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Combined injectable birth control
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<h2 id="medical-uses">Medical uses</h2> <p>CICs are administered by intramuscular injection into the <a href="/facts/Deltoid_muscle/se9ub2Ld">deltoid</a>, <a href="/facts/Gluteus_maximus/uwzV7yN1">gluteus maximus</a>, or <a href="/facts/Anterior_compartment_of_thigh/oMdq7mu3">anterior thigh</a>.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> They are ideally administered every 28 to 30 days, though they have been demonstrated to be effective up to 33 days.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> </p><p>Some CICs have been said to be used by <a href="/facts/Transgender_women/3g9BWBmA">transgender women</a> as a means of <a href="/facts/Feminizing_hormone_therapy/casqjU0p">feminizing hormone therapy</a> as well.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> </p> <h3>Available forms</h3> <a href="/facts/Combined_injectable_contraceptive/wtbebG3p">Combined injectable contraceptives</a> marketed for clinical use<table><tbody><tr><th>Composition</th><th>Dose</th><th>Vehicle</th><th>Brand Names</th><th>Availability</th></tr><tr><td><a href="/facts/Estradiol_valerate/norethisterone_enantate/z3Db9SYn">Estradiol valerate / Norethisterone enantate</a></td><td>5 mg /50 mg</td><td>Oil solution</td><td>Multiple<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a></td><td>Approved in at least 36 countries</td></tr><tr><td><a href="/facts/Estradiol_cypionate/medroxyprogesterone_acetate/M9lXL31a">Estradiol cypionate / Medroxyprogesterone acetate</a></td><td>5 mg /25 mg</td><td>Microcrystalline aqueous suspension</td><td>Multiple<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a></td><td>Approved in at least 18 countries</td></tr><tr><td rowspan="4"><a href="/facts/Estradiol_enantate/algestone_acetophenide/TwnRDHCw">Estradiol enantate / Algestone acetophenide</a>a</td><td>10 mg /150 mg</td><td>Oil solution</td><td>Multiple<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a></td><td>Approved in at least 19 countries</td></tr><tr><td>5 mg /75 mg</td><td>Oil solution</td><td>Anafertin†, Patector NF, Yectames</td><td>Approved at least 9 countries</td></tr><tr><td>10 mg /120 mg</td><td>Oil solution</td><td>Unalmes, Yectuna</td><td>Approved in at least 3 countries</td></tr><tr><td>10 mg /75 mg</td><td>Oil solution</td><td>Ova Repos†</td><td>Discontinued (firm was in Spain)</td></tr><tr><td><a href="/facts/Estradiol_benzoate_butyrate/algestone_acetophenide/S9bsFvEs">Estradiol benzoate butyrate / Algestone acetophenide</a></td><td>10 mg /150 mg</td><td>Oil solution?</td><td>Redimen, Soluna, Unijab, Unimens§</td><td>Approved in Peru and Singapore</td></tr><tr><td><a href="/facts/Estradiol_valerate/hydroxyprogesterone_caproate/MyAhD1k1">Estradiol valerate / Hydroxyprogesterone caproate</a></td><td>5 mg /250 mg</td><td>Oil solution</td><td>Chinese Injectable No. 1</td><td>Approved in China</td></tr><tr><td><a href="/facts/Estradiol/megestrol_acetate/CrzMbJIl">Estradiol / Megestrol acetate</a></td><td>3.5 mg /25 mg</td><td>Microcrystalline aqueous suspension</td><td>Chinese Injectable No. 2, Mego-E</td><td>Approved in China</td></tr><tr><td><a href="/facts/Estradiol_cypionate/hydroxyprogesterone_caproate/SDr3Ma2U">Estradiol cypionate / Hydroxyprogesterone caproate</a></td><td>5 mg /250 mg</td><td>Oil solution?</td><td>Sinbios†</td><td>Discontinued (firm was in Mexico)</td></tr><tr><td><a href="/facts/Estradiol_valerate/estradiol_benzoate/hydroxyprogesterone_caproate/76x4Gxec">Estradiol valerate / Estradiol benzoate / Hydroxyprogesterone caproate</a></td><td>10 mg /1 mg /250 mg</td><td>Oil solution?</td><td>Sin-Ol†</td><td>Discontinued (firm was in Mexico)</td></tr><tr><td colspan="5">Notes: All are given by <a href="/facts/Intramuscular_injection/PPNwW2wB">intramuscular injection</a> once a month. Footnotes: † = Discontinued. § = Never marketed. a = Unsorted brand names (doses unknown; for <a href="/facts/Estradiol_enantate/algestone_acetophenide/TwnRDHCw">E2-EN/DHPA</a>Tooltip estradiol enantate/algestone acetophenide): Evitas† and Femineo†. Sources: <a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a><a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a><a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a><a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a><a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a><a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a><a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a><a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a><a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a><a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a><a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a><a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a></td></tr></tbody></table> <p>A variety of different CICs, generally containing a short-acting natural <a href="/facts/Estradiol_ester/VKY8jo7J">estradiol ester</a> and a long-acting <a href="/facts/Progestin_ester/kwoQAD2g">progestin ester</a>, are available for clinical use.<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a><a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a><a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a><a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a><a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a> Estrogens that are used include <a href="/facts/Estradiol_valerate/ML8T7DPx">estradiol valerate</a>, <a href="/facts/Estradiol_cypionate/kaLBgAXC">estradiol cypionate</a>, <a href="/facts/Estradiol_enantate/XPXqDS6n">estradiol enantate</a>, <a href="/facts/Estradiol_benzoate_butyrate/wdkezCaP">estradiol benzoate butyrate</a>, and <a href="/facts/Estradiol_(medication)/a8tPPllE">estradiol</a>, while progestins that are used include <a href="/facts/Norethisterone_enantate/GrwqPRsn">norethisterone enantate</a>, <a href="/facts/Medroxyprogesterone_acetate/q6XACYYp">medroxyprogesterone acetate</a>, <a href="/facts/Algestone_acetophenide/JDj6dy9c">algestone acetophenide</a> (dihydroxyprogesterone acetophenide), <a href="/facts/Hydroxyprogesterone_caproate/rqTaBegr">hydroxyprogesterone caproate</a>, and <a href="/facts/Megestrol_acetate/Gdybmob0">megestrol acetate</a>.<a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a><a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a><a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a><a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a> <a href="/facts/Estradiol_benzoate/Cn6XNm6s">Estradiol benzoate</a> has a <a href="/facts/Duration_of_action/zdvfFshl">duration</a> that is too short for once-monthly CICs, and is not used in them.<a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a> Conversely, estradiol enantate is said to have a duration that is too long for once-monthly CICs, but is nonetheless used in them.<a class="footnote-ref" id="fnref:39" href="#fn:39"><sup>39</sup></a> </p> <h2 id="side-effects">Side effects</h2> <p>Side effects of CICs, besides menstrual bleeding changes, are minimal.<a class="footnote-ref" id="fnref:40" href="#fn:40"><sup>40</sup></a> The most prominent side effects of CICs are <a href="/facts/Menstrual_irregularity/U1Ax6t6F">menstrual irregularities</a> during the first 3 to 6 months of use.<a class="footnote-ref" id="fnref:41" href="#fn:41"><sup>41</sup></a> <a href="/facts/Dysmenorrhea/WFNGwoY9">Dysmenorrhea</a> has been reported in 30 to 65% of women.<a class="footnote-ref" id="fnref:42" href="#fn:42"><sup>42</sup></a> Other side effects include <a href="/facts/Breast_tenderness/pain/lgVfXrUy">breast tenderness/pain</a>, <a href="/facts/Headache/mdmmC9DP">headache</a>, and <a href="/facts/Libido/g1Eb72tA">libido</a> changes.<a class="footnote-ref" id="fnref:43" href="#fn:43"><sup>43</sup></a> Some <a href="/facts/Water_retention_(medicine)/Q6MI3KdH">fluid retention</a> can occur, but <a href="/facts/Weight_gain/jVbY8Eao">weight gain</a> is minimal.<a class="footnote-ref" id="fnref:44" href="#fn:44"><sup>44</sup></a> Local <a href="/facts/Injection_site_reaction/fREM9zKV">injection site reactions</a> have also been reported in 15 to 35% of women.<a class="footnote-ref" id="fnref:45" href="#fn:45"><sup>45</sup></a> </p><p>Effects of CICs on <a href="/facts/Coagulation/vnfEevM0">coagulation</a> and <a href="/facts/Fibrinolysis/moYzJ5Gx">fibrinolysis</a> are minimal and are not thought to be clinically relevant.<a class="footnote-ref" id="fnref:46" href="#fn:46"><sup>46</sup></a> Conversely, <a href="/facts/Combined_oral_contraceptive_pill/Wudd4dH7">combined oral contraceptive pills</a> containing <a href="/facts/Ethinylestradiol/aYRGLz8n">ethinylestradiol</a> have considerable effects on coagulation and fibrinolysis.<a class="footnote-ref" id="fnref:47" href="#fn:47"><sup>47</sup></a> The differences can be attributed to the lack of the <a href="/facts/First-pass_effect/jfDsbq7S">first-pass effect</a> with <a href="/facts/Parenteral_administration/LsyoHTzH">parenteral administration</a> as well as <a href="/facts/Chemical_structure/r5rT1Lj4">structural</a> and <a href="/facts/Pharmacology/4Rx8s7Ie">pharmacological</a> differences between estradiol and ethinylestradiol.<a class="footnote-ref" id="fnref:48" href="#fn:48"><sup>48</sup></a><a class="footnote-ref" id="fnref:49" href="#fn:49"><sup>49</sup></a> </p> <h2 id="pharmacology">Pharmacology</h2> <p>CICs contain an <a href="/facts/Estrogen_(medication)/mSKFraNu">estrogen</a> and a <a href="/facts/Progestin/8xMJYV3A">progestin</a>. The estrogen is generally a short-acting <a href="/facts/Estradiol_ester/VKY8jo7J">estradiol ester</a>, which acts as a <a href="/facts/Prodrug/cg0GNhH0">prodrug</a> of <a href="/facts/Estradiol_(medication)/a8tPPllE">estradiol</a>.<a class="footnote-ref" id="fnref:50" href="#fn:50"><sup>50</sup></a> Esters of estradiol are <a href="/facts/Natural_product/J4RsVhmP">natural</a> and <a href="/facts/Bioidentical/9pYbKmoo">bioidentical</a> estrogens, and are believed to have more favorable effects on <a href="/facts/Lipid_metabolism/wzC4nsn8">lipid metabolism</a>, <a href="/facts/Cardiovascular/WXwudzzc">cardiovascular</a> health, and <a href="/facts/Hemostasis/5v9dTBGt">hemostasis</a> than <a href="/facts/Synthetic_compound/gqCNaN45">synthetic</a> estrogens such as <a href="/facts/Ethinylestradiol/aYRGLz8n">ethinylestradiol</a>.<a class="footnote-ref" id="fnref:51" href="#fn:51"><sup>51</sup></a><a class="footnote-ref" id="fnref:52" href="#fn:52"><sup>52</sup></a><a class="footnote-ref" id="fnref:53" href="#fn:53"><sup>53</sup></a> The progestin is a long-acting <a href="/facts/Progestogen_ester/kwoQAD2g">progestogen ester</a>, which may or may not act as a prodrug.<a class="footnote-ref" id="fnref:54" href="#fn:54"><sup>54</sup></a> <a href="/facts/Progesterone_(medication)/U3NtGBtS">Progesterone</a> <a href="/facts/Chemical_derivative/JYcbLkbm">derivatives</a> including <a href="/facts/Medroxyprogesterone_acetate/q6XACYYp">medroxyprogesterone acetate</a>, <a href="/facts/Algestone_acetophenide/JDj6dy9c">algestone acetophenide</a> (dihydroxyprogesterone acetophenide), <a href="/facts/Hydroxyprogesterone_caproate/rqTaBegr">hydroxyprogesterone caproate</a>, and <a href="/facts/Megestrol_acetate/Gdybmob0">megestrol acetate</a> are <a href="/facts/Biological_activity/jJ14jyvc">active</a> themselves and are not prodrugs, whereas the <a href="/facts/Testosterone_(medication)/sqLR44L3">testosterone</a> derivative <a href="/facts/Norethisterone_enantate/GrwqPRsn">norethisterone enantate</a> is a prodrug of <a href="/facts/Norethisterone/G1DJxlre">norethisterone</a>. Regardless of whether they are prodrugs or not, <a href="/facts/Steroid_ester/chPdKtR5">steroid esters</a> form a <a href="/facts/Depot_injection/wkVMHHdB">depot</a> and have an extended <a href="/facts/Duration_of_action/zdvfFshl">duration of action</a> due to a <a href="/facts/Depot_effect/wkVMHHdB">depot effect</a> when administered by <a href="/facts/Intramuscular_injection/PPNwW2wB">intramuscular</a> or <a href="/facts/Subcutaneous_injection/L4srK61u">subcutaneous injection</a>. </p><p>Because CICs are administered <a href="/facts/Parenteral/LsyoHTzH">parenterally</a>, they bypass the <a href="/facts/First-pass_metabolism/jfDsbq7S">first-pass effect</a> in the <a href="/facts/Liver/Rtp4Fk2b">liver</a> and <a href="/facts/Intestine/nK2zwqBS">intestines</a> that occurs with <a href="/facts/Oral_administration/vNQcvLVx">oral administration</a> of estrogens.<a class="footnote-ref" id="fnref:55" href="#fn:55"><sup>55</sup></a> However, is estimated that about 20% of an administered dose does still eventually pass through the liver.<a class="footnote-ref" id="fnref:56" href="#fn:56"><sup>56</sup></a> Hence, these preparations are not completely liver-neutral.<a class="footnote-ref" id="fnref:57" href="#fn:57"><sup>57</sup></a> Nonetheless, they have dramatically reduced hepatic effects relative to oral ethinylestradiol.<a class="footnote-ref" id="fnref:58" href="#fn:58"><sup>58</sup></a> In addition, parenteral <a href="/facts/Estradiol_(medication)/a8tPPllE">estradiol</a> in general has about 4- or 5-fold reduced potency in the liver than oral estradiol.<a class="footnote-ref" id="fnref:59" href="#fn:59"><sup>59</sup></a> </p> <p>CICs have <a href="/facts/Antigonadotropic/9FC1hu51">antigonadotropic</a> effects via their estrogenic and progestogenic activity and inhibit <a href="/facts/Fertility/5S7Xull5">fertility</a> and suppress <a href="/facts/Sex_hormone/mI6bkHII">sex hormone</a> levels. A single intramuscular injection of <a href="/facts/Estradiol_valerate/norethisterone_enanthate/z3Db9SYn">estradiol valerate/norethisterone enanthate</a> (5 mg/50 mg) (Mesigyna) has been found to strongly suppress testosterone levels in men.<a class="footnote-ref" id="fnref:60" href="#fn:60"><sup>60</sup></a> Testosterone levels decreased from a baseline of ~503 ng/dL to a trough of ~30 ng/dL (a 94% decrease) which occurred at day 7 post-injection.<a class="footnote-ref" id="fnref:61" href="#fn:61"><sup>61</sup></a> </p> Estradiol levels with combined injectable contraceptives<a class="footnote-ref" id="fnref:62" href="#fn:62"><sup>62</sup></a><table><tbody><tr><th>Preparation</th><th>Form</th><th>Dose</th><th>Estradiol Cmax</th><th>Estradiol Tmax</th></tr><tr><td><a href="/facts/Estradiol_valerate/norethisterone_enanthate/z3Db9SYn">EV/NETE</a></td><td>Oil solution</td><td>5 mg/50 mg</td><td>232–428 pg/mL</td><td>2 days</td></tr><tr><td><a href="/facts/Estradiol_cypionate/medroxyprogesterone_acetate/M9lXL31a">EC/MPA</a></td><td>Aqueous suspension</td><td>5 mg/25 mg</td><td>184–736 pg/mL</td><td>2–4 days</td></tr><tr><td rowspan="2"><a href="/facts/Estradiol_enanthate/dihydroxyprogesterone_acetophenide/TwnRDHCw">EEn/DHPA</a></td><td rowspan="2">Oil solution</td><td>10 mg/150 mg</td><td>314–317 pg/mL</td><td>4.2–8.1 days</td></tr><tr><td>5 mg/75 mg</td><td>148 pg/mL</td><td>6.5 days</td></tr></tbody></table> <ul><li>v</li><li>t</li><li>e</li></ul> Potencies and durations of natural estrogens by intramuscular injection<table><tbody><tr><th rowspan="2">Estrogen</th><th rowspan="2">Form</th><th colspan="2">Dose (mg)</th><th rowspan="2">Duration by dose (mg)</th></tr><tr><th>EPD</th><th>CICD</th></tr><tr><td rowspan="4"><a href="/facts/Estradiol_(medication)/a8tPPllE">Estradiol</a></td><td>Aq. soln.</td><td>?</td><td>–</td><td><1 d</td></tr><tr><td>Oil soln.</td><td>40–60</td><td>–</td><td>1–2 ≈ 1–2 d</td></tr><tr><td>Aq. susp.</td><td>?</td><td>3.5</td><td>0.5–2 ≈ 2–7 d; 3.5 ≈ >5 d</td></tr><tr><td>Microsph.</td><td>?</td><td>–</td><td>1 ≈ 30 d</td></tr><tr><td rowspan="3"><a href="/facts/Estradiol_benzoate/Cn6XNm6s">Estradiol benzoate</a></td><td>Oil soln.</td><td>25–35</td><td>–</td><td>1.66 ≈ 2–3 d; 5 ≈ 3–6 d</td></tr><tr><td>Aq. susp.</td><td>20</td><td>–</td><td>10 ≈ 16–21 d</td></tr><tr><td>Emulsion</td><td>?</td><td>–</td><td>10 ≈ 14–21 d</td></tr><tr><td><a href="/facts/Estradiol_dipropionate/S9PgwSUN">Estradiol dipropionate</a></td><td>Oil soln.</td><td>25–30</td><td>–</td><td>5 ≈ 5–8 d</td></tr><tr><td><a href="/facts/Estradiol_valerate/ML8T7DPx">Estradiol valerate</a></td><td>Oil soln.</td><td>20–30</td><td>5</td><td>5 ≈ 7–8 d; 10 ≈ 10–14 d;40 ≈ 14–21 d; 100 ≈ 21–28 d</td></tr><tr><td><a href="/facts/Estradiol_benzoate_butyrate/wdkezCaP">Estradiol benz. butyrate</a></td><td>Oil soln.</td><td>?</td><td>10</td><td>10 ≈ 21 d</td></tr><tr><td rowspan="2"><a href="/facts/Estradiol_cypionate/kaLBgAXC">Estradiol cypionate</a></td><td>Oil soln.</td><td>20–30</td><td>–</td><td>5 ≈ 11–14 d</td></tr><tr><td>Aq. susp.</td><td>?</td><td>5</td><td>5 ≈ 14–24 d</td></tr><tr><td><a href="/facts/Estradiol_enanthate/XPXqDS6n">Estradiol enanthate</a></td><td>Oil soln.</td><td>?</td><td>5–10</td><td>10 ≈ 20–30 d</td></tr><tr><td><a href="/facts/Estradiol_dienanthate/MrxpadvF">Estradiol dienanthate</a></td><td>Oil soln.</td><td>?</td><td>–</td><td>7.5 ≈ >40 d</td></tr><tr><td><a href="/facts/Estradiol_undecylate/X7XRB96d">Estradiol undecylate</a></td><td>Oil soln.</td><td>?</td><td>–</td><td>10–20 ≈ 40–60 d;25–50 ≈ 60–120 d</td></tr><tr><td><a href="/facts/Polyestradiol_phosphate/ylYxmxQ2">Polyestradiol phosphate</a></td><td>Aq. soln.</td><td>40–60</td><td>–</td><td>40 ≈ 30 d; 80 ≈ 60 d;160 ≈ 120 d</td></tr><tr><td rowspan="2"><a href="/facts/Estrone_(medication)/dyUM6hgR">Estrone</a></td><td>Oil soln.</td><td>?</td><td>–</td><td>1–2 ≈ 2–3 d</td></tr><tr><td>Aq. susp.</td><td>?</td><td>–</td><td>0.1–2 ≈ 2–7 d</td></tr><tr><td><a href="/facts/Estriol_(medication)/o5rJfAJs">Estriol</a></td><td>Oil soln.</td><td>?</td><td>–</td><td>1–2 ≈ 1–4 d</td></tr><tr><td><a href="/facts/Polyestriol_phosphate/p6CV1HeG">Polyestriol phosphate</a></td><td>Aq. soln.</td><td>?</td><td>–</td><td>50 ≈ 30 d; 80 ≈ 60 d</td></tr><tr><td colspan="6"></td></tr></tbody></table> <ul><li>v</li><li>t</li><li>e</li></ul> Parenteral potencies and durations of progestogens<a class="footnote-ref" id="fnref:63" href="#fn:63"><sup>63</sup></a><a class="footnote-ref" id="fnref:64" href="#fn:64"><sup>64</sup></a><table><tbody><tr><th scope="col" rowspan="2">Compound</th><th scope="col" rowspan="2">Form</th><th scope="col" colspan="3">Dose for specific uses (mg)<a class="footnote-ref" id="fnref:65" href="#fn:65"><sup>65</sup></a></th><th scope="col" rowspan="2">DOA<a class="footnote-ref" id="fnref:66" href="#fn:66"><sup>66</sup></a></th></tr><tr><th scope="col">TFD<a class="footnote-ref" id="fnref:67" href="#fn:67"><sup>67</sup></a></th><th scope="col">POICD<a class="footnote-ref" id="fnref:68" href="#fn:68"><sup>68</sup></a></th><th scope="col">CICD<a class="footnote-ref" id="fnref:69" href="#fn:69"><sup>69</sup></a></th></tr><tr><td><a href="/facts/Algestone_acetophenide/JDj6dy9c">Algestone acetophenide</a></td><td>Oil soln.</td><td>–</td><td>–</td><td>75–150</td><td>14–32 d</td></tr><tr><td><a href="/facts/Gestonorone_caproate/3zL6eCGJ">Gestonorone caproate</a></td><td>Oil soln.</td><td>25–50</td><td>–</td><td>–</td><td>8–13 d</td></tr><tr><td><a href="/facts/Hydroxyprogesterone_acetate/rX1D6V4d">Hydroxyprogest. acetate</a><a class="footnote-ref" id="fnref:70" href="#fn:70"><sup>70</sup></a></td><td>Aq. susp.</td><td>350</td><td>–</td><td>–</td><td>9–16 d</td></tr><tr><td><a href="/facts/Hydroxyprogesterone_caproate/rqTaBegr">Hydroxyprogest. caproate</a></td><td>Oil soln.</td><td>250–500<a class="footnote-ref" id="fnref:71" href="#fn:71"><sup>71</sup></a></td><td>–</td><td>250–500</td><td>5–21 d</td></tr><tr><td><a href="/facts/Medroxyprogesterone_acetate/q6XACYYp">Medroxyprog. acetate</a></td><td>Aq. susp.</td><td>50–100</td><td>150</td><td>25</td><td>14–50+ d</td></tr><tr><td><a href="/facts/Megestrol_acetate/Gdybmob0">Megestrol acetate</a></td><td>Aq. susp.</td><td>–</td><td>–</td><td>25</td><td>>14 d</td></tr><tr><td><a href="/facts/Norethisterone_enanthate/GrwqPRsn">Norethisterone enanthate</a></td><td>Oil soln.</td><td>100–200</td><td>200</td><td>50</td><td>11–52 d</td></tr><tr><td rowspan="3"><a href="/facts/Progesterone_(medication)/U3NtGBtS">Progesterone</a></td><td>Oil soln.</td><td>200<a class="footnote-ref" id="fnref:72" href="#fn:72"><sup>72</sup></a></td><td>–</td><td>–</td><td>2–6 d</td></tr><tr><td>Aq. soln.</td><td>?</td><td>–</td><td>–</td><td>1–2 d</td></tr><tr><td>Aq. susp.</td><td>50–200</td><td>–</td><td>–</td><td>7–14 d</td></tr><tr><td colspan="7"></td></tr></tbody></table> <h2 id="history">History</h2> <p>The first CIC to be studied was <a href="/facts/Estradiol_valerate/hydroxyprogesterone_caproate/MyAhD1k1">estradiol valerate/hydroxyprogesterone caproate</a> (EV/OHPC) in 1963, and the second CIC to be studied was <a href="/facts/Estradiol_enantate/algestone_acetophenide/TwnRDHCw">estradiol enantate/algestone acetophenide</a> (E2-EN/DHPA) in 1964.<a class="footnote-ref" id="fnref:73" href="#fn:73"><sup>73</sup></a><a class="footnote-ref" id="fnref:74" href="#fn:74"><sup>74</sup></a> In 1967, E2-EN/DHPA was in the late stages of clinical development.<a class="footnote-ref" id="fnref:75" href="#fn:75"><sup>75</sup></a><a class="footnote-ref" id="fnref:76" href="#fn:76"><sup>76</sup></a> By 1969, the medication was available for medical use under the brand name Perlutal.<a class="footnote-ref" id="fnref:77" href="#fn:77"><sup>77</sup></a> Within a few years, it was marketed under other brand names such as Topasel and Ova-Repos as well.<a class="footnote-ref" id="fnref:78" href="#fn:78"><sup>78</sup></a><a class="footnote-ref" id="fnref:79" href="#fn:79"><sup>79</sup></a><a class="footnote-ref" id="fnref:80" href="#fn:80"><sup>80</sup></a><a class="footnote-ref" id="fnref:81" href="#fn:81"><sup>81</sup></a> In addition, several other CICs had been introduced for medical use by 1972.<a class="footnote-ref" id="fnref:82" href="#fn:82"><sup>82</sup></a> By 1976, two major CICs were in use: E2-EN/DHPA (brand names Perlutan, Topasel) in <a href="/facts/Spain/bIyrB8EY">Spain</a> and <a href="/facts/Latin_America/Qmx9Jx2a">Latin America</a>, and EV/OHPC (brand name Injectable No. 1) in <a href="/facts/China/lTjIXY5p">China</a>.<a class="footnote-ref" id="fnref:83" href="#fn:83"><sup>83</sup></a> These CICs have been described as first-generation CICs.<a class="footnote-ref" id="fnref:84" href="#fn:84"><sup>84</sup></a> Two second-generation CICs, <a href="/facts/Estradiol_cypionate/medroxyprogesterone_acetate/M9lXL31a">estradiol cypionate/medroxyprogesterone acetate</a> (EC/MPA; brand names Cyclofem and later Lunelle) and <a href="/facts/Estradiol_valerate/norethisterone_enantate/z3Db9SYn">estradiol valerate/norethisterone enantate</a> (EV/NETE; brand name Mesigyna), were introduced for clinical use in 1993.<a class="footnote-ref" id="fnref:85" href="#fn:85"><sup>85</sup></a><a class="footnote-ref" id="fnref:86" href="#fn:86"><sup>86</sup></a><a class="footnote-ref" id="fnref:87" href="#fn:87"><sup>87</sup></a> On 5 October 2000, <a href="/facts/Pharmacia/wccB2D1R">Pharmacia</a> received FDA approval for Lunelle Monthly Contraceptive Injection.<a class="footnote-ref" id="fnref:88" href="#fn:88"><sup>88</sup></a> In April 2003, Pharmacia was acquired by <a href="/facts/Pfizer/1ADDanWs">Pfizer</a> (makers of <a href="/facts/Depot_medroxyprogesterone_acetate/q6XACYYp">depot medroxyprogesterone acetate</a>). In October 2003, Lunelle was discontinued in the <a href="/facts/United_States/P0sCdLe5">United States</a>. </p> <h2 id="society-and-culture">Society and culture</h2> <h3>Availability</h3> <p>CICs are available in many countries throughout the world, including widely throughout <a href="/facts/Central_America/CXKgTuxC">Central</a> and <a href="/facts/South_America/PhrFEMk7">South America</a>, in <a href="/facts/Mexico/IT5bwhdh">Mexico</a> and the <a href="/facts/Caribbean/zRI9aMCh">Caribbean</a>, in <a href="/facts/China/lTjIXY5p">China</a>, in several <a href="/facts/Southeast_Asia/VafwT517">Southeast Asian</a> and <a href="/facts/Africa/XkqQUP9s">African</a> countries, and in <a href="/facts/Turkey/KIYAWAs0">Turkey</a>.<a class="footnote-ref" id="fnref:89" href="#fn:89"><sup>89</sup></a><a class="footnote-ref" id="fnref:90" href="#fn:90"><sup>90</sup></a><a class="footnote-ref" id="fnref:91" href="#fn:91"><sup>91</sup></a><a class="footnote-ref" id="fnref:92" href="#fn:92"><sup>92</sup></a><a class="footnote-ref" id="fnref:93" href="#fn:93"><sup>93</sup></a><a class="footnote-ref" id="fnref:94" href="#fn:94"><sup>94</sup></a><a class="footnote-ref" id="fnref:95" href="#fn:95"><sup>95</sup></a><a class="footnote-ref" id="fnref:96" href="#fn:96"><sup>96</sup></a><a class="footnote-ref" id="fnref:97" href="#fn:97"><sup>97</sup></a> They were also previously available in the <a href="/facts/United_States/P0sCdLe5">United States</a>, <a href="/facts/Portugal/lYzwDQ63">Portugal</a>, and <a href="/facts/Spain/bIyrB8EY">Spain</a>, but have been discontinued in these countries.<a class="footnote-ref" id="fnref:98" href="#fn:98"><sup>98</sup></a><a class="footnote-ref" id="fnref:99" href="#fn:99"><sup>99</sup></a> </p> <h2 id="research">Research</h2> <p>Many other CICs have been studied but have not been approved or marketed for clinical use.<a class="footnote-ref" id="fnref:100" href="#fn:100"><sup>100</sup></a><a class="footnote-ref" id="fnref:101" href="#fn:101"><sup>101</sup></a><a class="footnote-ref" id="fnref:102" href="#fn:102"><sup>102</sup></a><a class="footnote-ref" id="fnref:103" href="#fn:103"><sup>103</sup></a><a class="footnote-ref" id="fnref:104" href="#fn:104"><sup>104</sup></a><a class="footnote-ref" id="fnref:105" href="#fn:105"><sup>105</sup></a> </p><p>The following are marketed CICs at different doses than those that are approved: </p> <ul><li><a href="/facts/Estradiol_valerate/ML8T7DPx">Estradiol valerate</a> 2.5 to 5 mg + <a href="/facts/Norethisterone_enantate/GrwqPRsn">norethisterone enantate</a> 50 to 80 mg in an <a href="/facts/Oil_solution/x1TBecVv">oil solution</a><a class="footnote-ref" id="fnref:106" href="#fn:106"><sup>106</sup></a><a class="footnote-ref" id="fnref:107" href="#fn:107"><sup>107</sup></a></li> <li><a href="/facts/Estradiol_valerate/ML8T7DPx">Estradiol valerate</a> 10 mg + <a href="/facts/Hydroxyprogesterone_caproate/rqTaBegr">hydroxyprogesterone caproate</a> 500 mg in an oil solution<a class="footnote-ref" id="fnref:108" href="#fn:108"><sup>108</sup></a></li> <li><a href="/facts/Estradiol_cypionate/kaLBgAXC">Estradiol cypionate</a> 2.5 to 10 mg + <a href="/facts/Medroxyprogesterone_acetate/q6XACYYp">medroxyprogesterone acetate</a> 12.5 to 50 mg in a <a href="/facts/Microcrystalline/5z8xALpK">microcrystalline</a> <a href="/facts/Aqueous_suspension/S3xp96TL">aqueous suspension</a><a class="footnote-ref" id="fnref:109" href="#fn:109"><sup>109</sup></a><a class="footnote-ref" id="fnref:110" href="#fn:110"><sup>110</sup></a></li> <li><a href="/facts/Estradiol_enantate/XPXqDS6n">Estradiol enantate</a> 5 to 50 mg + <a href="/facts/Algestone_acetophenide/JDj6dy9c">algestone acetophenide</a> 75 to 200 mg in an oil solution<a class="footnote-ref" id="fnref:111" href="#fn:111"><sup>111</sup></a><a class="footnote-ref" id="fnref:112" href="#fn:112"><sup>112</sup></a></li></ul> <p>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.<a class="footnote-ref" id="fnref:113" href="#fn:113"><sup>113</sup></a> </p><p>The following are CICs that have never been marketed: </p> <ul><li><a href="/facts/Estradiol_valerate/ML8T7DPx">Estradiol valerate</a> 20 mg + <a href="/facts/Medroxyprogesterone_acetate/q6XACYYp">medroxyprogesterone acetate</a> 100 mg in a microcrystalline aqueous suspension<a class="footnote-ref" id="fnref:114" href="#fn:114"><sup>114</sup></a><a class="footnote-ref" id="fnref:115" href="#fn:115"><sup>115</sup></a></li> <li><a href="/facts/Estradiol_undecylate/X7XRB96d">Estradiol undecylate</a> 5 to 10 mg + <a href="/facts/Norethisterone_enantate/GrwqPRsn">norethisterone enantate</a> 50 to 70 mg in an oil solution<a class="footnote-ref" id="fnref:116" href="#fn:116"><sup>116</sup></a><a class="footnote-ref" id="fnref:117" href="#fn:117"><sup>117</sup></a><a class="footnote-ref" id="fnref:118" href="#fn:118"><sup>118</sup></a><a class="footnote-ref" id="fnref:119" href="#fn:119"><sup>119</sup></a></li> <li><a href="/facts/Estradiol_cypionate/kaLBgAXC">Estradiol cypionate</a> + <a href="/facts/Norethisterone_enantate/GrwqPRsn">norethisterone enantate</a><a class="footnote-ref" id="fnref:120" href="#fn:120"><sup>120</sup></a><a class="footnote-ref" id="fnref:121" href="#fn:121"><sup>121</sup></a></li> <li><a href="/facts/Estradiol_valerate/ML8T7DPx">Estradiol valerate</a> 10 mg + <a href="/facts/Methenmadinone_caproate/cSd0SGAf">methenmadinone caproate</a> 60 mg (Lutofollin)<a class="footnote-ref" id="fnref:122" href="#fn:122"><sup>122</sup></a><a class="footnote-ref" id="fnref:123" href="#fn:123"><sup>123</sup></a><a class="footnote-ref" id="fnref:124" href="#fn:124"><sup>124</sup></a></li> <li><a href="/facts/Estradiol_hexahydrobenzoate/BQHTlj4P">Estradiol hexahydrobenzoate</a> 5 mg (oil solution) + <a href="/facts/Norgestrel/JszyHb9c">norgestrel</a> 25 mg (aqueous suspension)<a class="footnote-ref" id="fnref:125" href="#fn:125"><sup>125</sup></a><a class="footnote-ref" id="fnref:126" href="#fn:126"><sup>126</sup></a><a class="footnote-ref" id="fnref:127" href="#fn:127"><sup>127</sup></a><a class="footnote-ref" id="fnref:128" href="#fn:128"><sup>128</sup></a><a class="footnote-ref" id="fnref:129" href="#fn:129"><sup>129</sup></a></li> <li><a href="/facts/Estradiol_cypionate/kaLBgAXC">Estradiol cypionate</a> 3.5 to 5 mg + <a href="/facts/Megestrol_acetate/Gdybmob0">megestrol acetate</a> 25 mg in a microcrystalline aqueous suspension (marketed in China?)<a class="footnote-ref" id="fnref:130" href="#fn:130"><sup>130</sup></a><a class="footnote-ref" id="fnref:131" href="#fn:131"><sup>131</sup></a><a class="footnote-ref" id="fnref:132" href="#fn:132"><sup>132</sup></a></li> <li><a href="/facts/Estradiol_valerate/ML8T7DPx">Estradiol valerate</a> 3 to 5 mg + <a href="/facts/Chlormadinone_caproate/bE60AX1k">chlormadinone caproate</a> 80 mg in an oil solution<a class="footnote-ref" id="fnref:133" href="#fn:133"><sup>133</sup></a><a class="footnote-ref" id="fnref:134" href="#fn:134"><sup>134</sup></a><a class="footnote-ref" id="fnref:135" href="#fn:135"><sup>135</sup></a></li> <li><a href="/facts/Estradiol_valerate/ML8T7DPx">Estradiol valerate</a> 5 mg + <a href="/facts/Megestrol_acetate/Gdybmob0">megestrol acetate</a> 15 mg in an <a href="/facts/Aqueous_suspension/S3xp96TL">aqueous suspension</a> of <a href="/facts/Gelatin/RDeVU6HT">gelatin</a> <a href="/facts/Microsphere/bYKcPY7F">microspheres</a> (50–80 μm)<a class="footnote-ref" id="fnref:136" href="#fn:136"><sup>136</sup></a><a class="footnote-ref" id="fnref:137" href="#fn:137"><sup>137</sup></a><a class="footnote-ref" id="fnref:138" href="#fn:138"><sup>138</sup></a><a class="footnote-ref" id="fnref:139" href="#fn:139"><sup>139</sup></a></li> <li><a href="/facts/Estradiol_(medication)/a8tPPllE">Estradiol</a> 5 mg + <a href="/facts/Levonorgestrel/BHJc8A96">levonorgestrel</a> 7 mg in an <a href="/facts/Aqueous_suspension/S3xp96TL">aqueous suspension</a> of monolithic <a href="/facts/Microspheres/bYKcPY7F">microspheres</a> (80 μm) or in a <a href="/facts/Macrocrystalline/gD35BVKK">macrocrystalline</a> suspension (15 μm)<a class="footnote-ref" id="fnref:140" href="#fn:140"><sup>140</sup></a><a class="footnote-ref" id="fnref:141" href="#fn:141"><sup>141</sup></a></li> <li><a href="/facts/Estradiol_cypionate/kaLBgAXC">Estradiol cypionate</a> 5 mg + <a href="/facts/Levonorgestrel_butanoate/Cy4Kkbmj">levonorgestrel butanoate</a> 7 mg in an <a href="/facts/Aqueous_suspension/S3xp96TL">aqueous suspension</a><a class="footnote-ref" id="fnref:142" href="#fn:142"><sup>142</sup></a></li> <li><a href="/facts/Estradiol_benzoate/Cn6XNm6s">Estradiol benzoate</a> 5 to 10 mg + <a href="/facts/Norethisterone_enanthate/GrwqPRsn">norethisterone enanthate</a> 50 to 100 mg<a class="footnote-ref" id="fnref:143" href="#fn:143"><sup>143</sup></a></li> <li><a href="/facts/Mestranol/KULLfePb">Mestranol</a> 1.0–1.2 mg + <a href="/facts/Norethisterone/G1DJxlre">norethisterone</a> 10–12 mg in a <a href="/facts/Microcrystalline/5z8xALpK">microcrystalline</a> <a href="/facts/Aqueous_suspension/S3xp96TL">aqueous suspension</a> of defined <a href="/facts/Particle_size/KWwwGkn4">particle sizes</a> (125–177 μm)<a class="footnote-ref" id="fnref:144" href="#fn:144"><sup>144</sup></a><a class="footnote-ref" id="fnref:145" href="#fn:145"><sup>145</sup></a><a class="footnote-ref" id="fnref:146" href="#fn:146"><sup>146</sup></a><a class="footnote-ref" id="fnref:147" href="#fn:147"><sup>147</sup></a></li> <li><a href="/facts/Ethinylestradiol/aYRGLz8n">Ethinylestradiol</a> + <a href="/facts/Norethisterone/G1DJxlre">norethisterone</a><a class="footnote-ref" id="fnref:148" href="#fn:148"><sup>148</sup></a></li> <li><a href="/facts/Estradiol_(medication)/a8tPPllE">Estradiol</a> 5 mg and <a href="/facts/Progesterone_(medication)/U3NtGBtS">progesterone</a> 100 to 300 mg in an <a href="/facts/Aqueous_suspension/S3xp96TL">aqueous suspension</a> of monolithic <a href="/facts/Microsphere/bYKcPY7F">microspheres</a> or in a <a href="/facts/Macrocrystalline/gD35BVKK">macrocrystalline</a> suspension<a class="footnote-ref" id="fnref:149" href="#fn:149"><sup>149</sup></a><a class="footnote-ref" id="fnref:150" href="#fn:150"><sup>150</sup></a><a class="footnote-ref" id="fnref:151" href="#fn:151"><sup>151</sup></a><a class="footnote-ref" id="fnref:152" href="#fn:152"><sup>152</sup></a><a class="footnote-ref" id="fnref:153" href="#fn:153"><sup>153</sup></a><a class="footnote-ref" id="fnref:154" href="#fn:154"><sup>154</sup></a><a class="footnote-ref" id="fnref:155" href="#fn:155"><sup>155</sup></a></li> <li><a href="/facts/Polyestradiol_phosphate/ylYxmxQ2">Polyestradiol phosphate</a> 40 mg + <a href="/facts/Medroxyprogesterone_acetate/q6XACYYp">medroxyprogesterone acetate</a> 150 mg<a class="footnote-ref" id="fnref:156" href="#fn:156"><sup>156</sup></a><a class="footnote-ref" id="fnref:157" href="#fn:157"><sup>157</sup></a><a class="footnote-ref" id="fnref:158" href="#fn:158"><sup>158</sup></a></li></ul> <h2 id="see-also">See also</h2> <ul><li><a href="/facts/Special_Programme_on_Human_Reproduction/4qYWC4Vh">Special Programme on Human Reproduction</a></li> <li><a href="/facts/Concept_Foundation/mP9bkIGF">Concept Foundation</a></li> <li><a href="/facts/Extended_cycle_combined_hormonal_contraceptive/G5KecYCI">Extended cycle combined hormonal contraceptive</a></li> <li><a href="/facts/Reproductive_Health_Supplies_Coalition/52Pqe8eQ">Reproductive Health Supplies Coalition</a></li> <li><a href="/facts/Estradiol-containing_oral_contraceptive/Q6jFfTwF">Estradiol-containing oral contraceptive</a></li></ul> <h2 id="further-reading">Further reading</h2> <ul><li>Garza-Flores J (April 1994). "Pharmacokinetics of once-a-month injectable contraceptives". <i>Contraception</i>. 49 (4): 347–59. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2F0010-7824%2894%2990032-9">10.1016/0010-7824(94)90032-9</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/8013219">8013219</a>.</li> <li>Sang GW (April 1994). "Pharmacodynamic effects of once-a-month combined injectable contraceptives". <i>Contraception</i>. 49 (4): 361–85. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2F0010-7824%2894%2990033-7">10.1016/0010-7824(94)90033-7</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/8013220">8013220</a>.</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Bagade O, Pawar V, Patel R, Patel B, Awasarkar V, Diwate S (2014). 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"Pharmacology of estrogens and progestogens: influence of different routes of administration" (PDF). Climacteric. 8 Suppl 1: 3–63. doi:10.1080/13697130500148875. PMID 16112947. S2CID 24616324. <a href="http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf" target="_blank">http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf</a> <a href="#fnref:58" class="footnote-back-ref">↩</a></p></li> <li id="fn:59"><p>Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration" (PDF). Climacteric. 8 Suppl 1: 3–63. doi:10.1080/13697130500148875. PMID 16112947. S2CID 24616324. <a href="http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf" target="_blank">http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf</a> <a href="#fnref:59" class="footnote-back-ref">↩</a></p></li> <li id="fn:60"><p>Valle Alvarez, Doris del Cisne (11 May 2011). Efecto de una Dosis de 50 mg de Enantato de Noretisterona y 5 mg de Valerato de Estradiol en los Niveles de Testosterona Total en Hombres Mexicanos Sanos [Effect of a Dose of 50 mg of Norethisterone Enanthate and 5 mg of Estradiol Valerate on Total Testosterone Levels in Healthy Mexican Men] (MSc). National Polytechnic Institute of Mexico. <a href="http://repositoriodigital.ipn.mx/handle/123456789/12490" target="_blank">http://repositoriodigital.ipn.mx/handle/123456789/12490</a> <a href="#fnref:60" class="footnote-back-ref">↩</a></p></li> <li id="fn:61"><p>Valle Alvarez, Doris del Cisne (11 May 2011). Efecto de una Dosis de 50 mg de Enantato de Noretisterona y 5 mg de Valerato de Estradiol en los Niveles de Testosterona Total en Hombres Mexicanos Sanos [Effect of a Dose of 50 mg of Norethisterone Enanthate and 5 mg of Estradiol Valerate on Total Testosterone Levels in Healthy Mexican Men] (MSc). National Polytechnic Institute of Mexico. <a href="http://repositoriodigital.ipn.mx/handle/123456789/12490" target="_blank">http://repositoriodigital.ipn.mx/handle/123456789/12490</a> <a href="#fnref:61" class="footnote-back-ref">↩</a></p></li> <li id="fn:62"><p>Garza-Flores J (April 1994). "Pharmacokinetics of once-a-month injectable contraceptives". Contraception. 49 (4): 347–59. doi:10.1016/0010-7824(94)90032-9. PMID 8013219. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:62" class="footnote-back-ref">↩</a></p></li> <li id="fn:63"><p>Sources: [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52] <a href="#fnref:63" class="footnote-back-ref">↩</a></p></li> <li id="fn:64"><p>All given by intramuscular or subcutaneous injection. <a href="/wiki/Intramuscular_injection" target="_blank">/wiki/Intramuscular_injection</a> <a href="#fnref:64" class="footnote-back-ref">↩</a></p></li> <li id="fn:65"><p>Progesterone production during the luteal phase is ~25 (15–50) mg/day. The OIDTooltip ovulation-inhibiting dose of OHPC is 250 to 500 mg/month. <a href="/wiki/Luteal_phase" target="_blank">/wiki/Luteal_phase</a> <a href="#fnref:65" class="footnote-back-ref">↩</a></p></li> <li id="fn:66"><p>Duration of action in days. <a href="#fnref:66" class="footnote-back-ref">↩</a></p></li> <li id="fn:67"><p>Usually given for 14 days. <a href="#fnref:67" class="footnote-back-ref">↩</a></p></li> <li id="fn:68"><p>Usually dosed every two to three months. <a href="#fnref:68" class="footnote-back-ref">↩</a></p></li> <li id="fn:69"><p>Usually dosed once monthly. <a href="#fnref:69" class="footnote-back-ref">↩</a></p></li> <li id="fn:70"><p>Never marketed or approved by this route. <a href="#fnref:70" class="footnote-back-ref">↩</a></p></li> <li id="fn:71"><p>In divided doses (2 × 125 or 250 mg for OHPC, 10 × 20 mg for P4). <a href="#fnref:71" class="footnote-back-ref">↩</a></p></li> <li id="fn:72"><p>In divided doses (2 × 125 or 250 mg for OHPC, 10 × 20 mg for P4). <a href="#fnref:72" class="footnote-back-ref">↩</a></p></li> <li id="fn:73"><p>Benagiano, G.; Primiero, F.M. (1983). "Long Acting Contraceptives Present Status". Drugs. 25 (6): 570–609. doi:10.2165/00003495-198325060-00003. ISSN 0012-6667. PMID 6223801. S2CID 45898359. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:73" class="footnote-back-ref">↩</a></p></li> <li id="fn:74"><p>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. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:74" class="footnote-back-ref">↩</a></p></li> <li id="fn:75"><p>Hecht-Lucari, G. (1967). Recientes Progresos de la Terapia Hormonal en Ginecología. Revista Colombiana de Obstetricia y Ginecología, 18(5), 307-319. 10.18597/rcog.2584 https://revista.fecolsog.org/index.php/rcog/article/view/2584 <a href="https://revista.fecolsog.org/index.php/rcog/article/view/2584" target="_blank">https://revista.fecolsog.org/index.php/rcog/article/view/2584</a> <a href="#fnref:75" class="footnote-back-ref">↩</a></p></li> <li id="fn:76"><p>Benagiano, G.; Primiero, F.M. (1983). "Long Acting Contraceptives Present Status". Drugs. 25 (6): 570–609. doi:10.2165/00003495-198325060-00003. ISSN 0012-6667. PMID 6223801. S2CID 45898359. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:76" class="footnote-back-ref">↩</a></p></li> <li id="fn:77"><p>Hispano americano. Tiempo. May 1969. p. 46. Entre los anovulatorios más usados están los siguientes: Prolestrín, Sequens, Anovlar, Sequentex, Orlex, Ginovlar, Enginón, Perlutal, Depo-proveda, Aconcén, Ovral, Retex, Lorophyn y otros menos solicitados. <a href="https://books.google.com/books?id=xpQYAQAAIAAJ" target="_blank">https://books.google.com/books?id=xpQYAQAAIAAJ</a> <a href="#fnref:77" class="footnote-back-ref">↩</a></p></li> <li id="fn:78"><p>Botella-Llusia, J. (1970). Les ovaires au cours de l'administration des sterpides anticonceptionnels. [The ovaries during administration of contraceptive steroids.] In: Netter, A. L'Inhibition de l'ovulation; Colloque de la Societe Nationale pour l'Etude de la Sterilite et de la Fecondite. (Inhibition of ovulation: Proceedings of the National Society for the Study of Sterility and Fertility.) Paris, Masson, 1970. p. 141-156 <a href="#fnref:78" class="footnote-back-ref">↩</a></p></li> <li id="fn:79"><p>Universidad Complutense de Madrid (1971). Revista de la Universidad de Madrid. Prensa de la Universidad de Madrid. p. 11. <a href="https://books.google.com/books?id=IlJdLcRUfLIC" target="_blank">https://books.google.com/books?id=IlJdLcRUfLIC</a> <a href="#fnref:79" class="footnote-back-ref">↩</a></p></li> <li id="fn:80"><p>Liria, R. H. (1972). Anticoncepcionismo (Un problema de hoy, de ayer y de siempre). In Anales de medicina y cirugía (Vol. 52, No. 230, pp. 329-348). https://www.raco.cat/index.php/AnalesMedicina/article/download/99455/152590 <a href="https://www.raco.cat/index.php/AnalesMedicina/article/download/99455/152590" target="_blank">https://www.raco.cat/index.php/AnalesMedicina/article/download/99455/152590</a> <a href="#fnref:80" class="footnote-back-ref">↩</a></p></li> <li id="fn:81"><p>Harry W. Rudel; Fred A. Kinel (September 1972). "Oral Contraceptives. Human Fertility Studies and Side Effects". In M. Tausk (ed.). Pharmacology of the Endocrine System and Related Drugs: Progesterone, Progestational Drugs and Antifertility Agents. Vol. II. Pergamon Press. pp. 385–469. ISBN 978-0080168128. OCLC 278011135. <a href="978-0080168128" target="_blank">978-0080168128</a> <a href="#fnref:81" class="footnote-back-ref">↩</a></p></li> <li id="fn:82"><p>Harry W. Rudel; Fred A. Kinel (September 1972). "Oral Contraceptives. Human Fertility Studies and Side Effects". In M. Tausk (ed.). Pharmacology of the Endocrine System and Related Drugs: Progesterone, Progestational Drugs and Antifertility Agents. Vol. II. Pergamon Press. pp. 385–469. ISBN 978-0080168128. OCLC 278011135. <a href="978-0080168128" target="_blank">978-0080168128</a> <a href="#fnref:82" class="footnote-back-ref">↩</a></p></li> <li id="fn:83"><p>J. Bringer; B. Hedon (15 September 1995). Fertility and Sterility: A Current Overview. CRC Press. pp. 47–. ISBN 978-1-85070-694-6. <a href="978-1-85070-694-6" target="_blank">978-1-85070-694-6</a> <a href="#fnref:83" class="footnote-back-ref">↩</a></p></li> <li id="fn:84"><p>J. Bringer; B. Hedon (15 September 1995). Fertility and Sterility: A Current Overview. CRC Press. pp. 47–. ISBN 978-1-85070-694-6. <a href="978-1-85070-694-6" target="_blank">978-1-85070-694-6</a> <a href="#fnref:84" class="footnote-back-ref">↩</a></p></li> <li id="fn:85"><p>d'Arcangues C (1993). "Once-a-month injectable contraceptives". World Health Forum. 14 (4): 439–40. PMID 8185807. <a href="/wiki/PMID_(identifier)" target="_blank">/wiki/PMID_(identifier)</a> <a href="#fnref:85" class="footnote-back-ref">↩</a></p></li> <li id="fn:86"><p>Pramilla Senanayake; Malcolm Potts (14 April 2008). Atlas of Contraception, Second Edition. CRC Press. pp. 50–. ISBN 978-0-203-34732-4. <a href="978-0-203-34732-4" target="_blank">978-0-203-34732-4</a> <a href="#fnref:86" class="footnote-back-ref">↩</a></p></li> <li id="fn:87"><p>Newton JR, D'arcangues C, Hall PE (1994). "A review of "once-a-month" combined injectable contraceptives". J Obstet Gynaecol (Lahore). 4 Suppl 1: S1–34. doi:10.3109/01443619409027641. PMID 12290848. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:87" class="footnote-back-ref">↩</a></p></li> <li id="fn:88"><p>"FDA Approves Combined Monthly Injectable Contraceptive". Contraception Report. 12 (3). 2001. Archived from the original on September 26, 2006. <a href="https://web.archive.org/web/20060926040811/http://www.contraceptiononline.org/contrareport/article01.cfm?art=176" target="_blank">https://web.archive.org/web/20060926040811/http://www.contraceptiononline.org/contrareport/article01.cfm?art=176</a> <a href="#fnref:88" class="footnote-back-ref">↩</a></p></li> <li id="fn:89"><p>"International Drug Names from". Drugs.com. Retrieved 2022-04-30. <a href="https://www.drugs.com/international/" target="_blank">https://www.drugs.com/international/</a> <a href="#fnref:89" class="footnote-back-ref">↩</a></p></li> <li id="fn:90"><p>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. <a href="978-0-85369-840-1" target="_blank">978-0-85369-840-1</a> <a href="#fnref:90" class="footnote-back-ref">↩</a></p></li> <li id="fn:91"><p>"Micromedex Products: Please Login". <a href="http://www.micromedexsolutions.com/micromedex2/librarian/" target="_blank">http://www.micromedexsolutions.com/micromedex2/librarian/</a> <a href="#fnref:91" class="footnote-back-ref">↩</a></p></li> <li id="fn:92"><p>IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; International Agency for Research on Cancer (1 January 1999). Hormonal Contraception and Post-menopausal Hormonal Therapy (PDF). IARC. p. 65. ISBN 978-92-832-1272-0. Archived from the original (PDF) on 28 August 2021. Retrieved 18 September 2018. <a href="978-92-832-1272-0" target="_blank">978-92-832-1272-0</a> <a href="#fnref:92" class="footnote-back-ref">↩</a></p></li> <li id="fn:93"><p>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. Archived from the original (PDF) on 2017-08-10. Retrieved 2016-08-24. <a href="https://web.archive.org/web/20170810000242/http://www.wjpps.com/download/article/1412071798.pdf" target="_blank">https://web.archive.org/web/20170810000242/http://www.wjpps.com/download/article/1412071798.pdf</a> <a href="#fnref:93" class="footnote-back-ref">↩</a></p></li> <li id="fn:94"><p>Pramilla Senanayake; Malcolm Potts (14 April 2008). Atlas of Contraception, Second Edition. CRC Press. pp. 50–. ISBN 978-0-203-34732-4. <a href="978-0-203-34732-4" target="_blank">978-0-203-34732-4</a> <a href="#fnref:94" class="footnote-back-ref">↩</a></p></li> <li id="fn:95"><p>Newton JR, D'arcangues C, Hall PE (1994). "A review of "once-a-month" combined injectable contraceptives". J Obstet Gynaecol (Lahore). 4 Suppl 1: S1–34. doi:10.3109/01443619409027641. PMID 12290848. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:95" class="footnote-back-ref">↩</a></p></li> <li id="fn:96"><p>Garza-Flores J (April 1994). "Pharmacokinetics of once-a-month injectable contraceptives". Contraception. 49 (4): 347–59. doi:10.1016/0010-7824(94)90032-9. PMID 8013219. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:96" class="footnote-back-ref">↩</a></p></li> <li id="fn:97"><p>IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; World Health Organization; International Agency for Research on Cancer (2007). Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy. World Health Organization. pp. 431–. ISBN 978-92-832-1291-1. <a href="978-92-832-1291-1" target="_blank">978-92-832-1291-1</a> <a href="#fnref:97" class="footnote-back-ref">↩</a></p></li> <li id="fn:98"><p>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. <a href="978-0-85369-840-1" target="_blank">978-0-85369-840-1</a> <a href="#fnref:98" class="footnote-back-ref">↩</a></p></li> <li id="fn:99"><p>"Micromedex Products: Please Login". <a href="http://www.micromedexsolutions.com/micromedex2/librarian/" target="_blank">http://www.micromedexsolutions.com/micromedex2/librarian/</a> <a href="#fnref:99" class="footnote-back-ref">↩</a></p></li> <li id="fn:100"><p>Newton JR, D'arcangues C, Hall PE (1994). "A review of "once-a-month" combined injectable contraceptives". J Obstet Gynaecol (Lahore). 4 Suppl 1: S1–34. doi:10.3109/01443619409027641. PMID 12290848. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:100" class="footnote-back-ref">↩</a></p></li> <li id="fn:101"><p>Garza-Flores J (April 1994). "Pharmacokinetics of once-a-month injectable contraceptives". Contraception. 49 (4): 347–59. doi:10.1016/0010-7824(94)90032-9. PMID 8013219. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:101" class="footnote-back-ref">↩</a></p></li> <li id="fn:102"><p>Koetsawang S (April 1994). "Once-a-month injectable contraceptives: efficacy and reasons for discontinuation". Contraception. 49 (4): 387–98. doi:10.1016/0010-7824(94)90034-5. PMID 8013221. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:102" class="footnote-back-ref">↩</a></p></li> <li id="fn:103"><p>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. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:103" class="footnote-back-ref">↩</a></p></li> <li id="fn:104"><p>Mokhtar K. Toppozada (1983). "Monthly Injectable Contraceptives". In Alfredo Goldsmith; Mokhtar Toppozada (eds.). Long-Acting Contraception. pp. 93–103. OCLC 35018604. <a href="https://scholar.google.com/scholar?cluster=14664537528797672080" target="_blank">https://scholar.google.com/scholar?cluster=14664537528797672080</a> <a href="#fnref:104" class="footnote-back-ref">↩</a></p></li> <li id="fn:105"><p>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. Archived from the original (PDF) on 2017-08-10. Retrieved 2016-08-24. <a href="https://web.archive.org/web/20170810000242/http://www.wjpps.com/download/article/1412071798.pdf" target="_blank">https://web.archive.org/web/20170810000242/http://www.wjpps.com/download/article/1412071798.pdf</a> <a href="#fnref:105" class="footnote-back-ref">↩</a></p></li> <li id="fn:106"><p>Newton JR, D'arcangues C, Hall PE (1994). "A review of "once-a-month" combined injectable contraceptives". J Obstet Gynaecol (Lahore). 4 Suppl 1: S1–34. doi:10.3109/01443619409027641. PMID 12290848. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:106" class="footnote-back-ref">↩</a></p></li> <li id="fn:107"><p>Garza-Flores J (April 1994). "Pharmacokinetics of once-a-month injectable contraceptives". Contraception. 49 (4): 347–59. doi:10.1016/0010-7824(94)90032-9. PMID 8013219. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:107" class="footnote-back-ref">↩</a></p></li> <li id="fn:108"><p>Newton JR, D'arcangues C, Hall PE (1994). "A review of "once-a-month" combined injectable contraceptives". J Obstet Gynaecol (Lahore). 4 Suppl 1: S1–34. doi:10.3109/01443619409027641. PMID 12290848. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:108" class="footnote-back-ref">↩</a></p></li> <li id="fn:109"><p>Newton JR, D'arcangues C, Hall PE (1994). "A review of "once-a-month" combined injectable contraceptives". J Obstet Gynaecol (Lahore). 4 Suppl 1: S1–34. doi:10.3109/01443619409027641. PMID 12290848. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:109" class="footnote-back-ref">↩</a></p></li> <li id="fn:110"><p>Garza-Flores J (April 1994). 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