A BRIEF REVIEW OF PROGESTINS IN PREGNANCY (JANUARY 2008)

A BRIEF REVIEW OF PROGESTINS IN PREGNANCY (October 7, 2008)

OVERVIEW

The purpose of this brief review is to promote participation in clinical trials to further define the safety and efficacy of the use of progestins in the prevention of preterm birth.

In 2003 results from two randomized clinical trials^[1]^,[2] and an ACOG Committee Opinion^[3] were published in support of the use of progesterone to reduce preterm birth. The data from the Meis trial¹ along with other data were submitted to the FDA in support of 17 alpha-hydroxyprogesterone caproate (17-OHP-C) as a treatment for the prevention of preterm birth in women with a history of preterm birth.^[4] The FDA held an Advisory Committee Meeting August 29, 2006 to discuss FDA’s concerns about the primary endpoint, about the unexpectedly high placebo rate, and about the occurrence of miscarriage and fetal death in the trial. A majority of the committee voted that the primary endpoint of the trial was not adequate, that the data from the trial did not provide substantial evidence of a reduction in fetal and neonatal mortality or morbidity, and there was unanimous agreement that further study was needed to evaluate the association of 17-OHP-C with an increased risk of miscarriage and stillbirth.^[4]

In October 2008, a new ACOG Committee Opinion[5] was published. In this opinion ACOG suggests that "...it is important to offer progesterone for pregnancy prolongation to only women with a documented history of a previous spontaneous preterm birth at less than 37 weeks of gestation."

There is an important disclaimer in the opinion: "This information should not be construed as dictating an exclusive course of treatment or procedure to be followed."

In addition, the word "recommend" DOES NOT appear in this opinion.

Also, the word "safety" DOES NOT appear in this opinion and safety is not discussed in any way.

It is up to the practitioner to share the facts about the safety and efficacy of the treatment with a patient when this treatment is offered.

In the absence of an FDA approved label the minutes of the 2006 FDA Advisory Committee [Attachment 1] can be used as the basis to discuss both the safety and efficacy of this treatment. The Advisory Committee is clear on 4 issues:

1. The primary endpoint of the pivotal trial (Meis et al) is not an adequate surrogate for a reduction in fetal and neonatal mortality or morbidity.

2. There is no substantial evidence that the treatment reduces fetal and neonatal morbidity or mortality.

3. Further study is needed to evaluate the potential association of the treatment with increased risk of second trimester miscarriage and stillbirth.

4. Another clinical trial of 17-OHP-C is needed to investigate further safety or effectiveness.

As of October 7, 2008, 17-OHP-C is still not approved by the FDA as safe and effective for use in pregnancy.

In 2007, three additional publications presented data on natural progesterone (not 17-OHP-C) in the prevention of preterm birth in singleton pregnancies. The first presented evidence that the use of vaginal progesterone can prevent preterm birth in women with an extremely short cervix, ≤15mm^[5]; infant outcomes were not significantly improved in that trial. The second trial was designed to evaluate the use of vaginal progesterone in women with a history of preterm birth.^[6] While women with a preterm birth did not benefit from progesterone therapy in that trial^[6], a secondary analysis of women with a shortened cervix prior to treatment suggested a benefit in the delay of delivery and the infants of these women were significantly healthier.^[7] A scientific review of the prevention of spontaneous preterm birth focusing on the role of a shortened cervix in identifying patients who may benefit from protesterone was also published last year.^[8]

Prior to the FDA advisory committee meeting, a Cochrane Review published online regarding the use of progestins to prevent preterm birth concluded: Not enough evidence for progesterone in pregnancy for women at increased risk of giving birth too soon.^[9] They included in their summary that important maternal and infant outcomes have been poorly reported to date and that information regarding the potential harms of progesterone therapy to prevent preterm birth is limited.

Based on the conclusion of the FDA advisory committee, the Cochrane Review and on the data discussed below, there is not enough evidence of safety and efficacy at this time to make a progestin the standard of care in the prevention of preterm birth. The patient population to be treated, the ideal progesterone formulation, the optimal route of drug delivery, and the safety of the treatments remain unknown. Thus, it is reasonable to support ongoing placebo controlled trials of progestins in the prevention of preterm birth in women at risk.

REVIEW

1. NATURAL (BIOIDENTICAL) PROGESTERONES
There are two natural progesterone hormones that are commonly discussed

a. PROGESTERONE (P) – This is the progestin produced by the corpus luteum in the luteal phase of the menstrual cycle and during the first trimester of pregnancy and (following the luteal-placental shift) in the largest quantity by the placenta. Natural progesterone is FDA approved for use in the first trimester of pregnancy in some formulations.

b. 17 hydroxyprogesterone (17 OHP) - This is also a natural hormone produced in much lower quantities during pregnancy.

2. SYNTHETIC (ARTIFICIAL) PROGESTINS

a. 17 hydroxyprogesterone caproate (17-OHP-C) – This synthetic progestin is made artificially by converting natural progesterone into a synthetic progestin. It is a similar artificial progestin to the progestin drug commonly used in hormone replacement therapy, medroxyprogesterone acetate (MPA), which was recently shown to have unexpected side effects when used in thousands of women in menopause.^[10]^,^[11] It is also similar to an artificial progestin used in cancer therapy, megesterol acetate (MEGACE). It is not the same chemical as the natural 17 hydroxyprogesterone.
(Attachment 1)

b. 17-OHP-C, MPA, and MEGACE are all FDA pregnancy category D progestins meaning the FDA believes there is evidence of fetal harm.
(Attachment 2)

c. Although in test-tube experiments there is evidence that human liver microsomes are capable of metabolizing 17-OHP-C to natural hydroxyprogesterone (17OHP), the delivery of 17-OHP-C by injection bypasses hepatic first-pass metabolism. There is already evidence that some women receiving weekly injections of 250 mg of the synthetic 17-OHP-C still have below normal levels of natural hydroxyprogesterone during this treatment.^[12] (Attachment 3) A recent study was reported that shows that after a 250mg injection of 17-OHP-C, 17-OHP-C can be measured in the plasma and remains in the plasma possibly for 45 days (5 times the T1/2).^[13] (Attachment 4) This confirms that 17-OHP-C is neither rapidly nor appreciably converted to a natural progesterone.

3. Lack of SUFFICIENT FETAL AND Infant Outcomes Data

Fetal adverse events are rare even in clinical trials. Events possibly related to fetal toxicity and to fetal teratogenicity need to be evaluated. Long-term infant outcomes were not evaluated in either the NIH trial published in the New England Journal of Medicine comparing 17-OHP-C to placebo in the prevention of preterm birth, or the Fonseca trial published in the American Journal of Obstetrics and Gynecology comparing natural progesterone administered vaginally to placebo in the prevention of preterm birth.

a. The NIH trial reported in the New England Journal of Medicine (2003) did not include infant outcomes beyond the initial hospitalization in the original protocol.^{NOTEREF _Ref188412224 \h
\* MERGEFORMAT 1}While there is considerable evidence that 17-OHP-C is not teratogenic,^[14] in the NIH study there was a signal regarding fetal harm^{NOTEREF
_Ref188412224 \h \* MERGEFORMAT 1} relating to fetal toxicity (not teratogenicity).

i. All 5 pregnancy losses before 20 weeks occurred in the women receiving 17-OHP-C, there were none with placebo.

ii. There was a 50% increase in intrauterine fetal death among women receiving 17-OHP-C compared to placebo although due to the sample size this increase was not statistically significant.

iii. In the most conservative assessment, if the lost-to-follow-up cases are considered cases of fetal loss, then there was evidence of a possible statistically significant increase in fetal loss with compared with placebo using a significance level of 5.7% (i.e., the p-value was 0.057) rather than the nominal 5% level. (Attachment 5)

b. A meta-analysis of 17-OHP-C published in BJOG in 1990 by Keirse^[15] showed a possible signal for an increase in miscarriage with an odds ratio 1.3 (0.61-2.74).

c. A meta-analysis of the only 3 trials conducted to date evaluating 250 mg of 17-OHP-C given by weekly injections beginning 12-17 weeks gestation in the prevention of preterm birth shows a statistically significant increase in miscarriage. (Attachment 6)

d. Two previous reproductive toxicology studies of 17-OHP-C in animals are noteworthy. The first, in mice, had an increased fetal loss with 17-OHP-C compared to placebo which was statistically significant for only the middle dose.^[16] No dose response was evident. The study was not conducted to current reproductive toxicology standards. (Attachment 7)

The second, in rhesus monkeys, showed that total embryolethality resulted following the administration of 17-OHP-C alone and in combination with estradiol valerate at both 1X and 10X the human dose equivalent dose. The authors concluded that long-term in utero exposure to 17-OHP-C is embryolethal but not teratogenic at doses up to ten times the human therapeutic dose.^[17]

(Attachment 8)

e. A complete review of the embryo-fetal toxicity signals of 17 alpha-hydroxyprogesteorne caproate in high-risk pregnancies was recently published by Christian et. al. ^[18]
(Attachment 9)

f. The FDA presented a view of the Meis trial data that suggested an association between 17-OHP-C use and the occurrence of miscarriage and early fetal death. ⁴ (Attachment 10) The FDA presented a view of the Meis trial data that suggested that the risk of fetal/neonatal death was greatest for 17-OHP-C in the first 66 days of therapy. ⁴ (Attachment 11)

g. The FDA advisory committee was in unanimous agreement that further study was needed to evaluate the association of with an increased risk of miscarriage and stillbirth.⁴ (Attachment 12)

4. Questions about placebo response in NIH study.

A letter to the editor in the New England Journal of Medicine in 2003 from the OB/GYN department at Duke University^[19] questioned the efficacy results in the NIH trial of 17-OHP-C versus placebo in the prevention of preterm birth due to the presence of castor oil in the placebo. (Attachment 13)

a. Castor oil is known to induce labor.

i. Castor oil has been used for over 2000 years (since ancient Egypt) to induce labor.^[20]

ii. 93% of nurse midwives surveyed in 1999 used castor oil to induce labor.^[21]

iii. The only study published which evaluated castor oil in the induction of labor found that among women 40-42 weeks gestation without contractions: 58% went into labor within 24 hours of ingesting castor oil compared to only 4% of untreated controls.^{NOTEREF _Ref188427786 \h \* MERGEFORMAT
20} (Attachment 14)

b. The methods section of the NIH publication in the NEJM predicted that “On the basis of data from a previous study by the Maternal-Fetal Medicine Units Network, we estimated that 37% of the women in the placebo group would deliver before 37 weeks of gestation.”^{NOTEREF _Ref188412224 \h \* MERGEFORMAT 1},^[22]

i. A survey of birth certificates in the state of Georgia over a 15 year period showed that if a first birth lasted <28 weeks the chance of delivering the second pregnancy preterm was 29-36%.^[23]

ii. The Fonseca trial placebo rate was 29%.^{NOTEREF
_Ref188427987 \h \* MERGEFORMAT 2}

iii. It has been published that the risk of delivering preterm with 1 previous preterm birth is 16-19%, with 2 previous preterm births is 32-41%, and with 3 previous preterm births is 67%.^[24] The average number of previous preterm births in the NIH trial was 1.5.^{NOTEREF _Ref188412224 \h \* MERGEFORMAT 1}

v. At the advisory committee meeting the FDA presented the results of the 150 patients who were excluded from the Meis trial analysis. ⁴(Attachment 15) The FDA expressed concern that the placebo rate in the published trial data was not consistent with the results from the excluded trial data.⁴ (Attachment 16)

vi. In the transcript from the Advisory committee meeting several of the committee members expressed concern over whether or not efficacy has been demonstrated in the trial. ⁴

5. NATURAL PROGESTERONE’s EFFECT ON MYOMETRIAL CONTRACTIONS

The Fonseca trial showed that natural progesterone given vaginally significantly reduced the background myometrial contraction rate compared to placebo.^{NOTEREF _Ref188427987 \h \* MERGEFORMAT 2}In addition, Fonseca also showed a significant reduction in the preterm birth rate associated with the use of natural progesterone given vaginally (29% placebo rate reduced to 14% with vaginal progesterone). Infant outcomes were not reported in the manuscript.^{NOTEREF _Ref188427987 \h \*
MERGEFORMAT 2}
The NIH trial of 17-OHP-C did not evaluate myometrial contractions. A recent study reported in Reproductive Biology and Endocrinology showed that 17-OHP-C does not inhibit oxytocin induced myometrial contractions.^[25](Attachment 17)

6. Additional placebo controlled trials of progestins in the prevention of preterm birth are warranted.

In September 2004 Marc Keirse published a review and opinion of the NIH trial and the Fonseca trial.^[26] In his review Dr. Keirse wrote: “Critical analysis of the reports provides no convincing evidence that either one of these treatments is worth pursuing outside the context of controlled research to determine, first, whether and, second, how the treatments might work.”

According to the 2006 Cochrane Review by Dodd⁹, there is not enough evidence of safety and efficacy to make a progestin the standard of care in the prevention of preterm birth at this time. (Attachment 18)

It is very reasonable to support ongoing placebo controlled trials of progestins in the prevention of preterm birth in women at risk due to a previous preterm birth.

7. recent trials suggesting a benefit of progesterone in women with a short cervix.

In August 2007 Fonseca and Nicolaides published their findings on the evaluation of progesterone to prolong gestation in women with a very short cervix (≤15mm)in mid-pregnancy (24 weeks).^[27] While the frequency of preterm birth was significantly decreased, there was no significant improvement in infant outcomes in that trial.

In October 2007 O’Brien⁶ (Attachment 19) and DeFranco⁷ (Attachment 20) published the results of the largest randomized trial to date of the use of progesterone for the prevention of preterm birth in singleton pregnancies. While the use of progesterone did not appear to delay delivery in women with a baseline cervical length over 32mm at the 17-23week ultrasound, in women with a baseline cervical length less than 32mm there appeared to be a progesterone effect; and the progesterone effect increased as the length of the cervix at baseline decreased such that in the cohort with a baseline cervical length <28mm significantly fewer deliveries occurred ≤32 weeks in women randomized to progesterone compared to placebo. In addition, the infants of women with a cervical length <28mm at baseline were healthier based on significantly fewer admissions to the NICU and significantly fewer NICU days overall. An editorial review by Roberto Romero ⁸ (Attachment 21) addresses the role of sonographic cervical length in identifying patients who may benefit from progesterone treatment.

For more information. please visit : http://www.clinicaltrials.gov/ct2/show/NCT00615550?term=Short+Cervix&rank=3

[REFERENCES]

[1] Meis PJ, Klebanoff M, Thorn E, Dombrowski MP, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. New Engl J Med 2003;348(24);2379-2385

[2] Fonseca EB, Bittar RE, Carvalho HB, Zugaib M. Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: A randomized placebo-controlled double-blind study. Am J Obstet Gynecol 2003;188(2):419-424

[3] ACOG committee opinion no. 291, November 2003. Obstet & Gynecol 2003;102(5);1115-1116.

[4] http://www.fda.gov/ohrms/dockets/ac/cder06.html#rhdac

[5] Fonseca et al. Progesterone and the risk of preterm birth among women with a short cervix. NEJM 2007; 357 (5): 462-469.

[6] O'Brien JM et al. Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol 2007; 30:687-696. http://www3.interscience.wiley.com/journal/99020267/home (free download)

[7] DeFranco EA et al. Vaginal progesterone is associated with a decrease in risk for early preterm birth and improved neonatal outcome in women with a short cervix: a secondary analysis from a randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol 2007; 30:697-705. http://www3.interscience.wiley.com/journal/99020267/home (free download)

[8] Romero R. Prevention of sponatneous preterm birth: the role of sonographic cervical length in identifying patients who may benefit from progesterone treatment. Ultrasound Obstet Gynecol 2007; 30: 675-686. http://www3.interscience.wiley.com/journal/99020267/home (free download)

[9] Dodd JM, Flenady V, Cincotta R, Crowther CA; The Cochrane Database of Systematic Reviews 2006 Issue 1 Art. No.: CD004947. DOI: 10.1002/14651858.CD004947.pub2. www.cochrane.org/reviews/en/ab004947.html

[10] Writing Group for the Women's Health Initiative Investigators. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women Principal Results From the Women's Health Initiative Randomized Controlled Trial : JAMA. 2002;288:321-333.

[11] Mary Cushman, MD, MSc; Lewis H. Kuller, MD; Ross Prentice, PhD; Rebecca J. Rodabough, MS; Bruce M. Psaty, MD, PhD; Randall S. Stafford, MD, PhD; Steven Sidney, MD; Frits R. Rosendaal, MD, PhD; for the Women’s Health Initiative Investigators.. Estrogen Plus Progestin and Risk of Venous Thrombosis: JAMA. 2004;292:1573-1580.

[12] Johnson JWC, Lee PA, Zachary AS, Calhoun S, Migeon CJ. High-risk prematurity--progestin treatment and steroid studies. Obstet Gynecol 1979;54(4):412-418

[13] Caritis et al. Pharmacokinetics of 17-Alpha-Hydroxyprogesterone Caproate (17-OHPC) in Women with Twin Gestation. Reproductive Sciences, vol 14, no 1, supplement, January 2007.

[14] www.hydroxyprogesterone.com/ hydroxyprogesterone-safety.html – accessed 10 November 2005.

[15] Keirse MJNC, Progestogen administration in pregnancy may prevent preterm delivery. British Journal of Obstetrics and Gynecology. 1990; 97: 149-154.

[16] Seegmiller RE, Nelson GW, Johnson CK. Evaluation of the Teratogenic Potential of Delalutin (17alpha-Hydroxyprogesterone Caproate) in Mice. Teratology, 1983; 28: 201-208.

[17] Hendrix AG, et al. Embriotoxicity of sex steroidal hormones in nonhuman primates: II. Hydroxyprogesterone caproate, estradiol valerate. Teratology 1987 February. 35 (1): 129.

[18] Christian MS, Brent RL, Calda P. Embryo-fetal toxicity signals for 17-alpha-hydroxyprogesterone caproate in high risk pregnancies: A review of the non-clinical literature for embryo-fetal toxicity with progestins. J or Maternal Fetal and Neonatal Med, Feb 2007: 20(2); 89-112.

[19] Brancazio LR, Murtha AP, Heine RP. Prevention of Recurrent Preterm Delivery by 17 Alpha-Hydroxyprogesterone Caproate. NEJM, September 11, 2003; 349: 1087

[20] Garry D, Figueroa R, Guillaume J, Cucco V. Use of castor oil in pregnancies at term. Altern Ther Health Med. 2000 Jan;6(1):77-9.

[21] McFarlin et al. A National Survey of Herbal Preparation Use by Nurse Midwives for Labor Stimulation. Journal of Nurse-Midwifery; vol 44, no 3, May/June 1999, pg 205.

[22] Iams JD, Newman RB, Thom EA, et al. Frequency of uterine contractions and the risk of spontaneous preterm delivery. NEJM 2002: 346:250-255

[23] Adams MM, Elam-Evans LD, Wilson HG, Gilbertz DA. Rates of and factors associated with recurrence of preterm delivery. JAMA 2000;283(12):1591-1596

[24] Bloom SL, Yost NP, McIntire DD, Leveno KJ. Recurrence of Preterm Birth in Singleton and Twin Pregnancies. Obstetrics and Gynecology, September 2001, vol 98; Num 3; pgs 379-385

[25] Sexton DJ, O’Reilly MW, Friel AM, Morrison JJ. Functional effects of 17alpha-hydroxyprogesterone caproate on human myometrial contractility in vitro. Reprod Biol Endocrinol. 2004; vol 2: page 80.

[26] Keirse MJNC, Progesterone and Preterm: Seventy Years fo “Deja Vu” or “Still To Be Seen”? BIRTH, September 2004; vol 31, No 3: pgs 230-235.

[27] Fonseca et al. Progesterone and the risk of preterm birth among women with a short cervix. NEJM 2007; 357 (5): 462-469.

[Attachment 1]

[Attachment 2]

Found on - http://www.perinatology.com/exposures/Drugs/FDACategories.htm (accessed 18 January 2008)

perinatology.com
FDA Use-in-Pregnancy Ratings

CATEGORY	INTERPRETATION
A	Adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalities to the fetus in any trimester of pregnancy.
B	Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate and well-controlled studies in pregnant women. OR Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester.
C	Animal studies have shown an adverse effect and there are no adequate and well-controlled studies in pregnant women. OR No animal studies have been conducted and there are no adequate and well-controlled studies in pregnant women.
D	Adequate well-controlled or observational studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective.
X	Adequate well-controlled or observational studies in animals or pregnant women have demonstrated positive evidence of fetal abnormalities or risks. The use of the product is contraindicated in women who are or may become pregnant.

REFERENCES
1. FDA Consumer magazine Volume 35, Number 3 May-June 2001
2. Physicians Desk Reference 57th ed. Montvale, NJ: Thomson PDR; 2004: 3539
3. Briggs GG,Freeman RK, Yaffe SJ, Drugs in Pregnancy and Lactation 6th edition,Baltimore, MD: Williams & Wilkins,2002.

Please review the Disclaimer before using this site.
Copyright © 2002-2005 by Focus Information Technology. All rights reserved.
The information provided on this site is updated periodically. It is likely that the information presented will not include all information currently available. Keep in mind the limitations of this information.
Created: 11/27/2002
Updated: 11/30/2003
Updated: 3/14/2004

Found on -

http://www.safefetus.com/DrugDetail.asp?DrugId=1081&TradeName=Proluton%20Depot%20/%20Primolut%20Depot&TradeId=2189 (accessed 18 January 2008)

Generic Name	Hydroxyprogesterone Caproate
Trade Name	Proluton Depot / Primolut Depot
Manufacturer	Schering AG

Risk Category

Positive evidence of human fetal risk exists.
Potential benefits may warrant use of the drug in pregnant women despite potential risks (e.g. life threatening situations or serious illness).

Found on -

http://www.safefetus.com/DrugDetail.asp?DrugId=212&TradeName=Medroxyprogesterone&TradeId=2545 (accessed 18 January 2008)

Generic Name	MedroxyProgesterone Acetate
Trade Name	Depo-Provera
Manufacturer	Pharmacia & Upjhon

Risk Category

Positive evidence of human fetal risk exists.
Potential benefits may warrant use of the drug in pregnant women despite potential risks (e.g. life threatening situations or serious illness).

Found on -

http://www.accessdata.fda.gov/scripts/cder/onctools/labels.cfm?GN=megestrol%20acetate(abridged) (accessed 18 January 2008)

Application
Supplement Number	016979
Complete Label
Formatted in PDF	MEGACE
Description
Mechanism of Action	MEGACE ® (megestrol acetate tablets, USP) is a synthetic, antineoplastic and progestational drug. Megestrol acetate is a white, crystalline solid chemically designated as 17 ??-acetyloxy-6- methylpregna-4,6-diene-3,20-dione. Solubility at 37° C in water is 2 mcg per mL, solubility in plasma is 24 mcg per mL. Its molecular weight is 384.51. The empirical formula is C24H 32O4 and the structural formula is represented as follows: megestrol acetate, USP MEGACE is supplied as tablets for oral administration containing 20 mg and 40 mg megestrol acetate. MEGACE tablets contain the following inactive ingredients: acacia, calcium phosphate, FD&C Blue No. 1 Aluminum Lake, lactose, magnesium stearate, silicon dioxide olloidal, and starch.
Generic Drug Name	megestrol acetate tablets
Manufacturer
Manufacturer	Bristol-Myers Squibb Company Princeton, NJ 08543 USA
Distributor
Distributor	Bristol-Myers Squibb Company Princeton, NJ 08543 USA
Indications and Usage
Summary	MEGACE is indicated for the palliative treatment of advanced carcinoma of the breast or endometrium (i.e., recurrent, inoperable, or metastatic disease). It should not be used in lieu of currently accepted procedures such as surgery, radiation, or chemotherapy.
Contraindications
Summary	History of hypersensitivity to megestrol acetate or any component of the formulation.
Warnings
Summary	Megestrol acetate may cause fetal harm when administered to a pregnant woman. Fertility and reproduction studies with high doses of megestrol acetate have shown a reversible feminizing effect on some male rat fetuses. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking (receiving) this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. The use of MEGACE in other types of neoplastic disease is not recommended. (See also PRECAUTIONS: Carcinogenesis, Mutagenesis, and Impairment of Fertility section). The glucocorticoid activity of MEGACE Tablets has not been fully evaluated. Clinical cases of new onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and overt Cushing’s syndrome have been reported in association with the chronic use of MEGACE. In addition, clinical cases of adrenal insufficiency have been observed in patients receiving or being withdrawn from chronic MEGACE therapy in the stressed and non-stressed state. Furthermore, adrenocorticotropin (ACTH) stimulation testing has revealed the frequent occurrence of asymptomatic pituitary-adrenal suppression in patients treated with chronic MEGACE therapy. Therefore, the possibility of adrenal insufficiency should be considered in any patient receiving or being withdrawn from chronic MEGACE therapy who presents with symptoms and/or signs suggestive of hypoadrenalism (e.g., hypotension, nausea, vomiting, dizziness, or weakness) in either the stressed or non-stressed state. Laboratory evaluation for adrenal insufficiency and consideration of replacement or stress doses of a rapidly acting glucocorticoid are strongly recommended in such patients. Failure to recognize inhibition of the hypothalamic-pituitaryadrenal axis may result in death. Finally, in patients who are receiving or being withdrawn from chronic MEGACE therapy, consideration should be given to the use of empiric therapy with stress doses of a rapidly acting glucocorticoid in conditions of stress or serious intercurrent illness (e.g., surgery, infection).
Precautions
Summary	General Close surveillance is indicated for any patient treated for recurrent or metastatic cancer. Use with caution in patients with a history of thromboembolic disease. Use in Diabetics Exacerbation of pre-existing diabetes with increased insulin requirements has been reported in association with the use of MEGACE. Information for the Patients Patients using megestrol acetate should receive the following instructions. 1. This medication is to be used as directed by the physician. 2. Report any adverse reaction experiences while taking this medication. Laboratory Tests Breast malignancies in which estrogen and/or progesterone receptors are positive are more likely to respond to MEGACE. Carcinogenesis, Mutagenesis and Impairment of Fertility Administration of megestrol acetate to female dogs for up to 7 years is associated with an increased incidence of both benign and malignant tumors of the breast. Comparable studies in rats and studies in monkeys are not associated with an increased incidence of tumors. The relationship of the dog tumors to humans is unknown but should be considered in assessing the benefit-to-risk ratio when prescribing MEGACE and in surveillance of patients on therapy. (See WARNINGS section.) Pregnancy Pregnancy Category D. (See WARNINGS section.) Nursing Mothers Because of the potential for adverse effects on the newborn, nursing should be discontinued if MEGACE is required for treatment of cancer. Pediatric Use Safety and effectiveness in pediatric patients have not been established.

[Emphasis Added]

[Attachment 3]

High-Risk Prematurity – Progestin Treatment and Steroid Studies

Johnson et al

Obstetrics and Gynecology

Vol 54, No. 4, October 1979

In this study Johnson described the findings of plasma progesterone and hydroxyprogesterone. Plasma levels of natural progesterone and of natural hydroxyprogesterone were measured in women receiving 250 mg/week of 17 alpha-hydroxyprogesterone caproate (17-OHP-C) and in women who served as untreated controls.

With regard to natural progesterone levels, women receiving the 250 mg/week 17OHCP injections were divided into 2 groups depending on whether they delivered at term or preterm. Women who delivered at term had significantly higher levels of natural progesterone than women who delivered preterm regardless of the fact that all of these women received 17-OHP-C injections.

With regard to natural hydroxyprogesterone, women receiving the 250 mg/week 17OHCP injections were also divided into 2 groups depending on whether they delivered at term or preterm. Women who delivered at term had significantly higher levels of natural hydroxyprogesterone than women who delivered preterm regardless of the fact that all of these women received 17-OHP-C injections.

While there are a number of possible explanations for the low levels of natural hydroxyprogesterone in some women receiving weekly 17-OHP-C injections, this finding requires further research to define the metabolic profile of the synthetic progestin, 17-OHP-C, in pregnant women in the second and third trimesters.

[Attachment 4]

Caritis SN and Venkataramanan R for the Network of Maternal – Fetal Medicine Units

Pharmacokinetics of 17-Alpha-Hydroxyprogesterone Caproate (17-OHPC) in women with Twin Gestation.

Objective: …to determine the pharmacokinetics of 17-OHPC in women with twin gestation

Methods: …weekly IM injections of 17-OHPC for at least 4 injections. 17-OHPC determined by LC-MS (llq- 0.5ng/ml)

Results:

AUC (ng/ml/day)- 70.2 +/- 29.3

Cmax (ng/ml) – 13.0 +/- 6.2

Tmax (days) – 1.2 +/- 0.45

T1/2 –(days) – 9.1 +/- 4.2

[Attachment 5]

Prevention of Recurrent Preterm Delivery by 17 Alpha-Hydroxyprogesterone Caproate

New England Journal of Medicine

Volume 348, No 24

June 12, 2003

Pages 2379-2385

Table 1 Characteristics of the 463 Women at Randomization

(page 2382)

17-OHP-C n=310

placebo n=153

Table 2 Outcomes of Pregnancy According to Treatment Assignment

(page 2383)

17-OHP-C n=306

placebo n=153

Contains the data on the pregnancy loss <20 weeks with 5(1.6%) in the Progesterone group and 0 in the placebo group.

Table 3 Fetal and Neonatal Outcomes According to Maternal Treatment Assignment

(page 2384)

17-OHP-C n=306

placebo n=153

Contains the data on the intrauterine fetal death with 6/306 (2.0%) in the Progesterone group and 2/153 (1.3%) in the placebo group.

The text on page 2382 at the bottom of the first column states that there were 4 infant outcomes that are unknown. Comparing Table 1 to Tables 2&3, all lost to follow-up infants were in the 17-OHP-C group.

Miscarriages and intrauterine fetal deaths are clearly cases of fetal harm. The lost-to-follow-up cases are possible cases of fetal harm. One approach for a conservative assessment of “fetal harm” is to combine miscarriage, fetal death, and lost-to-follow-up. This includes 15 cases on 17 OHPC and 2 cases on placebo. The chi-square for this data is significant at p=0.057, suggesting that 17OPHC may be associated with more fetal harm than placebo.

[Attachment 6]

This meta-analysis includes only studies of 17-OHP-C where the dose was 250 mg/week, where the treatment was started 12-17 weeks gestation, and where the indication for use was prevention of preterm birth.

Study

Miscarriage

17-OHP-C

Miscarriage

Placbo

Johnson*

1975

3 of 23

(13%)

0 of 27

(0)

Yemini*

1985

8 of 39

(21%)

3 of 40

(8%)

Meis

2003

5 of 306

(1.6%)

0 of 153

(0)

TOTALS

**p=0.048

16 of 368**

(4.3%)

3 of 220**

(1.4%)

* Data reported in the Keirse meta-analysis⁶

[Attachment 7]

Found on –

www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve& db=PubMed&list_uids=6648824&dopt=Abstract (accessed 18 January 2008)

Teratology. 1983 Oct;28(2):201-8.

Embryo-fetal toxicity signals for 17alpha-hydroxyprogesterone caproate in high-risk pregnancies: a review of the non-clinical literature for embryo-fetal toxicity with progestins.

Christian MS, Brent RL, Calda P.

Argus International, Horsham, PA 19044, USA. mschristian@comcast.net

OBJECTIVE: A large National Institutes of Health (NIH) study showed that pharmacy-compounded 17alpha-hydroxyprogesterone caproate (17-OHP-C) reduced the incidence of preterm birth. The study results included a signal that 17-OHP-C may be associated with an increase in the rate of miscarriages and stillbirths. The most probable cause of an increased incidence of miscarriage/stillbirths may be the use of 17-OHP-C in high-risk patients. The current search of the non-clinical literature was performed to identify whether there were any signals from studies in animals that might suggest concerns for the safe use of progestins generally, and 17-OHP-C specifically, in the prevention of preterm birth in humans. METHODS: An extensive literature search was performed for progesterone, 17-hydroxyprogesterone, and 17-OHP-C, using Medline and Toxline databases, textbooks, and then the obtained publications. Because 17-OHP-C does not have a standardized clinical formulation or optimal route of administration identified, all formulations, vehicles, routes and doses were included in the search, as well as treatment during any stage of pregnancy. All publications obtained were reviewed for relevancy; those in German, French, Italian or Russian were translated. RESULTS: None of the relevant non-clinical studies conducted in mice, rats, rabbits, guinea pigs, horses or non-human primates met current standards for determining reproductive and developmental effects as part of the process of drug development. Most studies focused on the potential of 17-OHP-C for teratogenicity. Many studies used supra-pharmacologic and/or high multiples of human exposure in their study design. Overall, 17-OHP-C was consistently shown to be less potent than progesterone, and neither progesterone nor 17-OHP-C consistently adversely affected maternal weight, embryo-fetal viability or caused malformations. One study in rhesus monkeys raises concerns because resorption/abortion occurred at the human equivalent dose of 17-OHP-C, 10 mg/kg; this finding did not occur in cynomolgus monkeys. The absence of information regarding the serum levels of both progesterone and 17-OHP-C in the animal studies and in humans, as well as presumed inter-species metabolic differences, make it difficult to conclude that the findings with 17-OHP-C in rhesus monkeys and the signal in the NIH trial are related. A few studies in rats raised questions regarding potential effects on postnatal development, but in the absence of better study designs, the relevancy of these findings to human risk are also questionable at best. CONCLUSION: There is a signal for embryo-fetal toxicity associated with 17-OHP-C in the two largest clinical trials conducted to date; there is also a signal for embryo-fetal toxicity with 17-OHP-C in rhesus monkeys and possibly one in rodent species. The relationship between these signals is unclear given the absence of state-of-the-art reproductive toxicology studies and human pharmacokinetic studies.

[Attachment 10]

http://www.fda.gov/ohrms/dockets/ac/cder06.html#rhdac

go to “slides”, “Barbara Wesley”, slide #9. (accessed 18 January 2008)

[Attachment 11]

http://www.fda.gov/ohrms/dockets/ac/cder06.html#rhdac

go to “slides”, “Barbara Wesley”, slide #13. (accessed 18 January 2008)

[Attachment 12]

http://www.fda.gov/ohrms/dockets/ac/cder06.html#rhdac

go to “minutes”, “page 7”, “question #4”. (accessed 18 January 2008)

[Attachment 13]

• Duke University Medical Center (NEJM, correspondence, vol. 349, September 11, 2003)

– “After reading the article by Meis et al (June 12 issue), we strongly discourage practitioners from using 17 alpha-hydroxyprogesterone caproate in the care of women who have had preterm deliveries, until more investigation is done.”

– “We speculate that the high rate of preterm delivery in the placebo group was due to the injections of castor oil.”

– “We believe that practitioners should use caution before adopting this regimen for their patients at risk for preterm delivery.”

[Attachment 14]

Found on -

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10631825&query_hl=9 (accessed 18 January 2008)

Altern Ther Health Med. 2000 Jan;6(1):77-9.

Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.

O'Brien JM, Adair CD, Lewis DF, Hall DR, Defranco EA, Fusey S, Soma-Pillay P, Porter K, How H, Schackis R, Eller D, Trivedi Y, Vanburen G, Khandelwal M, Trofatter K, Vidyadhari D, Vijayaraghavan J, Weeks J, Dattel B, Newton E, Chazotte C, Valenzuela G, Calda P, Bsharat M, Creasy GW.

Perinatal Diagnostic Center, Central Baptist Hospital, Lexington, Kentucky, USA. jobrien@bhsi.com

OBJECTIVE: Preterm birth is the leading cause of perinatal morbidity and mortality worldwide. Treatment of preterm labor with tocolysis has not been successful in improving infant outcome. The administration of progesterone and related compounds has been proposed as a strategy to prevent preterm birth. The objective of this trial was to determine whether prophylactic administration of vaginal progesterone reduces the risk of preterm birth in women with a history of spontaneous preterm birth. METHODS: This randomized, double-blind, placebo- controlled, multinational trial enrolled and randomized 659 pregnant women with a history of spontaneous preterm birth. Between 18 + 0 and 22 + 6 weeks of gestation, patients were assigned randomly to once-daily treatment with either progesterone vaginal gel or placebo until either delivery, 37 weeks' gestation or development of preterm rupture of membranes. The primary outcome was preterm birth at </= 32 weeks of gestation. The trial was analyzed using an intent-to-treat strategy. RESULTS: Baseline characteristics were similar in the two treatment groups. Progesterone did not decrease the frequency of preterm birth at </= 32 weeks. There was no difference between the groups with respect to the mean gestational age at delivery, infant morbidity or mortality or other maternal or neonatal outcome measures. Adverse events during the course of treatment were similar for the two groups. CONCLUSION: Prophylactic treatment with vaginal progesterone did not reduce the frequency of recurrent preterm birth (</= 32 weeks) in women with a history of spontaneous preterm birth. The effect of progesterone administration in patients at high risk for preterm delivery as determined by methods other than history alone (e.g. sonographic cervical length) requires further investigation. Copyright (c) 2007 ISUOG

[Attachment 20]

(accessed 18 January 2008)

Ultrasound Obstet Gynecol. 2007 Oct;30(5):697-705. Links

Vaginal progesterone is associated with a decrease in risk for early preterm birth and improved neonatal outcome in women with a short cervix: a secondary analysis from a randomized, double-blind, placebo-controlled trial.

DeFranco EA, O'Brien JM, Adair CD, Lewis DF, Hall DR, Fusey S, Soma-Pillay P, Porter K, How H, Schakis R, Eller D, Trivedi Y, Vanburen G, Khandelwal M, Trofatter K, Vidyadhari D, Vijayaraghavan J, Weeks J, Dattel B, Newton E, Chazotte C, Valenzuela G, Calda P, Bsharat M, Creasy GW.

Department of Obstetrics and Gynecology and Center for Preterm Birth Research, Washington University School of Medicine, St. Louis, Missouri, USA. defrancoe@wudosis.wustl.edu

OBJECTIVE: To investigate the efficacy of vaginal progesterone to prevent early preterm birth in women with sonographic evidence of a short cervical length in the midtrimester. METHODS: This was a planned, but modified, secondary analysis of our multinational, multicenter, randomized, placebo-controlled trial, in which women were randomized between 18 + 0 and 22 + 6 weeks of gestation to receive daily treatment with 90 mg of vaginal progesterone gel or placebo. Cervical length was measured with transvaginal ultrasound at enrollment and at 28 weeks of gestation. Treatment continued until either delivery, 37 weeks of gestation or development of preterm rupture of membranes. Maternal and neonatal outcomes were evaluated for the subset of all randomized women with cervical length < 28 mm at enrollment. The primary outcome was preterm birth at </= 32 weeks. RESULTS: A cervical length < 28 mm was identified in 46 randomized women: 19 of 313 who received progesterone and 27 of 307 who received the placebo. Baseline characteristics of the two groups were similar. In women with a cervical length < 28 mm, the rate of preterm birth at </= 32 weeks was significantly lower for those receiving progesterone than it was for those receiving the placebo (0% vs. 29.6%, P = 0.014). With progesterone, there were fewer admissions into the neonatal intensive care unit (NICU; 15.8% vs. 51.9%, P = 0.016) and shorter NICU stays (1.1 vs. 16.5 days, P = 0.013). There was also a trend toward a decreased rate of neonatal respiratory distress syndrome (5.3% vs. 29.6%, P = 0.060). CONCLUSION: Vaginal progesterone may reduce the rate of early preterm birth and improve neonatal outcome in women with a short sonographic cervical length. Copyright (c) 2007 ISUOG

[Attachment 21]

(accessed 18 January 2008)

Ultrasound Obstet Gynecol. 2007 Oct;30(5):675-86. Links

Prevention of spontaneous preterm birth: the role of sonographic cervical length in identifying patients who may benefit from progesterone treatment.

Romero R.

_________________________________________________________________________________________________________

January 2008