Combined injectable birth control

Combined injectable contraceptives (CICs) are a form of hormonal birth control for women. They consist of monthly injections of combined formulations containing an estrogen and a progestin to prevent pregnancy.

Combined injectable birth control
Background
TypeHormonal
First useBy 1969
Failure rates (first year)
Perfect use0–0.2%[1]
Typical use?
Usage
Duration effect1 month
User reminders?
Advantages and disadvantages
STI protectionNo
BenefitsEspecially good if poor pill compliance

CICs are different from progestogen-only injectable contraceptives (POICs), such as depot medroxyprogesterone acetate (DMPA; brand names Depo-Provera, Depo-SubQ Provera 104) and norethisterone enantate (NETE; brand name Noristerat), which are not combined with an estrogen and are given once every two to three months instead of once a month.[2]

Hormonal contraception works primarily by preventing ovulation, but it may also thicken the cervical mucus inhibiting sperm penetration.[3][4][5] Hormonal contraceptives also have effects on the endometrium,[6][7] that theoretically could affect implantation,[8][9][10][11]

Medical uses

CICs are administered by intramuscular injection into the deltoid, gluteus maximus, or anterior thigh.[1] They are ideally administered every 28 to 30 days, though they have been demonstrated to be effective up to 33 days.[1]

Some CICs have been said to be used by transgender women as a means of feminizing hormone therapy as well.[12]

Available forms
Combined injectable contraceptives marketed for clinical use
CompositionDoseVehicleBrand NamesAvailability
Estradiol valerate / Norethisterone enantate5 mg EV
50 mg NETE		Oil solutionMultiple[lower-alpha 1]Approved in at least 36 countries
Estradiol cypionate / Medroxyprogesterone acetate5 mg EC
25 mg MPA		Microcrystalline aqueous suspensionMultiple[lower-alpha 2]Approved in at least 18 countries
Estradiol enantate / Algestone acetophenidea10 mg E2-EN
150 mg DHPA		Oil solutionMultiple[lower-alpha 3]Approved in at least 19 countries
5 mg E2-EN
75 mg DHPA		Oil solutionAnafertin†, Patector NF, YectamesApproved at least 9 countries
10 mg E2-EN
120 mg DHPA		Oil solutionUnalmes, YectunaApproved in at least 3 countries
10 mg E2-EN
75 mg DHPA		Oil solutionOva Repos†Discontinued (firm was in Spain)
Estradiol benzoate butyrate / Algestone acetophenide10 mg EBB
150 mg DHPA		Oil solution?Redimen, Soluna, Unijab, Unimens§Approved in Peru and Singapore
Estradiol valerate / Hydroxyprogesterone caproate5 mg EV
250 mg OHPC		Oil solutionChinese Injectable No. 1Approved in China
Estradiol / Megestrol acetate3.5 mg E2
25 mg MGA		Microcrystalline aqueous suspensionChinese Injectable No. 2, Mego-EApproved in China
Estradiol cypionate / Hydroxyprogesterone caproate5 mg EC
250 mg OHPC		Oil solution?Sinbios†Discontinued (firm was in Mexico)
Estradiol valerate / Estradiol benzoate / Hydroxyprogesterone caproate10 mg EV
1 mg EB
250 mg OHPC		Oil solution?Sin-Ol†Discontinued (firm was in Mexico)
Notes: All are given by intramuscular injection once a month. Footnotes: † = Discontinued. § = Never marketed. a = Unsorted brand names (doses unknown; for E2-EN/DHPA): Evitas† and Femineo†. Sources: [13][2][14][15][16][17][18][19][20][21][22][23]
  1. Chinese Injectable No. 3, Efectimes, Ginediol, Mesigyna, Mesilar, Meslart, Mesocept, Mesygest, Nofertyl, Nofertyl Lafrancol, Noregyna, Norestrin, Norifam, Norigynon, Nostidyn, Sexseg, Solouna
  2. Ciclofem, Ciclofemina, Cyclofem, Cyclofemina, Cyclogeston, Femelin, Femydrol, Gestin, Harmonis, Lunella, Lunelle†, Novafem
  3. Acefil, Agurin†, Atrimon†, Ciclomes, Ciclovar, Ciclovular, Cicnor†, Clinomin, Cycloven, Daiva, Damix, Deladroxate§, Deprans, Deproxone, Exuna, Ginestest, Ginoplan†, Gynomes, Horprotal, Listen, Luvonal, Neogestar, Neolutin, Nomagest, Nonestrol, Normagest, Normensil, Novular, Oterol, Ovoginal, Patector, Patectro, Perludil, Perlumes, Perlutal, Perlutale, Perlutan, Perlutin, Perlutin-Unifarma, Permisil, Preg-Less, Pregnolan, Primyfar†, Progestrol†, Protegin, Proter, Seguralmes, Synovular, Topasel, Unigalen, Uno-Ciclo, Vagital

A variety of different CICs, generally containing a short-acting natural estradiol ester and a long-acting progestin ester, are available for clinical use.[24][15][2][16][13] Estrogens that are used include estradiol valerate, estradiol cypionate, estradiol enantate, estradiol benzoate butyrate, and estradiol, while progestins that are used include norethisterone enantate, medroxyprogesterone acetate, algestone acetophenide (dihydroxyprogesterone acetophenide), hydroxyprogesterone caproate, and megestrol acetate.[15][2][16][13] Estradiol benzoate has a duration that is too short for once-monthly CICs, and is not used in them.[25] Conversely, estradiol enantate is said to have a duration that is too long for once-monthly CICs, but is nonetheless used in them.[25]

Side effects

Side effects of CICs, besides menstrual bleeding changes, are minimal.[26] The most prominent side effects of CICs are menstrual irregularities during the first 3 to 6 months of use.[1] Dysmenorrhea has been reported in 30 to 65% of women.[26] Other side effects include breast tenderness/pain, headache, and libido changes.[26] Some fluid retention can occur, but weight gain is minimal.[26] Local injection site reactions have also been reported in 15 to 35% of women.[26]

Effects of CICs on coagulation and fibrinolysis are minimal and are not thought to be clinically relevant.[27] Conversely, combined oral contraceptive pills containing ethinylestradiol have considerable effects on coagulation and fibrinolysis.[27] The differences can be attributed to the lack of the first-pass effect with parenteral administration as well as structural and pharmacological differences between estradiol and ethinylestradiol.[28][29]

Pharmacology
Idealized curves of estradiol levels over a period of 30 days after injection of different estradiol esters in women.[16]

CICs contain an estrogen and a progestin. The estrogen is generally a short-acting estradiol ester, which acts as a prodrug of estradiol.[24] Esters of estradiol are natural and bioidentical estrogens, and are believed to have more favorable effects on lipid metabolism, cardiovascular health, and hemostasis than synthetic estrogens such as ethinylestradiol.[30][31][32] The progestin is a long-acting progestogen ester, which may or may not act as a prodrug.[24] Progesterone derivatives including medroxyprogesterone acetate, algestone acetophenide (dihydroxyprogesterone acetophenide), hydroxyprogesterone caproate, and megestrol acetate are active themselves and are not prodrugs, whereas the testosterone derivative norethisterone enantate is a prodrug of norethisterone. Regardless of whether they are prodrugs or not, steroid esters form a depot and have an extended duration of action due to a depot effect when administered by intramuscular or subcutaneous injection.

Because CICs are administered parenterally, they bypass the first-pass effect in the liver and intestines that occurs with oral administration of estrogens.[24] However, is estimated that about 20% of an administered dose does still eventually pass through the liver.[24] Hence, these preparations are not completely liver-neutral.[24] Nonetheless, they have dramatically reduced hepatic effects relative to oral ethinylestradiol.[28] In addition, parenteral estradiol in general has about 4- or 5-fold reduced potency in the liver than oral estradiol.[28]


Parenteral potencies and durations of progestogens[lower-alpha 1][lower-alpha 2]
Compound Form Dose for specific uses (mg)[lower-alpha 3] DOA[lower-alpha 4]
TFD[lower-alpha 5] POICD[lower-alpha 6] CICD[lower-alpha 7]
Algestone acetophenideOil soln.-–75–15014–32 d
Gestonorone caproateOil soln.25–50––8–13 d
Hydroxyprogest. acetate[lower-alpha 8]Aq. susp.350––9–16 d
Hydroxyprogest. caproateOil soln.250–500[lower-alpha 9]–250–5005–21 d
Medroxyprog. acetateAq. susp.50–1001502514–50+ d
Megestrol acetateAq. susp.-–25>14 d
Norethisterone enanthateOil soln.100–2002005011–52 d
ProgesteroneOil soln.200[lower-alpha 9]––2–6 d
Aq. soln.?––1–2 d
Aq. susp.50–200––7–14 d
Notes and sources:
  1. Sources: [33][34][35][36][37][38][39][40][41][32][25][2][42][43][44][45][46][47][48][49]
  2. All given by intramuscular or subcutaneous injection.
  3. Progesterone production during the luteal phase is ~25 (15–50) mg/day. The OID of OHPC is 250 to 500 mg/month.
  4. Duration of action in days.
  5. Usually given for 14 days.
  6. Usually dosed every two to three months.
  7. Usually dosed once monthly.
  8. Never marketed or approved by this route.
  9. In divided doses (2 × 125 or 250 mg for OHPC, 10 × 20 mg for P4).

History

The first CIC to be studied was estradiol valerate/hydroxyprogesterone caproate (EV/OHPC) in 1963, and the second CIC to be studied was estradiol enantate/algestone acetophenide (E2-EN/DHPA) in 1964.[26][25] In 1967, E2-EN/DHPA was in the late stages of clinical development.[50][26] By 1969, the medication was available for medical use under the brand name Perlutal.[51] Within a few years, it was marketed under other brand names such as Topasel and Ova-Repos as well.[52][53][54][55] In addition, several other CICs had been introduced for medical use by 1972.[55] By 1976, two major CICs were in use: E2-EN/DHPA (brand names Perlutan, Topasel) in Spain and Latin America, and EV/OHPC (brand name Injectable No. 1) in China.[56] These CICs have been described as first-generation CICs.[56] Two second-generation CICs, estradiol cypionate/medroxyprogesterone acetate (EC/MPA; brand names Cyclofem and later Lunelle) and estradiol valerate/norethisterone enantate (EV/NETE; brand name Mesigyna), were introduced for clinical use in 1993.[57][14][15] On 5 October 2000, Pharmacia received FDA approval for Lunelle Monthly Contraceptive Injection.[1] In April 2003, Pharmacia was acquired by Pfizer (makers of depot medroxyprogesterone acetate). In October 2003, Lunelle was discontinued in the United States.

Society and culture

Availability
Known availability of CICs in countries throughout the world (as of September 2018).

CICs are available in many countries throughout the world, including widely throughout Central and South America, in Mexico and the Caribbean, in China, in several Southeast Asian and African countries, and in Turkey.[21][22][23][13][2][14][15][16][17] They were also previously available in the United States, Portugal, and Spain, but have been discontinued in these countries.[22][23]

Research

Many other CICs have been studied but have not been approved or marketed for clinical use.[15][16][58][25][59][2]

The following are marketed CICs at different doses than those that are approved:

The half-progestin-dose formulation of estradiol valerate/norethisterone enantate (5 mg / 25 mg) is also known as HRP-103 and the half-progestin-dose formulation of estradiol cypionate/medroxyprogesterone acetate (5 mg / 12.5 mg) is also known as HRP-113.[60]

The following are CICs that have never been marketed:

See also

References
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