ATERIA EDICA

Volume 2, Issue 7 December 2013

tion, the quadrivalent cover the B/ Brisbane/60/2008 B strain.1

New Influenza Vaccines Included in the two broader categories of vaccines (quadrivalent or trivalent) are many individual influen- for the 2013-2014 Season za vaccines. For the 2013-2014 season alone, there are six newly approved vaccines. Four of these six vaccines Kristen Fawcett, PharmD candidate are new quadrivalent formulations, one is a new cell culture-based trivalent formulation and one is a new recombinant hemagglutinin trivalent formulation.1 he CDC’s Advisory Committee on Immuniza- Each has its own unique clinical considerations tion Practices (ACIP) recommend that all per- for use, and some of the new influenza vaccines may T sons aged ≥6 months old receive an influenza afford patients the opportunity to be vaccinated who vaccine yearly. Influenza is most severe and most likely may previously not have been eligible because of a to lead to complications in those patients aged ≥65 contraindication such as an egg allergy. The objectives years and those aged <2 years.1 Yet there are other in- of this article are to discuss the clinically meaningful dividuals who are considered to be at high risk from differences between the six new influenza vaccines. influenza (Box).2 Complications from influenza can range from secondary bacterial to encepha- QUADRIVALENT FORMULATIONS lopathy, acute renal failure and myocarditis.3 Influenza is also the cause of many outpatient medical visits and The new quadrivalent influenza vaccines include worker absenteeism among otherwise healthy adults.1 FluMist Quadrivalent, Fluarix, FluLaval, and Fluzone Therefore, prevention of influenza with is Quadrivalent. These quadrivalent vaccines provide key. coverage against two different lineages of influenza B Current influenza vaccines are either trivalaent or viruses, the Yamagata lineage and the Victoria lineage. quadrivalent. The difference between the two types of Every year an influenza B virus from one of these two vaccines is the trivalent vaccines contain two influenza lineages is chosen to include in the annual trivalent in- A strains and one influenza B strain, whereas the quad- fluenza vaccines. The advantage of the quadrivalent rivalent vaccines cover an additional influenza B strain. Both types of vaccines for the 2013-2014 season cover Box | Individuals at high risk for complications the A/California/7/2009 (H1N1) and A/ from influenza. Victoria/361/2011 (H3N2) influenza strains.1 The B  Persons aged 50 years old and older influenza strain contained in both trivalent and quadri-  Children younger than 5 years old (especially children 1 valent vaccines is B/Massachusetts/2/2012. In addi- younger than 2 years old)

 Pregnant women or women who are planning on be- coming pregnant during the influenza season INSIDE THIS ISSUE: NEW INFLUENZA VACCINES FOR THE 2013-2014  Persons with chronic medical conditions (i.e. chronic pulmonary, cardiovascular, renal, hepatic, cognitive, SEASON neurologic, hematologic or metabolic diseases) COULD A VACCINE BE THE  Immunocompromised individuals GROUNDBREAKING SOLUTION TO NICOTINE  American Indians/Alaska Natives DEPENDENCE?  Individuals with a body mass index of 40 or greater  Residents of nursing homes or chronic care facilities 1 M M ATERIA EDICA www.ucdenver.edu/pharmacy/materiamedica Volume 2, Issue 7 Dec 2013 vaccine is that both B lineages are covered, eliminating TRIVALENT FORMULATIONS the need to predict which lineage will predominate each season. Given predicting the B lineage that will Trivalent influenza vaccines are what have been predominate is not always successful, it is especially available for years and what are most commonly used beneficial to cover both lineages because it is uncertain for influenza vacciation. They contain two influenza A if there is cross protection against with one viruses and one influenza B virus. The standard meth- lineage through against the other line- od of production for the trivalent, and now the quadri- age.4 Additionally, any cross protection is likely low.5 valent vaccines, involves producing the vaccines in the The seasons where influenza B is high and the allantoic cavity of embryonated chicken eggs.7 It is a wrong lineage is chosen is when problems arise. To manual procedure that involves disinfecting each egg, solve this, a quadrivalent vaccine that includes a se- inoculating the egg with the virus, incubating each egg, cond influenza B strain from the other influenza B harvesting each egg, and finally purifying the final type lineage was developed. This extra coverage of the product from the egg. Depending on the yield gathered quadrivalent vaccines has its benefits. Data collected from each egg, it may require up to two eggs per dose from 2001 through 2010 indicate that this increased of .7 coverage might have prevented an average of 300,000 The efficiency of this current production method infections, 1,700 hospitalizations and about 200 deaths of inactivated influenza vaccines is limited. This meth- in the United States every year.4 od is simply not fast enough to meet the demands of a While the benefit of switching from a trivalent vac- pandemic, and persons with egg allergies or egg hyper- cine to a quadrivalent vaccine seems clear, there are sensitivities have always been advised against receiving some drawbacks to consider. It has been suggested an influenza vaccine. New methods of producing influ- that for a given level of vaccine capacity during each enza vaccines present numerous benefits. Fortunately, season, fewer doses of the quadrivalent vaccine would there are two new trivalent vaccines available for the be able to be produced than would be with the triva- 2013-2014 influenza season that each use a unique lent vaccine.4 This is because the existing volume to method of production, Flucelvax and FluBlok. produce influenza vaccines would need to be divided Flucelvax is a cell-culture-derived influenza vaccine by four vaccine viruses versus three.4 However, even (CCIV). These vaccines can be produced in large quan- though fewer vaccines would be able to be produced tities and without extensive planning. Flucelvax is pro- with a quadrivalent vaccine, the number produced is duced in Madin-Darby canine kidney (MDCK) cells.7 still predicted to exceed the number of influenza vac- The viruses are propagated in cell culture and then har- cines administered during an influenza season.4 The vested, allowing for patients with egg allergies to be vaccines’ clinical trials are summarized in Table 1 and vaccinated. Using the MDCK cells for production al- clinical considerations are summarized in Table 2. For lows for higher-yield and higher-volume production all formulations, the two primary precautions for use than the standard chicken-egg method. The MDCK are moderate-to severe illness with or without fever cell method also permits the growth to be adapted so and a history of Guillian-Barre syndrome within 6 there is less need for additives like and anti- weeks of receiving previous influenza vaccine. biotics.7

Table 1 | Clinical trials of influenza vaccines available during the 2013-2014 flu season. Vaccine Efficacy Safety

Fluarix, Fluzone and  HAI titers non-inferior to trivalent vaccines  Similar between groups 10 FluLaval Quadrivalent  Rates of seroprotection and seroconversion were similar 11,12 FluMist Quadrivalent  HAI titers were non-inferior to trivalent vaccines  Similar between groups in adults in children and adults  Fever was more common compared  Rates of seroprotection and seroconversion to trivalent group in children were similar 13 Flucelvax  Flucelvax is effective against culture-confirmed  Similar to currently-marketed products influenza in adults 14 FluBlok  Immunogenic and effective  Similar between groups  Protected against antigenic drift HAI = hemagluttination inhibition . 2 M M ATERIA EDICA www.ucdenver.edu/pharmacy/materiamedica Volume 2, Issue 7 Dec 2013 Table 2 | Clinical considerations with new influenza vaccines.1 Indications & Vaccine Contraindications Route Other Notes

FluMist  H/o severe allergic reaction to any compo-  Patients aged  Only needle-free seasonal influenza vac- Quadriva- nent of the vaccine or after a previous dose 2 years old cine available lent of any influenza vaccine through 49  History of severe allergic reaction to any of: years old egg, protein, gentamicin, gelatin or arginine  Intranasal  Concomitant aspirin therapy in children and adolescents  ACIP recommends against use in the follow- ing:  Ages <2 years of ≥50 years  Children aged 2-4 years old whose par- ents/caregivers report that a provider has told them during the preceding 12 months that their child had wheezing or asthma or whose medical record indicates a wheez- ing episode has occurred during the pre- ceding 12 months  Persons with asthma  Persons with chronic pulmonary, cardio- vascular (except isolated hypertension), renal, hepatic, neurologic/neuromuscular, hematologic, or metabolic disorders  Immunosuppressed persons  Close contacts/caregivers of severely im- munosuppressed who require a protected environment  Pregnant women

Fluarix  H/o severe allergic reaction to any compo-  Patients aged  Tip caps located on syringes may contain Quadriva- nent of the vaccine or after a previous dose ≥3 years natural rubber latex lent of any influenza vaccine  Intramuscular  H/o a severe allergic reaction to egg protein

Fluzone  H/o severe allergic reaction to any compo-  Patients aged  Patients 6 months old through 35 months Quadriva- nent of the vaccine or after a previous dose ≥6 months old: 0.25 mL dose lent of any influenza vaccine  Intramuscular  Patients 36 months old and older: 0.5 mL  H/o a severe allergic reaction to egg protein dose

FluLaval  H/o severe allergic reaction to any compo-  Patients aged Qudriva- nent of the vaccine or after a previous dose ≥3 years lent of any influenza vaccine  Intramuscular  H/o a severe allergic reaction to egg protein

Flucelvax  H/o severe allergic reaction to any compo-  Patient aged  Novel cell-culture based influenza vaccine nent of the vaccine or after a previous dose ≥18 years  Virus seed is cultured in chicken eggs, of any influenza vaccine  Intramuscular and can still contain trace amounts of egg  H/o a severe allergic reaction to egg protein protein, and therefore is not recommended for patients with severe egg allergy  Tip caps located on syringes may contain natural rubber latex

FluBlok  H/o severe allergic reaction to any compo-  Patients aged  Only influenza vaccine that is completely nent of the vaccine 18 to 49 egg-free; appropriate for patients with se- years old vere egg allergy  Intramuscular  Novel manufacturing that involves recom- binant viral proteins  Shorter expiration date (16 weeks from date of manufacture) 3 M M ATERIA EDICA www.ucdenver.edu/pharmacy/materiamedica Volume 2, Issue 7 Dec 2013 FluBlok is the first trivalent influenza vaccine in 3. Dawood FS, Chaves SS, Peres A, et al. Complications the U.S. that contains recombinant viral proteins rather and associated bacterial coinfections among children than antigens derived from live virus.8 FluBlok is de- Hospitalized With Seasonal or Pandemic Influenza, veloped from a recombinant baculovirus vector and United States, 2003-2010. J Infect Dis. 2013 [Epub then expressed in a continuous insect cell line.8 There ahead of print]. 4. Reed C, Meltzer MI, Finelli L, Fiore A. Public health are several advantages to this production method. impact of including two lineages of influenza B in a Firstly, this method is egg-free, and therefore persons quadrivalent seasonal influenza vaccine. Vaccine with egg allergy can receive this vaccine without any 2012;30(11):1993-8. risk.9 It also has a fast turnaround time of less than 2 5. Belshe RB, Coelingh K, Ambrose CS, Woo JC, Wu X. months, allowing us to be more prepared in an emer- Efficacy of live attenuated influenza vaccine in children gency situation. In addition, since this method does against influenza B viruses by lineage and antigenic sim- not require attenuated influenza virus, there is no need ilarity. Vaccine 2010;28:2149–56. for a special biocontainment facility and there are no 6. Ambrose CS, Levin MJ. The rationale for quadrivalent additional steps to remove and purify the virus.10 influenza vaccines. Hum Vaccin Immunother 2012;8 (1):81-8. 7. Ambrozaitis A, Groth N, Bugarini R, Sparacio V, Pod- SUMMARY & DISCUSSION da A, Lattanzi M. A novel mammalian cell-culture tech- nique for consistent production of a well-tolerated and While the benefit of the quadrivalent vaccines is immunogenic trivalent subunit influenza vaccine. Vac- the greater coverage, the benefit of the new trivalent cine 2009;27(43):6022-9. vaccines is their unique methods of production. The 8. Traynor K. First recombinant flu vaccine approved. new quadrivalent vaccines have the potential to pre- Am J Health Syst Pharm 2013;70(5):382. vent countless infections, hospitalizations and deaths 9. Yang LP. Recombinant trivalent influenza vaccine in almost every influenza season to come. The new (flublok(®)): a review of its use in the prevention of trivalent vaccines could be particularly useful in pan- seasonal influenza in adults. Drugs 2013;73(12):1357- demic settings, which inevitably arise and can be very 66. destructive. Since the new trivalent vaccines have a 10. Greenberg DP, Robertson CA, Noss MJ, et al. Safety unique mechanism of production, it is much safer to and immunogenicity of a quadrivalent inactivated influ- enza vaccine compared to licensed trivalent inactivated use Flucelvax or FluBlok in patients with egg allergies influenza vaccines in adults. Vaccine 2013;31:770-6. than any other influenza vaccine. Even though 11. Block SL, Yi T, Sheldon E, et al. A randomized, double Flucelvax and FluBlok are much safer alternatives, -blind noninferiority study of quadrivalent live attenuat- FluBlok is considered to be safer than Fluvelvax in ed influenza vaccine in adults. Vaccine 2011;29:9391-7. these patients because it is completely egg free.1 12. Block SL, Falloon J, Hirschfield JA, et al. Immunogen- With six new influenza vaccines on the market this icity and safety of a quadrivalent live attenuated influen- season, hopefully more people will try to get vaccinat- za vaccine in children. Pediatr Infect Dis J 2012;31:745- ed. We have the potential to target new patient popula- 51. tions, prevent more strains of the influenza virus as 13. Flucelvax [package insert]. Cambridge, MA: Novartis well as be more prepared than ever in the event of an Vaccines; July 2013. emergency. 14. Treanor JJ, El Sahly H, King J, et al. Protective efficacy of a trivalent recombinant hemagglutinin protein vac-

cine (FluBlok) against influenza in healthy adults: a ran-  domized, placebo-controlled trial. Vaccine 2011;29 (44):7733–9. REFERENCES 15. CDC. Influenza vaccines- United States, 2013-2014 influenza season. August 20th, 2013. http://www/ 1. Centers for Disease Control and Prevention (CDC). cdc.gov/flu/protect/vaccine/vaccines.htm. (Accessed Prevention and control of seasonal influenza with vac- November 5th, 2013). cines. Recommendations of the Advisory Committee on Immunization Practices (ACIP)--United States, 2013 -2014. MMWR Recomm Rep. 2013;62(RR-07):1-43. 2. Centers for Disease Control and Prevention. Preven- tion and control of influenza with vaccines: recommen- dations of the Advisory Committee on Immunization  Practices (ACIP), 2010. MMWR Recomm Rep 2010;59 (RR-8):1-62. 4 M M ATERIA EDICA www.ucdenver.edu/pharmacy/materiamedica Volume 2, Issue 7 Dec 2013 nicotine (Abs), which bind to circulating Could a Nicotine Vaccine be the nicotine, resulting in an antigen-antibody complex too Groundbreaking Solution to Nicotine large to cross the blood brain barrier. Thus, nicotine Dependence? cannot stimulate the release of DA and NE resulting in less satisfaction from smoking and a reduction in the

Ellen Balkema, RPh, PharmD candidate positive reinforcing effects of nicotine. The is administered as a series of intramuscular in- jections, e.g., once monthly for 3-5 months, with the igarette smoking is the leading cause of pre- aim of producing serum antibody levels for several ventable death worldwide, causing increased months. Nicotine vaccine doses of 100 mcg, 200 mcg, C cardiovascular risks, respiratory diseases, and and 400 mcg have been used in clinical trials, although cancer.1According to the Center for Disease Control as previously mentioned, these doses have not been and Prevention, 5.4 million people die each year sec- approved for use and thus may be different from final ondary to tobacco-related illness.2 This figure is ex- approved doses if or when an agent is approved. The pected to rise to >8 million people by the year 2030. half-life of these nicotine conjugate vaccines is approx- The estimated direct medical care cost related to tobac- imately 90 days. Consequently, booster shots are re- co use is $96 billion annually.3 quired periodically to maintain antibody levels. There are seven first line medications that can help people quit smoking. Currently FDA-approved treat- Clinical Trials ments have shown up to 33% cessation rates after 6 In a study done by Cornuz et al, the nicotine vac- months (Table 1). These medications act on the cen- cine NIC002 (formerly known as Nicotine-QB or Nic- tral nervous system and include nicotine replacement QB, developed by Cytos Biotechnology, Zurich, Swit- (in the form of a patch, lozenge, gum, nasal spray, and zerland) was evaluated for efficacy, inhaler), varenicline (Chantix®) and bupropion sus- immunogenicity, safety and tolerability for six months, tained-release (Zyban®). Nortriptyline, a tricyclic anti- with an additional six month follow up (Table 2).8 depressant, and clonidine, an α2-agonist, are considered Study participants (n=384) were randomly assigned to second line agents. Despite improved smoking cessa- receive five-100 mcg monthly nicotine tion with appropriate use of these products, long-term or placebo immunizations, in addition to counseling. smoking cessation clearly remains suboptimal. Conse- Patients in the nicotine vaccine arm achieved a 100% quently, other novel approaches may be necessary to antibody response after a single vaccination. At 2 improve smoking cessation rates. One such novel ap- months post-immunization, significantly more partici- proach may be immunotherapeutics: initial tests, in- pants receiving the nicotine vaccine quit smoking ver- volving injections of nicotine-specific immunoglobulin sus those receiving placebo (47.2% vs. 35%, respec- G in lab rats in the early 2000’s, resulted in 65% reduc- tively; p=0.036). The difference after 3-6 months was tions in nicotine concentrations in the brain.4 Immuno- not significant and the vaccine did not help to relieve logical approaches, such as nicotine vaccines have been the urge to smoke or withdrawal symptoms. However, studied in phase II and phase III clinical trials over the when the per-protocol treatment population was divid- last decade. A number of these vaccines are in devel- ed into three equal categories of high, medium, and opment; however, none are licensed anywhere for use low area under the curve (AUC) anti-nicotine antibiody in smoking cessation or for relapse prevention. (Ab) responders, continuous abstinence (2-6 months) The primary purpose of this article is to review the was greatest for participants with high titers, 56.6% vs. current evidence for the nicotine vaccine. 31.3% for placebo. Medium and low Ab responders had 32.1% abstinence rates, similar to placebo. The CONJUGATED NICOTINE VACCINE most common adverse effect reported for the NIC002 vaccine was flu-like symptoms, which appeared 2-12 Pharmacology hours after and lasted 24 hours post-dose Nicotine is a small molecule that crosses into the (Table 3). central nervous system (CNS) and binds to receptors A proof of concept study by Hatsukami et al, using releasing (DA) and (NE) NicVAX (3’AmNIc-rEPA, Nabi Biopharmaceuticals, causing pleasure and dependence. The conjugate nico- Rockville, Maryland, U.S.), was done to evaluate the tine vaccine (nicotine linked with a carrier protein or relationship between smoking cessation outcomes and virus-like particle) stimulates the formation of anti- immunogenicity.9 Vaccine doses of 200 mcg and 400 5 M M ATERIA EDICA www.ucdenver.edu/pharmacy/materiamedica Volume 2, Issue 7 Dec 2013 Table 1 | Dosing and administration of current medications for tobacco cessation.5-7 Est. Abstinence Rate Medication OTC/Rx Status & Cost Available Dosing, Instructions, and Duration (%) 6 Months Post-quit

Varenicline  Rx (no generic)  0.5 mg, 1 mg 33.2 (95% CI 28.9-37.8)  $586 per 12-week  Start with 0.5 mg daily x 3 days, then 0.5 mg for 2 mg/day course BID x 4 days, then 1 mg BID  Start 1 week before quit date  Adjust dose CrCl < 30 mL/min  Duration 12 weeks

Nicotine  Rx (no generic)  1 mg = 1 dose = 1 spray each nostril. Use 26.7 (95% CI 21-32.7) Nasal  $215 per 4-10 ml spray every 30-60 minutes PRN craving. Max 40 Spray doses/day  Duration 2-3 months

Nicotine  OTC (generic available)  21 mg, 14 mg, and 7 mg/24 hour (daily patch) 26.5 (95% CI 21.3-32.5) Patch  All: $51.29 per 14  If smoking >10 cigs per day start with highest – high dose Nicotine (>25 patches dose, if smoking 5-10 cigs per day use mid mg) range dose 23.4 (95% CI 21.3-25.8)  Duration 8 weeks.

Nicotine  Rx (no generic)  80 puffs = 1 mg, requires 3-4 puffs per minute 24.8 (95% CI 19.1-31.6) Inhaler  $204.89 per kit (168 for 20-30 minutes. Use PRN or every hour. spray cartridge) Each cartridge is good for approximately 20 minutes of continuous puffing.  Duration 2-3 months

Clonidine  Rx (generic available)  Initial dosing: 0.1 mg po BID or 0.1 mg trans- 25.0 (95% CI 15.7-37.3) (Second  Oral: 0.1 mg tablets; $5 dermal line agent) for 4 week course  Can be titrated up to: 0.2 mg po BID or 0.2  Transdermal: 0.1 mg/ mg transdermal *Not FDA- day 7 day patch;  Duration 3-10 weeks approved $101.60/month 0.2 mg/  Start on or up to 3 days before quit date; dis- day 7 day patch; continue use gradually over 2-4 days $223.04/month  Contraindications: Avoid transdermal if on anticoagulation therapy, severe cardiovascu- lar disease or hemodynamically unstable

Bupropion  Rx (generic available)  150 mg/day for 3 days then 150 mg po BID 25.0 (95% CI 15.7-37.3) SR  Brand: $289.10 per 7- (start one week before quit date) ® (Zyban ) week course  Contraindications: seizure d/o, major head  Generic: $78 per 7- trauma, eating disorder, on Wellbutrin or week course MAO inhibitors

Nortriptyline  Rx (generic available)  Titrate from 25 mg QHS slowly to 75-100 mg 22.5 (95% CI 16.8-29.4) (second line  $21 for 12-week course daily agent)  Start 10-28 days prior to quit date and may need to continue beyond 12 weeks *Not FDA-  Contraindications: do not use with MAO in- approved hibitor or during recovery from MI mcg were administered using two separate immuniza- group also showed the highest rates of prolonged ab- tion schedules, either four or five injections. Partici- stinence up to 12 months. No significant differences in pants receiving the 400 mcg vaccine dose as five injec- results were seen between the low-Ab group and place- tions had the highest mean Ab concentrations bo. Study participants commonly reported aches and throughout the 52 week follow-up period. The analysis tenderness at the injection site. General discomfort/ involved stratification for active treatment into high malaise, myalgia, and headache were the most com- Ab responders, defined as the top 30% of responders monly reported systemic adverse effects. There was no by AUC, and low Ab responders, the remaining 70%. significant difference in local or systemic reactions be- The high-Ab group was significantly more likely to at- tween placebo and the NicVAX treatment group. tain 8 continuous weeks of smoking abstinence (from More recent studies include two identical phase III weeks 19 through 26) versus placebo. The high-Ab trials, each with 1000 participants, comparing six 400 6 M M ATERIA EDICA www.ucdenver.edu/pharmacy/materiamedica Volume 2, Issue 7 Dec 2013 Table 2 | Clinical trials of the nicotine vaccines for smoking cessation.8,9 Study Design Treatment Arms Endpoints Results

Cornuz  Phase II, Ran-  Five monthly 100 mcg  Abstinence from Abstinence rates for active ver- 2008 domized, Place- injections (n=229) or pla- smoking, confirmed sus placebo ITT population: 8 NIC002 bo-controlled, cebo injections (n=111) by carbon monoxide  2 months: 47.2% vs. 35.1% Double-blind  Both groups received concentration < 10 (p=0.036) Multicenter individual counseling ppm  3-6 months: 30.1% vs. 26.1%  Target quit date from week 3 to month 4  Other primary out- (p=0.44) set at 1 month comes: safety, im- Abstinence rates 2-6 months,  N=341 partici- munogenicity tolera- per protocol population: NRT pants who bility users and participants with in- smoked 10–40 complete Ab assessments re- cigarettes/day moved (N=159):  High Ab responders 56.6% (p=0.004)  Medium Ab responders 32.1% (p=0.920)  Low Ab responders 32.1% (p=0.920)  Placebo 31.3% Hatsukami  Phase II, ran-  Placebo (n=100)  Determine if higher Continuous abstinence from 2011 domized, place-  Vaccine 200 mcg sched- serum anti-nicotine weeks 19-26 (8 week period): a NicVAX bo-controlled, ule 1 (n=50) Ab responders (top  24.6% (P=0.024) for (3”AMNic- double blind,  Vaccine 200 mcg sched- 30% AUC) are asso- NicVAX high Ab responders 9 b rEPA) multicenter ule 2 (n=50) ciated with higher  9.3% (P=0.46) for NicVAX  N=301 partici-  Vaccine 400 mcg sched- abstinence rates low Ab responders a pants who ule 1 (n=50) weeks 19-26  12% for placebo smoked ≥15  Vaccine 400 mcg sched-  Secondary outcome:  OR 2.69 (95% CI 1.14-6.37) cigarettes/day ule 2b (n=51) continuous absti- for NicVAX high Ab respond- nence from weeks ers versus placebo 19-52 Secondary outcome: absti-  Abstinence was vali- nence rates from weeks 19-52: dated by measure-  19.7% (P=0.044) for NicVAX ment of exhaled car- high Ab responders bon dioxide  10% for placebo  7.1% (P=0.43) for NicVAX low Ab responders  OR 2.64 (95% CI 1.03-6.79) for NicVAX high Ab respond- ers versus placebo aSchedule 1: vaccine administered at weeks 0, 6, 12, and 26 (four ). bSchedule 2: vaccine administered at weeks 0, 4, 8, 16, and 26 (five vaccinations). mcg NicVAX injections to placebo. However, on No- label varenicline and either six 400 mcg injections of vember 7, 2011, Nabi Biopharmaceuticals announced NicVAX or placebo. Prolonged abstinence from week negative results for both trials since the primary end- 9 to 52 weeks was evaluated. Published study results point of long term smoking abstinence was not are still pending at the time of this writing. met.10,11 Furthermore, they reported no statistically sig- Finally, researchers at the Biodesign Institute at nificant difference between the vaccine and placebo. Arizona State University are working on a different Limited information regarding these two trials is availa- approach to developing a nicotine vaccine.15 The pro- ble from ClinicalTrials.gov, but neither trial has been ject is partially funded by a $3 million grant from the published fully.12, 13 Another recently completed study, National Institute of Drug Abuse. This novel approach assesses the efficacy of NicVAX co-administered with uses DNA scaffolding material to synthetically assem- varenicline (Champix®) and intensive counseling as an ble antigen components to enhance immunity to nico- aid in smoking cessation and relapse prevention.14 This tine dependence. The DNA approach may be ideal was the first study to assess efficacy of a nicotine vac- because it is a double helix and has a very precise base cine in combination with an evidence-based pharma- pair coding, which allows researchers to incorporate cotherapy. Participants received 12 weeks of open- the nicotine antigen into the DNA quit easily. 7 M M ATERIA EDICA www.ucdenver.edu/pharmacy/materiamedica Volume 2, Issue 7 Dec 2013 Table 3 | Percent of patients experiencing adverse effects in clinical trials of conjugate nicotine vaccines.8,9 NIC002 Placebo Adverse effect (n=229) (n=111) Odds ratio (95% CI) Flu-like symptoms 69.4 12.5 15.9 (8.5-29.8) Pyrexia 41.9 8.0 8.3 (4.0-17.1) Headache 40.2 26.8 1.8 (1.1-3.0) Nasopharyngitis 31.9 25.9 1.3 (0.8-2.2) Injection site pain 19.7 1.8 13.5 (3.2-56.5) Rigors (chills) 13.5 0.0 -- Myalgia 13.5 5.4 2.8 (1.1-6.8) Back pain 10.9 10.7 1.0 (0.5-2.1) Weight increased 10.5 11.6 0.9 (0.4-1.8) Rhinitis 9.2 10.7 0.8 (0.4-1.8) Influenza 7.0 10.7 0.6 (0.3-1.4)

NicVAX 400 mcg (5 vaccinations) Placebo Adverse effect (n=51) (n=100) P value Local ache 96.1 96 0.129 Local tenderness 98 95 0.126 Local swelling/induration 56.9 60 0.827 Local burning 45.1 42 0.988 Local erythema 43.1 39 0.180 Local heat 43.1 42 0.661 Myalgia 88.2 86 0.315 General discomfort/malaise 82.4 79 0.803 Headache 70.6 67 0.945 Nausea 49 44 0.501 Vomiting 15.7 6 0.111 Fever 11.8 10 0.403

SUMMARY REFERENCES

Current evidence does not support immunization 1. Doering PL, Li RM. Chapter 75. Substance-related dis- with the conjugate nicotine vaccine for long-term orders: Alcohol, Nicotine, and caffeine. In: Wells BG, ed. Pharmacotherapy: A Pathophysiologic Approach, smoking cessation. Vaccine candidates currently under 8th ed. New York: McGraw-Hill; 2011. Accessed development will likely undergo significant changes 10/18/2013. Available at: http:// before becoming available on the market. Post-hoc www.accesspharmacy.com/content.aspx? analyses from clinical trials suggest that higher anti- aID=7987625. body titers will be needed to improve long-term effica- 2. Center for Disease Control and Prevention. Smoking cy of these agents. However, long-term unintended and Tobacco Use. Accessed 10/7/13. Available at: consequences of nicotine vaccines are unknown. For http://www.cdc.gov/tobacoo/global/index.htm. example, prolonged blocking of nicotine receptors may 3. Preventing Tobacco Use Among Youth and Young induce compensatory smoking or precipitate withdraw- Adults. A Report of the Surgeon General. 2012 Exec- al symptoms, leading smokers to smoke more. This utive Summary. Accessed 10/18/13. Available at: concern will have to be evaluated in future studies. It http://www.surgeongeneral.gov/library/reports/ preventing-youth-tobacco-use/exec-summary.pdf. should be noted that clinical trials thus far have been 4. Pentel PR, Malin DH, Ennifar S, et al. A nicotine con- conducted by pharmaceutical companies as part of the jugate vaccine reduces nicotine distribution to brain and drug development process. Although adverse events attenuates its behavioral and cardiovascular effects in were common, they were rated mild or moderate and rats. Pharmacol Biochem Behav 2000;65:191–198. generally included flu-like symptoms. A number of 5. Fiore MC, Jaen CR, Baker TB, et al. Treating Tobacco vaccines are being studied; none are currently FDA- Use and Dependence: 2008 Update. Quick Reference approved. Better vaccines and more trials are needed. Guide for Clinicians. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service.  April 2009. 6. Fiore MC, Jaen CR, Baker TB, et al. Treating tobacco 8 M M ATERIA EDICA www.ucdenver.edu/pharmacy/materiamedica Volume 2, Issue 7 Dec 2013 use and dependence: 2008 update. Clinical Practice Guideline. Department of Health and Human Services, 2008. Available at: http://www.ahrq.gov/ professionals/clinicians-providers/guidelines- recommendations/tobacco/clinicians/update/ treating_tobacco_use08.pdf. 7. Pricing obtained from Cardinal Health Pharmaceutical Distribution; pharmacy wholesale price. 8. Cornuz J, Zwahlen S, Jungi WF, et al. A Vaccine against Nicotine for Smoking Cessation: A Randomized Con- trolled Trial. PLoS ONE 3(6): e2547. doi:10.1371/ journal.pone.0002547. 9. Hatsukami DK, Jorenby DE, Gonzales, et al. Immuni- genicity and Smoking-Cessation Outcomes for a Novel Nicotine Imunotherapeutic. Clinical Pharmacology & Therapeutics 2011;89:392-9. 10. Nabi Biopharmaceuticals Announces Results of Second NiVAX® Phase III . Accessed November 10, 2013. Available at: http://www.drugs.com/ clinical_trials/nabi-biopharmaceuticals-announces- results-second-nicvax-phase-iii-clinical-trial-12641.html. 11. Fahim RE, Kessler PD, Fuller SA, Kalnik MW. Nico- tine Vaccines. CNS Neurol Disord Drug Targets 2011; 10(8):905-15. 12. ClinicalTrials.gov. NCT00836199. NicVAX/Placebo as an Aid for Smoking Cessation. A Phase 3, Multi-Center, Randomized, Double-Blind, Placebo-Controlled Study to Assess Efficacy, Immunogenicity and Safety of 3’- Aminomethylnicotine-P. Aeruginosa r-Exoprotein A Conjugate Vaccine (NicVAX) as an Aid to Smoking Cessation. Accessed October 30, 2013. Available at: http://clinicaltrials.gov/ct2/show/NCT00836199? term=nct00836199&rank=1. 13. ClinicalTrials.gov. NCT01102114. A Second Study of NicVAX/Placebo as an Aid for Smoking Cessation. A Second Phase 3, Multi-Center, Randomized, Double- Blind, Placebo-Controlled Study to Assess Efficacy, Immunogenicity and Safety of 3’-Aminomethylnicotine- P. Aeruginosa r-Exoprotein A Conjugate Vaccine MATERIA MEDICA (NiVAX) as an Aid to Smoking Cessation. Accessed October 30, 2013. Available at: http:// A publication of the Department of Clinical clinicaltrials.gov/ct2/show/NCT01102114? Pharmacy, Skaggs School of Pharmacy and term=NCT01102114&rank=1. Pharmaceutical Sciences 14. Hoogsteder P, Kotz D, Spiegel P, et al. The efficacy and safety of a nicotine conjugate vaccine (NicVAX®) University of Colorado or placebo co-administered with varenicline (Champix®) for smoking cessation: study protocol of a Editor phase IIb, double blind, randomized, placebo Steven M. Smith, PharmD, MPH, BCPS controlled trial. BMC Public Health 2012;12:1052. 15. The State Press. Researchers developing nicotine Associate Editor vaccine. Accessed on October 10, 2013. Available at: Katy E. Trinkley, PharmD, BCACP http://www.statepress.com/2013/07/16/researchers- developing-nicotine-vaccine/. The material contained in this newsletter has been prepared by the  Skaggs School of Pharmacy for informational purposes only. The   articles are the work product of the individual authors to whom each article is attributed. The articles contained herein should not be used  without proper permission or citation. Should you have questions about any of the content in this newsletter please contact the Editor. 9 M M ATERIA EDICA www.ucdenver.edu/pharmacy/materiamedica Volume 2, Issue 7 Dec 2013