Combined injectable birth control

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Combined injectable birth control
Type Hormonal
First use About 1980[citation needed]
Failure rates (first year)
Perfect use 0–0.2%[1]
Typical use ?
Duration effect 1 month
User reminders ?
Advantages and disadvantages
STI protection No
Benefits Especially good if poor pill compliance

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.

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

A variety of different CICs, generally containing a short-acting natural estradiol ester and a long-acting progestin ester, are available for clinical use.[13][14][2][15][16] 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.[14][2][15][16] Estradiol benzoate has a duration that is too short for once-monthly CICs, and is not used in them.[17] Conversely, estradiol enantate is said to have a duration that is too long for once-monthly CICs, but is nonetheless used in them.[17]

Combined injectable contraceptives marketed for clinical use

Composition Dose Vehicle Brand Names Availability
• Estradiol valerate
• Norethisterone enantate
5 mg
50 mg
Oil solution Chinese Injectable No. 3, Efectimes, Ginediol, Mesigyna, Mesilar, Meslart, Mesocept, Mesygest, Nofertyl, Nofertyl Lafrancol, Noregyna, Norestrin, Norifam, Norigynon, Nostidyn, Sexseg, Solouna Approved in at least 36 countries, including Argentina, the Bahamas, Barbados, Bolivia, Brazil, Chile, Colombia, Costa Rica, the Dominican Republic, Ecuador, Egypt, El Salvador, Ghana, Grenada, Guatemala, Guyana, Haiti, Honduras, Jamaica, Kenya, Mexico, Nicaragua, Panama, Paraguay, Peru, St. Lucia, Turkey, Uruguay, Venezuela, and Zimbabwe
• Estradiol cypionate
• Medroxyprogesterone acetate
5 mg
25 mg
Microcrystalline aqueous suspension Ciclofem, Ciclofemina, Cyclofem, Cyclofemina, Cyclogeston, Femelin, Femydrol, Gestin, Harmonis, Lunella, Lunelle, Novafem Approved in at least 18 countries, including Bolivia, Brazil, Chile, China, Colombia, Costa Rica, El Salvador, Guatemala, Hong Kong, Indonesia, Malaysia, Mexico, Panama, Peru, Puerto Rico, Thailand, the United States, and Zimbabwe
• Estradiol enantate
• Algestone acetophenide
10 mg
150 mg
Oil solution 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 Approved in at least 19 countries, including Argentina, Belize, Brazil, Chile, Colombia, Costa Rica, the Dominican Republic, Ecuador, El Salvador, Guatemala, Honduras, Hong Kong, Mexico, Nicaragua, Panama, Paraguay, Peru, Portugal, and Spain
5 mg
75 mg
Oil solution Anafertin, Patector NF, Yectames Approved at least 9 countries, including Costa Rica, the Dominican Republic, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, Panama, and Spain
10 mg
120 mg
Oil solution Unalmes, Yectuna Approved in at least 3 countries, including Brazil, Chile, and Paraguay
10 mg
75 mg
Oil solution Ova Repos Discontinued (firm was in Spain)
• Estradiol benzoate butyrate
• Algestone acetophenide
10 mg
150 mg
Oil solution? Redimen, Soluna, Unijab, Unimens§ Approved in Peru and Singapore
• Estradiol valerate
• Hydroxyprogesterone caproate
5 mg
250 mg
Oil solution Chinese Injectable No. 1 Approved in China
• Estradiol
• Megestrol acetate
3.5 mg
25 mg
Microcrystalline aqueous suspension with a defined particle size range Chinese Injectable No. 2, Mego-E Approved in China
• Estradiol cypionate
• Hydroxyprogesterone caproate
5 mg
250 mg
Oil solution? Sinbios Discontinued (firm was in Mexico)
• Estradiol valerate
• Estradiol benzoate
• Hydroxyprogesterone caproate
10 mg
1 mg
250 mg
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: See template.

Side effects

The most prominent side effects of CICs are menstrual irregularities during the first 3 to 6 months of use.[1]


Idealized curves of estradiol levels over a period of 30 days after injection of different estradiol esters in women.[15] Four data points were used to generate the curves (day 0, peak day, a third day, and day 30).[15] The measurements from which the points were drawn were taken at 24-hour intervals.[15]

CICs contain an estrogen and a progestin. The estrogen is generally a short-acting estradiol ester, which acts as a prodrug of estradiol.[13] 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.[18][19][20]The progestin is a long-acting progestogen ester, which may or may not act as a prodrug.[13] 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.[13] However, is estimated that about 20% of an administered dose does still eventually pass through the liver.[13] Hence, these preparations are not completely liver-neutral.[13] Nonetheless, they have dramatically reduced hepatic effects relative to oral ethinylestradiol.[21] In addition, parenteral estradiol in general has about 4- or 5-fold reduced potency in the liver than oral estradiol.[21]

Parenteral potencies and durations of steroidal estrogens

Estrogen EPD (14 days) CIC-D (month) Duration
Estradiol 40–60 mg 10 mg ≈ 2 days
Estradiol benzoate 25–30 mg 5–10 mga 0.3–1.7 mg ≈ 2–3 days 5 mg ≈ 4–6 days
Estradiol benzoate (cryst. susp.) 20 mg ? mg ≈ 21 days
Estradiol dipropionate 25–30 mg 5 mg ≈ 5–8 days
Estradiol valerate 20–30 mg 5 mg 5 mg ≈ 7–8 days 10 mg ≈ 10–14 days
Estradiol cypionate 20–30 mg 5 mg 5 mg ≈ 11–14 days
Estradiol enantate ? 5–10 mg 10 mg ≈ 20–30 days
Estradiol undecylateb ? 5–10 mga 10–12.5 mg ≈ 40–60 days 25–50 mg ≈ 60–120 days
Polyestradiol phosphate 40–60 mg 40–50 mg ≈ 28–30 days 320 mg = >84 daysc
Estriol ? 1 mg ≈ <1 day
Polyestriol phosphate ? 50 mg ≈ 30 days 80 mg ≈ 60 days
Note: All are via i.m. injection of oil solution unless noted otherwise. Footnotes: a = Studied but never marketed. b = An effective OID of EU is 20–30 mg/month. c = The t1/2 of PEP after a 320-mg dose is 70 days. Sources: See template.

Parenteral potencies and durations of progestogens

Progestogen Type Class TFD
(14 days)
(2–3 months)
Algestone acetophenide Synthetic Pregnane ? 75–150 mg 100 mg ≈ 14–32 days
Cyproterone acetate Synthetic Pregnane ? 300 mg ≈ 20 days
Dydrogesterone (cryst. susp.)a Synthetic Retropregnane ? 100 mg ≈ 16–38 days
Gestonorone caproate Synthetic Norpregnane 50 mg 25–50 mg ≈ 8–13 days
Hydroxyprogesterone acetate (cryst. susp.)a Synthetic Pregnane 350 mg 150–350 mg ≈ 9–16 days
Hydroxyprogesterone caproate Synthetic Pregnane 250–500 mgb 250–500 mg 65–500 mg ≈ 5–21 days
Lynestrenol phenylpropionatea Synthetic Estrane ? 50–100 mg ≈ 14–30 days
Medroxyprogesterone acetate (cryst. susp.) Synthetic Pregnane 50–100 mg 150 mg 25 mg 50–150 mg ≈ 14–50+ days
Megestrol acetate (cryst. susp.) Synthetic Pregnane ? 25 mg ?
Norethisterone enanthate Synthetic Estrane 100–200 mg 200 mg 50 mg 50–200 mg ≈ 11–52 days
Oxogestone phenylpropionatea Synthetic Pregnane ? 100 mg ≈ 19–20 days
Progesterone Bioidentical Pregnane 200 mgb 25–350 mg ≈ 2–6 days
Progesterone (cryst. susp.) Bioidentical Pregnane 50–200 mg 50–300 mg ≈ 7–14 days
Note: All are via i.m. or s.c. injection of oil solution unless noted otherwise. P4 production during the luteal phase is ~25 (15–50) mg/day. The OID of OHPC is 250 to 500 mg/month. Footnotes: a = Studied but never marketed (either as a medication or by this route). b = In divided doses (2 × 125 or 250 mg for OHPC, 10 × 20 mg for P4). Sources: Main: See template.


Two CICs were introduced for clinical use by 1976: estradiol enantate/algestone acetophenide (E2-EN/DHPA; brand names Perlutan, Topasel) in Spain and Latin America, and estradiol valerate/hydroxyprogesterone caproate (EV/OHPC; brand name Injectable No. 1) in China.[22] These CICs have been described as first-generation CICs.[22] 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.[23][24][14]

United States

Society and culture


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.[25][26][27][16][2][24][14][15][28] They were also previously available in the United States, Portugal, and Spain, but have been discontinued in these countries.[26][27]


Many other CICs have been studied but have not been approved or marketed for clinical use.[14][15][29][17][30][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.[31]

The following are CICs that have never been marketed:

See also


  1. ^ a b c d e "FDA Approves Combined Monthly Injectable Contraceptive". Contraception Report. 12 (3). 2001. Archived from the original on September 26, 2006.
  2. ^ a b c d e f Bagade O, Pawar V, Patel R, Patel B, Awasarkar V, Diwate S (2014). "Increasing use of long-acting reversible contraception: safe, reliable, and cost-effective birth control" (PDF). World J Pharm Pharm Sci. 3 (10): 364–392. ISSN 2278-4357.
  3. ^ Tamara Callahan MD , Aaron Caughey MD , Blueprints Obstetrics and Gynecology, 2013
  4. ^ KD Tripathi , Essentials of Medical Pharmacology, 2013
  5. ^ Dc Dutta's Textbook of Obstetrics, 2014
  6. ^ K. A. Petrie, A. H. Torgal, C. L. Westhoff, Matched-pairs analysis of ovarian suppressionduring oral vs. vaginal hormonal contraceptive use, „Contraception” 2011, t. 84, p. e2-3
  7. ^ R. L. Birtch, O. A. Olatunbosum, R. A. Pierson, Ovarian follicular dynamics during conventional vs continuous oral contraceptive use, „Contraception” 2006, t. 73, p. 235. p. 239.
  8. ^ K. Bugge, K. S. Richter, J. Bromer, et al., Pregnancy rates following in vitro fertilization are reduced with a thin endometrium, but are unrelated to endometrial thickness above 10 millimeters,„Fertility and Sterility” 2004, t. 82, p. S199.
  9. ^ T. Fiumino, A. Kuwata, A. Teranischi et al., Significance of endometrium thickness to evaluate endometrial receptivity for embryos in natural cycle, „Fertility and Sterility” 2008, t. 90,p. S159.
  10. ^ K. S. Richter, K. R. Bugge, J. G. Bromer, Relationship between endometrial thickness and embryo implantation, based on 1. 294 cycles of in vitro fertilization with transfer of two blastocyst-stage embryos, „Fertility and Sterility” 2007, t. 87, p. 53.
  11. ^ Rivera R, Yacobson I, Grimes D (1999). "The mechanism of action of hormonal contraceptives and intrauterine contraceptive devices". Am J Obstet Gynecol. 181 (5 Pt 1): 1263–9. doi:10.1016/S0002-9378(99)70120-1. PMID 10561657.
  12. ^ Don Kulick (12 January 2009). Travesti: Sex, Gender, and Culture among Brazilian Transgendered Prostitutes. University of Chicago Press. pp. 64–66. ISBN 978-0-226-46101-4.
  13. ^ a b c d e f V. Unzeitig; Rick H.W. van Lunsen (15 February 2000). Contraceptive Choices and Realities: Proceedings of the 5th Congress of the European Society of Contraception. CRC Press. pp. 133, 136. ISBN 978-1-85070-067-8.
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  17. ^ a b c d e f g h i j k Toppozada MK (April 1994). "Existing once-a-month combined injectable contraceptives". Contraception. 49 (4): 293–301. doi:10.1016/0010-7824(94)90029-9. PMID 8013216.
  18. ^ Michael Oettel; Ekkehard Schillinger (6 December 2012). Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. Springer Science & Business Media. pp. 235–237, 261, 271. ISBN 978-3-642-60107-1. Natural estrogens considered here include: [...] Esters of 17β-estradiol, such as estradiol valerate, estradiol benzoate and estradiol cypionate. Esterification aims at either better absorption after oral administration or a sustained release from the depot after intramuscular administration. During absorption, the esters are cleaved by endogenous esterases and the pharmacologically active 17β-estradiol is released; therefore, the esters are considered as natural estrogens.
  19. ^ Nagrath Arun; Malhotra Narendra; Seth Shikha (15 December 2012). Progress in Obstetrics and Gynecology--3. Jaypee Brothers Medical Publishers Pvt. Ltd. pp. 419–. ISBN 978-93-5090-575-3.
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  25. ^
  26. ^ a b Sweetman, Sean C., ed. (2009). "Sex hormones and their modulators". Martindale: The Complete Drug Reference (36th ed.). London: Pharmaceutical Press. p. 2082. ISBN 978-0-85369-840-1.
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