CA3058996A1 - Cytisinicline in the treatment of smoking addiction for refractory subjects - Google Patents

Abstract

Use of cytisine in the of treatment of refractory nicotine addiction in particular patient groups is provided, as is the use of cytisine as a smoking cessation treatment. A dosage regimen including 3.0 mg pills for such use are provided.

Description

CYTISINICLINE IN THE TREATMENT OF SMOKING ADDICTION FOR
REFRACTORY SUBJECTS
FIELD OF THE INVENTION
The present invention relates to the use of cytisinicline (commonly referred to as cytisine) as a smoking cessation treatment, and in particular to a dosage regimen for such use.
BACKGROUND
Nicotine is an addictive substance that is rapidly absorbed during cigarette smoking.
The drug distributes quickly and is thought to interact with neuronal nicotinic acetylcholine receptors (nAChRs) in the central nervous system (CNS). Nicotine addiction results, at least in part, from this interaction. Although many smokers attempt to cease smoking, few succeed without pharmacological supportive treatment.
Tobacco smoking contributes to some 7 million premature deaths each year worldwide. Smoking is highly addictive, with more than 95% of unaided attempts at cessation failing to last 6 months. It has been estimated that for every year that a person delays stopping smoking beyond his or her mid-30s, that person loses 3 months of life expectancy. The World Health Organization's Framework Convention on Tobacco Control identifies evidence-based approaches to promote smoking cessation, which include mass-media campaigns, tax increases on tobacco, and help for smokers wanting to stop.
The pharmacotherapies currently available in the US and Western Europe to help smokers stop include nicotine replacement therapy (NRT) and two non-nicotine containing medications: bupropion (Zybane, Glaxo-SmithKline) and varenicline (Chantix /Champixe, Pfizer). NRT and bupropion appear to have about equal efficacy.
Varenicline is more effective than single NRT and bupropion, although combination NRT
is comparable in efficacy.
(-)-Cytisine (cytisinicline; commonly referred to simply as cytisine) is a plant-based alkaloid isolated from seeds of Cytisus laburnum L. (Golden chain). References herein to cytisine refer to (-)-cytisine, cytisinicline.
Cytisine's mechanism of action has assisted basic pharmacologists in understanding the complex pharmacology of the various subtypes of the nicotinic acetylcholine receptor. These studies have shown that both nicotine and cytisine bind =

strongly and preferentially to pre-synaptic a1pha4, beta2 (a4132) receptors that mediate the release of dopamine in the shell of the nucleus accumbens. This receptor subtype has been implicated in the development and maintenance of nicotine dependence and was the primary target for the drug varenicline, referred to above.
Tabex , containing the active substance cytisine, has been licensed and marketed in Central and Eastern Europe for several decades by Sopharma PLC (Sophia, Bulgaria).
Tabex is supplied as a compressed film-coated tablet containing 1.5 mg cytisine tablets, the tablets to be taken orally with water in accordance with a specified titration schedule over a 25-day period. On days 1-3, six 1.5 mg cytisine tablets are taken separately at two-hourly intervals, giving a total dose of 9 mg of cytisine on each of those days. On days 4-12, five 1.5 mg cytisine tablets are taken separately at two and a half-hourly intervals, giving a total dose of 7.5 mg of cytisine on each of those days. On days 13-16, four 1.5 mg cytisine tablets are taken separately at three-hourly intervals, giving a total dose of 6 mg of cytisine on each of those days. On days 17-20, three 1.5 mg cytisine tablets are taken separately at four to five-hourly intervals, giving a total dose of 4.5 mg of cytisine on each of those days. On days 21-24, two 1.5 mg cytisine tablets are taken separately at six-hourly intervals, giving a total dose of 3 mg of cytisine on each of those days. Finally, on day 25, a single 1.5 mg cytisine tablet is taken to complete the course of treatment.
Despite its widespread use, cytisine has not been market-approved for use outside Central and Eastern Europe. However, two recent Phase 3 studies have been conducted and published in 2011 and 2014 in the New England Journal of Medicine. The overall objectives in these trials were to confirm the efficacy and safety of cytisine according to current clinical development standards. Both studies were carried out using the commercial 25-day titration schedule as described above.
The 2011 study (West R, Zatonski W, Cedzynska M, et al. Placebo-Controlled Trial of Cytisine for Smoking Cessation, New England Journal of Medicine 2011;365:1193-200) describes a Phase 3 study with the primary outcome measure being sustained, biochemically-verified smoking abstinence for 12 months after the end of treatment. This study showed an improved Relative Risk for substained abstinence for cytisine compared with placebo.
The 2014 study (Walker N, Howe C, Glover M, et al. Cytisine versus nicotine for smoking cessation, New England Journal of Medicine 2014;371:2353-62) describes a

-2-Phase 3 study with the primary outcome measure being continuous self-reported abstinence from smoking one month after a quit date and a secondary outeome measure including the Relative Risk for continuous abstinence. This study showed that cytisine was 1.43 times more likely than nicotine patches with gum or lozenges to help participants stop smoking and remain non-smokers for six months.
Thus, the efficacy of the 1.5 mg dose of cytisine using the 25-day titration described above in smoking cessation has been confirmed in these recent studies.
A need exists for nicotine addiction treatments with patient-friendly regimens that are less costly, more effective, have an improved safety profile, and/or can more successfully treat individuals who have failed to quit nicotine using the known treatments.
SUMMARY
In one aspect, provided herein is the use of cytisine to address nicotine addiction in a subject, comprising providing cytisine in a unit dose of 3.0 mg cytisine three times daily to a subject in need thereof.
In some embodiments, the use of cytisine is over a 6 week duration. In some embodiments, cytisine is provided for 12 weeks.
In some embodiments, the unit dose of cytisine comprises two tablets, each tablet containing 1.5 mg cytisine. In some embodiments, the unit dose of cytisine comprises single tablet containing 3.0 mg cytisine. In some embodiments, each unit dose tablet is a compressed, film coated tablet.
In another aspect, provided herein is the use of cytisine, or a method of treating of nicotine addiction in a subject, comprising administering cytisine to a subject in need thereof, wherein the subject is a refractory patient who has failed treatment with one or more nicotine addiction treatments.
In some embodiments, the subject is a refractory patient who has failed treatment with one or more nicotine addiction treatments. In some embodiments, the subject is a refractory patient who has failed treatment with two or more nicotine addiction treatments.
In some embodiments, the nicotine addiction treatments are selected from nicotine replacement therapy (NRT), administration of bupropion, administration of varenicline, electronic cigarettes, vaping, and a combination thereof. In some embodiments, the subject smoked ten or more cigarettes per day prior to the use of cytisine. In some embodiments,

-3-the subject has expired air CO concentration of about 10 ppm or greater prior to the use of cytisine.
In some embodiments, the use of cytisine or the method further comprises providing behavioral support to the subject.
DETAILED DESCRIPTION
In one aspect, provided herein is a method of treatment method of treating of nicotine addiction in a subject, comprising administered cytisine provided in a unit dose of about 1.5 mg to about 5.0 mg cytisine three to six times daily to a subject in need thereof.
In some embodiments of the methods disclosed herein, the unit dose is about 3.0 mg administered three times daily. Administration of cytisine in accordance with the methods disclosed resulted in significantly better smoking cessation rate, as compared with the administration of the commercial 1.5 mg per unit dose titration schedule.
In some embodiments, the length of the administration is up to about 26 weeks.
In certain embodiments the length of the administration is from about 6 weeks to about 12 weeks, and in some embodiments, the cytisine is administered as described above for about 6 weeks.
Compared with the commercial 25-day titration schedule with unit doses of 1.5 mg cytisine, the percentage of smokers with continuous abstinence is surprisingly higher in the subjects treated according to the methods disclosed herein, as demonstrated, for example, in FIGURE 7.
Any suitable cytisine pharmaceutical composition or formulation can be used in the methods described herein. In some embodiments, cystisine can be formulated in tablet form, for example, as compressed film-coated tablets for oral administration.
The unit dose can comprise a single tablet, such as a tablet containing 3.0 mg cytisine, or it can comprise two or more tablets which together contain the unit dose, e.g., 3.0 mg cytisine. For example, the unit dose of 3.0 mg can comprise two tablets, each containing 1.5 mg cytisine, such as two Tabex tablets. Each Tabex tablet is typically formulated as a compressed film-coated tablet containing 1.5 mg cytisine in a single tablet together with a number of tablet- forming excipients (calcium sulfate, cellulose powder, colloidal silica, magnesium stearate) and coated with a coloured film-coat including polyvinyl alcohol, titanium dioxide and iron oxides.

-4-Alternatively, the cytisine may be formulated in a capsule or another vehicle for oral administration; or in a composition for nasal or topical administration.
The tablets and other dosage forms (hereinafter all referred to as "compositions") can contain one or more excipients, such as those common in the art.
Excipients that can be employed in the compositions include, for example, fillers, disintegrants, preserving agents, lubricants, and wetting agents.
Examples of fillers that can be used include lactose (for example, either anhydrous or monohydrate), cellulose, starch (for example, corn and/or wheat starch), calcium phosphates, calcium sulfates, and mannitol.
Preserving agents prevent bacterial or fungal contamination of the formulation and include various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, and sorbic acid.
Suitable lubricants include stearic acid and its salts. One example of a lubricant for use in the compositions of the disclosure is magnesium stearate.
The pharmaceutical compositions can further comprise sweetening, flavoring, or coloring agents.
A skilled in the art person will be well aware of suitable fillers, preserving agents, and lubricants other than those specifically mentioned above, as well as suitable sweetening, flavoring, and coloring agents, and other additives.
The pharmaceutical compositions of cytisine useful in the methods of the disclosure can comprise a coating, for example a film coating, and can be coated according to any method known in the art, for example, using collidone, shellac, gum arabic, talc, titanium dioxide, or sugar.
The pharmaceutical compositions comprising cytisine can be prepared by any suitable method. For example, capsules can be prepared by mixing cytisine with one or more inert carriers such as lactose or sorbitol and packing into gelatin capsules. Tablets can be made by known compression methods.
In some embodiments of the methods, the subject is a refractory patient. As used herein, a "refractory patient" or "refractory subject" is a subject who has failed treatment with one or more known nicotine addiction treatments. The nicotine addiction treatments include both the regulatory agency-approved treatments and smoking cessation methods such as vaping and behavioral support, including web-based smoking cessation programs

-5-and texting interventions. In some embodiments, the nicotine addiction treatments include FDA-approved, first-line smoking cessation medications such as nicotine replacement therapy (NRT), bupropion, and varenicline. Nicotine replacement therapy can be the form of patch, gum, lozenge, spray, and inhaler.
In some embodiments, the subject is a refractory patient who has failed treatment with two or more nicotine addiction treatments. In some embodiments, the subject is a refractory patient who has failed nicotine addiction treatments comprising nicotine replacement therapy (NRT), administration of bupropion, administration of varenicline, electronic cigarettes, vaping, or a combination thereof.
Any patient with nicotine addiction can be treated by the methods disclosed herein.
In some embodiments, the subject is a smoker, for example, a smoker who smokes about 3 or more cigarettes a day. In some embodiments, the subject is a smoker who smokes about 5 or more or about 10 or more cigarettes a day. In some embodiments, the subject has measurable expired air CO concentration of about 10 ppm or greater prior to the administration of cytisine.
Thus, in a second aspect, provided herein is a method of treating of nicotine addiction in a subject, comprising administered cytisine to a subject in need thereof, wherein the subject is a refractory patient who has failed treatment with one or more nicotine addiction treatments. Doses, treatment regimens, and routes, of administration useful in the methods disclosed herein include those described above. Suitable unit doses include doses between about 1.0 mg and about 6 mg which can be administered three to six times daily, for example, at about equal intervals. For example, in some embodiments, the methods comprise administering cytisine provided in a unit dose of 3.0 mg cytisine three times daily to a refractory patient. Any suitable duration of administration can be used in the methods disclosed herein, for example, about 26 weeks, about 12 weeks, or about 6 weeks. In some embodiments, the treatment is administered for about 6 weeks.
In some embodiments, the methods disclosed herein can further comprise providing behavioral support to the subject, for example, a refractory patient.
While each of the elements of the present invention is described herein as containing multiple embodiments, it should be understood that, unless indicated otherwise, each of the embodiments of a given element of the present invention is capable of being

-6-used with each of the embodiments of the other elements of the present invention and each such use is intended to form a distinct embodiment of the present invention.
The referenced patents, patent applications, and scientific literature referred to herein are hereby incorporated by reference in their entirety as if each individual publication, patent or patent application were specifically and individually indicated to be incorporated by reference. Any conflict between any reference cited herein and the specific teachings of this specification shall be resolved in favor of the latter.
Likewise, any conflict between an art-understood definition of a word or phrase and a definition of the word or phrase as specifically taught in this specification shall be resolved in favor of the latter.
As can be appreciated from the disclosure above, the present invention has a wide variety of applications. The invention is further illustrated by the following examples, which are only illustrative and are not intended to limit the definition and scope of the invention in any way.
EXAMPLES
Study Design A six-arm, multi-center, double-blind, randomized, placebo-controlled study conducted in male or female adults >18 years of age, smoking 10+ cigarettes daily, and willing to set a quit date that is 5-7 days after being randomized on the study. The dosing schedules were as shown in FIGURE 1.
The study was double-blinded to dose but not to the administration schedule, and the study arms were as shown in FIGURE 2. Study treatment started the day after randomization such that study treatment was initiated prior to the quit date, as shown in FIGURE 3.
Subjects were selected to meet all inclusion and exclusion criteria.
Percent reduction in in number of cigarettes smoked during treatment was selected as the primary outcome and was calculated as follows:
100 [ B __________________________________ x DX 1001%
where N = total number of cigarettes smoked, B = number of cigarettes smoked at baseline, and D = number of days of treatment.

-7-Quit Rates as confirmed by expired CO <10 ppm were the study's secondary outcomes.
The subject demographics are summarized in FIGURE 4, and their smoking history is shown in FIGURE 5.
Efficacy Conclusions Smoking diary compliance, on which the primary analysis was based in part, was high for all treatment arms. Study drug compliance was >94% for all treatment arms with slightly higher compliance with the tid schedule (>98%).
Results from the primary analyses demonstrated a significant reduction in percentage of expected cigarettes smoked (cigarette score) in the both commercial arms but not in the tid arms. When pooling the placebo arms, the cigarette score was significantly reduced in both commercial arms, the 1.5 mg tid arm and approached significance in the 3.0 mg tid arm. Subjects treated with 1.5 mg or 3 mg cytisine using the commercial schedule smoked approximately 14% to 16% fewer cigarettes than expected versus pooled placebo. Subjects treated with 1.5 mg or 3 mg cytisine on the tid schedule smoked approximately 9% to 12% fewer cigarettes than expected versus the pooled placebo arm.
Although the decreases on the tid schedule were not as high as those seen on the commercial schedule, it should be noted that subjects in the placebo arm on the tid schedule reported a higher reduction in cigarettes smoked than subjects in the placebo arm on the commercial schedule. The tid placebo subjects smoked only one-third as many cigarettes as they normally would (LS mean: 35.30%) versus the commercial placebo subjects at one-half as many cigarettes smoked (LS mean: 47.10%), which possibly masked the cytisine treatment effect on the tid schedule.
Expired CO levels were measured during this study as an objective biochemical marker for reduction in smoking. In all cytisine-treated arms, the reduction in CO (55% to 62%) was consistent with reported reduction in cigarettes smoked (e.g. a range of 25% to 32% as a cigarette scores represents a 75% to 68% reduction in cigarettes smoking).
Conversely, in the placebo-treated arms, the reported reductions in the number of cigarettes smoked (e.g. 41% for cigarette score, representing a 59% reduction in cigarettes smoked) was not paralleled by a corresponding reduction in CO at only 29%. A similar pattern for plasma cotinine levels was observed with far greater reductions in cotinine levels in the cytisine arms compared to placebo arms.

-8-The changes in these objective markers suggest that, in general, placebo-treated subjects over-reported their reduction in cigarettes smoked. It also suggests that the real differences in cigarette scores between subjects treated with cytisine and those treated with placebo were greater than those actually observed.
Results for the initial quit rate at Week 4 demonstrated both arms of the tid schedule had high odds of success of quitting smoking compared with placebo; subjects in the 3.0 mg cytisine arm had the best odds of success for quitting smoking: OR:
6.31(95% CI: 2.28, 18.45). The OR for the 1.5 mg cytisine arm on the tid schedule was 5.81 (95%
CI: 2.12, 16.87). On the commercial schedule, the ORs for the 1.5. and 3.0 mg cytisine arms were 5.59 (95% CI: 2.03, 16.29) and 5.38 (95% CI: 1.95, 15.72), respectively.
For the prolonged abstinence from Week 5 to Week 8 endpoint, both arms of the tid schedule had higher odds of success for abstinence compared with placebo;
subjects in the 3.0 mg cytisine arm had the best odds of success for abstinence from Weeks 5 to 8, with an OR of 5.04 (95% CI: 1.42, 22.32). The OR for the 1.5 mg cytisine arm on the tid schedule was 4.33 (95% CI: 1.21, 19.30). On the commercial schedule, the ORs for the 1.5 mg cytisine and 3.0 mg arms were 3.23 (95% CI: 0.86, 14.85) and 2.24 (95% CI:
0.55, 10.82), respectively.
Subjects in the cytisine arms on the tid schedule also had higher odds of smoking abstinence at the Week 6, 7, and 8 timepoints compared with subjects in the corresponding arms on the commercial schedule versus placebo, as demonstrated by higher ORs at each timepo int.
Discussion This 6-arm, multicenter, double-blind, randomized study was designed to evaluate the effectiveness of 1.5 mg cytisine versus placebo using the commercial titration schedule approved in Central and Eastern Europe. The study also evaluated the effectiveness of a simplified tid dosing schedule for 1.5 mg and an increased dose of 3 mg (using both the commercial titration and simplified tid dosing schedules). The overall goal of the study was to obtain estimates of effect size for efficacy and safety endpoints that will be used to inform the design of future Phase 3 studies.
In total, 254 male or female adults >18 years of age who smoked >10cigarettes daily and were willing to set a quit date 5 to 7 days after randomization were enrolled in the study. Demographics and baseline characteristics were generally well balanced across both

-9-schedules and treatment arms. Overall, the study population represented highly addictive smokers who on average were 48.4 years old and had been smoking for 32 years, meaning that most of them had started smoking in their adolescent years. In addition, they had an average of 4.5 prior quit attempts with the last quit attempt approximately 3.7 years prior to entering the study and were currently smoking on average a pack of cigarettes a day.
Analyses from the international EAGLES trial3 provided clear evidence that smoking at a young age and being of US origin was associated with lower success rates for quitting. The lower success rate in US smokers supports the view that smokers in the US may have reached a point in the tobacco epidemid such that those who continue to smoke, despite strong cultural pressures not to, have particular characteristics that make it more difficult for them to stop smoking.
Study drug compliance was high for all treatment arms with the tid schedule better (98.18%) than the commercial schedule (94.90%).
Results from the primary analyses demonstrated a significant reduction in percentage of expected cigarettes smoked (cigarette score) in the both commercial titration arms. When pooling the placebo arms, the cigarette score was significantly reduced in both commercial arms, the 1.5mg tid arm and approached significance in the 3.0 mg tid arm.
Subjects treated with 1.5 mg or 3 mg cytisine using the commercial schedule smoked approximately 14% to 16% fewer cigarettes than expected versus placebo.
Subjects treated with 1.5 mg or 3 mg cytisine on the tid schedule smoked approximately 9% to 12% fewer cigarettes than expected versus the placebo arm.
Expired CO levels were also measured during this study as an objective biochemical marker for reduction in smoking. In all cytisine-treated arms, the reduction in CO (55% to 62% reduction) was consistent with the reported reduction in cigarettes smoked (e.g. a range of 25% to 32% as cigarette scores represents a 75% to 68%
reduction in cigarettes smoking). Conversely, in the placebo-treated arms, the reported reductions in the number of cigarettes smoked (e.g. 41% as the cigarette score, representing a 59%
reduction in cigarettes smoked) was not paralleled by a corresponding reduction in CO at only 29%. A similar pattern for plasma cotinine levels was observed with far greater reductions in cotinine levels in the cytisine arms compared to placebo arms.
The changes in these objective markers suggest that, in general, placebo-treated subjects over-reported their reduction in cigarettes smoked. It also suggests that the real

-10-differences in cigarette scores between subjects treated with cytisine and those treated with placebo were greater than those actually observed.
Results for an initial quit rate at Week 4 for all cytisine-treated arms demonstrated significantly increased initial rates (50 to 54%) compared with pooled placebo (16%), and with ORs ranging from 5.38 to 6.31. Prolonged abstinence from weeks 5 to 8 (i.e., for 4 weeks off treatment) also demonstrated significantly increased prolonged quit rates of 16-to 30% in the cytisine-treated arms compared to 8% for pooled placebo and with ORs ranging from 3.23 to 5.04. Overall, the initial and prolonged quit rates were highest for the 3 mg tid arm at 54% and 30%, respectively, and with the greatest ORs of 6.31 and 5.04, respectively.
Overall, there were no safety concerns following dosing in the 1.5 mg cytisine or 3.0 mg treatment arms on both schedules, and no new or unexpected AEs were identified during the study. TEAEs were experienced by approximately half the study population in all treatment arms. The tid dosing schedule had slightly fewer TEAEs overall.
Across both schedules, the SOCs with the highest incidence of TEAEs in any treatment arm were infections and infestations, psychiatric disorders, and gastrointestinal disorders. Common TEAEs were AEs that had been previously reported in other studies or within the Investigator's Brochure.
All TEAEs were mild or moderate in severity on the commercial schedule and all events except 2 were mild or moderate on the tid schedule: Subject 106-131experienced a severe head injury, and Subject 108-115 experienced a severe case of influenza. Neither event was considered related to study drug.
There were no relevant mean changes or shifts from baseline in laboratory parameters over time or 12-lead ECG results. The overall incidence of potentially clinically significant changes in vital sign measurements was low, with the lowest incidence occurring on the tid schedule.
Overall, no new safety signals were observed during the conduct of this study.
The results are further summarized in FIGURES 5-10.
Overall Conclusions Results from the primary analyses demonstrated a reduction in percentage of expected cigarettes smoked in both schedules versus pooled placebo.

-11-Results for the initial quit rate endpoint demonstrated both cytisine arms of the tid schedule had high odds of success compared with placebo; subjects in the 3.0 mg cytisine arm had the best odds of success for quitting smoking at Week 4.
For the prolonged abstinence from Week 5 to Week 8 endpoint, both arms of the tid schedule had high odds of success compared with placebo; subjects in the 3.0 mg cytisine arm had the best odds of success for abstinence from Weeks 5 to 8.
The study demonstrated that cytisine is an effective aid to smoking cessation with an advantageous adverse event profile, and 3.0 mg tid dosing is more efficacious overall with no increase in adverse events.
Overall, there were no safety concerns following dosing in the 1.5 mg cytisine or 3.0 mg arms on either schedule.

-12-

Claims (46)

We claim:

1. The use of cytisine to overcome nicotine addiction, comprising providing a unit dose of 3.0 mg cytisine three times daily to a subject in need thereof.

2. The use of claim 1, wherein cytisine is provided for about 6 weeks.

3. The use of claim 1, wherein cytisine is provided for about 12 weeks.

4. The use of any one of claims 1-3, wherein the unit dose of cytisine comprises two tablets, each tablet containing 1.5 mg cytisine.

5. The use of any one of claims 1-3, wherein the unit dose of cytisine comprises a single tablet containing 3.0 mg cytisine.

6. The use of claim 4 or claim 5, wherein each unit dose tablet is a compressed, film coated tablet.

7. The use of any one of claims 1-6, wherein the subject is a refractory patient who has failed treatment with one or more nicotine addiction treatments.

8. The use of any one of claims 1-7, wherein the subject is a refractory patient who has failed treatment with two or more nicotine addiction treatments.

9. The use of claims 7 or claim 8, wherein the nicotine addiction treatments are selected from nicotine replacement therapy (NRT), administration of bupropion, administration of varenicline, electronic cigarettes, vaping, and any combination thereof.

10. The use of any one of claims 1-9, wherein the subject smoked ten or more cigarettes per day prior to the provision of cytisine.

11. The use of any one of claims 1-10, wherein the subject has expired air CO
concentration of about 10 ppm or greater prior to the provision and consumption of cytisine.

12. The use of any one of claims 1-11, wherein the use further comprises providing behavioral support to the subject.

13. The use of cytisine in the treatment of nicotine addiction, comprising providing cytisine to a subject in need thereof, wherein the subject is a refractory patient who has failed treatment with one or more nicotine addiction treatments.

14. The use of claim 13, wherein the subject has failed treatment with two or more nicotine addiction treatments.

15. The use of claims 13 or claim 14, wherein the nicotine addiction treatments comprise nicotine replacement therapy (NRT), administration of bupropion, administration of varenicline, electronic cigarettes, vaping, or a combination thereof.

16. The use of any one of claims 13-15, wherein cytisine is provided in a unit dose of about 1.0 mg to about 6.0 mg cytisine three to six times daily to a subject in need thereof.

17. The use of any one of claims 13-16, wherein cytisine is provided in a unit dose of 3.0 mg cytisine three times daily to a subject in need thereof.

18. The use of any one of claims 13-16, wherein cytisine is provided in a unit dose of 3.0 mg cytisine three times daily to a subject in need thereof.

19. The use of any one of claims 13-18, wherein cytisine is provided for about 6 weeks.

20. The use of any one of claims 13-18, cytisine is provided for about 12 weeks.

21. The use of claim 17, wherein the unit dose of cytisine comprises two tablets, each tablet containing 1.5 mg cytisine.

22. The use of claim 17, wherein the unit dose of cytisine comprises a single tablet containing 3.0 mg cytisine.

23. The use of claim 21 or claim 22, wherein each unit dose tablet is a compressed, film coated tablet.

24. A method of treating of nicotine addiction in a subject, comprising administering cytisine provided in a unit dose of 3.0 mg cytisine three times daily to a subject in need thereof.

25. The method of claim 24, wherein cytisine is administered for about 6 weeks.

26. The method of claim 24, wherein cytisine is administered for about 12 weeks.

27. The method of any one of claims 24-26, wherein the unit dose of cytisine comprises two tablets, each tablet containing 1.5 mg cytisine.

28. The method of any one of claims 24-26, wherein the unit dose of cytisine comprises single tablet containing 3.0 mg cytisine.

29. The method of claim 27 or claim 28, wherein each unit dose tablet is a compressed, film coated tablet.

30. The method of any one of claims 24-29, wherein the subject is a refractory patient who has failed treatment with one or more nicotine addiction treatments.

31. The method of any one of claims 24-30, wherein the subject is a refractory patient who has failed treatment with two or more nicotine addiction treatments.

32. The method of claims 30 or claim 31, wherein the nicotine addiction treatments are selected from nicotine replacement therapy (NRT), administration of bupropion, administration of varenicline, electronic cigarettes, vaping, and a combination thereof.

33. The method of any one of claims 24-32, wherein the subject smoked ten or more cigarettes per day prior to the administration of cytisine.

34. The method of any one of claims 24-33, wherein the subject has expired air CO concentration of about 10 ppm or greater prior to the administration of cytisine.

35. The method of any one of claims 24-34, wherein the method further comprises providing behavioral support to the subject.

36. A method of treating of nicotine addiction in a subject, comprising administering cytisine to a subject in need thereof, wherein the subject is a refractory patient who has failed treatment with one or more nicotine addiction treatments.

37. The method of claim 36, wherein the subject has failed treatment with two or more nicotine addiction treatments.

38. The method of claims 36 or claim 37, wherein the nicotine addiction treatments comprise nicotine replacement therapy (NRT), administration of bupropion, administration of varenicline, electronic cigarettes, vaping, or a combination thereof.

39. The method of any one of claims 36-38, wherein cytisine is provided in a unit dose of about 1.0 mg to about 6.0 mg cytisine three to six times daily to a subject in need thereof.

40. The method of any one of claims 36-38, wherein cytisine is provided in a unit dose of 3.0 mg cytisine three times daily to a subject in need thereof.

41. The method of any one of claims 36-38, wherein cytisine is provided in a unit dose of 3.0 mg cytisine three times daily to a subject in need thereof.

42. The method of any one of claims 36-39, wherein cytisine is administered for about 6 weeks.

43. The method of any one of claims 36-39, cytisine is administered for about 12 weeks.

44. The method of claim 40, wherein the unit dose of cytisine comprises two tablets, each tablet containing 1.5 mg cytisine.

45. The method of claim 40, wherein the unit dose of cytisine comprises single tablet containing 3.0 mg cytisine.

46. The method of claim 44 or claim 45, wherein each unit dose tablet is a compressed, film coated tablet.