The medical letter on drugs and therapeutics september 14 2015

Vaccine effectiveness is highest 50-80% in young adults; lower in the elderly when the match is close, but even when the match is poor, vaccination has been shown to reduce the risk of l

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IN THIS ISSUE

ISSUE

1433

Volume 56

Published by The Medical Letter, Inc • A Nonprofi t Organization

ISSUE No

1477

on Drugs and Therapeutics Objective Drug Reviews Since 1959

Influenza Vaccine for 2015-2016 p 125

Choice of Contraceptives p 127

125

on Drugs and Therapeutics Objective Drug Reviews Since 1959

Take CME Exams

ISSUE

1433

Volume 56

ISSUE No

1477 Choice of Contraceptives p 127

ALSO IN THIS ISSUE

Annual vaccination against influenza A and B viruses

is recommended for everyone ≥6 months old without a

specifi c contraindication.1

EFFECTIVENESS — The effectiveness of the seasonal

vaccine in preventing influenza in healthy adults

depends on the match between the vaccine and

circulating strains Vaccine effectiveness is highest

(50-80% in young adults; lower in the elderly) when

the match is close, but even when the match is poor,

vaccination has been shown to reduce the risk of

laboratory-confi rmed influenza, hospitalization for

influenza, and death.2,3

Quadrivalent vs Trivalent – All of the trivalent and

quadrivalent seasonal influenza vaccines available in

the US contain the same two influenza A virus

anti-gens Trivalent vaccines contain only one influenza B

virus antigen Quadrivalent vaccines contain virus

antigens from the two genetic lineages of influenza B

that have been circulating globally since the 1980s,

increasing the likelihood that the vaccine will provide

protection against currently circulating strains.4

Live vs Inactivated – Comparative studies in adults

18-49 years old have generally found the inactivated

and live-attenuated vaccines to be similarly effective

or the inactivated vaccine to be more effective.5-7

Early randomized trials in children found the

live-attenuated vaccine to be more effective than the

inactivated vaccine In 2014, the CDC Advisory

Committee on Immunization Practices (ACIP)

recommended use of the live-attenuated vaccine

over the inactivated vaccine in healthy children 2-8

years old Observational data from recent seasons,

however, have not found the live-attenuated vaccine

to be consistently more effective in children.8,9 For the

Influenza Vaccine for 2015-2016

Recommendations COMPOSITION

Trivalent Vaccine (Inactivated)

A/California/7/2009 H1N1-like A/Switzerland/9715293/2013 H3N2-like

B/Phuket/3073/2013-like (Yamagata lineage)

Quadrivalent Vaccine (Live-Attenuated or Inactivated)

A/California/7/2009 H1N1-like A/Switzerland/9715293/2013 H3N2-like

B/Phuket/3073/2013-like (Yamagata lineage) B/Brisbane/60/2008-like (Victoria lineage)

WHO SHOULD BE VACCINATED

Everyone ≥6 months old without a specifi c contraindication, including pregnant women

TIMING

Now through the end of the influenza season (about May 2016) 1

CHOICE OF VACCINE 2

Healthy Children 2-17 years old 3

Live-attenuated vaccine (FluMist Quadrivalent) or

standard-dose inactivated vaccine 4

Healthy Adults <65 years old

Standard-dose inactivated vaccine 5 or live-attenuated vaccine (18-49 years)

Adults ≥65 years old

Fluzone High-Dose or standard-dose inactivated vaccine5

Pregnant Women

Standard-dose inactivated vaccine 5

Patients with Egg Allergy

FluBlok (≥18 years)6

Patients with Needle Aversion

Afluria with needle-free injector or Fluzone Intradermal

DOSAGE

Standard-Dose Inactivated Vaccine

Children 6-35 months old: 0.25 mL IM 7 Adults and children ≥3 years old: 0.5 mL IM 7

Intradermal Vaccine

Adults ≤64 years old: 0.1 mL

Live-Attenuated Vaccine

Children and adults 2-49 years old: 0.1 mL in each nostril 7

1 Serum antibodies reach maximum levels in most adults about 2 weeks after vaccination and generally persist for at least 6-8 months.

2 See Table 2 for available vaccines and specifi c age recommendations.

3 For 2015-2016, the ACIP no longer recommends a preference for the live-attenuated vaccine over the inactivated vaccine in children 2-8 years old

4 The ACIP recommends that Afluria not be administered to children <9

years old due to a possible increased risk of fever and febrile seizures.

5 Quadrivalent vaccine is preferred when available.

6 Other inactivated vaccines may be used with caution.

7 Children 6 months to 8 years old who are being vaccinated for the fi rst time or who have not received at least 2 lifetime doses of the trivalent or quadrivalent vaccine before July 1, 2015 should receive 2 doses at least 4 weeks apart Children in this age group who received ≥2 doses of trivalent

or quadrivalent vaccine at any time before July 1, 2015 require only 1 dose.

Related article(s) since publication

2015-2016 season, the ACIP has not recommended

either vaccine over the other for use in children.1

High-Dose vs Standard-Dose – Older adults may have

a lower antibody response to influenza vaccination

than younger adults and their antibody levels may

decline more rapidly.10-12 In a randomized study in

31,989 adults ≥65 years old, the high-dose vaccine

(Fluzone High-Dose) induced signifi cantly higher

antibody responses and was superior to the

standard-dose vaccine in preventing laboratory-confi rmed

influenza illness (1.4% incidence with the high-dose

vaccine vs 1.9% with the standard-dose vaccine),

with a lower risk of serious adverse events.13-15

Large retrospective cohort studies have found the

high-dose vaccine and the standard-dose vaccine

to be similarly effective or the high-dose vaccine

to be more effective in reducing hospitalization for

influenza-related illness in older patients.16,17

CARDIOVASCULAR BENEFITS — A meta-analysis of

6 randomized trials found that influenza vaccination

was associated with a reduced risk of major adverse cardiovascular events in patients at high risk for cardiovascular disease; the reduction in risk was greatest in those with a recent history of acute coronary syndrome.18

PREGNANCY — Vaccination of pregnant women not

only protects them against influenza-associated illness, which can be especially severe during pregnancy, but also protects their infants for up to the

fi rst 6 months of life.19,20

ADVERSE EFFECTS — Influenza vaccination has been

associated with Guillain-Barré syndrome, but the absolute risk is very low, and influenza infection itself has also been associated with the syndrome.21,22

Inactivated – Except for soreness at the injection

site, adverse reactions to inactivated vaccines are

uncommon In clinical trials, Fluzone High-Dose and

Fluzone Intradermal Quadrivalent have caused more

injection-site reactions than standard-dose vaccines

Delivery of Afluria by needle-free jet injector has caused

Table 2 Seasonal Influenza Vaccines for 2015-2016

Vaccine Formulations Mercury Content Recommended Age Cost 1

Inactivated Influenza Vaccine (IIV)

Trivalent (IIV3)

5 mL multidose vial 24.5 mcg/0.5 mL dose ≥9 years 3,4 11.55

Fluvirin (Novartis) 0.5 mL syringe 2 <1 mcg/0.5 mL dose ≥4 years 15.23

5 mL multidose vial 25 mcg/0.5 mL dose ≥4 years 14.01

Fluzone (Sanofi Pasteur) 5 mL multidose vial 25 mcg/0.5 mL dose ≥6 months 7 10.69

Quadrivalent (IIV4)

FluLaval Quadrivalent (GSK) 5 mL multidose vial <25 mcg/0.5 mL dose ≥3 years 15.05

5 mL multidose vial 25 mcg/0.5 mL dose ≥6 months 7 16.15

Fluzone Intradermal  Quadrivalent10 0.1 mL microinjection syringe 2 none 18-64 years 20.00 9

Live-Attenuated Influenza Vaccine (LAIV)

(Medimmune)

1 Private sector cost (including excise tax) per dose as of August 3, 2015 according to the CDC Vaccine Price List Available at http://www.cdc.gov/vaccines/ programs/vfc/awardees/vaccine-management/price-list/ Accessed September 3, 2015.

2 Sold in boxes of 10.

3 FDA-approved for use in persons ≥5 years old The ACIP recommends that Afluria not be administered to children <9 years old due to a possible increased

risk of fever and febrile seizures.

4 Adults 18-64 years old can receive the vaccine via a needle and syringe or a needle-free jet injector.

5 Recombinant hemagglutinin vaccine Considered to be egg-free.

6 Cell culture-based vaccine Contains trace amounts of egg protein.

7 Dose for children 6-35 months old is 0.25 mL and for those ≥3 years old is 0.5 mL.

8 Fluzone High-Dose is an alternative to standard-dose inactivated vaccines for persons ≥65 years old; it contains 60 mcg of hemagglutinin antigen from each

strain compared to 15 mcg in the conventional vaccine.

9 Approximate WAC per dose WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly August 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy.

10 Contains 9 mcg of hemagglutinin antigen from each strain.

11 Each syringe-like sprayer contains a single 0.2-mL dose given intranasally (0.1 mL in each nostril); sold in boxes of 10.

12 Not recommended for pregnant women, persons who are immunosuppressed or have an egg allergy, or children 2-4 years old who have asthma or have had a wheezing episode in the previous 12 months.

11 JY Song et al Long-term immunogenicity of influenza vaccine among the elderly: risk factors for poor immune response and persistence Vaccine 2010; 28:3929

12 J Castilla et al Decline in influenza vaccine effectiveness with time after vaccination, Navarre, Spain, season 2011/12 Euro Surveill 2013; 18:pii:20388

13 CA DiazGranados et al Effi cacy of high-dose versus standard-dose influenza vaccine in older adults N Engl J Med 2014; 371:635.

14 CA DiazGranados et al Prevention of serious events in adults 65 years of age or older: a comparison between high-dose and stan-dard-dose inactivated influenza vaccines Vaccine 2015 July 26 (epub).

15 CA DiazGranados et al Effi cacy and immunogenicity of high-dose influenza vaccine in older adults by age, comorbidities, and frailty Vaccine 2015; 33:4565.

16 DM Richardson et al Comparative effectiveness of high-dose ver-sus standard-dose influenza vaccination in community-dwelling veterans Clin Infect Dis 2015; 61:171.

17 HS Izurieta et al Comparative effectiveness of high-dose versus standard-dose influenza vaccines in US residents aged 65 years and older from 2012 to 2013 using Medicare data: a retrospective cohort analysis Lancet Infect Dis 2015; 15:293.

18 JA Udell et al Association between influenza vaccination and cardiovascular outcomes in high-risk patients: a meta-analy-sis JAMA 2013; 310:1711

19 MG Thompson et al Effectiveness of seasonal trivalent influenza vaccine for preventing influenza virus illness among pregnant women: a population-based case-control study during the

2010-2011 and 2010-2011-2012 influenza seasons Clin Infect Dis 2014; 58:449

20 SA Madhi et al Influenza vaccination of pregnant women and protection of their infants N Engl J Med 2014; 371:918

21 JC Kwong et al Risk of Guillain-Barré syndrome after seasonal influenza vaccination and influenza health-care encounters: a self-controlled study Lancet Infect Dis 2013; 13:769

22 LL Polakowski et al Chart-confi rmed Guillain-Barré syndrome after 2009 H1N1 influenza vaccination among the Medicare population, 2009-2010 Am J Epidemiol 2013; 178:962.

more mild to moderate local reactions than delivery by

needle and syringe

Live – The intranasal live-attenuated vaccine is

generally well tolerated, but it can cause runny nose,

nasal congestion, and sore throat Rapid influenza

diagnostic tests may be falsely positive if used within

a week after vaccination with FluMist Quadrivalent.

Patients vaccinated with the live attenuated vaccine

may shed the vaccine-strain virus for a few days

after vaccination, but person-to-person transmission

has been rare, and serious illness resulting from

transmission has not been reported Nevertheless,

persons who care for severely immunocompromised

patients in protected environments should not receive

the live vaccine or should avoid contact with the

patients for 7 days after receiving it

CONCLUSION — Seasonal influenza vaccine is

recommended for everyone ≥6 months old without a

specifi c contraindication, including pregnant women

Quadrivalent vaccine is generally preferred when it

is available The high-dose vaccine may be more

effective than the standard-dose vaccine in preventing

influenza illness in adults ≥65 years old, and it appears

to be safe ■

1 LA Grohskopf et al Prevention and control of influenza with

vaccines: recommendations of the Advisory Committee on

Im-munization Practices, United States, 2015-16 influenza season

MMWR Morb Mortal Wkly Rep 2015; 64:818.

2 KL Nichol et al Effectiveness of influenza vaccine in the

com-munity-dwelling elderly N Engl J Med 2007; 357:1373.

3 M Darvishian et al Effectiveness of seasonal influenza vaccine in

community-dwelling elderly people: a meta-analysis of

test-nega-tive design case-control studies Lancet Infect Dis 2014; 14:1228.

4 T Heikkinen et al Impact of influenza B lineage-level mismatch

between trivalent seasonal influenza vaccines and circulating

viruses, 1999-2012 Clin Infect Dis 2014; 59:1519.

5 AS Monto et al Comparative effi cacy of inactivated and live

at-tenuated influenza vaccines N Engl J Med 2009; 361:1260.

6 CS Ambrose et al The relative effi cacy of trivalent live

attenu-ated and inactivattenu-ated influenza vaccines in children and adults

Influenza Other Respir Viruses 2011; 5:67

7 CJ Phillips et al Comparison of the effectiveness of trivalent

inactivated influenza vaccine and live, attenuated influenza

vaccine in preventing influenza-like illness among US military

service members, 2006-2009 Clin Infect Dis 2013; 56:11.

8 Advisory Committee on Immunization Practices (ACIP)

Sum-mary Report: October 29–30, 2014 (meeting minutes) Atlanta,

Georgia: US Department of Health and Human Services, CDC;

2014 Available at www.cdc.gov/vaccines/acip/meetings/

downloads/min-archive/min-2014-10.pdf Accessed

Septem-ber 3, 2015.

9 Advisory Committee on Immunization Practices (ACIP)

Sum-mary Report: February 26, 2015 (meeting minutes) Atlanta,

Geor-gia: US Department of Health and Human Services, CDC; 2015

Available at www.cdc.gov/vaccines/acip/meetings/downloads/

min-archive/min-2015-02.pdf Accessed September 3, 2015.

10 K Goodwin et al Antibody response to influenza vaccination in

the elderly: a quantitative review Vaccine 2006; 24:1159

Choice of Contraceptives

▶ Implants, intrauterine devices (IUDs), and sterilization are the most effective contraceptive methods avail-able Pills, patches, rings, and injectables, when used correctly, are also highly effective in preventing preg-nancy Barrier and fertility-based methods have the highest rates of failure.1,2

AN IMPLANT — Nexplanon, a single-rod implant

containing the progestin etonogestrel, is placed under the skin on the inside of the non-dominant upper arm and is effective for up to 3 years As with other progestin-based methods, bleeding irregularities are common Implants, once placed, require no adherence and provide long-term protection against pregnancy Fertility returns rapidly after removal.3

INTRAUTERINE DEVICES — The 4 IUDs currently

available in the US are all highly effective in preventing

Related article(s) since publication

Table 1 Effi cacy of Contraceptives

Failure Rate 1

Method Use Use Some Advantages Some Adverse Effects/Disadvantages

Implant Convenience; long-term contraception; Irregular bleeding; removal complications

Nexplanon 0.05% 0.05% no patient compliance required; rapid

return of fertility after removal Intrauterine devices (IUDs) Convenience; long-term contraception; Rare uterine perforation; risk of infection with

no patient compliance required; rapid insertion; anemia return of fertility after removal

ParaGard T 380A 0.8% – Effective for 10 years; nonhormonal Irregular/heavy bleeding and dysmenorrhea

Mirena 0.2% – Decreased menstrual bleeding and Irregular bleeding in fi rst 3-6 months, followed

dysmenorrhea by amenorrhea; ovarian cysts

Liletta 0.15%2 – Decreased menstrual bleeding and Irregular bleeding in fi rst 3-6 months; ovarian

Skyla 0.4% – Smaller T-frame and narrower inser- Irregular bleeding in fi rst 3-6 months; ovarian

tion tube cysts; amenorrhea in only 6% of users after 1 year Sterilization

Female 0.5% 0.5% Long-term contraception; no patient Potential for surgical complications; regret among

compliance required young women; reversal often not possible and

expensive Male 0.15% 0.10% Long-term contraception; no patient Pain at surgical site; regret among young men;

compliance required reversal often not possible and expensive Injectable Convenience; same as progestin-only Delayed return to fertility; irregular bleeding and

Depo-Provera 6% 0.2% oral contraceptives amenorrhea; weight gain; may decrease bone

mineral density Combination 9% 0.3% Protection against ovarian and endo- Increased rate of thromboembolism, stroke, and oral contraceptives metrial cancer, PID, and dysmenorrhea myocardial infarction in older smokers; nausea;

headache; contraindicated with breastfeeding Progestin-only 9% 0.3% Protection against PID, iron-defi ciency Irregular, unpredictable bleeding; must take at oral contraceptives anemia, and dysmenorrhea; safe in same time every day

breastfeeding women and those with cardiovascular risk

Transdermal Convenience of once-weekly applica- Dysmenorrhea and breast discomfort may be

Xulane 9% 0.3% tion; same benefi ts as combination more frequent than with oral contraceptives;

oral contraceptives application site reactions; detachment; increased

Vaginal Excellent cycle control; rapid return to Discomfort; vaginal discharge

NuvaRing 9% 0.3% fertility after removal; convenience of

once-monthly insertion Diaphragm 12% 6% Low cost; may reduce risk of cervical High failure rate; cervical irritation; increased risk with spermicide cancer of urinary tract infection and toxic shock syndrome;

some require fi tting by healthcare professional; may be diffi cult to obtain; available only by prescription

Cervical cap 16-32% 9-26% Low cost; effective for 48 hours; reap- High failure rate; cervical irritation; pap smear

plication of spermicide not required abnormalities; limited sizes available; increased

risk of toxic shock syndrome; may be diffi cult to obtain; available only by prescription

Condom without spermicide

Female 21% 5% Protection against STIs; covers exter- High failure rate; diffi cult to insert; poor

nal genitalia; OTC ability Male 18% 2% Protection against STIs; OTC High failure rate; allergic reactions; poor

Withdrawal 22% 4% No drugs or devices High failure rate

Sponge 12-24% 9-20% OTC; low cost; no fi tting required; pro- High failure rate; contraindicated during menses;

vides 24 hours of protection increased risk of toxic shock syndrome Fertility awareness-based 24% – Low cost; no drugs or devices High failure rate; may be diffi cult to learn; requires

Standard Days method – 5%

TwoDay method – 4%

Ovulation method – 3%

Symptothermal method – 0.4%

Spermicide 28% 18% OTC High failure rate; local irritation; must be reapplied alone with repeat intercourse; increased risk of HIV

transmission

No method 85% 85% — —

STIs = sexually transmitted infections; PID = pelvic inflammatory disease; OTC = over the counter

1 Risk of unintended pregnancy during fi rst year of use; adapted from J Trussel and KA Guthrie in RA Hatcher et al, Contraceptive Technology, 20 th revised ed., New York: Ardent Media, 2011.

2 DL Eisenberg et al Contraception 2015; 92:10.

pregnancy IUDs have high satisfaction and

continu-ation rates and may be the most cost-effective of all

reversible methods of contraception

ParaGard T 380A, a copper-containing IUD, is

FDA-approved for up to 10 years of use It has been shown

to be effective for up to 20 years in some women.4

Mirena is FDA-approved for up to 5 years of use, but

it has been shown to be effective for up to 7 years It

releases 20 mcg/day of levonorgestrel initially, which

decreases gradually to 10 mcg/day over 5 years

Mirena has an approved secondary indication for

heavy menstrual bleeding

Skyla is FDA-approved for up to 3 years of use It

releases 14 mcg/day of levonorgestrel initially, which

decreases gradually to 5 mcg/day over 3 years

Skyla is slightly smaller than Mirena, which might

be advantageous in nulliparous women One study

comparing Mirena with 2 smaller devices, including

one similar to Skyla, found that women receiving the

smaller devices were more likely to report little or no

pain than those undergoing Mirena placement.5

Liletta, which is the same size as Mirena, releases

18.6 mcg/day of levonorgestrel initially, which

decreases gradually to 12.6 mcg over 3 years It is

FDA-approved for up to 3 years of use.6

Benefi ts – IUDs, once inserted, require no

adherence and provide long-term protection against

pregnancy; fertility is restored upon removal All

of the levonorgestrel-releasing IUDs can reduce

dysmenorrhea

Adverse Effects – Uterine perforation can occur during

IUD placement The copper IUD may cause heavy

bleeding and cramping All of the IUDs can cause

irregular or heavy bleeding in the fi rst 3-6 months after

placement IUD-associated infection is mainly related

to insertion; women who have a low risk of acquiring

a sexually transmitted infection are unlikely to develop

an IUD-associated infection Ovarian cysts have been

reported with all levonorgestrel-releasing IUDs

STERILIZATION — Tubal sterilization procedures can

be done abdominally or hysteroscopically Abdominal

procedures are performed using various techniques to

cut, cauterize, or clip the fallopian tubes via laparoscopy

or minilaparotomy Hysteroscopic methods involve

placing devices into the fallopian tubes that cause (after

several months) tubal occlusion Essure is the only

such device currently approved in the US.7 Its labeling

states that tubal occlusion should be confi rmed three

months post-operatively; an alternate form of birth control should be used until the confi rmatory test

ORAL CONTRACEPTIVES — Most oral contraceptives

available in the US are a combination of the estrogen ethinyl estradiol and a progestin The estrogen and progestin content of these pills has been reduced over the years to decrease the incidence of adverse effects The lower-dose formulations (≤20 mcg of ethinyl estradiol) are effective, but they may have a higher risk

of failure and can cause changes in bleeding patterns (irregular, frequent, or prolonged) A table listing some common oral hormonal contraceptives can be found online at medicalletter.org/downloads/TML1477b-2.pdf

Monophasic vs Multiphasic – Monophasic oral

contraceptives contain fi xed doses of estrogen and progestin in each active pill Multiphasic oral contraceptives vary the dose of one or both hormones during the pill cycle Many multiphasic pills have

a lower total hormone dose per cycle; there is no convincing evidence that they cause fewer adverse effects or improve bleeding patterns compared to monophasic pills

Shorter or Fewer Hormone-Free Intervals – Most

traditional oral contraceptives are packaged as a 21/7 cycle (21 days of active tablets and 7 days of placebo), resulting in 13 scheduled bleeding episodes each year Newer regimens include fewer hormone-free days per 28-day cycle (2-4 placebo tablets) or extended cycles with fewer withdrawal bleeds per year Most studies found that use of extended-cycle contraceptives results

in fewer menstrual symptoms such as headache, bloating, and menstrual pain.8 Several products are designed and packaged for extended cycles, but any traditional 21/7 oral contraceptive can be used continuously by skipping some or all of the placebo pills

Non-Contraceptive Benefi ts – Women who take

combination oral contraceptives have a reduced risk

of both epithelial ovarian and endometrial cancer.This benefi t is detectable within one year of use and appears

to persist for years after discontinuation Other benefi ts include a reduction in dysfunctional uterine bleeding and dysmenorrhea, a lower incidence of ectopic pregnancy and benign breast disease, and an increase in hemoglo-bin concentrations Many women also benefi t from the convenience of menstrual regularity All combination oral contraceptives increase sex hormone binding globulin and decrease free testosterone concentrations, which can lead to improvements in hirsutism and acne Combination oral contraceptives are also often used off-label to treat polycystic ovary syndrome

Choice of a Progestin – Progestins such as desogestrel

and norgestimate have less androgenic activity and are

claimed to improve acne more than older progestins,

but these claims have not been substantiated by

controlled trials Combination oral contraceptives

containing drospirenone, a synthetic progestin with

antiandrogenic and antimineralocorticoid activity,

have been shown to improve symptoms associated

with premenstrual dysphoric disorder (PMDD),

hirsutism, and acne, but whether they are more

effective than other combination oral contraceptives

for these indications is not known.9

Adverse Effects – Estrogens can cause nausea

contraceptives with lower doses of ethinyl estradiol

have a higher incidence of bleeding disturbances

Unexpected bleeding or spotting is common with all

extended-cycle or continuous regimens, particularly

during the initial cycles

Other Risks – Older formulations of combination oral

contraceptives containing ≥50 mcg of ethinyl estradiol

were associated with an increased risk of myo

-cardial infarction and ischemic stroke, particularly in

women who smoked or had uncontrolled hypertension;

these risks are decreased with formulations that have

lower doses of ethinyl estradiol Users of contraceptives

with lower estrogen doses have a risk of venous

thromboembolism (VTE) that is 2-3 times higher than

that of non-users; this risk is lower, however, than the

risk of VTE associated with pregnancy

A case-control study in over 10,000 women with

VTE found that current exposure to any combination

contraceptive was associated with an increased risk

of VTE (adjusted odds ratio 2.97) compared to no

exposure in the previous year Exposure to certain

progestins (desogestrel, gestodene, drospirenone, and

cyproterone) was associated with a higher risk of VTE

(odds ratios ranged from 1.52 to 1.80) compared to

levonorgestrel.10

Estrogen-containing contraceptives are not

recom-mended for smokers (≥15 cigarettes/day) who are ≥35

years old or for women who have hypertension, coronary

artery disease, heart failure, cerebrovascular disease,

diabetes with end-organ damage, or migraine headaches

with focal neurological symptoms, or for those who

are at risk for VTE Their use is also contraindicated in

women with a history of breast cancer, a thromboembolic

disorder, or liver disease Progestin-only or nonhormonal

methods are preferred in women at increased risk of

cardiovascular or thromboembolic events

Progestin-Only – “Minipills,” which are taken daily

without a hormone-free interval, are predominantly used by breastfeeding women and those in whom estrogen is poorly tolerated or contraindicated, such

as women ≥35 years old who smoke Irregular bleeding

is common with progestin-only pills; taking the pill

at the same time each day is crucial in preventing breakthrough bleeding and pregnancy

Drug Interactions – Some drugs taken concurrently,

including rifampin (Rifadin, and others), several

anti-HIV drugs, anticonvulsants, and St John’s wort, can induce the metabolism of oral contraceptives and decrease their effectiveness Contraceptive failure has also been reported with concurrent use of some antibiotics, including penicillins and tetracy-clines; a cause-and-effect relationship has not been established

OTHER HORMONAL CONTRACEPTIVES — Injectable Contraceptives – Injectable contraceptives containing

medroxyprogesterone are effective and eliminate the need for daily adherence Medroxyprogesterone

acetate is injected intramuscularly (Depo-Provera, and generics) or subcutaneously (Depo-SubQ Provera

104) once every 3 months Amenorrhea is common

and irregular bleeding can occur Weight gain, headache, and decreases in bone mineral density have been reported Because of the risk of loss of bone mineral density, labeling for both injectable products recommends discontinuing their use after 2 years unless no acceptable alternative is available, but the American College of Obstetricians and Gynecologists has urged practitioners to continue the injections after 2 years when their clinical judgement is that such use is appropriate.11 The return of fertility can

be delayed for 6-12 months (median 10 months) after the last injection

Transdermal Patch – Xulane, a generic version of the (no

longer marketed) Ortho Evra patch, delivers an average

daily dose of 20 mcg of ethinyl estradiol and 0.15 mg of norelgestromin A new patch is applied to the buttock, lower abdomen, back, or upper outer arm each week for

3 weeks, followed by one patch-free week Its effi cacy

is similar to that of combination oral contraceptives, although it may be less effective in women who weigh

≥90 kg The adverse effects and risks of the patch are similar to those of combination oral contraceptives, but patch users are exposed to higher average levels of estrogen than users of combination oral contraceptives containing 30-35 mcg of ethinyl estradiol Compliance may be improved compared to oral contraceptives, but breakthrough bleeding is more common in the fi rst 2

cycles Skin irritation at the application site can occur and

may lead to discontinuation

Vaginal Contraceptive Ring – NuvaRing is inserted

intravaginally by the patient (no fi tting is necessary)

and left in place for 3 weeks, followed by one

ring-free week It can be left in place for up to 4 weeks

and the number of ring-free days can be reduced It

delivers a daily dose of 15 mcg of ethinyl estradiol

and 0.12 mg of etonogestrel, the active metabolite

of desogestrel If the ring is removed for more than

3 hours, backup contraception should be used until

the ring has been in place for 7 consecutive days The

ring offers excellent cycle control and a rapid return

to fertility after removal Reasons for discontinuation

have included device-related discomfort, headaches,

and vaginal discharge Its effi cacy is similar to that of

combination oral contraceptives, but users report less

nausea, acne, irritability, and depression

EMERGENCY CONTRACEPTION — Hormonal methods

of emergency contraception, which apparently

prevent or delay ovulation, can prevent 50-80% of

pregnancies.12

Progestin-Only ECPs – Progestin-only emergency

contraception pills (ECPs) available in the US include

Plan B One-Step, Next Choice One Dose, and several

generic formulations of these Since 2013,

progestin-only ECPs have been available over the counter with

no age restrictions All progestin-only ECPs use

levonorgestrel, either as a single dose of 1.5 mg or as

two doses of 0.75 mg taken 12 hours apart

Progestin-only ECPs should be started as soon as possible within

72 hours after unprotected intercourse, although

some studies indicate that they may be effective if

taken within 5 days.13 Side effects include headache,

abdominal pain, and breast tenderness Nausea and

vomiting occur less frequently with levonorgestrel

alone than with estrogen-progestin combinations

Progestin-only ECPs decrease in effi cacy with

increasing body mass index (BMI).14

Antiprogestin ECPs – Ulipristal acetate (Ella), an

antiprogestin, is FDA-approved for emergency

contraception.15 It is only available by prescription

and is approved for use up to 5 days after unprotected

intercourse Ulipristal acetate is the most effective

hormonal option for emergency contraception A

meta-analysis found that women who took ulipristal

acetate for emergency contraception within 120

hours after unprotected intercourse were less likely

to become pregnant than those who took

progestin-only ECPs.16 Its adverse effects are similar to those of

levonorgestrel Ulipristal acetate should be considered a

fi rst-line hormonal option for emergency contraception, especially for overweight or obese women.17

Copper IUD – A copper IUD inserted within 5 days

after intercourse is the most effective method of emergency contraception.14 Pregnancy rates as low

as 0.1% have been reported with use of the copper IUD.18 It may cause heavy bleeding and cramping IUD-associated infection is mainly related to insertion; women who are at low risk of acquiring a sexually transmitted infection have a minimal risk of

an IUD-associated infection

Combined ECPs – Many oral contraceptives can also

be used in doses suitable for emergency contraception;

26 combined estrogen and progestin (usually ethinyl estradiol and levonorgestrel) oral contraceptives are available in the US for this indication All are recommended for use in 2 doses 12 hours apart They are somewhat less effective than other hormonal methods Doses should be taken as soon as possible within 72 hours after unprotected intercourse Patients who vomit within 1 hour of administration should repeat the dose

Adverse Effects – Nausea and vomiting occur

less frequently with levonorgestrel alone than with estrogen-progestin combinations Headache, abdominal pain, and breast tenderness have been reported with both progestin-only and combination oral contraceptives No fetal malformations caused

by unsuccessful use of hormones for emergency contraception have been reported

BARRIER CONTRACEPTIVES — The effectiveness

of barrier contraceptives is highly user-dependent These methods have much higher failure rates than hormonal contraceptives, IUDs, or sterilization

Diaphragms and Cervical Caps – Diaphragms and

cervical caps are used with spermicide and placed over the cervix Diaphragms can be inserted up

to 6 hours before intercourse and should not be removed for 6 hours afterward; they should not be left in place for more than 24 hours because of the danger of toxic shock syndrome Spermicide must

be reapplied for each act of intercourse Cervical caps can be left in place for up to 48 hours, and

do not require additional spermicide with repeated intercourse Whether these devices have protective effects against HIV or other sexually transmitted infections is unclear Diaphragms and cervical caps are not routinely stocked in pharmacies and may be diffi cult to obtain

Condoms – Only condoms prevent both pregnancy

and sexually transmitted infections, including

HIV infection Both male and female condoms are

available Most male condoms in the US are latex; they

are effective when used correctly, but can break when

stored improperly or used with oil-based lubricants

Alternatives for patients with latex sensitivity include

lamb intestine and synthetic polyurethane condoms

Lamb condoms do not protect against viral infections

Synthetic polyurethane male condoms are more likely

to break than latex condoms, and may be less effective

in preventing pregnancy Female condoms have

the advantage of improved coverage of the external

genitalia, possibly offering better protection against

STIs They can be used with either an oil- or

water-based lubricant

Sponge – The Today sponge is an over-the-counter

barrier contraceptive containing the spermicide

nonoxynol-9 It is moistened in water and placed over

the cervix The sponge is effective immediately after

insertion and, if left in place, intercourse may be repeated

for up to 24 hours The sponge should remain in place

for 6 hours after the last act of intercourse It should

be removed after 24-30 hours because of the risk of

toxic shock syndrome Sponges have been inferior to

diaphragms in both effectiveness and continuation

rates.The availability of the sponge is inconsistent

Spermicides – Nonoxynol-9 is available as a foam, fi lm,

gel, cream, suppository, and tablet It must be placed

in the vagina no more than 1 hour before intercourse

and reapplied before each act of intercourse The

spermicide should be in contact with the cervix;

suppositories, fi lms, and tablets need to dissolve in

order to be effective

FERTILITY AWARENESS-BASED METHODS — Fertility

awareness-based methods of contraception involve

avoidance of intercourse or use of barrier methods

during the presumed fertile days of the menstrual

cycle The approaches now recommended rely on

observation of changes in cervical mucus (ovulation),

changes in body temperature (symptothermal), and

estimation of the range of fertile days in the woman’s

usual menstrual cycle (Calendar Rhythm, TwoDay, and

Standard Days methods) Relatively long periods of

abstinence are necessary with all of these methods,

and failure rates are high

CONCLUSION — Intrauterine devices (IUDs) and

hormonal implants require no compliance on the

part of the woman and are probably the most

cost-effective of all reversible contraceptives Oral

contraceptives containing a low dose of estrogen (≤35 mcg) and a progestin are highly effective and have non-contraceptive benefi ts Barrier contraceptives have fewer systemic adverse effects than hormonal contraceptives, but have much higher failure rates

For emergency contraception, ulipristal acetate (Ella)

is the most effective hormonal option, but the copper

IUD (ParaGard T 380A) is the most effective method

overall ■

1 AR Aiken and J Trussell Recent advances in contraception F1000Prime Rep 2014; 6:113.

2 J Trussell and KA Guthrie Choosing a contraceptive: effi cacy, safety, and personal consideration In: RA Hatcher et al Con-traceptive Technology: 20 th revised edition New York: Ardent Media 2011.

3 In brief: etonogestrel (Nexplanon) contraceptive implant Med Lett Drugs Ther 2012; 54:12.

4 I Sivin Utility and drawbacks of continuous use of a copper T IUD for 20 years Contraception 2007; 75(6Suppl):S70.

5 K Gemzell-Danielsson et al A randomized, phase II study de-scribing the effi cacy, bleeding profi le, and safety of two low-dose levonorgestrel-releasing intrauterine contraceptive sys-tems and Mirena Fertil Steril 2012; 97:616.

6 Liletta - A third levonorgestrel-releasing IUD Med Lett Drugs Ther 2015; 57:99.

7 SG Chudnoff et al Hysteroscopic essure inserts for permanent contraception: extended follow-up results of a phase III multi-center international study J Minim Invasive Gynecol 2015 April

24 (epub).

8 A Edelman et al Continuous or extended cycle vs cyclic use

of combined hormonal contraceptives for contraception Co-chrane Database Syst Rev 2014; (7):CD004695.

9 Three new oral contraceptives Med Lett Drugs Ther 2006; 48:77.

10 Y Vinogradova et al Use of combined oral contraceptives and risk of venous thromboembolism: nested case-control stud-ies using the QResearch and CPRD databases BMJ 2015; 350:h2135.

11 American College of Obstetrics and Gynecologists ACOG Com-mittee Opinion No 602: depot medroxyprogesterone acetate and bone effects Obstet Gynecol 2014; 123:1398.

12 DT Baird Emergency contraception: how does it work? Reprod Biomed Online 2009; 18 suppl 1:32.

13 G Piaggio et al Effect on pregnancy rates of the delay in the administration of levonorgestrel for emergency contraception:

a combined analysis of four WHO trials Contraception 2011; 84:35.

14 American College of Obstetrics and Gynecologists Practice bulletin summary No 152: emergency contraception Obstet Gynecol 2015; 126:685.

15 Ella: a new emergency contraceptive Med Lett Drugs Ther 2011; 53:3.

16 AF Glasier Ulipristal acetate versus levonorgestrel for emer-gency contraception: a randomised non-inferiority trial and meta-analysis Lancet 2010; 375:555.

17 A Glasier et al The rationale for use of ulipristal acetate as fi rst line in emergency contraception: biological and clinical evi-dence Gynecol Endocrinol 2014; 30:688.

18 K Cleland et al The effi cacy of intrauterine devices for emer-gency contraception: a systematic review of 35 years of experi-ence Hum Reprod 2012; 27:1994.

Table 2 Some Oral Hormonal Contraceptives

Monophasic Combinations

Zovia 1/50E 28 (Actavis) ethynodiol diacetate (1) ethinyl estradiol (50) $24.70

Ogestrel 0.5/50 28 (Actavis) norgestrel 4 (0.5) ethinyl estradiol (50) 33.70

Kelnor 1/35 28 (Teva Women's) ethynodiol diacetate (1) ethinyl estradiol (35) 22.20

Necon 1/35 28 (Actavis) norethindrone (1) ethinyl estradiol (35) 22.10

Brevicon 28 (Actavis) norethindrone (0.5) ethinyl estradiol (35) 62.20

Balziva 28 (Teva Women's) norethindrone (0.4) ethinyl estradiol (35) 32.30

MonoNessa 28 (Actavis) norgestimate (0.25) ethinyl estradiol (35) 21.70

Desogen 28 (Merck) desogestrel (0.15) ethinyl estradiol (30) 47.70

Yasmin 28 (Bayer) drospirenone (3) ethinyl estradiol (30) 93.90

Levora 28 (Actavis) levonorgestrel (0.15) ethinyl estradiol (30) 23.20

Loestrin Fe 1.5/30 28 (Teva Women's)6 norethindrone acetate (1.5) ethinyl estradiol (30) 97.20

Cryselle 28 (Teva Women's) norgestrel 4 (0.3) ethinyl estradiol (30) 22.90

Yaz (Bayer)7,8 drospirenone (3) ethinyl estradiol (20) 93.90

Aviane 28 (Teva Women's) levonorgestrel (0.1) ethinyl estradiol (20) 23.70

Loestrin Fe 1/20 28 (Teva Women's)6 norethindrone acetate (1) ethinyl estradiol (20) 97.10

Necon 1/50 28 (Actavis) norethindrone (1) mestranol (50) 22.10

Fe = contains iron

1 Different progestins are not equivalent on a milligram basis.

2 Ethinyl estradiol and mestranol are not equivalent on a milligram basis; the results of some studies indicate that 30-35 mcg of ethinyl estradiol is equivalent to

50 mcg of mestranol

3 Approximate WAC for a one month's supply WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly August 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy.

4 The progestin norgestrel contains two isomers; only levonorgestrel is bioactive The amount of norgestrel in each tablet is twice the amount of levonorgestrel.

5 Also available in a 21-day regimen.

6 Also available in a 21-day regimen that does not contain iron.

7 Also FDA-approved for moderate acne.

8 Yaz is taken as active pills for 24 days and placebo for 4 days.

9 Also contains 451 mcg of levomefolate calcium per tablet Addition of levomefolate increases folate levels in order to reduce the risk of neural tube defect in a

pregnancy conceived during or shortly after oral contraceptive use Beyaz is taken for 24 days followed by 4 days of levomefolate calcium alone