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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Natural progesterone is a crystalline substance similar to androsterone. It induces extensive progestational development necessary for implantation of the ovum.

Specific Substances

    A) GENERAL TERMS
    1) Progestational agents
    2) Progestins
    Etonogestrel
    1) Molecular Formula: C22-H28-02
    2) CAS 54048-10-1
    3) Etonogestreli
    4) Etonogestrel
    5) Etonogestrelum
    Levonorgestrel
    1) Molecular Formula: C21H28O2
    2) CAS 121714-72-5
    3) LNG
    4) 13-beta-ethyl-17-alpha-ethynyl-17-beta-hydroxygon-4-en-3-one
    Medrogestone
    1) AY 62022
    2) 6,17alpha-dimethyl-6-dehydroprogesterone
    3) 6,17-Dimethylpregna-4,6-diene-3,20-dione
    MedroxyPROGESTERone
    1) 17alpha-Hydroxy-6alpha-methylpro-
    2) gesterone
    3) 6alpha-methyl-17alpha-hydroxy-
    4) progesterone
    5) 6alpha-methyl-4-pregnen-17alpha-
    6) ol-3,20-dione
    7) 17-Hydroxy-6-methylpregn-4-ene-3,
    8) 20-dione
    Norethandrolone
    1) 17-Hydroxy-19-norpregn-4-en-3-one
    2) 17alpha-ethyl-19-nortestosterone
    3) 17alpha-ethyl-17-hydroxy-4-norandrosten-3-one
    4) 17alpha-ethyl-17-hydroxy-19-norandrost-4-en-3
    5) -one
    Norethindrone
    1) Anhydrohydroxynorprogesterone
    2) 17-Hydroxy-19-norpregn-4-en-20-yn-3-one
    3) 19-nor-17alpha-ethynyltestosterone
    4) 17alpha-Ethynyl-19-nortestosterone
    5) 19-nor-17alpha-ethynyl-17beta-hydroxy-4-
    6) androsten-3-one
    7) 19-nor-17alpha-ethynylandrosten-
    8) 17beta-ol-3-one
    9) 19-Norethisterone
    Norethynodrel
    1) 17-Hydroxy-19-nor-17alpha-
    2) pregn5(10)-en-20-yn-3-one
    3) 17alpha-ethynyl-17-hydroxy-5(10)
    4) -estren-3-one
    5) 13-methyl-17-ethynyl-17-hydroxy-
    6) 1,2,3,4,6,7,-8,9,11,12,13,14,16,
    7) 17-tetradecahydro-15H-cyclopental
    8) (alpha)-phenanthren-3-one
    Progesterone
    1) Corporin
    2) delta-4-Pregnene-3,20-dione
    3) Luteohormone
    4) Luteosterone
    5) Luteum hormone
    6) Pregn-4-ene-3,20-dione
    7) Progestin
    8) CAS 57-83-0
    17alpha-Hydroxyprogesterone
    1) 17-Hydroxypregn-4-ene-3,20-dione
    2) 4-pregnen-17alpha-ol-3,20-dione
    17alpha-Hydroxyprogesterone Caproate
    1) 17-((1-Oxo-hexyl)oxy)pregn-4-ene-3,20-dione
    2) 17-hydroxypregn-4-ene-3,20-dione hexanoate
    3) 17alpha-hydroxyprogesterone hexanoate

    1.2.1) MOLECULAR FORMULA
    1) HYDROXYPROGESTERONE CAPROATE: C27H40O4
    2) NORETHINDRONE ACETATE: C22H28O3
    3) PROGESTERONE: C21H30O2

Available Forms Sources

    A) FORMS
    1) A variety of prescription products are available as oral, parenteral, and transdermal dosage forms. An intrauterine progesterone contraceptive system (Progestasert(R)), releasing 65 mcg/day progesterone for one year, is available (Prod Info Progestasert(R), intrauterine progesterone contraceptive system, 1986) as well as a levonorgestrel-releasing intrauterine system (Skyla(R)) releasing 5 mcg/day to 14 mcg/day over a 3 year period (Prod Info SKYLA(TM) intrauterine system, 2013).
    2) The specific drug entities are hydroxyprogesterone, levonorgestrel, medrogestone, medroxyPROGESTERone, megestrol, norethandrolone, norethindrone, norethynodrel, and progesterone.
    a) Please refer to MEGESTROL management for more information.
    B) SOURCES
    1) Progestins are hormones naturally secreted by the ovary mainly from the corpus luteum during the second half of the menstrual cycle, from the placenta during pregnancy and adrenal glands in both sexes. Progestins are also available as synthetic steroidal compounds.
    C) USES
    1) Progestins are used for a number of purposes, including treatment of amenorrhea, abnormal uterine bleeding, hypoventilation, contraception (routine, as well as emergency contraception) and management of bleeding during post-menopausal therapy (Sutton et al, 1975).
    2) LEVONORGESTREL: Levonorgestrel (LNG) is used as a contraceptive to prevent pregnancy (Prod Info SKYLA(TM) intrauterine system, 2013).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Rarely do acute ingestions result in obvious clinical manifestations. Most adverse effects relate to chronic or high-dose therapy. Chronic toxicity can result in jaundice, headache, dizziness, irregular menses, mastalgia, bloating, depression, and decreased libido.
    0.2.5) CARDIOVASCULAR
    A) Chronic toxicity may produce an increased risk of thromboembolism.
    0.2.7) NEUROLOGIC
    A) Besides weight gain, headache, dizziness, irregular menses, mastalgia, and decreased libido, chronic ingestion may also aggravate epilepsy and migraine.
    0.2.9) HEPATIC
    A) Cholestatic jaundice, hepatitis, or porphyria may occur.
    0.2.20) REPRODUCTIVE
    A) MedroxyPROGESTERone acetate, norethindrone acetate, and norethynodrel are classified as FDA pregnancy category X. Ethisterone and hydroxyprogesterone are classified as FDA pregnancy category D. Hydroxyprogesterone caproate and progesterone are classified as FDA pregnancy category B. Ingestion of progestins during early pregnancy may cause virilization of the female fetus, chromosomal abnormalities, or congenital malformations.

Laboratory Monitoring

    A) With chronic toxicity, obtain a baseline CBC, hepatic and renal function tests.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    B) Single acute overdoses will seldom result in toxicity. Supportive treatment is adequate in most situations.
    C) In chronic toxicity obtain a baseline CBC, hepatic and renal function tests, and treat symptomatically.

Range Of Toxicity

    A) Toxicity is unlikely following an acute overdose. There are insufficient data in the literature to assess the range of toxicity in terms of mg/kg ingested.

Clinical Effects

Summary Of Exposure

    A) Rarely do acute ingestions result in obvious clinical manifestations. Most adverse effects relate to chronic or high-dose therapy. Chronic toxicity can result in jaundice, headache, dizziness, irregular menses, mastalgia, bloating, depression, and decreased libido.

Vital Signs

    3.3.4) BLOOD PRESSURE
    A) It has been suggested that the progestin content of oral contraceptives is associated with increases in blood pressure (Royal College of General Practitioners, 1977).

Heent

    3.4.3) EYES
    A) INTRAOCULAR PRESSURE has been reported to increase in one case.
    1) CASE REPORT - An increase of 5 mmHg was seen in a postmenopausal female who was given 10 mg orally (Paterson & Miller, 1963).

Cardiovascular

    3.5.1) SUMMARY
    A) Chronic toxicity may produce an increased risk of thromboembolism.
    3.5.2) CLINICAL EFFECTS
    A) THROMBOEMBOLIC DISORDER
    1) Chronic therapy may result in thromboembolic events (Ambrus et al, 1976).

Neurologic

    3.7.1) SUMMARY
    A) Besides weight gain, headache, dizziness, irregular menses, mastalgia, and decreased libido, chronic ingestion may also aggravate epilepsy and migraine.
    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) Headache may be a manifestation of chronic toxicity. Pseudotumor cerebri occurs with depot medroxyPROGESTERone use (Bahemuka, 1981).
    B) DROWSY
    1) Somnolence was seen in humans given 200 to 500 mg of progesterone intravenously (Sollmann, 1964).

Hepatic

    3.9.1) SUMMARY
    A) Cholestatic jaundice, hepatitis, or porphyria may occur.
    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) SUMMARY - Cholestatic jaundice, hepatitis, or porphyria may occur. Hepatitis has been associated with ingestion of therapeutic doses of progesterone (Sujuan et al, 1988).
    B) DRUG-INDUCED PORPHYRIA
    1) Acute attacks of porphyria can be precipitated by progesterone (Moore & McColl, 1987; Eales, 1971; Granick & Kappas, 1967).
    a) SYMPTOMS are nonspecific and may mimic other, more common diseases (Anderson, 1991).
    1) Common signs and symptoms of an acute attack may include abdominal pain, nausea, vomiting, constipation, tachycardia, hypertension, depression, anxiety, irritability, fatigue or other mood changes, restlessness, fine tremors, excessive sweating, pain in the limbs, head, neck, or chest, muscle weakness, or sensory loss.
    2) These patients may be predisposed to chronic hypertension and impaired renal function.
    3) Seizures or peripheral motor neuropathy may also occur.
    b) LABORATORY FINDINGS - Increased urinary excretion of porphyrin precursors delta-aminolevulinic acid and porphobilinogen (Anderson, 1991).
    C) CHOLESTATIC HEPATITIS
    1) Progestins may cause cholestatic jaundice (Prod Info Gesterol(R) 50, progesterone, 1990) Prod Info Hydroxyprogesterone caproate, 1990).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) AMENORRHEA
    1) Oligomenorrhea or amenorrhea may be seen with chronic toxicity (Whitelaw, 1966).
    a) Abnormalities in the menstrual cycle may occur with contraceptive use of progestins. Common effects are spotting, irregular and infrequent menstrual cycles, and amenorrhea (von Eickstedt & Lang, 1988).
    2) Women who receive only progestin contraception develop more functional ovarian cysts.
    B) LACK OF LIBIDO
    1) Decreased libido may be seen in chronic toxicity (Gilman et al, 1985).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) BLOOD COAGULATION PATHWAY FINDING
    1) LACK OF EFFECT
    a) Unopposed progestins or progestins cycled with estrogen have not been found to adversely affect coagulation factors (Bush, 1986).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) CASE REPORT - Mucha-Habermann Disease was seen in a 35-year-old who had taken 35 mg/day orally. Scattered papular lesions and hemorrhagic papules developed over a 5-day course (Hollander & Grots, 1973).
    B) ALOPECIA
    1) Alopecia has rarely occurred during treatment (Prod Info, 1985).
    C) ACNE
    1) Levonorgestrel minipill may be associated with acne (Prod Info Levora(R), 2001).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) Short-term use of unopposed progestin therapy was not reported to be associated with altered carbohydrate metabolism or hyperglycemia (Fritz & Speroff, 1983).
    B) VIRILIZATION
    1) Androgenic effects such as hirsutism, acne, and voice deepening may be seen with androgenic-type progestins (JEF Reynolds , 1988).

Reproductive

    3.20.1) SUMMARY
    A) MedroxyPROGESTERone acetate, norethindrone acetate, and norethynodrel are classified as FDA pregnancy category X. Ethisterone and hydroxyprogesterone are classified as FDA pregnancy category D. Hydroxyprogesterone caproate and progesterone are classified as FDA pregnancy category B. Ingestion of progestins during early pregnancy may cause virilization of the female fetus, chromosomal abnormalities, or congenital malformations.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALY
    1) MEDROXYPROGESTERONE ACETATE
    a) MedroxyPROGESTERone in oral doses of 80 to 120 mg daily (from the 5th to the 7th week of pregnancy until at least the 18th week) was not associated with the occurrence of teratogenic effects in a study involving 1016 pregnancies. The drug was administered for recurrent pregnancy loss or threatened abortion. Congenital abnormalities were observed in 15 of 366 infants in the medroxyPROGESTERone group and 15 of 428 in the untreated group (4.1% and 3.5%, respectively). The data suggests that medroxyPROGESTERone given in high doses during the first trimester of pregnancy does not pose a measurable teratogenic risk (Yovich et al, 1988).
    b) A retrospective cohort study examined more than 2000 infants exposed to female sex hormones between 1954 and 1963. Compared with a control group, the total number of malformations and malformations of the genitals in male infants, were higher among exposed children than unexposed (Hemminki et al, 1999). It is important to note that modern contraceptives contain lower doses of hormones than at the time these infants were exposed.
    c) A review and meta-analysis of prospective studies to date of the association between oral contraceptive use during or just prior to pregnancy and the frequency of congenital malformations in offspring was reported (Bracken, 1990). No significant elevations in relative risk were found for all malformations taken together, or for heart defects or limb reduction defects that were both evaluated separately.
    d) Oral contraceptive use immediately prior to or during pregnancy appears to present a risk (not exceeding 5%) with regard to the incidence of visible malformations. Data on the contraceptive usage of 3,002 mothers of children with malformations was prospectively collected. Compared to matched control mothers, the types of malformations seen were similar among contraceptive users and nonusers. A risk ratio of 0.95 was reported for the oral contraceptive users, that actually represents a slightly smaller risk of malformation in infants (Savolainen et al, 1981).
    e) Inadvertent exposure to medroxyPROGESTERone acetate during the early stages of pregnancy resulted in little or no increase in risk of birth defects. There was no evidence of adverse effects (ie, physical health, intellectual, social, or sexual development) in children exposed to medroxyPROGESTERone in utero and followed to adolescence (Prod Info DEPO-PROVERA CI(R) suspension for IM injection, 2010; Prod Info depo-subQ provera 104(TM) suspension for injection, 2009).
    f) Although a clear association has not been made between medroxyPROGESTERone, and hypospadias, labial fusion, and clitoral enlargement, there is an increased risk of these conditions in children whose mothers were exposed to medroxyPROGESTERone acetate during the first trimester of pregnancy (Prod Info PROVERA(R) oral tablets, 2007).
    B) LACK OF EFFECT
    1) HYDROXYPROGESTERONE
    a) In a vehicle placebo-controlled clinical trail (n=310), there was no evidence of teratogenicity in infants whose mothers received hydroxyprogesterone IM at weekly doses of 250 mg during the second and third trimesters of their pregnancies. Long-term (2 to 5 years) follow-up safety data (n=194) also did not demonstrate teratogenic risk to infants (Prod Info MAKENA(TM) IM injection, 2011).
    b) Although there have been case reports of altered genitalia in both male and female offspring whose mothers were treated with hydroxyprogesterone (Schardein, 1985), there have been several studies that did not find an association with hydroxyprogesterone and any type of congenital anomaly (Resseguie et al, 1985; Michaelis et al, 1983; Katz et al, 1985; Heinonen et al, 1977).
    2) PROGESTERONE
    a) REVERSAL OF MIFEPRISTONE-INDUCED ABORTION: In a case series, progesterone administration was effective in 4 of 6 patients for the reversal of mifepristone-induced abortion. All subjects (age, 19 to 25 years) chose to attempt reversal of pregnancy termination after ingestion of mifepristone, but prior to ingestion of misoprostol. The gestational age at intervention was 7 to 11 weeks in 5 cases and unknown in 1 case. In the 4 successful cases, patients received an initial dose of progesterone in oil 200 mg IM 30 to 72 hours after mifepristone ingestion, with additional doses of progesterone in oil 200 mg IM or oral micronized progesterone administered at various schedules and durations. In one unsuccessful case, the patient received progesterone in oil 200 mg IM for 1 dose (timing of mifepristone unknown) with abortion completed shortly thereafter. In the other unsuccessful case, the patient received progesterone 200 mg oral capsule intravaginally 7 hours following mifepristone administration, plus 2 doses of progesterone in oil 200 mg IM at 18 hours and at day 2, with abortion completed on day 3. In the 4 successful cases, viable infants were subsequently delivered between 37 and 40 weeks gestation, without neonatal complications or birth defects (Delgado & Davenport, 2012).
    3) ETHINYL ESTRADIOL/ETONOGESTREL
    a) An increased risk of birth defects has not ben demonstrated in infants following maternal use before or during early pregnancy. There is no evidence of teratogenicity, particularly in limb reduction or cardiovascular defects when women inadvertently used the combination contraceptive early in pregnancy (Prod Info NuvaRing(R) vaginal ring, 2013).
    C) ANIMAL STUDIES
    1) HYDROXYPROGESTERONE
    a) MICE AND RATS: There was no evidence of impaired fertility or fetal harm when mice and rats were exposed to hydroxyprogesterone caproate doses up to 95 and 5 times the human dose, respectively (Prod Info MAKENA(TM) IM injection, 2011).
    b) MONKEYS: No evidence of teratogenicity occurred in either rhesus or cynomolgus monkeys (Prod Info MAKENA(TM) IM injection, 2011).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The following agents have been classified as FDA pregnancy category X: MEDROXYPROGESTERONE ACETATE, NORETHINDRONE ACETATE, NORETHYNODREL (Briggs et al, 1994),
    2) The following agents have been classified as FDA pregnancy category D: ETHISTERONE and HYDROXYPROGESTERONE (Briggs et al, 1994; Briggs et al, 1994)
    3) The following agent has been classified as FDA pregnancy category B: HYDROXYPROGESTERONE CAPROATE and PROGESTERONE (Prod Info PROMETRIUM(R) capsules, 2004; Prod Info MAKENA(TM) IM injection, 2011)
    4) The manufacturer has not published a pregnancy category for this agent, but it is contraindicated during pregnancy: ETHINYL ESTRADIOL/ETONOGESTREL (Prod Info NuvaRing(R) vaginal ring, 2013).
    B) CARDIOVASCULAR DEFECTS
    1) MEDROXYPROGESTERONE ACETATE
    a) In a review of the effects of several progestational agents, including medroxyPROGESTERone, an increase in the incidence of cardiovascular defects was observed (Heinonen et al, 1977a); however, reevaluation of the data indicated that there was no association between progestin therapy and cardiac defects (Wiseman & Dodds-Smith, 1984). A retrospective analysis found a higher number of infants with congenital heart defects were exposed to oral contraceptives compared to healthy children. Two out of 18 infants with heart defects were exposed to hormones in utero (Janerich et al, 1977).
    C) CHROMOSOMAL ANOMALIES
    1) Congenital malformations such as Tetralogy of Fallot or chromosomal anomalies such as genitourinary abnormalities, may also occur (Heinonen, 1977; Evans, 1980).
    2) MEDROXYPROGESTERONE ACETATE
    a) Although there have been case reports of altered genitalia in both male and female offspring whose mothers were treated with medroxyPROGESTERone (Prod Info Provera(R), 1994; Schardein, 1985a), there have been several studies that did not find an association with medroxyPROGESTERone and any type of congenital anomaly (Resseguie et al, 1985a; Michaelis et al, 1983a; Katz et al, 1985a; Heinonen et al, 1977a).
    D) VIRILISM
    1) Maternal ingestion during early pregnancy may cause virilization of the female fetus (Lebech & Ottesen, 1984). Congenital malformations such as Tetralogy of Fallot or chromosomal anomalies such as genitourinary abnormalities, may also occur (Heinonen, 1977; Evans, 1980).
    2) NORETHINDRONE ACETATE
    a) Norethindrone acetate may cause virilization of the female fetus in the first trimester of pregnancy. Mild virilization of the external genitalia of female fetuses has been noted with some progestational drugs (Prod Info AYGESTIN(R) oral tablets, 2007).
    E) FETAL MALFORMATIONS
    1) Studies have shown no significant adverse effects on fetal development in association with long-term use of oral progestins . However, pregnancy should be ruled out before hormonal contraceptive use (Prod Info ORTHO MICRONOR(R) oral tablets, 2008).
    F) HYPOSPADIAS
    1) MEDROXYPROGESTERONE ACETATE
    a) Maternal ingestion of medroxyPROGESTERone acetate may increase the risk of hypospadias in male infants during the first trimester of pregnancy (Prod Info PROVERA(R) oral tablets, 2007).
    G) ABORTION
    1) Use of progestins during pregnancy may cause abortions (JEF Reynolds , 1988).
    2) MEDROXYPROGESTERONE ACETATE
    a) The FDA maintains that progestational agents are not effective for the prevention of recurrent abortion, and that the majority of spontaneous abortions are due to defective ova. The FDA further warns that the uterine-relaxant properties of progestogens may delay spontaneous abortions of fertilized defective ova, thus putting these women at increased risk of complications. For these reasons, as well as reported cases of genital abnormalities in both male and female offspring, the FDA recommends that progestational agents not be used during the first 4 months of pregnancy (Prod Info Provera(R), 1994).
    b) MedroxyPROGESTERone has been used to prevent spontaneous abortion in early pregnancy, but the effectiveness of this therapy is not established (Keirse, 1990; Daya, 1989; Goldstein et al, 1989).
    3) PROGESTERONE
    a) REVERSAL OF MIFEPRISTONE-INDUCED ABORTION: In a case series, progesterone administration was effective in 4 of 6 patients for the reversal of mifepristone-induced abortion. All subjects (age, 19 to 25 years) chose to attempt reversal of pregnancy termination after ingestion of mifepristone, but prior to ingestion of misoprostol. The gestational age at intervention was 7 to 11 weeks in 5 cases and unknown in 1 case. In the 4 successful cases, patients received an initial dose of progesterone in oil 200 mg IM 30 to 72 hours after mifepristone ingestion, with additional doses of progesterone in oil 200 mg IM or oral micronized progesterone administered at various schedules and durations. In one unsuccessful case, the patient received progesterone in oil 200 mg IM for 1 dose (timing of mifepristone unknown) with abortion completed shortly thereafter. In the other unsuccessful case, the patient received progesterone 200 mg oral capsule intravaginally 7 hours following mifepristone administration, plus 2 doses of progesterone in oil 200 mg IM at 18 hours and at day 2, with abortion completed on day 3. In the 4 successful cases, viable infants were subsequently delivered between 37 and 40 weeks gestation, without neonatal complications or birth defects (Delgado & Davenport, 2012).
    H) ANIMAL STUDIES
    1) HYDROXYPROGESTERONE
    a) MONKEYS: There was evidence of embryolethality in rhesus monkeys; however, cynomolgus monkeys exposed to 1 and 10 times the human dose every week between gestational days 20 and 146 had no evidence of embryolethality (Prod Info MAKENA(TM) IM injection, 2011).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Detectable amounts of progestins have been identified in the breast milk, including hydroxyprogesterone caproate, medroxyPROGESTERone acetate, and norethindrone acetate (Prod Info MAKENA(TM) IM injection, 2011; Prod Info AYGESTIN(R) oral tablets, 2007).
    2) In many studies, there have been no adverse effects of progestin on nursing or the health of the nursing infant (Prod Info MAKENA(TM) IM injection, 2011).
    3) Postmarketing cases of reduced milk production have been reported in nursing mothers. Detectable steroid levels of progestins in infant plasma have been noted (Prod Info PLAN B(R)ONE-STEP oral tablets, 2009; Prod Info ORTHO MICRONOR(R) oral tablets, 2008).
    4) LEVONORGESTREL
    a) Use of levonorgestrel as emergency contraceptive in breastfeeding mothers did not require interruption of nursing. The most commonly reported maternal adverse effect was vaginal bleeding; however, this was reported less frequently in the study group compared with the control group. There were no reported adverse effects in the breastfeeding infants. The maternal subjective estimation of milk volume production was decreased in 7% of mother's administered levonorgestrel (n=71) and 6% of mothers in the control group (n=69). Breastfeeding was reinitiated in less than 8 hours in 75% of mothers (Polakow-Farkash et al, 2013).
    5) MEDROXYPROGESTERONE ACETATE
    a) According to the CDC, depot medroxyPROGESTERone use during breastfeeding from 1 month to greater than 6 months postpartum is acceptable without restriction and the advantages of use at less than 1 month postpartum generally outweigh the theoretical and proven risks to the infant (Centers for Disease Control and Prevention, 2010).
    b) Although medroxyPROGESTERone acetate is known to be secreted in breast milk, the developmental and behavioral effects were studied through puberty in children with exposure through breast milk, and no adverse effects were observed. There were no reported adverse effects in the amount, quality and composition of the breast milk (Prod Info depo-subQ provera 104(TM) suspension for injection, 2009).
    c) In a prospective, non-randomized trial involving 319 postpartum women, there were no adverse events associated with the use of progestin-only contraception administered within the first 3 days of delivery (Halderman & Nelson, 2002). According to information put forth by the American College of Obstetrics and Gynecologists, progestin-only oral contraceptives may be started 2 to 3 weeks postpartum. Alternatively, depot medroxyPROGESTERone acetate or hormonal implants can be started after 6 weeks postpartum. Combined estrogen-progestin contraceptives may be started at 6 weeks postpartum if lactation is well established, and the infant's nutritional intake is appropriate (American College of Obstetricians and Gynecologists, 2007).
    d) MedroxyPROGESTERone is distributed in breast milk at very small concentrations not significant to a nursing infant. After receiving medroxyPROGESTERone 150 mg intramuscularly in a depot formulation, the following breast milk concentrations have been reported: 1.36 to 10.03 nanograms (ng)/mL at 1 week; 1.45 to 3.36 ng/mL at 2 weeks; 1.68 to 2.38 ng/mL at 4 weeks; 0.76 ng/mL at 50 to 56 days; 0.56 ng/mL at 87 days (Schwallie, 1981).
    e) MedroxyPROGESTERone is considered compatible with breastfeeding by the American Academy of Pediatrics (Anon, 2001). It has been suggested that progesterone-only contraceptive methods may be safely employed within 3 days postpartum (Halderman & Nelson, 2002). The American College of Obstetrics and Gynecologists recommends that depot medroxyPROGESTERone acetate or hormonal implants not be started before 6 weeks postpartum, and combined estrogen-progestin contraceptives started 6 weeks postpartum only if lactation is well established and the infant's nutritional intake is appropriate (American College of Obstetricians and Gynecologists, 2007).
    6) ETHINYL ESTRADIOL/ETONOGESTREL
    a) The effects of using etonogestrel/ethinyl estradiol while nursing are unknown. However, combined hormonal contraceptives are excreted in breast milk and can reduce milk production. It is recommended that an alternate form of contraception be used during breastfeeding and until the child is completed weaned from breast milk (Prod Info NuvaRing(R) vaginal ring, 2013).
    B) LACK OF EFFECT
    1) MEDROXYPROGESTERONE ACETATE
    a) No adverse effects were noted in children of breastfeeding women who received depot-medroxyPROGESTERone. After 4.5 years of follow-up, no ill effects on growth and development or health status were noted in the breastfed children of women who received depot-medroxyPROGESTERone for contraception (n=128) compared with children of women who used mechanical contraceptives, no contraceptives, or who had undergone sterilization (n=142) (Jimenez et al, 1984).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects on fertility from exposure to HYDROXYPROGESTERONE or MEDROXYPROGESTERONE (Prod Info MAKENA(TM) IM injection, 2011; Prod Info PROVERA(R) oral tablets, 2007).
    B) ANIMAL STUDIES
    1) HYDROXYPROGESTERONE
    a) RATS: There was no evidence of impaired fertility or reproductive toxicity when rats were administered IM hydroxyprogesterone at gestational exposures up to 5 times the recommended human dose. There were no adverse effects on reproductive ability or fetal harm in 3 generations of rats in this study (Prod Info MAKENA(TM) IM injection, 2011).
    2) ETHINYL ESTRADIOL/ETONOGESTREL
    a) RATS: Fertility impairment was temporary in rats, with fertility returning after treatment was withdrawn (Prod Info NuvaRing(R) vaginal ring, 2013).

Carcinogenicity

    3.21.3) HUMAN STUDIES
    A) OVARIAN CARCINOMA
    1) CASE SERIES: In a retrospective study of 5,000 African American women who received depot medroxyPROGESTERone for contraception, no increased incidence in breast, ovarian, or uterine corpus cancer was seen up to 13 years later (Liang et al, 1983).
    B) HEPATIC CARCINOMA
    1) There is considerable evidence suggesting that after induction by chemical carcinogens, sex hormones act as promoters of hepatocarcinogenesis (Porter et al, 1987; Toh, 1973; Yager & Yager, 1980; Sumi et al, 1980; Vesselinovitch & Mihailovich, 1967; Schulte-Hermann, 1974; Schulte-Hermann et al, 1979; Schulte-Hermann et al, 1981).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) With chronic toxicity, obtain a baseline CBC, hepatic and renal function tests.
    4.1.2) SERUM/BLOOD
    A) HEMATOLOGIC
    1) With chronic toxicity obtain a baseline CBC.
    B) BLOOD/SERUM CHEMISTRY
    1) Obtain baseline hepatic and renal function tests with chronic toxixity.
    4.1.3) URINE
    A) URINARY LEVELS
    1) PORPHYRIA - Increased urinary excretion of porphyrin precursors delta-aminolevulinic acid and porphobilinogen is suggestive of an acute attack of porphyria (Anderson, 1991).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) With chronic toxicity, obtain a baseline CBC, hepatic and renal function tests.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Acute toxicity appears to be low. Gastric decontamination is probably only necessary after large ingestions.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Single acute overdoses will seldom result in toxicity. Gastric decontamination should be considered after large or mixed ingestions.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) DRUG OVERDOSE
    1) In acute single overdosage, toxicity is unlikely.
    2) Supportive treatment will be adequate in most situations.
    B) CHRONIC POISONING
    1) Discontinue medication and monitor for signs of severe toxicity and treat symptomatically.
    2) Obtain a baseline CBC, hepatic and renal function tests.

Range Of Toxicity

Summary

    A) Toxicity is unlikely following an acute overdose. There are insufficient data in the literature to assess the range of toxicity in terms of mg/kg ingested.

Therapeutic Dose

    7.2.1) ADULT
    A) LEVONORGESTREL
    1) CONTRACEPTION: LILETTA(TM) INTRAUTERINE SYSTEM: 52 mg device implanted in the uterine cavity (Prod Info LILETTA(TM) intrauterine system, 2015)
    B) MEDROXYPROGESTERONE ACETATE
    1) AMENORRHEA, SECONDARY: TABLET: 5 to 10 mg orally daily for 5 to 10 days (Prod Info PROVERA(R) oral tablets, 2009)
    2) ABNORMAL UTERINE BLEEDING: TABLET: 5 to 10 mg orally daily for 5 to 10 days beginning on day 16 or 21 of the menstrual cycle (Prod Info PROVERA(R) oral tablets, 2009)
    3) CONTRACEPTION: INTRAMUSCULAR SUSPENSION: 150 mg every 3 months by deep, IM injection in the gluteal or deltoid muscle (Prod Info DEPO-PROVERA(R) CI IM injection suspension, 2011)
    4) CONTRACEPTION: SUBCUTANEOUS SUSPENSION: 1 injection (104 mg per 0.65 mL) subQ into the anterior thigh or abdomen once every 3 months (Prod Info DEPO-SUBQ PROVERA 104(TM) subcutaneous injection, 2010)
    5) ENDOMETRIAL HYPERPLASIA: TABLET: 5 to 10 mg orally daily for 12 to 14 consecutive days per month, either beginning on day 1 or day 16 of the cycle; given as part of regimen with conjugated estrogens (Prod Info PROVERA(R) oral tablets, 2009)
    6) ENDOMETRIOSIS-ASSOCIATED PAIN: INJECTABLE SUSPENSION (DEPO-SUBQ PROVERA 104(TM)): 1 injection (104 mg per 0.65 mL) subQ into the anterior thigh or abdomen once every 3 months (12 to 14 weeks) (Prod Info DEPO-SUBQ PROVERA 104(TM) subcutaneous injection, 2010)
    C) NORETHINDRONE
    1) CONTRACEPTION: TABLET: One 0.35 mg tablet orally daily (Prod Info ORTHO MICRONOR(R) oral tablets, 2014)
    D) NORETHINDRONE ACETATE
    1) AMENORRHEA, SECONDARY OR DYSFUNCTIONAL UTERINE BLEEDING: TABLET: 2.5 to 10 mg orally daily on Day 5 through Day 25 of the menstrual cycle or for 5 to 10 days during the last half of the menstrual cycle (Prod Info norethindrone acetate oral tablets, 2012).
    2) ENDOMETRIOSIS: TABLET: 5 mg orally daily for 2 weeks, increasing by 2.5 mg a day at two-week intervals to reach a total dose of 15 mg a day (Prod Info norethindrone acetate oral tablets, 2012).
    E) NORETHINDRONE ACETATE/ESTRADIOL
    1) Continuous Combined Regimen
    a) Estradiol 0.05 mg/norethindrone acetate 0.14 mg/day (9 cm(2)) OR estradiol 0.05 mg/norethindrone acetate 0.25 mg (16 cm(2)) transdermally to the lower abdomen. System is to be worn continuously and uninterrupted. Replace with a new system every 3 to 4 days (twice weekly) during a 28-day cycle (Prod Info CombiPatch(R) transdermal system patch, 2015).
    2) Sequential Combined Regimen
    a) For the first 14 days of a 28-day cycle:, 1 Vivelle-Dot(R) system (estradiol 0.05 mg/day) transdermally. Replace the system every 3 to 4 days (twice weekly) (Prod Info CombiPatch(R) transdermal system patch, 2015).
    b) For the remaining 14 days of a 28-day cycle: 1 CombiPatch(R) system (estradiol 0.05 mg/norethindrone acetate 0.14 mg/day (9 cm(2)) OR estradiol 0.05 mg/norethindrone acetate 0.25 mg (16 cm(2))) transdermally on the lower abdomen. Wear the system continuously, and replace the system every 3 to 4 days (twice weekly) (Prod Info CombiPatch(R) transdermal system patch, 2015).
    F) PROGESTERONE
    1) AMENORRHEA, SECONDARY: CAPSULE: 400 mg orally at bedtime for 10 days (Prod Info PROMETRIUM(R) oral capsules, 2013)
    2) AMENORRHEA, SECONDARY: GEL: 4% gel (45 mg) intravaginally every other day up to a total of 6 doses; if no response, may increase to 8% gel (90 mg) intravaginally every other day up to a total of 6 doses (Prod Info Crinone(R) vaginal gel, 2013)
    3) AMENORRHEA, SECONDARY: INJECTION: 5 to 10 mg IM daily for 6 to 8 days (Prod Info progesterone intramuscular oil, 1999)
    4) ENDOMETRIAL HYPERPLASIA: CAPSULES: 200 mg orally at bedtime for 12 sequential days per 28-day cycle to postmenopausal women with a uterus who are receiving daily conjugated estrogens (Prod Info PROMETRIUM(R) oral capsules, 2013)
    5) ABNORMAL UTERINE BLEEDING: INTRAMUSCULAR: 5 to 10 mg IM daily for 6 doses (Prod Info progesterone intramuscular injection, 2013)
    6) FEMALE INFERTILITY: GEL: 90 mg (8% gel) vaginally once or twice daily; if pregnancy occurs, up to 10 to 12 weeks (Prod Info Crinone(R) vaginal gel, 2013)
    7) FEMALE INFERTILITY: VAGINAL INSERT: 100 mg vaginally 2 to 3 times daily starting the day after oocyte retrieval and continuing for up to 10 weeks total duration (Prod Info ENDOMETRIN(R) vaginal insert, 2012)
    7.2.2) PEDIATRIC
    A) LEVONORGESTREL
    1) CONTRACEPTION: LILETTA(TM) INTRAUTERINE SYSTEM: BEFORE MENSTRUATION: Use not indicated (Prod Info LILETTA(TM) intrauterine system, 2015)
    2) CONTRACEPTION: LILETTA(TM) INTRAUTERINE SYSTEM: AFTER MENSTRUATION: 52 mg device implanted in the uterine cavity (Prod Info LILETTA(TM) intrauterine system, 2015)
    B) NORETHINDRONE
    1) CONTRACEPTION: AFTER MENSTRUATION: TABLET: One 0.35 mg orally daily (Prod Info ORTHO MICRONOR(R) oral tablets, 2014)
    C) NORETHINDRONE ACETATE/ESTRADIOL
    1) Safety and effectiveness have not been established in pediatric patients (Prod Info CombiPatch(R) transdermal system patch, 2015).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) Toxicity is unlikely following acute overdose. Insufficient data in the literature to assess the range of toxicity in terms of mg/kg ingested.

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) MEDROGESTERONE
    B) MEDROXYPROGESTERONE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) >1500 mg/kg (RTECS, 2001)
    2) LD50- (INTRAPERITONEAL)RAT:
    a) >900 mg/kg (RTECS, 2001)
    C) PROGESTERONE
    1) LD50- (INTRAPERITONEAL)RAT:
    a) 327 mg/kg (RTECS, 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) PROGESTERONE (Sollmann, 1964) -
    1) Quiets uterine spontaneous movements
    2) Inhibits the uterine response to posterior pituitary stimulation
    3) Uterine: Small doses decrease activity, large doses increase contraction strength and frequency
    4) Heart: In animal studies isolated heart muscle was depressed both inotropically and chronotropically.
    5) Anesthesia: Was seen in rats given high doses.
    6) Tumors: Regression of certain types of tumor masses has been seen.
    B) These agents interact with chromatin (DNA) and therefore increase RNA synthesis (USPDI, 1988).
    C) Large doses decrease the amount of luteinizing hormone released from the anterior pituitary (USPDI, 1988).
    D) The synthetic chemical derivatives of progesterone are more effective, more potent, more specific in action, and have a longer duration of action than oral progesterone.

Physicochemical

Physical Characteristics

    A) HYDROXYPROGESTERONE CAPROATE is a white to practically white crystalline solid or powder that has a melting point of 120 to 124 degrees C; the solution for IM injection is clear and yellow in color (Prod Info MAKENA(TM) IM injection, 2011); hydroxyprogesterone caproate is not soluble in water (USPDI, 1988).
    B) MEDROGESTONE is a crystalline solid (Budavari, 1996).
    C) MEDROXYPROGESTERONE has a melting point of 220 to 223.5 degrees C (Budavari, 1996).
    D) MEDROXYPROGESTERONE ACETATE is a white to off-white, odorless, crystalline powder that is soluble in dioxane and acetone; freely soluble in chloroform; sparingly soluble in alcohol and methanol; slightly soluble in ether; insoluble in water; and melts between 200 and 210 degrees C (Prod Info DEPO-PROVERA CI(R) IM injectable suspension, 2010).
    E) NORETHANDROLONE is a crystalline solid that is not water soluble (Budavari, 1996).
    F) NORETHINDRONE is a crystalline solid (Budavari, 1996) that is not water soluble (USPDI, 1988).
    G) NORETHINDRONE ACETATE is not water soluble (USPDI, 1988).
    H) NORETHYNODREL is a crystalline solid (Budavari, 1996).
    I) NORGESTREL is insoluble in water (USPDI, 1988).
    J) PROGESTERONE is a white or creamy white, odorless, crystalline powder that is soluble in dioxane, alcohol, and acetone; sparingly soluble in vegetable oils; practically insoluble in water; and melts between 126 and 131 degrees C (Prod Info PROMETRIUM(R) oral capsules, 2009).

Molecular Weight

    A) HYDROXYPROGESTERONE: 330.45
    B) HYDROXYPROGESTERONE CAPROATE: 428.6 (Prod Info MAKENA(TM) IM injection, 2011)
    C) MEDROGESTONE: 340.51
    D) MEDROXYPROGESTERONE: 344.48
    E) NORETHANDROLONE: 302.44
    F) NORETHINDRONE: 298.41
    G) NORETHYNODREL: 298.41
    H) PROGESTERONE: 314.47 (Prod Info PROMETRIUM(R) oral capsules, 2009)

References

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