol consumption in specific target populations |
Family Applications After (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/928,317 Abandoned US20140005216A1 (en) | 2012-06-27 | 2013-06-26 | Nalmefene for reduction of alcohol consumption in specific target populations |
US15/093,097 Active US9642849B2 (en) | 2012-06-27 | 2016-04-07 | Nalmefene for reduction of alcohol consumption in specific target populations |
US15/466,024 Active US10034874B2 (en) | 2012-06-27 | 2017-03-22 | Nalmefene for reduction of alcohol consumption in specific target populations |
Country Status (35)
Country | Link |
---|---|
US (4) | US20140005217A1 (de) |
EP (4) | EP3345604B1 (de) |
JP (3) | JP6258933B2 (de) |
KR (1) | KR20150023396A (de) |
CN (1) | CN104411313A (de) |
AU (1) | AU2013283281B2 (de) |
BR (1) | BR112014032555A2 (de) |
CA (1) | CA2874703C (de) |
CL (1) | CL2014003484A1 (de) |
CO (1) | CO7160087A2 (de) |
CY (3) | CY1118579T1 (de) |
DK (3) | DK3138564T3 (de) |
EA (1) | EA029908B1 (de) |
ES (3) | ES2663532T3 (de) |
FI (1) | FI3345604T3 (de) |
HK (2) | HK1208185A1 (de) |
HR (3) | HRP20230762T8 (de) |
HU (3) | HUE036272T2 (de) |
IL (1) | IL236035B (de) |
LT (3) | LT3138564T (de) |
ME (2) | ME03030B (de) |
MX (1) | MX371373B (de) |
MY (1) | MY166914A (de) |
NZ (1) | NZ702191A (de) |
PH (1) | PH12014502798A1 (de) |
PL (3) | PL3138564T3 (de) |
PT (3) | PT3345604T (de) |
RS (2) | RS57046B1 (de) |
RU (1) | RU2665373C2 (de) |
SG (1) | SG11201408704WA (de) |
SI (3) | SI2866808T1 (de) |
SM (1) | SMT201600471B (de) |
UA (1) | UA114199C2 (de) |
WO (1) | WO2014001427A1 (de) |
ZA (1) | ZA201409525B (de) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20170071590A1 (en) * | 2015-09-10 | 2017-03-16 | Suture Armor Llc | Suture anchor |
US9642849B2 (en) | 2012-06-27 | 2017-05-09 | H. Lundbeck A/S | Nalmefene for reduction of alcohol consumption in specific target populations |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014170353A1 (en) * | 2013-04-17 | 2014-10-23 | H. Lundbeck A/S | Nalmefene for treatment of patients with sleep disorder |
US20170042887A1 (en) | 2014-04-22 | 2017-02-16 | Otsuka Pharmaceutical. Co., Ltd. | Combination of Brexpiprazole and Nalmefene and Use Thereof for Treating Substance-Related Disorders |
KR20190122431A (ko) | 2018-04-20 | 2019-10-30 | 삼성전자주식회사 | 반도체 메모리 소자 |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3814768A (en) | 1971-11-26 | 1974-06-04 | Lewenstein E | 6-methylene-6-desoxy dihydro morphine and codeine derivatives and pharmaceutically acceptable salts |
US4535157A (en) | 1983-11-01 | 1985-08-13 | Key Pharmaceuticals, Inc. | Process for making 6-desoxy-6-methylenenaloxone and 6-desoxy-6-methylenenaltrexone |
US5086058A (en) * | 1990-06-04 | 1992-02-04 | Alko Ltd. | Method for treating alcoholism with nalmefene |
JP2005508888A (ja) * | 2001-08-14 | 2005-04-07 | バイオティ セラピーズ コーポレイション | アルコール依存症またはアルコール中毒を治療する方法 |
UA102128C2 (en) * | 2008-12-05 | 2013-06-10 | Х. Луннбек А/С | Nalmefene hydrochloride dihydrate |
BRPI1010975B1 (pt) | 2009-05-25 | 2021-08-24 | H. Lundbeck A/S | Métodos para preparar nalmefeno a partir de naltrexona em uma reação de wittig e para isolar o nalmefeno |
AU2011325563B2 (en) | 2010-11-05 | 2015-08-20 | H. Lundbeck A/S | Method for the manufacturing of naltrexone |
RU2552290C1 (ru) | 2011-03-31 | 2015-06-10 | Ак Кимя Итхалат-Ихрацат Ве Санайии А.С. | Соединения опиоидных антагонистов и их применение при лечении склеродермии |
US20140005217A1 (en) | 2012-06-27 | 2014-01-02 | H. Lundbeck A/S | Nalmefene for reduction of alcohol consumption in specific target populations |
-
2013
- 2013-06-26 US US13/928,332 patent/US20140005217A1/en not_active Abandoned
- 2013-06-26 US US13/928,317 patent/US20140005216A1/en not_active Abandoned
- 2013-06-27 LT LTEP16187426.8T patent/LT3138564T/lt unknown
- 2013-06-27 JP JP2015519085A patent/JP6258933B2/ja active Active
- 2013-06-27 MX MX2014015488A patent/MX371373B/es active IP Right Grant
- 2013-06-27 RS RS20180359A patent/RS57046B1/sr unknown
- 2013-06-27 DK DK16187426.8T patent/DK3138564T3/en active
- 2013-06-27 ES ES16187426.8T patent/ES2663532T3/es active Active
- 2013-06-27 HU HUE16187426A patent/HUE036272T2/hu unknown
- 2013-06-27 LT LTEP13732471.1T patent/LT2866808T/lt unknown
- 2013-06-27 PT PT172060345T patent/PT3345604T/pt unknown
- 2013-06-27 CA CA2874703A patent/CA2874703C/en active Active
- 2013-06-27 DK DK17206034.5T patent/DK3345604T3/da active
- 2013-06-27 RU RU2014151156A patent/RU2665373C2/ru active
- 2013-06-27 ME MEP-2018-68A patent/ME03030B/de unknown
- 2013-06-27 PL PL16187426T patent/PL3138564T3/pl unknown
- 2013-06-27 EP EP17206034.5A patent/EP3345604B1/de active Active
- 2013-06-27 EP EP16187426.8A patent/EP3138564B1/de not_active Revoked
- 2013-06-27 LT LTEP17206034.5T patent/LT3345604T/lt unknown
- 2013-06-27 PL PL17206034.5T patent/PL3345604T3/pl unknown
- 2013-06-27 EP EP13732471.1A patent/EP2866808B1/de not_active Revoked
- 2013-06-27 SG SG11201408704WA patent/SG11201408704WA/en unknown
- 2013-06-27 KR KR1020147035322A patent/KR20150023396A/ko active IP Right Grant
- 2013-06-27 CN CN201380034056.2A patent/CN104411313A/zh active Pending
- 2013-06-27 SI SI201330449A patent/SI2866808T1/sl unknown
- 2013-06-27 HR HRP20230762TT patent/HRP20230762T8/hr unknown
- 2013-06-27 PT PT137324711T patent/PT2866808T/pt unknown
- 2013-06-27 UA UAA201500199A patent/UA114199C2/uk unknown
- 2013-06-27 DK DK13732471.1T patent/DK2866808T3/en active
- 2013-06-27 PT PT161874268T patent/PT3138564T/pt unknown
- 2013-06-27 SI SI201332054T patent/SI3345604T1/sl unknown
- 2013-06-27 SI SI201330973T patent/SI3138564T1/en unknown
- 2013-06-27 ES ES13732471.1T patent/ES2609122T3/es active Active
- 2013-06-27 PL PL13732471T patent/PL2866808T3/pl unknown
- 2013-06-27 BR BR112014032555A patent/BR112014032555A2/pt not_active Application Discontinuation
- 2013-06-27 MY MYPI2014003570A patent/MY166914A/en unknown
- 2013-06-27 EP EP23163177.1A patent/EP4223296A3/de active Pending
- 2013-06-27 NZ NZ702191A patent/NZ702191A/en not_active IP Right Cessation
- 2013-06-27 AU AU2013283281A patent/AU2013283281B2/en not_active Ceased
- 2013-06-27 EA EA201492152A patent/EA029908B1/ru not_active IP Right Cessation
- 2013-06-27 HU HUE13732471A patent/HUE031110T2/en unknown
- 2013-06-27 RS RS20161173A patent/RS55456B1/sr unknown
- 2013-06-27 ES ES17206034T patent/ES2950492T3/es active Active
- 2013-06-27 HU HUE17206034A patent/HUE063313T2/hu unknown
- 2013-06-27 ME MEP-2016-286A patent/ME02587B/de unknown
- 2013-06-27 FI FIEP17206034.5T patent/FI3345604T3/fi active
- 2013-06-27 WO PCT/EP2013/063461 patent/WO2014001427A1/en active Application Filing
-
2014
- 2014-12-02 IL IL236035A patent/IL236035B/en active IP Right Grant
- 2014-12-15 PH PH12014502798A patent/PH12014502798A1/en unknown
- 2014-12-22 CO CO14280546A patent/CO7160087A2/es not_active Application Discontinuation
- 2014-12-22 CL CL2014003484A patent/CL2014003484A1/es unknown
- 2014-12-23 ZA ZA2014/09525A patent/ZA201409525B/en unknown
-
2015
- 2015-09-11 HK HK15108930.9A patent/HK1208185A1/xx not_active IP Right Cessation
-
2016
- 2016-04-07 US US15/093,097 patent/US9642849B2/en active Active
- 2016-12-14 HR HRP20161717TT patent/HRP20161717T1/hr unknown
- 2016-12-27 SM SM201600471T patent/SMT201600471B/it unknown
-
2017
- 2017-01-03 CY CY20171100004T patent/CY1118579T1/el unknown
- 2017-03-22 US US15/466,024 patent/US10034874B2/en active Active
- 2017-09-22 JP JP2017182608A patent/JP2018039810A/ja not_active Withdrawn
-
2018
- 2018-02-28 HR HRP20180363TT patent/HRP20180363T1/hr unknown
- 2018-03-27 CY CY20181100346T patent/CY1120097T1/el unknown
- 2018-11-20 HK HK18114830.5A patent/HK1255683A1/zh unknown
-
2019
- 2019-04-25 JP JP2019083718A patent/JP6857684B2/ja active Active
-
2023
- 2023-07-25 CY CY20231100359T patent/CY1126140T1/el unknown
Non-Patent Citations (4)
Title |
---|
ClinicalTrials.gov (2009) in view of Sinclair et al. (US 5,086,058) and further in view of Sharpe (Ann. Clin Biochem; 38: 652-664) * |
ClinicalTrials.gov (2010) * |
Sharpe (Ann. Clin Biochem; 38: 652-664) * |
Starosfa et al (J. psychaitr. Pract (2006) 12(2):80-89). * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9642849B2 (en) | 2012-06-27 | 2017-05-09 | H. Lundbeck A/S | Nalmefene for reduction of alcohol consumption in specific target populations |
US10034874B2 (en) | 2012-06-27 | 2018-07-31 | H. Lundbeck A/S | Nalmefene for reduction of alcohol consumption in specific target populations |
US20170071590A1 (en) * | 2015-09-10 | 2017-03-16 | Suture Armor Llc | Suture anchor |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10034874B2 (en) | Nalmefene for reduction of alcohol consumption in specific target populations | |
EP3578173B1 (de) | Darreichungsform mit oxycodon und naloxon | |
JP2021500377A (ja) | 遅延放出デフェリプロン錠剤及びその使用法 | |
ES2337622T3 (es) | Uso de composiciones que contienen antagonistas del receptor opioide kappa para el tratamiento de trastornos disociativos. | |
CA2735913A1 (en) | A method for combating adverse effects arising from antipsychotic treatment | |
RU2552290C1 (ru) | Соединения опиоидных антагонистов и их применение при лечении склеродермии | |
WO2021132302A1 (ja) | 透析移行又は腎死の抑制のための薬剤 | |
US20160058753A1 (en) | Nalmefene for Treatment of Patients with Mood Disorder | |
IsHak et al. | Overview of approved psychiatric medications 2008-2023: A systematic review | |
CA3237151A1 (en) | Methods and compositions for treating conditions associated with central hypoventilation | |
WO2022240612A1 (en) | Use of complement factor d inhibitor for treatment of generalized myasthenia gravis | |
WO2014170353A1 (en) | Nalmefene for treatment of patients with sleep disorder | |
WO1999007403A1 (fr) | Medicaments nootropes |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: H. LUNDBECK A/S, DENMARK Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:TORUP, LARS;ABBARIKI, AFSANEH;BLADSTROEM, ANNA;AND OTHERS;SIGNING DATES FROM 20130620 TO 20130624;REEL/FRAME:031780/0750 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |