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COMPREHENSIVE MEDICATION EVALUATION
Amethia, Ashlyna, Camrese, Daysee, Introvale, Jolessa, Quartette, Quasense, Seasonale, Seasonique, Setlakin
Catawba Unit
Indian Health Service
Department of Pharmacy Services
INTRODUCTION: In 2010, there were 42,000 unintended pregnancies in South Carolina alone.1 Approximately 2.8 million
unintended pregnancies occur in the United States each year; in every 1000 women between ages 15-19 in 2009, 55.5
American Indian/Alaska Natives gave birth compared to 25.6 whites.2 There is a clear need for access to contraceptives
in the Native American community. While 28-day cyclic regimen birth control is available, many women desire to
lessen the frequency of the cyclic menstrual period. As there is no medical need for monthly menstruation, it is a
worthwhile endeavor to provide prevention of menstrual pain and inconvenience.3 In addition to lessening menstrual
symptoms, continuous oral contraceptives may be effective at reducing symptoms related to other gynecologic
conditions such as ovarian cysts,pelvic pain, and endometriosis. Efficacy studies ofextended and continuouscycle OCPs
demonstrate that these regimens are as effective as cyclic administration.3
GENERIC: ethinyl estradiol and levonorgestrel (extended-cycle)4
TRADE NAME & MANUFACTURER: Amethia (Watson), Ashlyna (Glenmark Generics Ltd), Camrese (Teva), Daysee (Teva),
Introvale (Sandoz),Jolessa (Teva),Quartette (Teva),Quasense (Watson),Seasonale (Sandoz),Seasonique (Teva),Setlakin
(Northstar RxLLC)4
AHFS CATEGORY AND PHARMACOLOGICAL CLASS: 68.68.12 Contraceptives, oral4
FDA APPROVAL DATE and REVIEW CLASSIFICATION: Approved September5,2003. Classified standard reviewdrug5
INDICATIONS: Prevention of pregnancy4
CLINICAL PHARMACOLOGY:
Mechanismof action: Combination oral contraceptives act by suppression of gonadotropins. Although the
primary mechanism of this action is inhibition of ovulation,otheralterations include changes in the cervical mucus (which
increase the difficulty of sperm entry into the uterus) and changes in the endometrium (which reduce the likelihood of
implantation).4
PHARMACOKINETICS:
Absorption: No specific investigation of the absolute bioavailability of Seasonale in humans has been conducted.
However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration
(bioavailability nearly 100%) and is not subject to first-pass metabolism. Ethinyl estradiol is rapidly and almost
completely absorbed from the gastrointestinal tract but, due to first-pass metabolism in gut mucosa and liver, the
bioavailability of ethinyl estradiol is approximately 43%.4
Distribution: The apparent volume of distribution of levonorgestrel and ethinyl estradiol are reported to
be approximately 1.8 L/kg and 4.3 L/kg, respectively.Levonorgestrelis about 97.5 - 99% protein-bound,principally to sex
hormone binding globulin (SHBG) and, to a lesser extent, serum albumin. Ethinyl estradiol is about 95 - 97% bound to
serum albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis, which leads to decreased
levonorgestrel clearance. Following repeated daily dosing of combination levonorgestrel/ethinyl estradiol oral
contraceptives,levonorgestrelplasma concentrations accumulate more than predicted basedon single-dose kinetics,due in
part,to increased SHBG levels that are induced by ethinylestradiol,and a possible reductionin hepatic metabolic capacity.4
Metabolism:
Ethinyl estradiol: Hepatic via CYP3A4; undergoes first-pass metabolism; forms metabolites
Levonorgestrel: Forms conjugated in unconjugated metabolites4
Elimination: About 45% oflevonorgestreland its metabolites are excreted in the urine and about 32% are excreted in feces,
mostly as glucuronide conjugates.The terminal elimination half-life for levonorgestrelaftera single dose ofSeasonale was
about 30 hours. Ethinylestradiolis excreted in the urine and feces as glucuronide and sulfate conjugates, and it undergoes
enterohepatic recirculation.The terminalelimination half-life ofethinylestradiolaftera single dose ofSeasonale was found
to be about 15 hours.4

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CLINICAL EVALUATIONS:
A multicenter, randomized study of an extended cycle oral contraceptive
Population and Study Design: In this parallel,randomized, multicenteropen-label,1-yearstudy,Seasonale [30μg ethinyl
estradiol (EE)/150 μg levonorgestrel (LNG), and Nordette-28 (30 μg EE/150 μg LNG)] was evaluated in sexually active,
adult women (18–40 years) of childbearing potential. This study, known as SEA 301, became the primary data source for
the evidenced-based drugapproval. In the study,patients received eitherfour91-day cycles ofextended cycle regimen OC,
or13 cycles ofthe conventional28-day OCwith daily monitoring ofcompliance and bleeding via electronic diaries. Efficacy
was evaluated as themethod failure rate,calculated by life table analysis and the PearlIndex(the number ofpregnancies per
100 women per year of use) among women aged 18–35 who used the product as directed. Safety was evaluated by
assessment of self-reported adverse events and adverse events elicited at clinic visits,
clinical laboratory tests, vital signs (including weight), and physical examination.6
Anderson FD, Hait H. A multicenter, randomized study of an extended cycle oral contraceptive. Contraception. 2003;68(2):89–96. doi:10.1016/s0010-
7824(03)00141-0.
As evidenced by Table 3, while the initial risk of failure is higher in the extended-cycle regimen than in the conventional
cycle,as time progresses(by the 8th month)the riskis significantly higherthan in the constant failure rate ofextended-cycle
oral contraception.
Results:During the course ofthestudy,7patients became pregnant,4of456 (0.9%) treated with the extendedcycle regimen
and 3 of226 (1.3%) treated with the conventionalregimen. Diary data indicated use of othermethods ofbirth controland/or
noncompliance with study medication around the estimated date of conception for three of four extended cycle regimen
patients and one of three conventional regimen patients. Thus, one extended cycle and two conventional cycle regimen-
reported pregnancies were considered method failures. Adverseevents were comparable across the treatment groups;there
were no clinically meaningful changes in other laboratory values, body weight, vital signs (systolic and diastolic blood
pressure,heart rate ortemperature)orin physicalexam results from baseline to end ofstudy.Also,there were no reports of
endometrial hyperplasia or carcinoma.6
Long-term safety of an extended-cycle oral contraceptive (Seasonale):A 2-year multicenter open-label extensiontrial
Population and Study Design: The purpose ofthis studywas to assess the long-termsafety ofSeasonale; thiswas an open-
label, multicenter study in women who successfully completed 1 year of therapy in the Phase 3 Seasonale clinical trial.
Participants who completed the Phase 3 trial from 27 of the original sites were invited to participate.Patients who received
eitherthe 28-day (Nordette)or 91-day (Seasonale)OC treatments in the earlier study were assignedto the 91-day Seasonale
regimen. The primary objective was to demonstrate the safety of the Seasonale extended-cycle for up to an additional 2
years in women who had participated in the Phase 3 Seasonale clinical trial. The principal means of safety evaluation was
patient-reported adverse events.7

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Results: There were 189 women enrolled and treated with Seasonale from the 27 clinical sites. Table I (below) shows the
adverse event profile for the trial by frequency experienced. The most frequently reported adverse events were sinusitis
(19.1%), headache (16.9%), nasopharyngitis (16.4%), upper respiratory tract infection (16.4%), urinary tract infection
(10.1%), and dysmenorrhea (9.5%). The adverse events reported during this study are consistent with other OC clinical
trials, and breakthroughbleeding and/orspotting diminished during the study.This study demonstrates thelong-termsafety
of the 91-day extended cycle OC Seasonale.7
AndersonFD,Gibbons W,PortmanD. Long-termsafetyof anextended-cycleoralcontraceptive (Seasonale): A 2-yearmulticenteropen-labelextension
trial. American Journal ofObstetrics andGynecology.2006;195(1):92–96.doi:10.1016/j.ajog.2005.12.045
Safety and efficacy of an extended-regimen oral contraceptive utilizing continuous low-dose ethinyl estradiol
Population and Study Design: This trial provides detailed results ofa clinical study evaluating the safetyand efficacy of
Seasonique,a 91-day extended-regimen OC consisting of84 days of30 Ag EE/150 Ag LNG followed by 7 days of10 Ag
EE monotherapy. Efficacy was evaluated fromthe pregnancy rate in women ages 18–35 years,who completed at least one
full cycle of therapy,using the Pearlindex(the number of pregnancies per100 women, per yearof use)and life table
analyses.8
Results: Across 36study sites located throughoutthe United States,1006 patients were treated with Seasonique™. A total
of 708 women ages 18–35 years were treated for2177 extended-regimen 91-day cycles (equivalent to 7075 conventional
28-day cycles).During the course ofthe study,five patients became pregnant.Allofthese patients were on treatment at the
time of conception,but only three were consideredto be compliant with pill-taking at the time of conception. Serious
adverse eventsjudged to be possibly related to studydrug were reported in fourpatients.One patient reported a migraine.
The remaining three patients reportedevents related to thegallbladder; cholelithiasis,alone,and with pancreatitis,or
cholecystitis(one patienteach). Seasoniquekwas greaterthan 99% effective in preventing pregnancywhen taken as
directed. This clinical study demonstratesthat giving 10Ag of EE monotherapy during the usualbhormone-freeQinterval
in a 91-day extended regimen does not impact contraceptive efficacy and may contribute to an improvement in
breakthrough bleedingand spotting.8
CONTRAINDICATIONS:
 Patient with current/history of breast cancer or other estrogen- or progestin-dependent neoplasms,
 Hepatic tumors or disease
 Pregnancy
 Undiagnosed abnormal uterine bleeding
 Women at high risk of arterial or venous thrombotic diseases including: Cerebrovascular disease, coronary artery disease,
diabetes mellitus with vascular disease, DVT or PE (current or history of), hypercoagulopathies (inherited or acquired),
headaches with focal neurological symptoms, hypertension (uncontrolled), migraine headaches if >35 years of age,
thrombogenic valvular or rhythm diseases of the heart (eg, subacute bacterial endocarditis with valvular disease or atrial
fibrillation), women >35 years of age who smoke.4

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PRECAUTIONS & WARNINGS:
 Black Box Warning-Cigarette smoking increases the risk of serious cardiovascular events from combination oral
contraceptivesuse.Thisriskincreaseswith age,particularly in women over35years ofage,andwith thenumberofcigarettes
smoked. For this reason,combination oral contraceptives should not be used by women who are over35 years of age and
smoke.4
 Carbohydrate intolerance: May have adverse effects on glucose tolerance; use caution in women with diabetes.
 Lipid effects: Combination hormonal contraceptives may affect serum triglyceride and lipoprotein levels. Estrogen
compounds are generally associated with lipid effects such as increased HDL-cholesterol and decreased LDL-cholesterol.
Triglycerides may also be increased; use with caution in patients with familial defects of lipoprotein metabolism.4
 Retinal vascular thrombosis: Estrogens may cause retinal vascular thrombosis; discontinue if migraine, loss of vision,
proptosis,diplopia orothervisualdisturbances occur; discontinue permanently ifpapilledema or retinal vascularlesionsare
observed on examination.4
 Thromboembolism: May increase the riskofthromboembolism; discontinueuse ofcombination hormonalcontraceptivesif
an arterial or venous thrombotic event occurs. Women with inherited thrombophilias may have increased risk of venous
thromboembolism. 4
 Vaginal bleeding:Presentation ofirregular,unresolving vaginalbleeding warrants furtherevaluation includingendometrial
sampling, if indicated, to rule out malignancy; evaluate hypothalamic-pituitary-function in women with persistent (≥6
months) amenorrhea (especially associated with breast secretion) following discontinuation of therapy.4
ADVERSE REACTIONS: 4
 Edema, varicose vein aggravation
 Depression, migraine, mood changes
 Chloasma, melasma, rash (allergic)
 Amenorrhea, breakthrough bleeding, breast changes (enlargement, pain, secretion, tenderness), carbohydrate tolerance
decreased, fluid retention, lactation decreased (with use immediately postpartum), menstrual flow changes, spotting
 Abdominal bloating, abdominal cramps, abdominal pain, appetite changes, nausea, weight changes, vomiting
 Folate decreased
 Rhinitis
TOXICITY:
Toxicity may result in occasionalGI upset; it could also cause a hypersensitivity reaction, but overall the toxicity is low
in non-iron containing OCs. 4
DRUG INTERACTIONS: 4
 Avoid combination (category X) with: Amodiaquine, Anastrozole, Antihepaciviral Combination Products,
Dehydroepiandrosterone,Exemestane, Hemin, Indium 111 Capromab Pendetide, Tranexamic Acid, Tizantidine,
Ospemifene
 Consider therapy modification (category D) with: Anticoagulants,Aprepitant,Armodafinil, Artemether, Asunaprevir,
Barbiturates, Bexarotene, Bile Acid Sequestrants,Boceprevir, Bosentan,Carbamazepine, Carfilzomib, Clobazam,
Cobicistat, Colesevelam, strong CYP3A4 inducers, Dabrafenib, Elvitegravir, Enzalutamide, Eslicarbazepine,
Exenatide, Felbamate, Fosaprepitant, Fosphenytoin,Griseofulvin, Hyaluronidase, LamoTRIgine, Lesinurad,
Lixisenatide, Lomitapide, Lumacaftor, Mifepristone, Mitotane, Modafinil, Mycophenolate,Nafcillin, Nevirapine,
oxcarbazepine, Phenytoin,Pirfenidone, Pomalidomide, Protease Inhibitors, Prucalopride, Rifamycin Derivatives,
Rufinamide, Sugammadex, Telaprevir, Tipranavir, Topiramate, Vitamin K Antagonists
 St. John’s Wort diminishes the efficacy of oral contraceptives, making conception a possibility.
DOSAGE & ADMINISTRATION: 4
 Dose begins on first Sunday afteronset of menstruation; ifthe menstrual period starts on Sunday,take first tablet that very
same day.An additionalmethod ofcontraceptionshould be used until after the first 7 days of cons ecutive administration
 Introvale,Jolessa,Quasense,Seasonale [Ethinylestradiol0.03 mg and levonorgestrel0.15 mg]: One active tablet/dayfor84
consecutive days,followed by 1 inactive tablet/day for7 days; if all doses have been taken on schedule and one menstrual
period is missed, pregnancy should be ruled out prior to continuing therapy.
 Quartette,LoSeasonique. Seasonique[Ethinylestradiol0.03 mg and levonorgestrel0.15 mg and ethinyl estradiol 0.01 mg]:
One active tablet/dayfor84 consecutive days,followed by 1 low dose estrogentablet/dayfor7 days; ifall dos es havebeen
taken on schedule and one menstrual period is missed, pregnancy should be ruled out prior to continuing therapy.
Misseddoses:
 One dose missed: Take as soon as remembered or take 2 tablets the next day

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 Two consecutive dosesmissed:Take 2tablets as soonas remembered or2tablets the next 2days.An additionalnonhormonal
method of contraception should be used for 7 consecutive days after the missed dose.
 Three or more consecutive doses missed:Do not take the missed doses; continue taking 1tablet/day untilpackis complete.
Bleeding may occurduring the following week. An additionalnonhormonalmethod of contraception should be used for7
consecutive days after the missed dose.
 Any numberofpills during week 13: Throw away the missed pills and keep taking scheduled pills untilthe packis finished.
A back-up method of contraception is not needed
Renal Impairment Dose Adjustments: Specific guidelines not available; use with caution and monitorblood pressure closely.
Consider other forms of contraception
Hepatic Impairment Dose Adjustments: Contraindicated in hepatically-impaired patients
PRODUCT STORAGE: 4
 Store at roomtemperature.
 Store in a dry place. Do not store in a bathroomor in car.
 Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
RISK MANAGEMENT: 4
Pregnancy Safety: Category X or contraindicated for use during pregnancy
Lactation: Jaundice and breastenlargement in the nursinginfant have beenreportedfollowing the use ofcombination hormonal
contraceptives. They may also decrease the quality and quantity of breast milk; the theoretical concerns about decreased milk
production are greatest early in the postpartum period when milk production is being established. Combined hormonal
contraceptives should not be started <21 days postpartumdue to increased risk of VTE.
PRODUCT AVAILABILITY: 4
Product comes in a 28-day and 91-day oraltablet package,patch,andvaginalring. Forthe purposes ofthis comparison,extended-
cycle pill forms will be compared.
DISTRIBUTION ISSUES: Amethia is scheduled to be discontinued by McKesson.9
RECOMMENDED MONITORING: 4
 Before starting therapy,a physicalexam with reference to the breasts and pelvis are recommended, including a Pap smear.
 Pregnancy should be ruled out prior to use.
 Monitorpatient closely forloss ofvision,sudden onset ofproptosis,diplopia,migraine; blood pressure;signs and symptoms
of thromboembolic disorders; signsorsymptoms ofdepression; glycemic controlin patients with diabetes; lipid profiles in
patients being treated for hyperlipidemias.
COMPARABLE MEDICATIONS ON THE MARKET/COST COMPARISION: 9,10
Drug Name Package Size AWP Purchase Price
(Mckesson)
Unit Cost
Amethia 182 pills (X 1) $537.10 $391.44 $2.1508
Ashlyna 182 pills (X 1) $609.89 NOT AVAILABLE $3.35
Camrese 182 pills (X 1) $537.10 $116.46 $0.6399
Daysee 182 pills (X 1) $537.10 NOT AVAILABLE $2.95
Introvale 91 pills (X 1) $160.65 NOT AVAILABLE $1.76
Jolessa 91 pills (X 3) $482.02 $69.22 $0.2536
Quartette 91 pills (X 1) $422.02 $187.87 $2.0645
Quasense 91 pills (X 3) $482.09 $316.15 $1.1581
Seasonique 91 pills (X 1) $203.09 367.79 $2.0208
Setlakin 273 pills (X 1) $482.05 NOT AVAILABLE $1.76

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SOUND ALIKE/LOOK ALIKE NAMES:
Seasonique may be confused with seasonal allergies or Seasonale.4
CONCLUSION & FINAL RECOMMENDATION:
It is recommended to add an extended-cycle oralbirth controlforaddition to the formulary at the IHS Catawba Service Unit. Jolessa
would be appropriate due to its equivocal efficacy and safety profile in addition to its economical purchase price with McKesson.
Studies have shown thatnot only do a large fraction ofwomen wish to have less menstrualcycles throughoutthe year,but thatuse of
an extended-cycle regimen like Jolessa can provide decreased episodes ofpainfulmenstruation as well as less severe fluctuationsin
mood and depression. An extended-cycle birth controlalso provides benefit forpatients suffering frommenorrhagia, dysmenorrhea,
endometriosis,chronic pelvic pain,and anemia. Caution should be taken with women with a history ofclotting disorder; the riskis
no different than in monthly-cycle birth control. Because monthly-cycle birth control is already on formulary and extended-cycle
birth control poses no additional risks, it is fitting to add to the IHS Catawba Service Unit formulary.
REPORT PREPARED BY: Jade Abudia, PharmD Candidate 2017 on 21 October 2016
REFERENCES:
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3. Curtis KM, JatlaouiTC, TepperNK, et al. U.S. Selected Practice Recommendations forContraceptive Use,2016. MMWR
Recomm Rep 2016;65(No. RR-4):1–66. DOI: http://dx.doi.org/10.15585/mmwr.rr6504a1
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2003;68(2):89–96. doi:10.1016/s0010-7824(03)00141-0.
7. AndersonFD,Gibbons W, Portman D. Long-termsafety ofan extended-cycle oralcontraceptive(Seasonale):A 2-year
multicenter open-labelextension trial.American Journalof Obstetrics and Gynecology.2006;195(1):92–96.
doi:10.1016/j.ajog.2005.12.045
8. AndersonFD,Gibbons W, Portman D. Safety and efficacy of an extended-regimen oral contraceptive utilizing continuous
low-dose ethinylestradiol.Contraception.2006;73(3):229–234. doi:10.1016/j.contraception.2005.09.010.
9. McKesson Connect® Online [Internet]. San Francisco, CA: McKesson Corporation, 2016. Available at
www.connect.mckesson.com. Cited 2016 October 21.
10. Red Book [Internet].Micromedex 2.0. Greenwood Village. Available at http://www-micromedexsolutions-com.Accessed
June 28, 2016.