Professional Information

Estrogens and Progestins Oral Contraceptives (Systemic )

This monograph includes information on the following:

1) Desogestrel and Ethinyl Estradiol
2) Ethynodiol Diacetate and Ethinyl Estradiol
3) Levonorgestrel and Ethinyl Estradiol
4) Norethindrone Acetate and Ethinyl Estradiol
5) Norethindrone and Ethinyl Estradiol
6) Norethindrone and Mestranol
7) Norgestimate and Ethinyl Estradiol
8) Norgestrel and Ethinyl Estradiol

Note: For information pertaining to the use of progestin-only contraceptives, see Progestins (Systemic) .

INN:
Ethinyl estradiol—Ethinylestradiol ^{01}
Ethynodiol diacetate—Etynodiol ^{01}
Norethindrone— Norethisterone ^{01}

BAN:
Ethinyl estradiol—Ethinyloestradiol ^{01}
Ethynodiol diacetate—Ethynodiol ^{01}
Norethindrone—Norethisterone ^{01}

JAN:
Ethinyl estradiol—Ethinylestradiol ^{01}
Ethynodiol diacetate—Etynodiol acetate ^{01}
Norethindrone—Norethisterone ^{01}

VA CLASSIFICATION
Primary: HS104
Secondary: HS109

Commonly used brand name(s): Alesse³; Brevicon⁵; Brevicon 0.5/35⁵; Brevicon 1/35⁵; Cyclen⁷; Demulen 1/35²; Demulen 1/50²; Demulen 30²; Demulen 50²; Desogen¹; Estrostep⁴; Estrostep Fe⁴; Genora 0.5/35⁵; Genora 1/35⁵; Genora 1/50⁶; Intercon 0.5/35⁵; Intercon 1/35⁵; Intercon 1/50⁶; Jenest⁵; Levlen³; Levlite³; Levora 0.15/30³; Lo/Ovral⁸; Loestrin 1.5/30⁴; Loestrin 1/20⁴; Loestrin Fe 1.5/30⁴; Loestrin Fe 1/20⁴; Marvelon¹; Min-Ovral³; Minestrin 1/20⁴; Mircette¹; ModiCon⁵; N.E.E. 1/35⁵; N.E.E. 1/50⁵; Necon 0.5/35⁵; Necon 1/35⁵; Necon 1/50⁶; Necon 10/11⁵; Nelova 10/11⁵; Nelova 0.5/35E⁵; Nelova 1/35E⁵; Nelova 1/50M⁶; Nordette³; Norethin 1/35E⁵; Norethin 1/50M⁶; Norinyl 1+35⁵; Norinyl 1+50⁶; Norinyl 1/50⁶; Ortho 0.5/35⁵; Ortho 1/35⁵; Ortho 10/11⁵; Ortho 7/7/7⁵; Ortho Tri-Cyclen⁷; Ortho-Cept¹; Ortho-Cyclen⁷; Ortho-Novum 1/35⁵; Ortho-Novum 1/50⁶; Ortho-Novum 10/11⁵; Ortho-Novum 7/7/7⁵; Ovcon-35⁵; Ovcon-50⁵; Ovral⁸; Select 1/35⁵; Synphasic⁵; Tri-Cyclen⁷; Tri-Levlen³; Tri-Norinyl⁵; Triphasil³; Triquilar³; Trivora³; Zovia 1/35E²; Zovia 1/50E².

Other commonly used names are
Ethinylestradiol and Ethinyloestradiol —Ethinyl estradiol
; Ethynodiol, Etynodiol, and Etynodiol acetate —Ethynodiol diacetate
; and Norethindrone —Norethisterone
.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Category:

Contraceptive, systemic—Desogestrel and Ethinyl Estradiol; Ethynodiol Diacetate and Ethinyl Estradiol; Levonorgestrel and Ethinyl Estradiol; Norethindrone Acetate and Ethinyl Estradiol; Norethindrone and Ethinyl Estradiol ; Norethindrone and Mestranol; Norgestimate and Ethinyl Estradiol; Norgestrel and Ethinyl Estradiol;

Antiacne agent, systemic—Norethindrone Acetate and Ethinyl Estradiol (Triphasic formulation only) ^{284}; ^†Norgestimate and Ethinyl Estradiol (Triphasic formulation only) ^{40} ;

Antiendometriotic agent—Desogestrel and Ethinyl Estradiol; Ethynodiol Diacetate and Ethinyl Estradiol; Levonorgestrel and Ethinyl Estradiol; Norethindrone Acetate and Ethinyl Estradiol; Norethindrone and Ethinyl Estradiol ; Norethindrone and Mestranol; Norgestimate and Ethinyl Estradiol; Norgestrel and Ethinyl Estradiol;

Contraceptive, postcoital (systemic)—Levonorgestrel and Ethinyl Estradiol ; Norgestrel and Ethinyl Estradiol ^{50} ^{51} ^{52};

Estrogen-progestin—Desogestrel and Ethinyl Estradiol; Ethynodiol Diacetate and Ethinyl Estradiol; Levonorgestrel and Ethinyl Estradiol; Norethindrone Acetate and Ethinyl Estradiol; Norethindrone and Ethinyl Estradiol ; Norethindrone and Mestranol; Norgestimate and Ethinyl Estradiol; Norgestrel and Ethinyl Estradiol;

Gonadotropin inhibitor, female, noncontraceptive use—Desogestrel and Ethinyl Estradiol; Ethynodiol Diacetate and Ethinyl Estradiol; Levonorgestrel and Ethinyl Estradiol; Norethindrone Acetate and Ethinyl Estradiol; Norethindrone and Ethinyl Estradiol; Norethindrone and Mestranol; Norgestimate and Ethinyl Estradiol; Norgestrel and Ethinyl Estradiol;

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Pregnancy, prevention of—Combination estrogen-progestin oral contraceptives are indicated for the prevention of pregnancy.^{03}^{04}^{05}^{06}^{07}^{08}^{09}^{10}^{11}^{12}^{13}^{14}^{15}^{16}^{17}^{18}^{19}^{20}^{21}^{22}^{23}^{24}^{25}^{26}^{28}^{29}^{30}^{31}^{32}^{33}^{34}^{35}^{36}^{37}^{38}^{39}^{40}^{41}^{42}^{43}^{44}^{45} The lowest expected failure rate for women who use oral contraceptives consistently and correctly under clinical conditions is 0.1% in the first year of use; however, under nonclinical conditions the typical use is less perfect and typical failures may range from 0 to 6%. ^{226} ^{227} All regimens are considered equally effective for preventing pregnancy. ^{150} ^{229}
—The following table presents the results of studies examining contraceptive failure rates calculated using the life-table method. The first column lists the contraceptive method used. The second column indicates the percentage of women experiencing an accidental pregnancy in the first year of use of a contraceptive method while using the method perfectly under clinical conditions. The range of failure rates in the clinical trials may be explained by interstudy variations in study design or patient population characteristics, such as motivation, fecundity, or socioeconomic factors (including education). The third column indicates contraceptive failure rates in the first year of contraceptive use under clinical conditions for typical couples who start using a method (not necessarily for the first time). Failure rates among adolescents may be higher due to poorer compliance than in other age groups.^{07}^{53}^{54}

	Method used	Failure rate range (over 12 months) in clinical studies (%)	Typical first year failure rate (%)
None		78–94	85
Spermicides ^*		0.3–37	21
Periodic abstinence ^†		13–35	20
Withdrawal		7–22	19
Cervical cap with spermicide		6–27	18
Diaphragm with spermicide		2–23	18
Condom without spermicide		2–14	12
IUD
	Progesterone-releasing	1.9–2	2
	Copper-T 200	3–3.6
	Copper-T 200Ag ^‡	0–1.2
	Copper-T 220C ^§	0.9–1.8
	Copper-T 380A	0.5–0.8	0.8
	Copper-T 380S	0.9
Oral contraceptive			3
	Estrogen and progestin	0–6
	Progestin only	1–10
Medroxyprogesterone injection (90-day)		0–0.3	0.3
Levonorgestrel (subdermal)
	Six implants	0–0.09	0.09
	Two rods	0–0.2	0.3
Sterilization
	Female ^#	0–8	0.4
	Male	0–0.5	0.15

^* Spermicides studied include creams, foams, gels, jellies, and suppositories.^{53}^{54}
^† Methods studied include calendar, ovulation method, and symptothermal (cervical mucus method supplemented by basal body temperature post-ovulation). ^{53}^{54}
^‡ Life-table method rate is unavailable for Copper-T 200Ag and the Pearl method rate at 12 months was reported; these methods at 12 months are considered comparable. ^{04} ^{55}^{56}^{57}
^§ Copper-T 220C is manufactured with copper sleeves instead of copper wire; often used as a control in clinical studies. ^{07}
^# Methods studied include culdotomy laparoscopy, minilaparotomy, electrocoagulation, laparotomy, tubal diathermy and/or use of rings or clips.^{53}^{54}

[Contraception, emergency postcoital (prophylaxis)]¹—A combination of levonorgestrel ^{50} or norgestrel with ethinyl estradiol ^{51} ^{52} is used as emergency contraception (also called intraception, morning-after treatment, or postcoital contraception) for postcoital birth control, after pregnancy has been ruled out.^{52}^{247}^{248}^{249}^{250}^{251}^{252}^{253} The dosing method using high doses of estrogen-progestin hormones is commonly called the Yuzpe method. Using oral contraceptives for emergency postcoital contraception is preferable to using ethinyl estradiol alone because, although the failure rate is higher (2% versus 1%) with oral contraceptives, they cause fewer and less severe side effects to occur. ^{50} Treatment is initiated within the first 72 hours, preferably within the first 12 hours, after unprotected intercourse^{226}.

Acne vulgaris (treatment)¹—The triphasic formulation of norgestimate and ethinyl estradiol and the triphasic formulation of norethindrone and ethinyl estradiol are indicated to treat moderate acne vulgaris in females ,15 years of age or older, who have no known contraindications to oral contraceptive therapy, desire oral contraception, have achieved menarche, plan to stay on it for at least 6 months, and are unresponsive to topical anti-acne medications.^{285}^{40}^{284}

[Amenorrhea (treatment)] or
[Dysfunctional uterine bleeding (DUB) (treatment) ] or
[Dysmenorrhea (treatment)] or
[Hypermenorrhea (treatment)]—[Norethindrone and mestranol tablets (dose of 1/50)] ^{37} are indicated [and other estrogen-progestin combinations and doses are used]¹ as a hormonal treatment for hypoestrogenic or hyperandrogenic conditions, which may present as menstrual cycle abnormalities or unusual uterine bleeding, such as amenorrhea, dysfunctional uterine bleeding, or hypermenorrhea. ^{37} When treating amenorrhea and hypermenorrhea, the abnormality should be diagnosed first and then treated appropriately; oral contraceptives have limited use for treating conditions not caused by a hypoestrogenic or hyperandrogenic state. ^{268} Patients who require contraception as well as relief from primary dysmenorrhea may benefit from treatment with oral contraceptives^{236}^{237}^{238}^{258}. If contraception is not needed, prostaglandin-inhibiting medications, such as nonsteroidal anti-inflammatory drugs (NSAIDs), are used. If dysmenorrhea is not relieved by oral contraceptives or NSAIDs, endometriosis or another organic cause should be considered. ^{257}

Endometriosis (prophylaxis and treatment)—[ Norethindrone and mestranol tablets (dose of 1/50)] ^{37} are indicated [and other estrogen-progestin combinations and doses are used]¹ to reduce the size and growth of endometrial tissue. ^{257} ^{262}

[Hirsutism, female (treatment and treatment adjunct)]¹ or
[Hyperandrogenism, ovarian (treatment and treatment adjunct)]¹or
[Polycystic ovary syndrome (treatment) ]¹—When treating these conditions, the basic cause should be ascertained first, if possible, and treated accordingly. ^{269} When contraception is needed as well, oral contraceptives are used to help suppress hypothalamic-pituitary function in luteinizing hormone–dependent hyperandrogenism in conditions such as polycystic ovary syndrome^{239}^{240}^{241}^{242}^{264}. Oral contraceptive treatment results in regularity of the menstrual cycle and lessening of hirsutism in these conditions^{239}^{240}^{254}^{255}^{259}^{260}^{261}^{263}^{265}.

Acceptance not established
Only limited data are available evaluating the use of oral contraceptives as adjunct agents to replace the estrogen component as add-back therapy when gonadotropin-releasing hormone agonists are used to suppress the hypothalamic-pituitary axis. Using oral contraceptives as the estrogen replacement may be especially useful in women needing contraception as well. By replacing estrogen, hypoestrogenic side effects caused by the gonadotropin-releasing hormone agonist, such as bone loss and the associated vasomotor symptoms, are reduced. Further studies are needed to evaluate the safety and efficacy of this use.^{254}^{255}^{263}

Oral contraceptives, which are effective in dysmenorrhea, have been used to reduce premenstrual pain associated with the premenstrual syndrome in some patients, but generally oral contraceptives are not considered useful for this indication.^{243}^{257}

Unaccepted
Administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy.^{03}^{11}

Oral contraceptives should not be used during pregnancy for the treatment of threatened or habitual abortion.^{03}^{11}

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—

Estrogens:
    Ethinyl estradiol ^{01}.
    Mestranol ^{01}.

Progestins, 19-nortestosterone derivatives:
    Desogestrel ^{01}.
    Ethynodiol diacetate ^{01}.
    Levonorgestrel (levorotatory isomer) ^{01}.
    Norethindrone ^{01}.
    Norethindrone acetate ^{01}.
    Norgestimate ^{01}.
    Norgestrel (racemic mixture) ^{01}.

Molecular weight—
    Desogestrel: 310.48 ^{01}
    Ethinyl estradiol: 296.41 ^{01}
    Ethynodiol diacetate: 384.52 ^{01}
    Levonorgestrel: 312.45 ^{01}
    Mestranol: 310.44 ^{01}
    Norethindrone: 298.43 ^{01}
    Norethindrone acetate: 340.47 ^{01}
    Norgestimate: 369.51 ^{01}
    Norgestrel: 312.45 ^{01}

Mechanism of action/Effect:

Estrogen-progestin—Estrogens increase the cellular synthesis of chromatin (DNA), RNA, and various proteins in responsive tissues, and progestins increase the synthesis of RNA by means of an interaction with DNA. ^{257}

Contraceptive, systemic—The synergistic anti-ovulatory effect from the combined use of estrogen and progestin directly decreases the secretion of the gonadotropin-releasing hormone (GnRH) from the hypothalamus and is considered the main action. ^{53} This negative feedback mechanism disrupts ovulation by interfering with the hypothalamus-pituitary-ovary axis and gonadotropin secretion from the pituitary. Specifically, the progestin component blunts or suppresses luteinizing hormone (LH) release and the LH surge, which is necessary for ovulation, and the estrogen component blunts or suppresses the follicle-stimulating hormone (FSH), which prevents the selection and maturation of the dominant follicle. ^{50} Neither the estrogen nor the progestin hormone dose used in combination hormonal oral contraceptives alone would be able to suppress ovulation but together the estrogen and progestin hormones work synergistically to suppress ovulation successfully. Other contributing effects include delayed maturation of the endometrium, which prevents implantation of ova; and the development of viscous cervical mucus, which slows spermatic ingress. ^{50} ^{53} The effects on the endometrium and cervical mucus are considered the mechanisms of action for the estrogen-progestin oral contraceptives used for emergency contraception (intraception). ^{54}

Antiendometriotic agent—Oral contraceptives can produce a pseudopregnant state (especially when used continuously) in which the uterine endometrium and ectopic endometriotic implants undergo decidual reaction, necrosis, and eventual atrophy. Sometimes endometriotic symptoms may increase before improvement is noted. ^{257}

Gonadotropin inhibitor, female, noncontraceptive use—Suppressed ovarian steroidogenesis secondary to LH concentration reduction prevents ovarian cyst formation in functional ovarian cysts, corpus luteum cysts, or polycystic ovary syndrome. Although a decrease in occurrence of repetitively forming functional ovarian cysts is possible, treatment to either speed the resolution of existing ovarian cysts or to treat functional ovarian cysts secondary to ovulation induction has not been established. ^{50} The likelihood of suppressing ovarian cyst formation is greatest with 50-mcg ethinyl estradiol–containing monophasic formulations but 35-mcg ethinyl estradiol–containing monophasic formulations are used effectively, also. Suppression is least likely with triphasic formulations. ^{257} In addition to suppression of ovarian steroidogenesis, there is an increase in sex hormone–binding globulin, which binds testosterone and decreases the quantity of free hormone. This effectively reduces the androgenic symptoms of hirsutism, polycystic ovary syndrome, and hyperandrogenism. ^{242} Desogestrel and norgestimate additionally improve acne or hirsutism conditions because of their high level of progestational effects and absence of androgenic effects. Other progestins having androgenic properties, such as levonorgestrel, norgestrel, or norethindrone, may or may not worsen acne or hirsutism, depending on the progestin-estrogen dose relationship. ^{50} ^{176} ^{203}

Other actions/effects:

The following noncontraceptive effects have been observed with the use of oral contraceptives: menstrual cycle regularity, fewer occurrences of iron-deficient anemia associated with heavy menses flow or pelvic inflammatory disease; and fewer ectopic pregnancies. Although low-dose oral contraceptives may have less effect, high-dose formulations (containing ³ 50 mcg [0.05 mg] estrogen) used long-term have decreased the occurrence of benign breast disease, including fibroadenomas and fibrocystic breast disease. Also, oral contraceptives may protect against or delay development of benign or malignant endometrial and ovarian cancers, atherosclerosis, or rheumatoid arthritis (although some of these are still controversial). ^{50} ^{176} ^{203}

Norgestrel and levonorgestrel have the most androgenic activity of all the progestins. Norethindrone and ethynodiol diacetate possess slight estrogenic activity, and norethindrone has some androgenic activity. Norgestimate and desogestrel have high progestational activity and are low in androgenicity. ^{231} ^{232}

Absorption:

Both estrogen and progestin components are rapidly and well absorbed. ^{03} ^{06} ^{39} ^{47} ^{58} ^{228}

Ethinyl estradiol or

Mestranol—Relative bioavailability is 83% because these estrogens have both a first-pass effect and enterohepatic recirculation with similar blood concentrations achieved for both 50 mcg of mestranol-containing and 35 mcg of ethinyl estradiol–containing oral contraceptives. ^{03} ^{39} ^{58} ^{230}

Desogestrel—Desogestrel is primarily absorbed in the intestine as its active metabolite, etonogestrel, but because of a significant first-pass effect, the relative bioavailability of etonogestrel is 84%. ^{03} ^{06} ^{228}

Ethynodiol diacetate or

Norethindrone or

Norethindrone acetate—Ethynodiol diacetate and norethindrone acetate are completely hydrolyzed by intestinal tissue to norethindrone, which is then absorbed. All of these progestins are rapidly and well absorbed but because of a first-pass effect, 53% bioavailability results. ^{57}

Levonorgestrel or

Norgestimate or

Norgestrel—Intestinal absorption within 2 hours; completely bioavailable because these progestins do not exhibit a first-pass effect. ^{39} ^{57} ^{{ 224}}

Distribution:

Oral contraceptives are widely distributed. ^{257}

Ethinyl estradiol—Distributed into the uterus (0.9%), blood (8.8%), adipose tissue (28.2%), and other tissues. Fifty mcg of ethinyl estradiol taken orally would yield a concentration of 10 nanograms/100 mL a day in breast milk, which is not considered clinically significant. ^{58}

Desogestrel (with ethinyl estradiol administration)—Volume of distribution (Vol _D) is 143 ± 61 liters (L). ^{57}

Norethindrone (with ethinyl estradiol)—Vol _D is approximately 236 ± 60 L. ^{57}

Protein binding:

Oral contraceptives differ in their ability to increase the concentration of sex hormone–binding globulin (SHBG) that is induced by estrogen because contraceptive progestins differ in their ability to suppress this estrogenic effect. Also, contraceptive progestins have different affinities for albumin and SHBG. Therefore, progestins binding to serum proteins differ relative to how the estrogen and the progestin together affect serum proteins. For instance, a progestin with greater affinity for albumin than SHBG but faced with greater serum concentration of SHBG induced by estrogen would result in greater binding of progestin to SHBG. ^{228}

Ethinyl estradiol—High; specifically, ethinyl estradiol is 95% bound to albumin, but not to SHBG; ethinyl estradiol induces production of SHBG. ^{58} Tissue-specific receptor proteins form complexes with estrogens in estrogen-responsive tissues.

Desogestrel (with ethinyl estradiol administration)—High; albumin (66 ± 12%), SHBG (31 ± 12%), unbound (2.5 ± 0.2%). ^{57} Because desogestrel does not counteract the increase in SHBG caused by daily estrogen administration, nonlinear kinetics result; desogestrel binds to a threefold increase in SHBG, which is highest between the third and sixth months of treatment. ^{03} ^{06}

Levonorgestrel (with ethinyl estradiol administration)—High; proportion bound to albumin or SHBG varies by strength and phasic relationship of both levonorgestrel and estrogen. Specifically, 250 mcg levonorgestrel and 50 mcg ethinyl estradiol have decreased SHBG by 24%, 150 mcg levonorgestrel and 30 mcg ethinyl estradiol decreased SHBG by 10%, and triphasic formulations increased SHBG. Levonorgestrel's affinity for SHBG is greater than its affinity for albumin. ^{57}

Norethindrone—Without use of estrogen, norethindrone binds 61% to albumin and 35.5% to SHBG while 3.5% is unbound. With use of ethinyl estradiol, an 80 to 100% increase in SHBG may be expected, which will increase the SHBG-bound proportion of norethindrone. ^{57}

Biotransformation:

Desogestrel—In Phase I hydroxylation, desogestrel, a prodrug, is metabolized in the intestinal tract and by hepatic first-pass metabolism to the biologically active metabolite etonogestrel and several inactive metabolites. The metabolism is completed in Phase II, resulting in polar conjugated glucuronide and sulfate metabolites. ^{03} ^{06} ^{57} ^{59} ^{228}

Ethinyl estradiol or

Mestranol—Exhibits Phase I and Phase II metabolism. ^{58} Seventy percent of the prodrug, mestranol, converts to ethinyl estradiol by demethylation. Estrogen metabolites, mainly conjugates, are hydroxylated by enzymes of intestinal bacteria then reabsorbed via enterohepatic recirculation. ^{58} ^{257}

Ethynodiol diacetate or ^{57}

Norethindrone or

Norethindrone acetate—Hydrolysis of ethynodiol diacetate and norethindrone acetate to norethindrone occurs mainly in the intestines, but also in the liver. ^{57} Norethindrone is metabolized to sulfate (predominately in plasma) and glucuronide conjugates, which may prolong activity if active metabolites are discovered. Also, it is postulated that the aromatization of norethindrone to ethinyl estradiol by tissues such as the liver, ovaries, and placenta may be of clinical significance. ^{57}

Levonorgestrel or

Norgestrel—Metabolism of the inactive isomer L-(d)-norgestrel differs considerably from metabolism of the active isomer L-(l)-norgestrel; the latter is sulfated more rapidly than is the inactive isomer. ^{57}

Norgestimate—Considered an incomplete prodrug for levonorgestrel; has biological activity, but 85% of activity is thought to be due to norgestrel acetate and, to a much lesser extent, norgestrel. Metabolized to active metabolites, levonorgestrel and 17-deactyl norgestimate (has activity similar to norgestimate), as well as to other hydroxy compounds. ^{57} ^{{ 224}}

Half-life:

With ethinyl estradiol administration:

• Desogestrel or

• Levonorgestrel—Elimination, plasma: 8 to 13 hours. ^{03} ^{06} ^{57}

• Ethynodiol diacetate or

• Norethindrone or

• Norethindrone acetate—Elimination, plasma: 8 hours. ^{57}

• Norgestimate—Elimination, plasma: 30 to 71 hours for norgestimate; ^{57} ^{{ 224}} 17 to 30 hours for 17-deactyl norgestimate, a metabolite. ^{67}

With desogestrel administration:

• Ethinyl estradiol—Elimination, plasma: 26 hours. ^{03}

With norgestimate administration:

• Ethinyl estradiol—Elimination, plasma: 6 to 14 hours. ^{39}

Elimination:
        Desogestrel—

• Renal: 45%, of which 14 to 28% is unchanged, and 38 to 61% is excreted as glucuronide and 23 to 39% as sulfate conjugates. ^{57}

• Fecal: Up to 30%. ^{57}

        Ethinyl estradiol or
        Mestranol—

• Renal: 22 to 58%. ^{57} ^{58}

• Fecal: 30 to 53%. ^{57} ^{58}

• Biliary: 26 to 43% ^{57} ^{58}.

        Ethynodiol diacetate or ^{57}
        Norethindrone acetate or
        Norethindrone—

• Renal: 37 to 87%, of which 3% is unchanged, and 40% is excreted as glucuronide and 15% as sulfate conjugates. ^{57}

• Fecal: Up to 40%. ^{57}

        Levonorgestrel or
        Norgestrel—Renal, as inactive metabolites. ^{57}

        Norgestimate—

• Renal: 45 to 49% ^{39} ^{57}.

• Fecal: 16 to 49% ^{39} ^{57}.

Precautions to Consider

Carcinogenicity

Recent and current users of high-dose oral contraceptives (containing 50 mcg or more of estrogen) for at least 2 years have shown a progressive reduction of up to 40% in incidence of benign fibrocystic breast disease; it is unknown if low-dose oral contraceptives (containing less than 50 mcg of estrogen) have similar effects. ^{50}

Use of oral contraceptives in women between 25 and 39 years of age does not increase the risk of developing breast cancer at 45 years of age or older. ^{50} ^{63} ^{65} ^{75} Whether oral contraceptives increase the risk of breast cancer in certain subgroups of women, such as women under 20 years of age using oral contraceptives for more than 4 years ^{63} ^{70} ^{73} ^{75} or women 46 to 54 years of age using oral contraceptives for more than 3 years, is unresolved ^{63} ^{65} ^{75}. Some case-control studies have shown no association between oral contraceptive use and breast cancer in women under 20 years of age and a protective effect or no enhancement of risk in women 46 to 54 years of age. ^{65} ^{68} ^{69} Because risk factors vary for women of different age groups, parity, environment, and age at first use, controlling for these and other confounding factors and establishing whether additional risk occurs is difficult. The magnitude of increased risk, if it exists at all, is considered very small ^{64} ^{65} ^{70} ^{74} ^{75}, and does not warrant withholding the use of oral contraceptives in any subgroup of women ^{73} (including those women having a family history of either breast cancer or benign breast disease, or women having a history of benign breast disease) or restricting use for young nulliparous women. ^{63} ^{66} ^{67} Further analyses of risks associated with using low-dose oral contraceptives ^{66} as compared to high-dose contraceptives and to characterize effects of duration of use are being evaluated. ^{66} ^{68} ^{69} ^{76}

If an oral contraceptive containing 50 mcg of estrogen is taken for at least 12 months, a 15-year protective effect against the development of endometrial cancer persists after the oral contraceptive treatment is discontinued. Similar effects for low-dose oral contraceptives are expected but an evaluation is needed. ^{77} ^{78}

High and low doses of monophasic oral contraceptives used continuously for at least 3 years have shown a protective effect against ovarian cancer, an effect that is fully developed in 6 years and may persist for at least 10 years; shorter-term use has not shown a protective effect. Similar short- and long-term effects are expected for low-dose bi- and triphasic oral contraceptives since they suppress ovulation, but further evaluation is needed. ^{50} ^{79} ^{80} ^{81} ^{82} ^{83}

Epidemiologic studies suggest that women taking oral contraceptives for 8 or more years have an increased risk of developing hepatocellular carcinoma as compared to women not taking oral contraceptives. However, these cancers are extremely rare and occur in less than one per million women using oral contraceptives long-term. ^{87} ^{88}

Risk for dysplasia and carcinoma of the cervix is increased with oral contraceptive use for more than 1 year. The risk of invasive cervical cancer could increase twofold after 5 years of use; the greatest risk is in women using oral contraceptives for longer than 10 years. A great portion of the risk is thought to be due to the number of sexual partners a woman has and the age at first coitus, a factor that may be different between users and never-users. ^{50} ^{84} ^{85}

Tumorigenicity

Although benign and rare, liver cell adenomas, many of which regressed with the cessation of oral contraceptive use, have occurred in women using oral contraceptives for longer than 5 years. Liver cell adenomas should be suspected in patients having abdominal pain and tenderness, abdominal mass, or hypovolemic shock. These adenomas may rupture and may cause death through intra-abdominal hemorrhage. ^{50} ^{86} ^{88}

Mutagenicity

It is generally believed that there is no increased risk of mutagenicity or teratogenicity, including any development of fetal sexual malformation, when oral contraceptives are inadvertently taken in early pregnancy ^{102} ^{103}. This information is based on a small number of case reports, and well-designed studies still are needed. ^{103}

Pregnancy/Reproduction
Fertility—
Delayed fertility has been shown to occur rarely in users of oral contraceptives, especially in nulliparous women. In one study, the rate of impaired fertility normalized by 48 and 72 months for two groups of nulliparous women (25 to 29 years of age and 30 to 34 years of age, respectively). ^{92} Infertility rates have not been shown to increase. ^{50}

Pregnancy—
Studies have shown that combination oral contraceptives do not appear to increase the risk of birth defects when they are used before pregnancy. Studies have also shown that oral contraceptives, when taken inadvertently during early pregnancy, do not seem to have a teratogenic effect. However, oral contraceptives are not recommended for use during pregnancy and should be discontinued immediately if pregnancy is suspected. ^{03} ^{04} ^{05} ^{06} ^{07} ^{09} ^{10} ^{12} ^{13} ^{14} ^{15} ^{16} ^{17} ^{18} ^{19} ^{20} ^{22} ^{23} ^{24} ^{26} ^{27} ^{28} ^{29} ^{30} ^{31} ^{35} ^{36} ^{38} ^{39} ^{40} ^{41} ^{42} ^{43} ^{45} ^{89} ^{90} ^{91} ^{92} ^{93} ^{102}

Any patient who has missed two consecutive menstrual periods while taking oral contraceptives should discontinue their use; a nonhormonal contraceptive method should be used until pregnancy is ruled out. If the patient has not followed the dosing schedule, pregnancy should be ruled out after the first missed menstrual period. ^{03} ^{06} ^{07} ^{09} ^{12} ^{13} ^{16} ^{18} ^{20} ^{23} ^{24} ^{29} ^{30} ^{31} ^{36} ^{39} ^{40} ^{42} ^{43} ^{102}

When considering pregnancy, it is recommended that conception be delayed for 1 or 2 months after cessation of oral contraceptives or until after the first regular menses to accurately date the gestation period. ^{50}

FDA Pregnancy Category X. ^{03} ^{06} ^{07} ^{09} ^{12} ^{13} ^{16} ^{18} ^{20} ^{23} ^{24} ^{29} ^{30} ^{31} ^{36} ^{39} ^{40} ^{42} ^{43}

Postpartum or postabortion—Oral contraceptive use and the immediate postpartum period are both associated with an increased risk of thromboembolism occurrence. Therefore, to lessen any potential risk that may exist, oral contraceptives should be started no sooner than 2 weeks after delivery in women choosing to not breast-feed. Also, ovulation usually does not occur before this time and contraception is not needed. ^{50} However, the chance of early ovulation is high following abortion but the risk of thromboembolic phenomena is not great. Therefore, some clinicians recommend that use of a low-dose oral contraceptive may begin immediately after a first-trimester or second-trimester abortion. Also, immediate use of an oral contraceptive is recommended following a second-trimester premature delivery or after a pregnancy of less than 12 weeks; however, for a pregnancy of 12 or more weeks, use of a low-dose oral contraceptive is recommended after 2 weeks. ^{50}

Breast-feeding

Oral contraceptives are distributed into breast milk, and may diminish its quantity or quality or shorten the time of lactation, especially for those women who are only partially breast-feeding and have less physical stimulus for lactation. ^{50} ^{95} ^{96} Use of oral contraceptives by nursing mothers in the early postpartum period is generally not recommended. ^{94} When used by mothers who are exclusively breast-feeding, oral contraceptive therapy is recommended to begin after the third postpartum month or, if only partially or not breast-feeding, to begin in the third postpartum week. If contraception is needed prior to this, some clinicians begin low-dose oral contraceptives after lactation has been well-established. ^{50}

Adolescents

One of the most accepted, frequently prescribed, and, when used regularly, effective contraceptive methods for adolescents is oral contraceptives. ^{97} ^{98} ^{99} ^{100} ^{102} However, the pregnancy rate for adolescents using oral contraceptives is estimated at 6 to 12 per 100 woman years, which is higher than the pregnancy rate, 0.3 to 0.7 per 100 woman years, for all age groups of women. ^{100}

Studies generally have shown that adolescents tend to be less compliant users of any type of contraceptive. Any psychosocial factors involved and discussion of preconceived thoughts on side effects, including weight gain, fluid retention, or breakthrough uterine bleeding, are important areas for patient counseling to help aid in this age group's compliance problem with using oral contraceptives. ^{98} ^{101}

Dental

Increased concentrations of progestins increase the normal oral flora growth rate, leading to an increase in inflammation of the gingival tissues and increased bleeding. A strictly enforced program of teeth cleaning by a professional, combined with plaque control by the patient, will minimize severity. ^{46} ^{47} ^{48}

An increased incidence of local alveolar osteitis (dry socket) after dental extractions has been seen with the use of estrogen and progestin combination oral contraceptives. A direct correlation exists between the incidence of dry socket occurrence and increasing estrogen dose. Therefore, it is recommended that patients inform their dentist or oral surgeon that they are taking an estrogen and progestin contraceptive. ^{49}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Acetaminophen or
Ascorbic acid    (may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation)

^{285}
Amoxicillin or ^{109} ^{110} ^{111}
Ampicillin or ^{109} ^{110} ^{111}
Doxycycline or ^{120}
Penicillin V or ^{109} ^{110} ^{111}
Tetracycline ^{120} ^{121} ^{122}    (there have been rare case reports of reduced oral contraceptive effectiveness in women taking amoxicillin, ampicillin, doxycycline, penicillin V, or tetracycline, resulting in unplanned pregnancy. This is thought to be due to a reduction in enterohepatic circulation of estrogens, which may cause a lower estrogen plasma concentration than expected. Although the association is very weak, patients, especially long-term users of antibiotic therapy, should be advised of this information and given the option of using an alternate or additional method of contraception while taking any of these antibiotics, especially if the duration of antibiotic therapy is greater than 2 weeks ^{121})

Anticoagulants, coumarin- or indandione-derivative    (concurrent use with oral contraceptives has modestly increased, and in some cases decreased, the effectiveness of anticoagulants; however, the mechanism is unknown and appropriate studies have not been done. Because estrogens increase hepatic synthesis of procoagulant factors and decrease antithrombin III, it is possible that adjustment of the anticoagulant dosage based on prothrombin time determinations may be needed^{126}^{127}^{133})

Antidiabetic agents, sulfonylurea or
Insulin    (estrogen-containing oral contraceptives may cause glucose or insulin resistance in diabetic patients, resulting in a loss, probably slight, of metabolic control of plasma glucose concentration; unless the changes can be controlled with diet, this may necessitate an increased sulfonylurea or insulin dose and regular monitoring ^{125})

Atorvastatin    (coadministration of atorvastatin and certain oral contraceptives containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20%)

^{285}
Benzodiazepines    (metabolism of those benzodiazepines, such as diazepam, alprazolam, and triazolam, that undergo oxidation may be inhibited, resulting in delayed elimination of diazepam and triazolam and an increased risk of adverse effect^{113}^{278}. Although the pharmacokinetics of alprazolam were not affected with long-term use, a study has shown a greater sensitivity to alprazolam and psychomotor impairment with single doses of alprazolam in long-term contraceptive users; pharmacokinetic factors were not believed to contribute to this effect. Metabolism of those benzodiazepines that undergo conjugation, such as oxazepam, lorazepam, and temazepam, is not impaired ^{113})

    (reduction of oral contraceptive effectiveness has not been shown with concurrent use of benzodiazepines ^{115})

Caffeine    (oral contraceptives reduce or inhibit the hepatic metabolism of caffeine, thereby increasing the plasma concentration of caffeine up to 30 to 40%; patient may need to be counseled about the increased effects of caffeine if warranted ^{128})

Clofibrate    (concurrent use with oral contraceptives may lower the effectiveness of clofibrate ^{132})

» Corticosteroids, glucocorticoid    (concurrent use with estrogens may lower the metabolism of glucocorticoids, decrease the elimination of potent metabolites, decrease the protein binding of glucocorticoids, and increase the production of the protein-binding globulin, transcortin (also called cortisol-binding globulin). This leads to decreased clearance [approximately 30 to 50% for prednisolone] of the glucocorticoid free fraction, ^{130} prolonged elimination half-life, and increased effects of the glucocorticoids; lower doses of the glucocorticoid are needed with concurrent use of estrogen-containing oral contraceptives^{129}^{130}^{131})

» Cyclosporine ^{123}    (a case report has shown that concurrent use with oral contraceptives increased the plasma concentration of cyclosporine, which may increase its effects; monitoring of plasma cyclosporine concentration and hepatic factors for toxicity, reducing cyclosporine dose, or changing to nonhormonal contraception may be required to minimize the risk of cyclosporine toxicity ^{124})

» Hepatic enzyme inducers (see Appendix II ), especially:
Barbiturates ^{114}
Carbamazepine ^{115} ^{117}
Griseofulvin ^{118}
Phenytoin ^{115} ^{117}
Primidone ^{115}
Rifabutin ^{119}
Rifampin ^{119}    (concurrent use of these medications with oral contraceptives may induce hepatic enzyme oral contraceptive metabolism, especially of the estrogen component, which could result in reduced contraceptive reliability and increased incidence of breakthrough bleeding. High interindividual variability in hepatic enzyme induction exists. Patients should be advised to use a high-dose estrogen-containing contraceptive if oral contraceptives are used, or an alternative or additional method of contraception during use of any of these medications, especially if breakthrough bleeding occurs^{114}^{115})

    (additionally, phenobarbital and phenytoin have been shown to increase sex hormone–binding globulin [SHBG], which may lower the amount of free progestin available for biological action and contribute to the lowered effectiveness of the oral contraceptive^{114}^{115}^{117})

» Hepatotoxic medications, especially troleandomycin (see Appendix II ) ^{134}    (the estrogen component of oral contraceptives increases hepatic blood flow and size of the liver with increased vesiculation of the smooth and rough endoplasmic reticulum, which results in altered hepatic metabolism. It is possible that concurrent use of these medications with estrogens may increase the risk of hepatotoxicity; more frequent monitoring of hepatic function is needed ^{135})

» Ritonavir    (area under the plasma concentration–time curve [AUC] of estrogen is decreased by 40% during use of ritonavir; the estrogen dose of the oral contraceptive should be increased or an alternative form of birth control used with concurrent use of ritonavir ^{234})

» Smoking, tobacco    (polycyclic hydrocarbons in cigarette smoke are potent inducers of certain hepatic cytochrome P450 isoenzymes; the consequences of this effect on metabolism have not been fully explored but may influence the associated risks of using oral contraceptives and smoking concurrently. Although some studies showed inhibition of metabolism of a metabolite of ethinyl estradiol, smoking did not affect the metabolism of ethinyl estradiol ^{137})

    (oral contraceptives are not recommended with heavy tobacco use because of an increased risk of serious cardiovascular side effects, including cerebrovascular accident, transient ischemic attacks, thrombophlebitis, and pulmonary embolism. Risk increases with increased tobacco usage and with age, especially in women over 35 years of age. The mechanisms for these outcomes are still being explored.^{136}^{138} Some clinicians have used low-dose estrogen oral contraceptives in women who are light smokers or who use a nicotine patch^{50})

St. John's Wort (hypericum perforatum)    (herbal products containing St. John's Wort [hypericum perforatum] may induce hepatic enzymes [cytochrome P450] and p-glycoprotein transporter and may reduce the effectiveness of oral contraceptives; this may also result in breakthrough bleeding)

^{285}
Tamoxifen    (concurrent use with estrogens may interfere with the antiestrogenic therapeutic effect of tamoxifen)

» Theophylline    (although theophylline reduced the apparent clearance of ethinyl estradiol 30 to 35% in oral contraceptive users, clinical significance was not noted because of the wide interindividual variability in metabolism of the estrogen; however, reduction of the total plasma clearance of theophylline by 25 to 35% by oral contraceptives was considered clinically significant. These effects result in an increase in both the theophylline and ethinyl estradiol plasma concentration; a lower dose of the theophylline may be needed^{139}^{140}^{141})

Tricyclic antidepressants    (inhibition of imipramine oxidation by oral contraceptives results in higher plasma concentrations of imipramine; imipramine dose may need to be adjusted )

    (estrogen has facilitated the development of neuroleptic antipsychotic or tricyclic antidepressant medication–associated movement disorders, such as akathisia, but not tardive dyskinesia. It is not known if the low doses of estrogen used in oral contraceptives are also implicated in akathisia^{142}^{143})

    (rare cases of chorea have developed in women with chorea gravidarum using oral contraceptives, but oral contraceptives do not appear to create any additional risk in women not predisposed to develop chorea ^{144})

» Troglitazone    (troglitazone may induce drug metabolism by cytochrome P450 isoenzyme CYP3A4; ethinyl estradiol and norethindrone are substrates for this isoenzyme; therefore, caution is recommended when they are used concurrently with troglitazone)

    (concurrent use may decrease the plasma concentrations of ethinyl estradiol and norethindrone by approximately 30%, resulting in a loss of efficacy^{282})

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Aldosterone, serum or
Aldosterone, urine or
Renin, plasma    (the estrogen component decreases the plasma concentration of plasma renin but increases plasma renin activity; oral contraceptives should be discontinued at least 2 weeks, and preferably 4 weeks, before testing plasma renin activity^{145}^{146}^{147}^{148}^{190})

Antipyrine test    (lower values result because oral contraceptives significantly reduce antipyrine metabolism, particularly the oxidative mechanism ^{158})

Corticotropin-releasing hormone stimulation test or
Metyrapone test    (corticotropin plasma levels were reduced approximately 25% overall in a study of women using triphasic oral contraceptives who had been given a morning corticotropin-releasing hormone [CRH] stimulation test; normal basal levels were unchanged. Reduced response also has been noted for the metyrapone test with other oral contraceptives^{157}^{179})

Dexamethasone suppression test    (oral contraceptive users had a significantly higher plasma cortisol level pre- and post-dexamethasone testing; this effect caused by estrogen may persist for up to 1 month after oral contraceptive treatment ends ^{179})

Glucose tolerance test, oral    (significantly higher 2-hour oral glucose tolerance test results ^{175})

Norepinephrine-induced platelet aggregability    (may be increased ^{151})

Thyroid function tests:
Thyroxine (T ₄) determinations    (estrogen-induced thyroid-binding globulin elevates the amount of T ₄ that is protein bound; this effect reverses in about 2 months after discontinuation of oral contraceptives; serum free T ₄ concentrations are unchanged. Specifically, triphasic oral contraceptives containing 30 mcg of ethinyl estradiol have increased thyroid-binding globulin by about 20% and elevated total T ₄ by 40% ^{183})

Triiodothyronine (T ₃) determinations     (free T ₃ and reverse T ₃ are unchanged, but T ₃ resin uptake is decreased because estrogens increase serum thyroid-binding globulin [TBG]; total T ₃ radioimmunoassay [RIA] values are increased but proportionately less than total T ₄ values^{165}^{183}^{270})

With physiology/laboratory test values
Albumin or
Alkaline phosphatase    (levels were decreased in women taking norethindrone-ethinyl estradiol 1/35 throughout the 1-year treatment period in one study; these effects were not seen in the same study among women taking levonorgestrel-ethinyl estradiol 0.15/30 ^{185})

Androstenedione or
Ceruloplasmin, serum or
Dehydroepiandrosterone sulfate (DHEA-S) or
Pregnenolone or
Sex hormone-binding globulin (SHBG), serum or
Testosterone or
Thyroid-binding globulin or
Transferrin or cortisol-binding globulin, serum    (oral contraceptives increase protein synthesis of SHBG, thyroid-binding globulin, transferrin, and ceruloplasmin. The serum concentrations of total sex steroids, copper, and cortisol may also increase. The free thyroid concentration is unchanged, and thyroid function is unaltered. Response of the free non-protein-bound component may be variable ^{177} ^{178})

    (oral contraceptives" net effect on SHBG is the result of the opposing actions of the estrogen and progestin. A dose-related response to progestins of greater androgenicity, such as norgestrel, has a greater suppressive effect on the estrogen-induced increases of SHBG than do those with low androgenic effect, such as desogestrel or norgestimate, which have little suppressive effect on estrogen-induced SHBG levels and can result in a three- to fourfold increase in SHBG. However, further elevations of SHBG, above some level that remains undetermined, do not appear to result in any further decrease in free testosterone. For instance, one study showed that an elevation of SHBG by 92% and 175% decreased free testosterone similarly [by 35%].^{181}^{228} Ethinyl estradiol and norethindrone 1/35 and 1/50 increased SHBG levels by 183 to 390%; ethinyl estradiol and norgestrel increased SHBG by 12%. Testosterone levels are further changed by those progestins that have greater affinity for SHBG, such as levonorgestrel-containing oral contraceptives, that can displace testosterone from its SHBG binding site ^{181})

    (also, norgestrel-, ethynodiol diacetate–, and norethindrone-containing oral contraceptives reduce circulating DHEA-S by 28%, androstenedione by 47%, and testosterone by 40%, including the precursor, pregnenolone, by causing a decrease in corticotropin stimulation or by direct effect on hepatic enzyme inhibition. The complexity of these factors causes a variable clinical effect among individuals taking oral contraceptives ^{184} ^{190})

Antithrombin III    (may be decreased by most oral contraceptives, which contributes to decreased anticoagulant or increased fibrinolytic activity of oral contraceptives. A study showed that desogestrel increased fibrinolytic activity less than did a triphasic formulation of levonorgestrel but that there was significantly more activity in users of desogestrel than in nonusers. Although the increase in activity was generally within normal laboratory ranges, extreme values among individuals may need to be taken into consideration. Specifically, users of a triphasic formulation of levonorgestrel and ethinyl estradiol showed a slight increase in antithrombin III concentration at 12 weeks, followed by a decrease until the end of the 48-week study. In the same study, users of desogestrel and ethinyl estradiol showed a decreased concentration of antithrombin III at 24 weeks that returned to the normal range at 48 weeks ^{159} ^{160})

Apolipoprotein A ₁, A ₂, or B or
Cholesterol, total or
Triglycerides    (in general, the net effect on lipoproteins is the result of the opposing actions of the estrogen and progestin and depends on the ratio between the two hormones. The estrogen component increases triglyceride, very low density lipoproteins (VLDL), and total cholesterol concentrations and decreases low density lipoproteins (LDL). The progestin component, if androgenic, decreases high density lipoproteins (HDL) and increases LDL. The low concentrations of the androgenic progestins in oral contraceptives have slight effect, which is of clinical significance only for some predisposed individuals. Sometimes, older women with higher serum concentrations of cholesterol may experience a reduction caused by a lowering of the serum LDL concentrations. Triglycerides are increased by all oral contraceptives because of the predominant estrogen effects.^{152}^{163}^{167} The increase in total cholesterol caused by desogestrel- and norgestimate-containing oral contraceptives is considered favorable because it is the net result of the increase in HDL ₃-C (an estrogen effect) without an increase in HDL ₂-C concentrations. The increase in HDL ₂-C caused by other low-dose oral contraceptives is considered an androgenic effect of some of the 19–nortestosterone-derived progestins ^{{ 223}})

For monophasics
    (users of ethynodiol diacetate-ethinyl estradiol 1/35 showed the greatest increase in apolipoprotein A₁ and levonorgestrel-ethinyl estradiol 0.15/30 showed the smallest increase^{167}. Users of ethinyl estradiol-norgestrel have shown significant decrease in apolipoproteins A₁ and A₂ ^{163})

    (in one study, norethindrone-ethinyl estradiol 1/35 increased triglycerides to levels that continued throughout a 1-year treatment period while levonorgestrel-ethinyl estradiol 0.15/30 caused no change in triglyceride levels over a 1-year treatment period. Total cholesterol levels were slightly decreased for norethindrone-ethinyl estradiol 1/35 but returned toward baseline within the 1-year treatment period ^{185}. Levonorgestrel-ethinyl estradiol 0.15/30 slightly reduced total cholesterol levels at 3-month and 1-year treatment periods ^{185})

For triphasics
    (in a study comparing users of triphasic formulations with nonusers, levonorgestrel-ethinyl estradiol [7/7/7- and 9/5/7-day regimens] and norethindrone-ethinyl estradiol produced significant increases in plasma triglyceride [28 to 52%] and plasma apolipoprotein B levels [20 to 23%] in each treatment group at 6 months compared with levels in nonusers. In the contraceptive users, total plasma cholesterol concentrations increased 3 to 11% and plasma apolipoprotein A ₁ concentrations increased 5 to 12%. ^{173} The increases in the concentrations shown in a 12-month study remained within an acceptable clinical range ^{172}. Another study of oral triphasics showed a significant decrease in total cholesterol in users during the first week of use, an effect associated with a decrease in LDL; the total serum cholesterol returned to baseline over the next 3 weeks ^{164} )

Aspartate aminotransferase (AST [SGOT]), serum or
Bilirubin, total, serum or
Urobilinogen, urine    (these values are decreased with oral contraceptives containing 50 mcg of ethinyl estradiol; the incidence of abnormal liver test values is lower for oral contraceptives containing 35 mcg of ethinyl estradiol or 50 mcg of mestranol. Total bilirubin, urinary urobilinogen, and serum AST were significantly decreased at 3 months for norethindrone-ethinyl estradiol 1/35, but returned to baseline at 12 months. Users of levonorgestrel-ethinyl estradiol 0.15/30 showed only slightly decreased concentrations that were not considered clinically significant ^{185})

Clotting factors VII, VIII, IX, and X or ^{159}
Prothrombin time or ^{159}
Thromboplastin time, partial^{159}^{162}    (oral contraceptives shorten partial thromboplastin and prothrombin time, but these results are neither consistent nor do they occur in all individuals. Activation of the segments of the intrinsic and extrinsic system of coagulation by oral contraceptives enhances, depending on the factor, either the fibrinolysis or procoagulation or affects both. If baseline values were increased, the increase was within normal laboratory ranges in most cases, and did not consistently alter bleeding or clotting time^{160}^{162})

Cortisol, serum or urine    (the net effect of oral contraceptives on serum cortisol is the result of the opposing actions of the estrogen and progestin and depends on the ratio between the two hormones. Progestins, such as norethindrone, having glucocorticoid effects decrease corticotropin release and adrenal cortisol production. Estrogens augment corticotropin release by downregulating pituitary glucocorticoid receptors and increase adrenal cortisol responsiveness to corticotropin stimulation. This results in an increase in serum cortisol concentrations and a decrease in urinary cortisol clearance ^{182})

Glucose, plasma or serum or
Insulin    (reduced glucose tolerance and elevated fasting insulin and C-peptide values can occur with use of low-dose oral contraceptives during the first 12 months of use, returning to normal between 12 and 24 months of continued use. These changes from baseline were considered not to be of clinical significance in most prospective studies of low-dose oral contraceptives, as many values were still within the normal range. Levonorgestrel- or norgestrel-containing combinations caused the greatest insulin resistance, followed by combinations of desogestrel and low-dose norethindrone oral contraceptives. Levonorgestrel significantly increased second-phase pancreatic insulin production while desogestrel and norgestimate did not^{152}^{153}^{{ 154}}^{155}^{{ 156}}^{157}^{{ 223}}^{229})

Growth hormone    (physiologic levels may increase during the first year ^{190})

High density lipoproteins (HDL), serum    (low-dose oral contraceptives show no change or a decrease in value of HDL; the estrogen component increases HDL and the progestin component, if androgenic, lowers HDL. If the progestin is nonandrogenic, HDL is not influenced. In studies clinically comparing oral contraceptives, formulations containing levonorgestrel and norgestrel had a greater adverse effect on lipids than did less androgenic formulations such as those containing ethynodiol diacetate, norethindrone, or norethindrone acetate. However, if levonorgestrel or norgestrel is given in low doses or if the total dose given is limited, such as in biphasic or triphasic formulations, these potent androgenic progestins exhibit only mild lipid changes similar to those of less potent androgenic progestins given in monophasic formulations. Nonandrogenic formulations, such as desogestrel and norgestimate, had little effect on lipid profile^{166}^{167}^{169}^{170}^{172}^{173}^{186}^{187}^{188})

Low density lipoproteins (LDL), serum or
Very low density lipoproteins (VLDL), serum    (low-dose oral contraceptives show no change or an increase in value of LDL; the estrogen component decreases LDL and the progestin component, if androgenic, raises LDL. If the progestin is nonandrogenic, LDL is not influenced. In clinical studies comparing oral contraceptives, formulations containing levonorgestrel and norgestrel had a greater adverse effect on lipids than did less androgenic formulations, such as those containing ethynodiol diacetate, norethindrone, or norethindrone acetate. However, if levonorgestrel or norgestrel is given in low doses or if the total dose given is limited, such as in biphasic or triphasic formulations, these potent androgenic progestins exhibit only mild lipid changes similar to those of less potent androgenic progestins given in monophasic formulations. Nonandrogenic formulations, such as desogestrel and norgestimate, had little effect^{163}^{164}^{167}^{173}^{185})

Oxytocin, serum    (mean basal oxytocin levels were higher in women on oral contraceptives ^{174})

Plasminogen activity    (activity is increased above normal laboratory reference values^{160}^{161}^{162})

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Except under special circumstances, this medication should not be used when the following medical problems exist:
» Carcinoma, breast, known or suspected or
» Carcinoma, endometrium or
» Neoplasia, estrogen-dependent, known or suspected    (may worsen conditions; estrogen-containing oral contraceptives should be discontinued and nonhormonal contraceptives initiated, although sometimes progestin-only contraceptives are used for selected patients^{50}^{150}^{189})

» Cardiac insufficiency    (oral contraceptives should not be used in patients with marginal cardiac reserve; fluid retention sometimes caused by estrogens may aggravate this condition ^{268})

» Cerebrovascular disease, active or history of or
» Coronary artery disease, active or history of    (the estrogen component of oral contraceptives has a protective effect against atherosclerosis. Any association with risk in these conditions has been related to thrombosis or interference with cholesterol-lipoprotein profile, such as with levonorgestrel, a progestin, in doses greater than 150 to 250 mcg for those individuals predisposed to thrombosis. No correlation has been seen between coronary artery disease and use of low-dose oral contraceptives, including those formulated with levonorgestrel, in these women or in women who are not predisposed to these conditions. Oral contraceptives should be discontinued or strictly avoided if any cardiovascular or cerebrovascular accidents occur; users should switch to nonhormonal contraception. If oral contraceptives are used in women at risk, special monitoring may be required^{50}^{189})

    (the progestins norgestimate and desogestrel have minimal negative impact and may improve the cholesterol-lipoprotein profile, which is thought to additionally protect against cardiovascular disease along with the estrogen component of oral contraceptives ^{50})

» Hepatic disease, cholestatic, active or
» Hepatic tumors, benign or malignant, or history of    (metabolism of estrogens may be impaired; also, estrogens may worsen the condition. Oral contraceptives should be discontinued and nonhormonal contraception initiated; for those women with active hepatic disease, oral contraceptive use may be resumed after liver function tests return to normal^{50}^{150})

» Jaundice, obstructive or history of during pregnancy or
» Jaundice with prior oral contraceptives use    (estrogens may increase risk of recurrence but low-dose contraceptives have not done so consistently; risk is higher shortly after hormone exposure ^{284}; increased monitoring may be needed ^{284})

» Thrombophlebitis, thrombosis, or thromboembolic disorders, active or history of    (oral contraceptives are not recommended for women with predisposing factors, especially those who smoke tobacco or who have an underlying abnormality of the coagulation system, that place them at special risk for thrombosis. Although hormones can increase thrombin formation, the coagulation effect is offset by an increase in fibrolytic activity. Some women with coagulation disorders may successfully use oral contraceptives as evaluated by the physician if only a slight risk for a thrombogenic condition exists. Problems generally have not been associated with the low doses of hormones used for contraception for women not at risk for these conditions^{50}^{150}^{189})

» Uterine bleeding, abnormal or undiagnosed    (malignancy should be ruled out in cases of persistent or recurring abnormal uterine bleeding; use of a progestin-containing oral contraceptive may delay diagnosis by masking underlying conditions, including cancer^{50}^{150})

Risk-benefit should be considered when the following medical problems exist
Breast cancer, strong family history of or
Breast disease, benign    (although studies have failed to conclusively prove that use of oral contraceptives causes any excess risk for developing breast disease in these women ^{50}, caution and more frequent monitoring for potential problems may be warranted ^{189})

Chorea gravidarum    (oral contraceptives do not cause chorea gravidarum but rarely they have aggravated pre-existing conditions ^{144})

Diabetes mellitus    (use of oral contraceptives may slightly decrease glucose tolerance, slightly increase insulin release in patients with Type 2 diabetes mellitus, or produce a mild adverse effect on the cholesterol-lipoprotein profile. Depending on the oral contraceptive used, a change in the dose of the antidiabetic agent or more frequent monitoring for plasma glucose or lipid profile may be needed. If adverse metabolic effects cannot be controlled, the oral contraceptive should be discontinue^{50}^{150}^{215})

    (norethindrone-, ethynodiol diacetate-, norgestimate-, and desogestrel-containing oral contraceptives affect carbohydrate metabolism less than do levonorgestrel- or norgestrel-containing oral contraceptives; many clinicians recommend low-dose oral contraceptives, such as the triphasic oral contraceptives, for patients with diabetes mellitus ^{257})

    (use of oral contraceptives in patients with Type 1 diabetes mellitus who are 35 years of age or older or in any patient having diabetes mellitus complications is generally not recommended because of the potential increased risk of thrombosis. Healthy patients up to 35 years of age who have diabetes mellitus have minimal risk for adverse effects from oral contraceptive use and usually do not need an adjustment in their insulin dose. They may require more frequent monitoring of the cholesterol-lipoprotein profile and serum glucose concentration ^{50} ^{271})

Epilepsy    (oral contraceptives can be used effectively with this condition but their use may affect the pharmacokinetics of certain antiepileptic medications; dose changes for both medications and special monitoring may be needed ^{150}^{189})

Gallbladder disease, or history of, especially gallstones    (estrogens may alter the composition of gallbladder bile and can cause a rise in cholesterol saturation that may moderately accelerate the development of gallstones during the first 2 years of use in predisposed individuals. The overall risk is low and thought to be of minimal clinical importance; however, cautious use of oral contraceptives is recommended with known gallbladder disease^{50}^{191})

» Hepatic function impairment    (metabolism of estrogens may be impaired, resulting in a worsening of the condition; therefore, oral contraceptives should be discontinued and nonhormonal contraception initiated with active disease; oral contraceptive use may be resumed after liver function tests return to normal. Oral contraceptives are not thought to aggravate cirrhosis or exacerbate previous hepatitis ^{50})

Hypertension    (low-dose monophasic oral contraceptives have been shown to raise blood pressure in some normotensive women considered to be at high risk [although these women cannot be easily identified] or further raise blood pressure in hypertensive women. Use of low-dose multiphasic contraceptives may be an appropriate choice for these women ^{50} ^{189})

Immobilization, extended or
Surgery, major    (although controversial, many guidelines suggest that concurrent oral contraceptive usage increases the risk of postoperative thromboembolism in predisposed women, especially for smokers of tobacco or for those women with a history of thromboembolism. When possible or if appropriate, oral contraceptives should be discontinued at least 4 weeks before and for 2 weeks after an extended period of immobilization or scheduled major elective surgery. If not possible, prophylactic low-dose heparin therapy should be considered prior to surgery ^{50} ^{150})

Mental depression, or history of    (may be aggravated; however, low-dose contraceptives are considered to have minimal effect on mental depression; ^{50} the oral contraceptive should be discontinued if significant depression occurs, especially in women with a history of depression ^{151})

Migraine headaches    (since migraine headaches have been associated with an increased risk of stroke, discontinuation of oral contraceptives may be warranted if migraine headaches are recurring, persistent, or more severe with use of oral contraceptives, especially for those individuals predisposed to thrombosis^{50}^{150}^{189})

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood pressure determinations and
Hepatic function determinations and
Papanicolaou (Pap) test and
Physical examinations    (recommended as determined by physician—generally every 12 months for healthy women with no risk factors but every 6 months if needed when such risk factors exist, although breast and pelvic examinations are needed only annually. New oral contraceptive users should be reassessed at 3 months. Special attention should be given to breast, liver, and pelvic area in the physical exam and patients should be encouraged to self-examine breasts monthly ^{50})

    (special attention to rule out malignancy should be given to patients complaining of persistent or recurring uterine bleeding)

Glucose, serum and
Lipid profile, serum and
Lipoprotein profile, serum    (routine assessment is needed only for women at special risk, including women 35 years of age or older, women who have personal or strong family histories of heart disease, diabetes mellitus, or hypertension, or whose personal history includes gestational diabetes mellitus, xanthomatosis, or obesity ^{50})

For perimenopausal women using oral contraceptives
Gonadotropin determination    (FSH levels should be measured annually after the age of 52 years to determine when menopause occurs^{285}^{257}; levels should be measured during the end of the placebo week ^{285})

Side/Adverse Effects

Note: The risk of any serious adverse effect is minimal for healthy women using low-dose oral contraceptives. ^{50} ^{193} Some women who are at special risk have successfully used low-dose oral contraceptives, although in others the use of oral contraceptives rarely will increase the incidence of life-threatening effects, such as benign hepatic adenomas, hepatocellular carcinoma, ^{86} ^{87} ^{88} or thromboembolism or thromboembolic events such as deep vein thrombosis, cerebral or coronary ischemia and/or infarction, pulmonary embolism, or stroke. ^{81} ^{82} ^{84} ^{85} ^{86} ^{87} ^{88} ^{194} ^{195} ^{197} ^{199} ^{200} Pre-existing risk factors for these events include genetic predisposition (i.e., antiestrogen antibodies, activated protein C or antithrombin deficiencies or resistance, or genetic thrombotic disorder), hypertension, hyperlipidemia, obesity, diabetes, or smoking of cigarettes ^{137} ^{196} ^{199}.
Low-dose oral contraceptives are recommended for most women throughout their reproductive years without need for discontinuance. Mortality rates in oral contraceptive users are lower than those that are associated with childbirth. This is true even for smokers 35 years and older and nonsmokers 40 years and older. ^{50} ^{137} ^{201}
There is no evidence of an etiological relationship between oral contraceptive use and pituitary prolactinoma; however, the appearance of galactorrhea while on oral contraceptives merits investigation. ^{273}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for immediate medical attention
Incidence rare

Thromboembolism or thrombosis (abdominal pain, sudden, severe, or continuing; coughing up blood; headache, severe or sudden; loss of coordination, sudden; pains in chest, groin, or leg, especially calf of leg; shortness of breath, sudden, unexplained; slurring of speech, sudden; vision changes, sudden; weakness, numbness, or pain in arm or leg, unexplained)—mainly exhibited in women having predisposing or pre-existing conditions, especially for those who smoke tobacco, but the event may be idiopathic

Those indicating need for medical attention
Incidence more frequent, especially during the first 3 months of oral contraceptive use

Changes in the menstrual bleeding pattern or intermenstrual bleeding, such as amenorrhea (complete stoppage of menstrual bleeding over several months), absence of withdrawal bleeding ^{203}^{204}^{208}(occasional stoppage of menses over nonconsecutive months), breakthrough bleeding (vaginal bleeding between regular menstrual periods, which may require the use of a pad or a tampon), metrorrhagia ^{204}(prolonged bleeding), scanty menses ^{{ 202}}(very light menstrual bleeding), or spotting ^{{ 202}}^{203}^{204}^{208}(light vaginal bleeding between regular menstrual periods)

Note: Malignancy should be ruled out as the cause if persistent or recurring abnormal uterine bleeding occurs ^{50}.
Up to 46% of women using oral contraceptives experience changes in the intermenstrual uterine bleeding pattern. These problems become less frequent with duration of use; women who use high-dose oral contraceptives or who are changing formulations have fewer uterine bleeding problems than do women who are new users. Breakthrough bleeding occurs in 6 to 12% of women; some may require a change to a higher formulation with progestin or a change to a monophasic oral contraceptive after 3 months. ^{233} Intervention with therapeutic doses of estrogen and/or progestin may be necessary if breakthrough bleeding is heavy or further prolonged. ^{257}
For women experiencing changes in the menstrual bleeding pattern, 6 to 12%, 6 to 10%, and less than 1% of women will experience spotting, scanty menses, or metrorrhagia, respectively. Up to 12% of women using norethindrone-containing oral contraceptives and less than 2% of women using desogestrel-, norgestimate-, or levonorgestrel-containing oral contraceptives will experience an absence of withdrawal bleeding. Early or mid-cycle spotting or absence of withdrawal bleeding may be seen with use of low doses of monophasic contraceptives and may not be an unexpected side effect but is a major reason for discontinuance. A change to a different formulation with a greater estrogen:progestin ratio or less progestin, such as multiphasic formulations, or temporary supplementation with an estrogen, may improve these adverse effects. ^{{ 207}} ^{208} Failure of oral contraceptives to induce withdrawal uterine bleeding may be caused by insufficient estrogen activity to induce endometrial development. A change to a different formulation with increased estrogen:progestin ratio may improve this effect. ^{{ 207}}

Incidence less frequent

Glucose tolerance, mildly reduced (faintness; nausea; skin paleness; sweating)—usually for women with predisposing conditions^{208}^{215}^{272}

headaches or migraines, worsening or increased frequency of —21%^{{ 202}}^{203}^{204}

hypertension, worsening or exacerbation^{147}^{149}^{{ 202}}^{203}^{204}

vaginal candidiasis or vaginitis, sporadic or recurrent (vaginal discharge, thick, white, or curd-like, or vaginal itching or other irritation)—10 to 16%^{{ 202}}^{203}^{216}

Note: Several studies have confirmed that 15 to 18% of oral contraceptive users will experience an increase, but not a clinically significant elevation, in blood pressure. Another study has observed that 4% of contraceptive users will develop hypertension, especially when either a history of hypertension in pregnancy or a family history of hypertension exists. Severe or malignant hypertension has been rarely seen. ^{206} ^{209}
Although one large cross-sectional study has shown a 43 to 61% increase in the area under the plasma concentration–time curve for glucose, past or current use of oral contraceptives does not increase risk for developing Type 2 diabetes mellitus; the increase is considered transitory and reversible with discontinuation. ^{215} Oral contraceptive formulations vary in the degree to which they cause reduced glucose tolerance, which is usually mild, and may be of clinical importance only for a subset of women at particular risk. ^{215} In separate studies, norgestimate- and desogestrel-containing oral contraceptives showed minimal impact on glucose tolerance. ^{208}
Frequency and severity of headaches or migraines are reduced in some patients using oral contraceptives, but can be increased in others if they experience fluid retention. If headaches or migraines worsen considerably, discontinuation of oral contraceptives should be considered since this may be a prodomal symptom of stroke. ^{{ 202}}
Withdrawal of oral contraceptives does not seem to affect the frequency of recurrent vaginal candidiasis or vaginitis; the increased risk may depend on other factors, such as lifestyle. ^{216}

Incidence rare

Breast tumors (lumps in breast)—primarily in women having a predisposing or pre-existing condition^{74}^{75}^{222}

hepatic focal nodular hyperplasia, hepatitis,^{204}^{211} or hepatocellular carcinoma (pains in stomach, side, or abdomen, or yellow eyes or skin)—primarily in women having a predisposing or pre-existing condition, especially those who smoke tobacco^{211}

hepatic cell adenomas, benign (swelling, pain, or tenderness in upper abdominal area)

mental depression, slight worsening —in pre-existing conditions^{210}

Note: Association of increased incidence of breast tumors is controversial. One study of women 20 to 34 years of age who were long-term oral contraceptive users (10 or more years of use) or recent users (within 5 years of breast cancer diagnosis) found only 1 more case of invasive breast cancer per year among oral contraceptive users than in nonusers for every 100,000 women. ^{74} ^{75} ^{204} ^{222} It still has not been determined whether the risk of breast cancer increases for early users under 20 years of age or for long-term users. ^{74} ^{75}
Although very rare, hepatic cell adenomas should be considered in patients having abdominal pain and tenderness, abdominal mass, or hypovolemic shock ^{50} ^{150}; one third of patients are asymptomatic at diagnosis. Studies of developing countries that have a high incidence of primary liver cancer have not associated oral contraceptives with an increased risk; however, Western countries, with a low incidence of hepatic carcinoma, have shown a fivefold increase in incidence that persisted for 10 years or more in long-term (5 to 10 years) users of oral contraceptives after stopping treatment. Studies in the U.S., also a country with low incidence of hepatic carcinoma, have not confirmed this finding. Whether hepatic cell adenomas are premalignant is disputed. On occurrence, discontinuing the oral contraceptives is necessary and may result in spontaneous regression of the adenoma. ^{211} ^{213} ^{214}
Mental depression has improved for many women with pre-existing conditions; otherwise, no effect with oral contraceptive use usually is noted but severe depression should be reported to and treatment continuance evaluated by a physician. ^{210}

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent

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