Ospemifene (Osphena ): A New Treatment for Dyspareunia and Vaginal Atrophy

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1 ATERIA EDICA Volume 2, Issue 3 August 2013 Ospemifene (Osphena ): A New Treatment for Dyspareunia and Vaginal Atrophy Fallon Wu, PharmD candidate P ainful sexual intercourse, otherwise known as dyspareunia, is a common problem affecting an estimated 60% of postmenopausal women. 1 This high prevalence is largely due to hormonal changes, primarily a marked decline in estrogen, during menopause that lead to atrophy of the vaginal lining and accompanying symptoms of dryness, burning, and dyspareunia. 2 Greater than 90% of women with these symptoms have reported them to be bothersome. 1 Symptoms of dyspareunia often adversely affect a woman s sexual life and wellbeing. For example, women with dyspareunia report less of a desire to engage in sex than those who do not have dyspareunia. 3 Despite this condition being a common problem, women are often hesitant to report their symptoms to their primary care providers. A Swedish study found that only 28% of women who had ever had prolonged and severe dyspareunia had consulted a physician for their symptoms. 4 Treatment plays an integral role in improving quality of life and preventing complications such as postcoital bleeding and sexual dysfunction. 2 For mild cases of dyspareunia, nonhormonal vaginal moisturizers and lubricants often sufficiently control symptoms. 5 For patients who do not achieve an optimal response from INSIDE THIS ISSUE: OSPEMIFENE (OSPHENA ): A NEW TREATMENT FOR DYSPAREUNIA AND VAGINAL ATROPHY NEWS ABOUT AN OLD VACCINE: CURRENT RECOMMENDATIONS FOR PNEUMOCOCCAL VACCINATION these nonhormonal agents, estrogen products are often the next step in therapy. Available products include both topical and oral estrogen formulations. 6 However, systemically-absorbed estrogen formulations are associated with complications, including increased risk of venous thromboembolism and endometrial hyperplasia, prompting the development of novel treatments for symptoms related to vulvovaginal atrophy. 7 In February 2013, ospemifene was granted an FDA -approved indication for the treatment of moderate-tosevere dyspareunia due to vulvovaginal atrophy occurring after the onset of menopause. This agent is the first non-estrogen drug with an approved indication for this condition. 7,8 The purpose of this article is to review the pharmacology, pharmacokinetics, efficacy, and safety of ospemifene. PHARMACOLOGY & PHARMACOKINETICS Mechanism of Action Ospemifene is a selective estrogen receptor modifier (SERM). 8 As a SERM, ospemifene exhibits tissue- Editor s Summary: Ospemifene (Osphema ) Description & Indication Selective estrogen receptor modifier (SERM) Indicated for moderate-to-severe dyspareunia due to vulvovaginal atrophy after the onset of menopause Dosing Dosed 60 mg once daily with food; administer with a progestin in postmenopausal women with a uterus Efficacy Safety Superior to placebo in increasing the % of superficial cells, reducing the % of parabasal cells, reducing vaginal ph, and reducing vaginal dryness and dyspareunia symptom score No data with active comparators (i.e., HRT) Adverse events infrequent (<10% of patients); possible increased risk of hot flashes, mycotic infections 1

2 Figure Chemical structure of ospemifene. 9 specific effects, serving as an estrogen receptor agonist in some tissues and an antagonist in others. Ospemifene is believed to have a greater specificity for vaginal epithelium receptors than other commercially available SERMs (e.g., tamoxifen, raloxifene). Agonistic effects at these receptors are thought to account for this drug s beneficial effect on the vaginal lining. 9 Effects of ospemifene observed in other tissues include antagonistic effects on breast tissue and a reduction in bone turnover. 10,11 The chemical structure of ospemifene is displayed in the Figure. Pharmacokinetis Ospemifene achieves maximal blood concentrations between 1 and 8 hours following oral administration, and steady-state concentrations are reached by day 9 of daily administration. 8,12 In pharmacology studies, concurrent food intake with ospemifene was shown to increase drug concentrations two- to threefold. Ospemifene exhibits >99% protein binding and a volume of distribution of 448 L. 8 Primary metabolism of ospemifene to its major metabolite, 4- hydroxyospemifene, occurs in the liver by CYP enzymes 3A4, 2C9, and 2C19. Ospemifene is thought to be a weak inhibitor of CYP enzymes 2B6, 2C9, 2C19, 2C8, 2D6 and 3A4. Drug interactions observed in in vitro studies are highlighted in Table 1. Elimination mostly occurs through fecal excretion, but small amounts are also removed in the urine. 8 CLINICAL TRIALS In a phase 3, randomized, double-blind study, Bachmann, et al., assigned 826 postmenopausal women to receive either ospemifene 30 mg, ospemifene 60 mg, or placebo daily for 12 weeks. 13 Study participants were required to have standard histological markers of vulvovaginal atrophy ( 5% superficial cells on a vaginal smear; vaginal ph >5) and at least one moderate or severe symptom related to these atrophic changes. Participants taking hormonal therapy or those who had a previous history of thromboembolic disorder were among those excluded. All women were provided with a nonhormonal lubricant to use throughout the period. Coprimary endpoints measured included changes in the percentage of superficial and parabasal cells on the vaginal smear, vaginal ph, and a self-assessed most bothersome symptom score for either dryness or dyspareunia. The mean age of participants was 58 to 59. Dypsareunia and vaginal dryness were reported in 46% and 39% of the participants, respectively, at baseline. At the end of 12 weeks of treatment, an increase was seen in the percentage of superficial cells (a celltype typically present in the healthy vaginal environment) for the patients taking 30 mg and 60 mg ospemifene as compared to placebo (7.8%, 10.%, and 2.2%, respectively; p<0.001 for both strengths versus placebo). Similarly, a decreased percentage of parabasal cells (a cell-type typically elevated in atrophic conditions) was observed in the ospemifene groups as compared to placebo (p<0.001 for both ospemifene groups). Furthermore, compared with placebo, ospemifene therapy resulted in a reduction in vaginal ph, reflecting more normal conditions, at 4 and 12 weeks (p<0.001 for both strengths of ospemifene versus placebo at both 4 and 12 weeks). Self-reported symptom scores for vaginal dryness were lower for both the 30 mg (p=0.04) and 60 mg strengths (p=0.021) of ospemifene as compared to placebo. A reduction in symptomology score for dyspareunia was observed only for the ospemifene 60 mg dose relative to placebo (p=0.023). 11 In a second 12-week phase 3 trial by Portman, et al., ospemifene 60 mg was compared to placebo with similar effects on superficial and parabasal cell percentages, ph, and symptomology scores (Table 2). 14 In this study, researchers also examined changes in the external appearance of the vagina, in particular, the Table 1 Effect of co-administered drug on ospemifene observed in in vitro studies. 8 Co-administered drug Effect on CYP enzymes Effect on ospemifene C max Fluconazole 3A4/2C9/ 2C19 inhibitor Increased 1.7 fold Rifampin 3A4/2C9/ 2C19 inducer Decreased 51% Ketoconazole 3A4 inhibitor Increased 1.5 fold Omeprazole 2C19 inhibitor Increased 1.20 fold 2

3 Table 2 Results from ospemifene phase 3 efficacy studies. 13,14 Study Study population Bachmann, et al. (2010) 13 Portman, et al. (2013) 14 Inclusion criteria: Inclusion criteria: Postmenopausal women aged years Postmenopausal women aged years 5% superficial cells 5% superficial cells Vaginal ph >5.0 Vaginal ph >5.0 Moderate to severe dryness or dyspareunia Dyspareunia most bothersome symptom; or both severity = moderate-to-severe Treatment arms Coprimary endpoints Change in % superficial cells Change in % parabasal cells Exclusion criteria: Current use of any hormone therapy Pathological findings on endometrial biopsy Abnormal breast exam Suspicion of malignancy BMI 37 kg/m 2 SBP 180 or DBP 100 mm Hg Placebo (n=268) OSP 30 mg (n=282) OSP 60 mg (n=276) % superficial cells % parabasal cells Vaginal ph Most bothersome symptom score Placebo: +2.2% OSP 30 mg: +7.8% a OSP 60 mg: +10.8% a Placebo: +3.98% OSP 30 mg: -21.9% a OSP 60 mg: -30.1% a Change in vaginal ph Placebo: OSP 30 mg: a OSP 60 mg: a Change in vaginal dryness symptom score Change in dyspareunia symptom score NS = not significant; OSP = ospemifene. a p<0.001 vs. placebo. b p< vs. placebo. Placebo: OSP 30 mg: (p=0.04) OSP 60 mg: (p=0.021) Placebo: OSP 30 mg: (NS) OSP 60 mg: (p=0.023) Exclusion criteria: Current use of any hormone therapy Pathological findings on endometrial biopsy Abnormal breast exam, Suspicion of malignancy BMI 37 kg/m 2 SBP 180, DBP 100 mm Hg Placebo (n=302) OSP 60 mg (n=303) % superficial cells % parabasal cells Vaginal ph Most bothersome symptom score Placebo: +1.7% OSP 60 mg: +12.3% b Placebo: 0% OSP 60 mg: -40.2% b Placebo: OSP 60 mg: b Not studied Placebo -1.2 OSP 60 mg -1.5 b severity of petechiae, pallor, friability, redness, and mucosal dryness as secondary endpoints. Researchers ranked the severity of each of these parameters as being absent (none), mild, moderate, or severe. At 12 weeks, for each of these parameters, more participants in the ospemifene-treated group experienced a two level improvement (drop from "severe" to "mild" or from "moderate" to "none") or three level improvement(drop from "severe" to "none") in these parameters from baseline. For each parameter, percentages of participants experiencing a two-to-three level drop in ospemifene vs. placebo, respectively, were as follows: petechiae, 10.4% vs. 6.3%; pallor, 21.3% vs. 10.0%; friability, 13.2% vs. 7.7%; vaginal redness, 12.1% vs. 8.2%; and vaginal mucosal dryness, 36.6% vs. 13.7%. Statistical comparisons for these incidence rates have not been reported. SAFETY & ADVERSE EFFECTS Clinical trials have shown a relatively low incidence of adverse effects with ospemifene use. In the 12-week phase 3 clinical trial by Bachmann, et al., the most frequently reported adverse events included hot flashes (8.3%, 9.6%, 3.4% for ospemifene 60 mg, ospemifene 30 mg, and placebo, respectively), urinary tract infec- 3

4 Table 3 Most frequently reported adverse events in clinical trials of ospemifene Study Bachmann, et al. 13 (2010) a Simon, et al. 13 (2013) a Portman, et al. 14 (2013) b Adverse Effect PCB (n=268) OSP 30 (n=282) OSP 60 (n=276) PCB (n=49) OSP 30 (n=62) OSP 60 (n=69) PCB (n=302) OSP 60 (n=303) Hot flashes 3.4% 9.6% 8.3% 4.1% 3.2% 7.2% 4.3% 6.6% Urinary tract infection 2.2% 4.6% 7.2% 8.2% 6.5% 8.7% 3.6% 5.6% Headache 5.2% 6.0% 2.5% NR NR NR 4.0% 3.3% Vaginal discharge NR NR NR NR NR NR 0.7% 4.6% Vaginal candidiasis NR NR NR 2.0% c 8.1% c 4.3% c 0.3% 4.6% Mycotic infection d NR NR NR 2.0% c 8.1% c 4.3% c 0.3% 4.3% Nasopharyngitis NR NR NR 6.1% 0% 1.4% 4.0% 3.6% D/C due to Adverse Event 14.9% 5.3% 4.7% 2.0% 4.8% 5.8% 1.3% 3.3% D/C = discontinued; NR = not reported as frequent event; OSP 30 = ospemifene 30 mg; OSP 60 = ospemifene 60 mg; PCB = placebo. a Adverse events reported in 5% of participants in any group. b Adverse events reported in 3% or more of participants in the ospemifene group. c Data reported as a combination of vaginal candidiasis and vulvar and vaginal mycotic infections. d Vulvar and vaginal mycotic infections. tion (7.2%, 4.6%, and 2.2%), and headache (2.5%, 6.0%, 5.2%). 13 The phase 3 trial by Portman, et al., reported similar incidences for these adverse effects, but also noted additional frequent adverse effects of vaginal discharge, vaginal candidiasis, vulvar and vaginal mycotic infections, and nasopharyngitis. 14 In a 40-week safety extension of the 12-week Bachmann, et al. trial (total, 52 weeks) the prevalence of vaginal candidiasis and vulvar and vaginal mycotic infections were reported to be higher in the ospemifenetreated groups (2.0%, 8.1%, 4.3% for placebo, ospemifene 30 mg, and ospemifene 60 mg, respectively). 15 Similar rates of hot flashes were observed as in the initial 12-week study; however, urinary tract infection incidence in the ospemifene treated groups appeared to decrease with a longer duration of therapy (Table 3). Proliferative changes in the endometrium were noted in one patient in each of the ospemifene 30 mg and 60 mg treatment groups, whereas none were noted in the placebo group. An increase in the thickness of the endometrium was associated with ospemifene treatment, however, no cases of endometrial hyperplasia or carcinoma were reported. Additional side effects observed with ospemifene, based on pooled phase 2 and phase 3 trial data, include muscle spasms (3.2% vs. 0.9% for ospemifene 60 mg and placebo, respectively), and increased sweating (1.5% vs. 0.6%). 8 The estrogen only arm of the Women's Health Initiative study showed an increased risk of stroke (relative risk [RR] 1.39; 95% CI ) and DVT (RR 1.47; 95% CI ) with estrogen therapy. 16 Because ospemifene serves as an estrogen agonist in some tissues, there is concern that its use can lead to these adverse outcomes as well. When comparing ospemifene 60 mg/day to placebo, pooled incidence rates from phase 2 and phase 3 clinical trials were 0.72 vs per thousand women for thromboembolic stroke, 1.45 vs. 0 per thousand women for hemorrhagic stroke, and 1.45 vs per thousand women for DVT. 8 Statistical comparisons for these incidence rates have not been reported. Studies with larger populations and longer durations will likely need to be conducted to appropriately characterize the risk profile for these rarer complications. Studies have not yet been performed in patients with or at risk for breast cancer. More data are needed to evaluate the effect of ospemifene on breast cancer incidence. Contraindications listed in the package insert include undiagnosed abnormal genital bleeding, known/suspected estrogen-dependent neoplasia, active DVT/PE or history of these conditions, active thromboembolic conditions (stroke or MI) or history of these conditions, and pregnancy. 8 DOSING & ADMINISTRATION Though multiple strengths were studied in clinical trials, only the 60 mg strength of ospemifene has been granted an approved indication for use in patients with moderate-to-severe dyspareunia due to menopause. Ospemifene is administered once daily with food since food increases the bioavailability of this agent two- to threefold. 8 Generally, administration of an estrogen to a postmenopausal woman with a uterus should be accompanied with a progestin to decrease the risk of endometrial cancer. Because ospemifene has agonistic effects on endometrium estrogen receptors, it should be administered with a progestin in postmenopausal women 4

5 with a uterus. 8 Dosage adjustment is not required in renal impairment or mild-to-moderate hepatic impairment. Ospemifene has not been studied in patients with major hepatic impairment and should be used cautiously in these patients until more data are available. 8 COST Due to its recent approval, ospemifene is currently only available as a brand name product, Osphena. Table 4 provides a comparison of cash prices from several pharmacies in the Denver area. CONCLUSIONS Ospemifene is a novel agent with an approved indication for moderate-to-severe dyspareunia. In clinical trials, ospemifene has shown a beneficial effect on the restoration of normal proportions of superficial and parabasal cells and has been reported by study participants to improve symptoms of vaginal dryness and pain during sexual intercourse. This effect on the vaginal epithelium is a unique property that other currently available SERMs do not possess, likely owing to its specificity on vaginal epithelial estrogen receptors. The side effect profile is generally favorable, with the most common side effect being hot flashes, which are estimated to occur in ~7.5% of patients. 8 No cases of endometrial hyperplasia or cancer have been observed in studies up to one year in length. Though more data are needed to establish safety with long-term use, ospemifene offers a promising alternative to estrogen therapy for the treatment of vulvovaginal atrophy. REFERENCES 1. Santoro N, Komi JO. Prevalence and impact of vaginal symptoms among postmenopausal women. J Sex Med 2009;6(8): Bachmann, GA, Nevadunsky, NS. Diagnosis and treatment of atrophic vaginitis. Am Fam Physician 2000;61 (10): Table 4 Monthly cash price for ospemifene. Pharmacy Cash Price (1 mo supply) Walgreens $ King Soopers $ Safeway $ Walmart $ Bachmann GA, Leiblum SR, Kemmann E, et al. Sexual expression and its determinants in the post-menopausal woman. Maturitas 1984;6(1): Danielsson I, Sjoberg I, Stenlund H, et al. Prevalence and incidence of prolonged and severe dyspareunia in women: results from a population Study. Scand J Public Health 2003;31(2): Sinha, A, Ewies AA. Non-hormonal topical treatment of vulvovaginal atrophy: an up-to-date overview. Climacteric 2013;16(3): Sturdee DW, Panay N; Recommendations for the management of postmenopausal vaginal atrophy. Climacteric 2010;13(6): Elkinson S, Yang LP. Ospemifene: first global approval. Drugs 2013;73(6): Product Information: OSPHENA(TM) oral tablets, ospemifene. Shionogi Inc. (per manufacturer), Florham Park, NJ, Maximov PY, Lee TM, Jordan VC. The discovery and development of selective estrogen receptor modulators (SERMs) for clinical practice. Current clinical pharmacology 2013;8(2): Komi J, Heikkinen J, Rutanen EM, et al. Effects of ospemifene, a novel SERM, on biochemical markers of bone turnover in healthy postmenopausal women. Gynecol Endocrinol 2004;18(3): Taras TL, Wurz GT, DeGregorio MW. In vitro and in vivo biologic effects of Ospemifene (FC-1271a) in breast cancer. J Steroid Biochem Mol Biol 2001;77(4-5): Micromedex Healthcare Series, (electronic version). Thompson Micromedex, Greenwood Village, Colorado, USA. Available at: (accessed on 6/21/2013). 13. Bachmann GA, Komi JO. Ospemifene effectively treats vulvovaginal atrophy in postmenopausal women: results from a pivotal phase 3 study. Menopause 2010;17 (3): Portman DJ, Bachmann GA, Simon JA, et al. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy. Menopause 2013;20(6): Simon JA, Lin VH, Radovich C, et al. One-year longterm safety extension study of ospemifene for the treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus. Menopause 2013;20(4): Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004;291(14): Rite-Aid $ UCH Price currently unavailable 5

6 News About an Old Vaccine: Current Recommendations for Pneumococcal Vaccination Amy Yu San Lai, PharmD A dult vaccination coverage remains unacceptably low for most routinely recommended vaccines, according to the Centers for Disease Control (CDC). 1 Despite Healthy People 2020 targets for pneumococcal vaccination of 60% among high-risk adults aged years and 90% among all adults aged 65 years, in 2011, corresponding vaccination coverage was only 20.1% and 62.3%, respectively. 1,2 Vaccination covers Streptococcus pneumoniae, a grampositive bacteria, with 90 known serotypes. Although most serotypes can cause serious disease, 10 serotypes account for the majority (~62%) of pneumococcal infections worldwide. Pneumonia, bacteremia, and meningitis are serious sequelae that can occur as a result of S. pneumoniae infection. Table 1 describes the incidence and fatality rate of each of the pneumococcal sequelae in the United States. Of the three sequelae, pneumococcal pneumonia is the most common. S. pneumoniae is responsible for up to 36% of community-acquired pneumonia (CAP) and 50% of hospital-acquired pneumonia (HAP) events. About 25-30% of patients with pneumococcal pneumonia experience bacteremia. Patients with asplenia often experience a fulminant clinical course if they develop pneumococcal bacteremia. While S. pneumoniae accounts for 13-19% of all cases of bacterial meningitis in the U.S., a quarter of the patients with pneumococcal meningitis also have pneumococcal pneumonia. Invasive pneumococcal disease (IPD), includes meningitis and bacteremia, but not pneumonia. Conditions that increase the risk for IPD include decreased immune function from disease or drugs, functional or anatomic asplenia, chronic heart, pulmonary, liver, or renal disease, cigarette smoking, and cerebrospinal fluid leak. 3 Currently, two pneumococcal vaccines are commercially available in the U.S.: the 23-valent pneumococcal polysaccharide vaccine (PPSV23) and 13-valent Table 1 Case and fatality rates for pneumococcal infections. 3 Type Cases/year in U.S. Fatality Rate (Elderly) Pneumonia 175, % (unknown) Bacteremia 50,000 20% (60%) Meningitis 3,000-6,000 30% (80%) pneumococcal conjugate vaccine (PCV13), both of which have FDA-approved indications for use in adults. Table 2 describes the available pneumococcal vaccines and their serotype coverage. Table 3 lists the indications, contraindications, and adverse effects of PPSV23 and PCV13. The PPSV23 was licensed in 1983 and contains polysaccharide antigen from 23 types of pneumococcal bacteria that cause 88% of pneumococcal bacteremia cases, and 8% of bacteremic pneumococcal disease. 4 PPSV23 can be administered either intramuscularly or subcutaneously. Although it is safe to co-administer PPSV23 and Zoster vaccination, PPSV23 and Zoster vaccines should be separated by at least 4 weeks because co-administration leads to a reduced immune response to the Zoster vaccine. 4 The PCV13 is often thought of as the pediatric version of the pneumococcal vaccine, but is now recommended for adults aged 19 years with immunocompromising conditions (including chronic renal failure and nephrotic syndrome), functional or anatomic asplenia, cerebrospinal fluid leaks, or cochlear implants. 5 PCV13 also has an FDA-approved indication for use in adults aged 50 years. PCV13 is welltolerated, however concurrent administration with inactivated influenza vaccine may lead to diminished antibody response to PCV13. 6 In general, data consistently support that pneumococcal vaccines protect against IPD. However, conflicting data exist as to whether vaccination prevents pneumonia. Most studies do not demonstrate a reduction in either all-cause pneumonia or pneumococcal pneumonia following vaccination, 7-9 including 2 metaanalyses that found no reduction in all-cause pneumonia or pneumococcal pneumonia with PPSV23 vaccination. 7,8 However, one prospective cohort study identified a significant reduction in pneumococcal pneumonia, all-cause pneumonia and mortality in elderly patients with PPSV Another prospective study demonstrated that patients with CAP who had prior PPSV23 vaccination had about a 40% lower rate of mortality or ICU admission compared with patients Table 2 Vaccines and serotype coverage. Type Vaccine Serotype Coverage PPSV23 Pneumovax 23 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, 33F PCV13 Prevnar 13 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F PCV13 = Pneumococcal conjugate vaccine; PPSV23 = Pneumococcal polysaccharide vaccine. 6

7 Table 3 Vaccine indications and warnings. 5,7 Vaccine FDA-Approved Indications Contraindications Most common AEs PPSV23 Persons aged 50 years Persons aged >2 years who are at increased risk for pneumococcal disease Severe allergic reaction to any component of PPSV23 Injection-site reactions, headache, fatigue, myalgia PCV13 Persons aged 50 years for the prevention of pneumonia and invasive disease Children 6 weeks through: 5 years for prevention of otitis media 17 years for prevention of IPD AEs = adverse effects; IPD = invasive pneumococcal disease. Severe allergic reaction to any component of PCV13 or any diptheria toxoidcontaining vaccine Pain, redness, or swelling at injection site, limitation of arm movement, fatigue, headache, muscle pain, joint pain, decreased appetite, chills, or rash who were not vaccinated. 11 Pneumococcal vaccination is generally safe and cost-effective, and should be routinely recommended to patients in the high-risk groups. This manuscript examines the recently updated pneumococcal vaccine recommendations, including the use of PCV13 in immunocompromised patients, administration schedules for when both PPSV23 and PCV13 are indicated, and the cost-effectiveness of pneumococcal vaccination. NEW ACIP RECOMMENDATIONS Prior to the 2013 Advisory Committee on Immunization Practices (ACIP) recommendations, PPSV23 was primarily used for immunocompromised patients, as well as patients aged 65 years or older. The new ACIP recommendations include vaccination with PCV13 for certain patients (Box). 5 Although there are no published studies of PCV13 in immunocompromised patients, its use is supported by of PCV7 in immunocompromised adults. One of the studies was a placebo controlled trial that enrolled 496 patients, of which, 248 patients received PCV7 and 248 received placebo. 12 Of the 496 patients enrolled, 439 (88.5%) had HIV infection. The primary end point was an episode of pneumococcal disease caused by one of the vaccine serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) and serotype 6A. At study termination, both IPD and pneumonia only occurred in patients with HIV (239 of 273 patients in follow-up analysis had HIV). A total of 67 episodes of IPD occurred in 52 patients and among these episodes, 24 were caused by PCV7 serotypes or the 6A serotype. Of the 24 episodes caused by vaccine serotypes or the 6A serotype, 5 occurred in vaccine recipients and 19 in placebo (adjusted HR 0.31; 95% CI ). 12 This trial demonstrated that PCV13 has the added potential to protect against 6A serotype. Conversely, trials with PPSV23 have failed to demonstrate effectiveness in HIV infected patients. In this trial, 15 out of 697 patients in the PPSV23 arm and 10 out of 695 patients in the placebo arm reached the primary endpoint of IPD (HR 1.47; 95% CI ). 13 Although direct comparisons are not available, the data from these two trials suggests that PCVs better protect HIV patients against IPD, possibly because PCV13 protects against additional serotypes known to cause IPD. Another study also demonstrated that PCV7 is likely more effective than PPSV23 at eliciting antipneumococcal antibodies by comparing PCV7 and PPSV23 in adults 70 years and older. 14 The authors found that the initial dose of PCV7 elicits significantly improved antibacterial immune responses and immunological memory. Further, PCV7/PCV7 (vaccine was administered twice) induced antibody responses similar to that seen after the first PCV7 inoculation, and PCV7/ PPSV23-induced antibody responses were similar to or greater than antibody responses after administration of PPSV23 alone. PPSV23/PCV7 induced significantly lower responses compared with PCV7 alone. 14 The results from this study suggest that PCV vaccination followed by PPSV confers the greatest immune response. Later manufacturer-initiated clinical trials compared PCV13 and PPSV23 in adults aged 50 years. 15 These trials were designed to show that PCV13 could elicit a T-cell-dependent response that could be recalled or boosted through exposure, vaccination, or both. Healthy adults were randomly assigned to receive either PCV13 or PPSV23, and the response after a single dose was evaluated. The subjects also received a second dose of the vaccines either 1 year later or 3-4 Box Summary of ACIP 2013 changes. PCV13 is added to the recommended immunization schedule for the first time Timing of administration of PCV13 relative to PPSV23 PCV13 in adults with immunocompromising condition Clarification of number of PPSV23 doses before 65 Recommendation when vaccination status is unknown 7

8 years later. In PCV13-naïve adults, the immune responses to a dose of PCV13 was at least as good as the response to PPSV23 for all the serotypes and statistically superior for 9 of the 13 serotypes. Considering age group differences, the response to a dose of PCV13 in adults aged years was superior to those years. When subjects returned for a second vaccination with either PCV13 or PPSV years later, antibody levels had waned in all groups prior to revaccination. With a second dose of either PCV13 or PPSV23, a renewed immune response occurred only when the initial vaccination was PCV13. Revaccination with PCV13 also elicited a booster effect which was statistically significant for several serotypes. The result is the opposite for subjects who received 2 doses of PPSV23, which elicited a significantly inferior response for the majority of the serotypes compared to PCV Another trial compared the effects of PCV13 versus PPSV23 in adults who were previously vaccinated with PPSV23. Healthy subjects were re-vaccinated with either PPV13 or PPSV23, and the response to PCV13 was also at least as good as the response to PPSV23 and was statistically higher for most of the serotypes. Regardless of which vaccine the subject received, they were revaccinated 1 year later with PCV13. The study found that subjects who had previously received a dose of PCV13 had at least a non -inferior response, but those who had received PPSV23 a year ago had a significantly reduced response to PCV PPSV23 appeared to blunt the response to a prior dose of PCV13; therefore, when both vaccines are indicated, PCV13 should be administered prior to PPSV23. In summary, the ACIP recommendations stemmed from a compilation of evidence that suggests that PCV13 induces more immunologic memory than the polysaccharide vaccine and is more effective at reducing IPD in immunocompromised persons. Furthermore, PCV13 should be administered before PPSV23 when necessary for optimal vaccine response. The key recommendations of ACIP along with other organizations are summarized in Table 4. COST-EFFECTIVENESS A recent cost-effectiveness analysis, comparing PCV13 and PPSV23 in U.S. adults, measured the pneumococcal disease cases prevented and incremental costs per quality-adjusted life-year (QALY) gained. 22 The authors found that substituting PCV13 for PPSV23 resulted in $28,900 per QALY gained compared with no vaccination and was more cost-effective than PPSV23 at $34,600 per QALY gained. PCV13 was favored when compared with PPSV23 with the assumption that the effectiveness of PCV13 at preventing nonbacteremic pneumococcal pneumonia is high. 23 Another cost-effectiveness analysis was performed using a lifetime cohort model where persons with selected immunocompromising conditions were theoretically immunized with PCV13 at the time of diagnosis and then followed current PPSV23 vaccination guidelines starting one year later. 23 Using the current costs of PCV13 and PPSV23, as well as current administration recommendations, the modeled program resulted in a cost savings of $7.6 million. The model also resulted in 1,360 QALYs gained and averted 57 cases of IPD. 23 CONCLUSIONS Healthcare providers should routinely screen for patients who are indicated for pneumococcal vaccination. Based on the available evidence and costeffectiveness analyses, high risk patients, including those with immunocompromising conditions, asplenia, or chronic kidney failure, should be vaccinated with PCV13 first, followed by PPSV23 at least eight weeks later, then revaccinate with PPSV23 five years later as indicated. Although no strong evidence supports the efficacy of pneumococcal vaccination against pneumonia, PCV7, PCV13 and PPSV23 consistently reduce the incidence of IPD. Administration of pneumococcal vaccine is supported by multiple guidelines, and has been shown to be cost-effective. Clinicians should put forth efforts to help improve outcomes and reduce healthcare costs by increasing vaccination rates to expand coverage for pneumococcal disease. REFERENCES 1. Centers for Disease Control and Prevention (CDC). Noninfluenza vaccination coverage among adults-- United States, MMWR 2013;62: HealthyPeople.gov Topics & Objectives- Immunization and Infectious Diseases. Accessed 3/3/ Atkinson W, Wolfe S, Hamborsky J. Pneumococcal disease. Epidemiology and Prevention of Vaccine- Preventable Diseases 12th ed. Washington DC: Public Health Foundation; p Accessed 3/1/ Pneumovax 23 [prescribing information]. Whitehouse Station, NJ: Merck;

9 Table 4 Comparison of pneumococcal vaccine recommendations by ACIP, WHO, ADA, and IDSA. 5,17-21 Organization Key Recommendations Advisory PPSV23: Committee on All adults 65 yr Immunization Adults <65 yr with chronic lung/cv/kidney/liver disease, DM, alcoholism, cochlear implants, cerebrospinal fluid leaks, IC conditions, asplenia/splenic dysfunction (vaccinate 2 wk before splenectomy), Practices (ACIP) 9 sickle cell and other hemoglobinopathies, residents of nursing homes, smokers IC conditions: receive both PCV13 and PPSV23 HIV infection: vaccinate as soon as possible Cancer chemotherapy: avoid during chemotherapy or radiation therapy, wait at least 2 wk between vaccination and initiation of immunosuppressive therapy When indicated, vaccines should be administered to pt with uncertain vaccination status, PCV13 should be given first if both indicated REVACCINATION WITH PPSV23: One-time revaccination 5 yr after first dose for adults yr with CRF or nephrotic syndrome, functional or anatomic asplenia and IC conditions Persons who received 1 or 2 doses of PPSV23 before 65 should receive another dose at 65 or later if at least 5 years have passed No further doses needed for persons vaccinated 65 PCV13: Adults 19 years with IC conditions (including CRF), functional/anatomic asplenia, CSF leaks or cochlear implants not previously vaccinated: PCV13 followed by PPSV23 8 weeks later If previously received PPSV23: PCV13 1 year after the last PPSV23; those requiring additional PPSV23: first dose 8 weeks after PCV13 and 5 years since most recent PPSV23 Although FDA licensed for persons aged 50 yr, ACIP recommends PCV13 for adults aged 19 yr with specific medical conditions noted above World Health Organization (WHO) Nov American Diabetes Association (ADA) Infectious Disease Society of America (IDSA) 21 PCVs are safe in all target groups for vaccination, including IC individuals, with no CI except for very rare anaphylactic reactions Defer vaccination until after temperature >39 C Further data necessary to determine impact of PCV vaccination of individuals >50 years High priority to infants; health workers and travelers not at increased risk WHO-commissioned meta-analysis and a review of RCTs showed that results of PPV23 are consistent with a protective effect against IPD. There was efficacy against all-cause pneumonia in lowincome but not high-income countries in either the general population or adults with chronic illness. PPV was not associated with substantial reductions in all-cause mortality. 18 Give PPSV23 vaccine to all pt with DM 2 yr A one-time revaccination for individuals > 64 yr previously immunized when they were <65 yr if the vaccine was administered >5 yr ago Indications for revaccination: nephrotic syndrome, CKD, and other IC states, such as after transplantation Observational studies of patients with a variety of chronic illness, including DM, show that DM pt may be at increased risk of the bacteremic form of pneumococcal infection and have been reported to have a high risk of nosocomial bacteremia, with a mortality rate as high as 50%. 20 PPSV23 for persons 65 years and those with high-risk comorbid diseases Assess vaccination status at the time of hospital admission for all persons If indicated, administer either at hospital discharge or during outpatient treatment Assess need for immunization if admitted due to pneumonia Patients with an acute fever should not be vaccinated to prevent confusion of a febrile reaction to immunization with recurrent pneumonia Influenza and pneumococcal vaccines can be given at the same time in different arms Persons unwilling to stop smoking should be given the PPSV23 CAP = community acquired pneumonia; CI = contraindication; CRF = chronic renal failure; DM = diabetes mellitus; IC = immunocompromised; RCT = randomized controlled trial. 9

10 5. Centers for Disease Control and Prevention/ Advisory Committee on Immunization Practices (ACIP) recommended immunization schedule for adult aged 19 years and older-united States, MMWR 2013; 62; su6201a3.htm. Accessed 3/5/ Prevnar 13 [prescribing information]. Philadelphia, PA: Pfizer; Ortqvist A, Hedlund J, Burman LA, et al. Randomised trial of 23-valent pneumococcal capsular polysaccharide vaccine in prevention of pneumonia in middle-aged and elderly people. Swedish Pneumococcal Vaccination Study Group. Lancet 1998;351: Huss A, Scott P, Stuck AE, et al. Efficacy of pneumococcal vaccination in adults: a meta-analysis. CMAJ. 2009;180: Moberley SA, Holden J, Tatham DP, Andrews RM. Vaccines for preventing pneumococcal infection in adults. Cochrane Database Systematic Reviews 2008;1: CD Vila-Corcoles A, Ochoa-Gondar O, Hospital I, et al. Protective effects of the 23-valent pneumococcal polysaccharide vaccine in the elderly population: the EVAN -65 study. Clin Infect Dis 2006;43: Johnstone J, Marrie TJ, Eurich DT, Majumdar SR. Effect of pneumococcal vaccination in hospitalized adults with community-acquired pneumonia. Arch Intern Med 2007;167: French N, Gordon SB, Mwalukomo T, et al. A trial of a 7-valent pneumococcal conjugate vaccine in HIV- infected adults. N Engl J Med 2010;362: French N, Nakiyingi J, Carpenter LM, et al. 23-valent pneumococcal polysaccharide vaccine in HIV-1 infected Ugandan adults: double blind, randomised and placebo controlled trial. Lancet 2000;355: de Roux A, Schmole-Thoma B, Siber GR, et al. Comparison of pneumococcal conjugate polysaccharide and free polysaccharide vaccines in elderly adults: conjugate vaccine elicits improved antibacterial immune responses and immunological memory. Clin Infect Dis 2008;46: Jackson LA, Gurtman A, van Cleeff M, et al. Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine in pneumococcal vaccine naïve adults, years of age [abstract O426] Clin Microbiol Infect 2011;17:S Paradiso P. Pneumococcal conjugate vaccine for adults: a new paradigm. Clin Infect Dis 2012;55: World Health Organization (WHO). Position paper on pneumococcal vaccines. Weekly epidemiological record. 2012;87: Moberley S, Holden J, Tatham DP, Andrews RM, et al. Vaccines for preventing pneumococcal infection in adults. Cochrane Database or Systematic Reviews 2008; 1:CD Standards of medical care in diabetes Diabetes care 2013;36 Suppl 1:S Smith SA, Poland GA. Use of influenza and pneumococcal vaccines in people with diabetes. Diabetes Care 2000;23: Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Disease Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44:S Smith KJ, Wateska AR, Norwalk MP, et al. Costeffectiveness of adult vaccination strategies using pneumococcal conjugate vaccine compared with pneumococcal polysaccharide vaccine. JAMA 2012;307: Centers for Disease Control and Prevention. Use of 13- valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions. Recommendations of the Advisory Committee on Immunization Practices. MMWR 2012;61; MATERIA MEDICA A publication of the Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences University of Colorado Editor Steven M. Smith, PharmD, MPH, BCPS Associate Editor Katy E. Trinkley, PharmD, BCACP 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. 10