Cycrin^®

Warning

Progestational agents have been used, beginning with the first trimester of pregnancy, in an attempt to prevent habitual abortion. There is no adequate evidence that such use is effective when such drugs are given during the first 4 months of pregnancy. Furthermore, in the vast majority of women, the cause of abortion is a defective ovum, which progestational agents could not be expected to influence. In addition, the Use of progestational agents with their uterine-relaxant properties, in patients with fertilized defective ova, may cause a delay in spontaneous abortion. Therefore, the use of such drugs during the first 4 months of pregnancy is not recommended.

Several reports suggest an association between intrauterine exposure to progestational drugs in the first trimester of pregnancy and genital abnormalities in male and female fetuses. The risk of hypospadias, 5 to 8 per 1,000 male births in the general population, may be approximately doubled with exposure to these drugs. There are insufficient data to quantify the risk to exposed female fetuses, but insofar as some of these drugs induce mild virilization of the external genitalia of the female fetus, and because of the increased assocÇå–on of hypospadias in the male fetus, it is prudent to avoid the use of these drugs during the first trimester of pregnancy. If the patient is exposed to Cycrin (medroxyprogesterone acetate) during the first 4 months of pregnancy, or if she becomes pregnant while taking this drug, she should be apprised of the potential risks to the fetus.

Top of page

DESCRIPTION

Cycrin tablets contain medroxyprogesterone acetate, which is a derivative of progesterone. It is a white to off-white, odorless, crystalline powder, stable in air, melting between 200^oC and 210^oC. It is freely soluble in chloroform, soluble in acetone and in dioxane, sparingly soluble in alcohol and in methanol, slightly soluble in ether, and insoluble in water.

The chemical name for medroxyprogesterone acetate is pregn-4-ene-3,20-dione, 17-(acetyloxy)-6-methyl-,(6a)-. Its structural formula is:

Cycrin is available in tablet form for oral administration. Each tablet contains 2.5 mg, 5 mg, or 1 0 mg of medroxyprogesterone acetate and the following inactive ingredients: lactose, magnesium stearate, methylcellulose, and microcrystalline cellulose. Each dosage strength also contains the following:
5 mg-D&C Red #30 and FD&C Blue # 1,
10 mg-D&C Red #30 and D&C Yellow #10

Top of page

CLINICAL PHARMACOLOGY

Medroxyprogesterone acetate, administered orally or parenterally in the recommended doses to women with adequate endogenous estrogen, transforms proliferative into secretory endometrium. Androgenic and anabolic effects have been noted, but the drug is apparently devoid of significant estrogenic activity. While parenterally administered medroxyprogesterone acetate inhibits gonadotropin production, which in turn prevents follicular maturation and ovulation, available data indicate that this does not occur when the usually recommended oral dosage is given as single daily doses.

Top of page

INDICATIONS AND USAGE

Secondary amenorrhea; abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as fibroids or uterine cancer.

Top of page

CONTRAINDICATIONS

1. Thrombophlebitis, thromboembolic disorders, cerebral apoplexy, or patients with a past history of these conditions.
2. Liver dysfunction or disease.
3. Known or suspected malignancy of breast or genital organs.
4. Undiagnosed vaginal bleeding.
5. Missed abortion.
6. As a diagnostic test for pregnancy.
7. Known sensitivity to medroxyprogesterone acetate.

Top of page

WARNINGS

1. The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, cerebrovascular disorders, pulmonary embolism, and retinal thrombosis). Should any of these occur or be suspected, the drug should be discontinued immediately.
2. Beagle dogs treated with medroxyprogesterone acetate developed mammary nodules, some of which were malignant. Although nodules occasionally appeared in control animals, they were intermittent in nature, whereas the nodules in the drug-treated animals were larger, more numerous, persistent, and there were some breast malignancies with metastases. Their significance with respect to humans has not been established.
3. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or if there is a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, medication should be withdrawn.
4. Detectable amounts of progestin have been identified in the milk of mothers receiving the drug. The effect of this on the nursing infant has not been determined.
5. Usage in pregnancy is not recommended (see Boxed Warning).
6. Retrospective studies of morbidity and mortality in Great Britain and studies of morbidity in the United States have shown a statistically significant association between thrombophlebitis, pulmonary embolism, and cerebral thrombosis and embolism and the use of oral contraceptives. ^1-4 The estimate of the relative risk of thromboembolism in the study by Vessey and Doll³ was about sevenfold, while Sartwell and associates⁴ in the United States found a relative risk of 4.4, meaning that the users are several times as likely to undergo thromboembolic disease without evident cause as nonusers. The American study also indicated that the risk did not persist after discontinuation of administration, and that it was not enhanced by long, continued administration. The American study was not designed to evaluate a difference between products.

Top of page

PRECAUTIONS

1. The pretreatment physical examination should include special reference to breasts and pelvic organs, as well as Papanicolaou smear.
2. Because progestogens may cause some degree of fluid retention, conditions which might be influenced by this factor, such as epilepsy, migraine, asthma, cardiac or renal dysfunction, require careful observation.
3. In cases of breakthrough bleeding, as in all cases of irregular bleeding per vaginum, nonfunctional causes should be borne in mind. In cases of undiagnosed vaginal bleeding, adequate diagnostic measures are indicated.
4. Patients who have a history of psychic depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree.
5. Any possible influence of prolonged progestin therapy on pituitary, ovarian, adrenal, hepatic, or uterine functions awaits further study.
6. A decrease in glucose tolerance has been observed in a small percentage of patients on estrogen-progestin combination drugs. The mechanism of this decrease is obscure. For this reason, diabetic patients should be carefully observed while receiving progestin therapy.
7. The age of the patient constitutes no absolute limiting factor, although treatment with progestins may mask the onset of the climacteric.
8. The pathologist should be advised of progestin therapy when relevant specimens are submitted.
9. Because of the occasional occurrence of thrombotic disorders (thrombophlebitis, pulmonary embolism, retinal thrombosis, and cerebrovascular disorders) in patients taking estrogen-progestin combinations, and since the mechanism is obscure, the physician should be alert to the earliest manifestation of these disorders.
10. CONCOMITANT USE IN ESTROGEN REPLACEMENT THERAPY:
    Studies of the addition of a progestin product to an estrogen replacement regimen for 7 or more days of a cycle of estrogen administration have reported a lowered incidence of endometrial hyperplasia. Morphological and biochemical studies of the endometrium suggest that 1 0 to 13 days of a progestin are needed to provide maximal maturation of the endometrium and to eliminate any hyperplastic changes. Whether this will provide protection from endometrial carcinoma has not been clearly established. There are possible additional risks which may be associated with the inclusion of progestin in estrogen replacement regimens. The potential risks include adverse effects on carbohydrate and lipid metabolism. The dosage used may be important in minimizing these adverse effects.
11. Aminoglutethimide administered concomitantly with Cycrin may significantly depress the bioavailability of Cycrin.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
Long-term intramuscular administration Of Medroxyprogesterone acetate has been shown to produce mammary tumors in beagle dogs (see "Warnings" above). There was no evidence of a carcinogenic effect associated with the oral administration of medroxyprogesterone acetate to rats and mice. Medroxyprogesterone acetate was not mutagenic in a battery of in vitro or in vivo genetic toxicity assays.

Medroxyprogesterone acetate at high doses is an antifertility drug and high doses would be expected to impair fertility until the cessation of treatment.

INFORMATION FOR THE PATIENT
See Patient Information at the end of insert.

Top of page

ADVERSE REACTIONS

PREGNANCY: (See Boxed Warning for possible adverse effects on the fetus.)

BREAST: Breast tenderness or galactorrhea has been reported rarely.

SKIN: Sensitivity reactions consisting of urticaria, pruritus, edema, and generalized rash have occurred in an occasional patient. Acne, alopecia, and hirsutism have been reported in a few cases.

THROMBOEMBOLIC PHENOMENA:
Thromboembolic phenomena, including thrombophlebitis and pulmonary embolism, have been reported. The following adverse reactions have been observed in women taking progestins, including Cycrin (medroxyprogesterone acetate tablets):
breakthrough bleeding
spotting
change in menstrual flow
amenorrhea
edema
change in weight (increase or decrease)
changes in cervical erosion and cervical secretions
cholestatic jaundice
anaphylactoid reactions and anaphyaxis
rash (allergic) with and without pruritus mental depression
pyrexia
insomnia
nausea
somnolence

A statistically significant association has been demonstrated between use of estrogen-progestin combination drugs and the following serious adverse reactions: thrombophlebitis; pulmonary embolism; and cerebral thrombosis and embolism. For this reason patients on progestin therapy should be carefully observed.

Although available evidence is suggestive of an association, such a relationship has been neither confirmed nor refuted for the following serious adverse reactions: neuro-ocular lesions, e.g., retinal thrombosis and optic neuritis.

The following adverse reactions have been observed in patients receiving estrogen-progestin combination drugs:
rise in blood pressure in susceptible individuals premenstrual-like syndrome
changes in libido
changes in appetite
cystitis-like syndrome
headache
nervousness
dizziness
fatigue
backache
hirsutism
loss of scalp hair
erythema multiforme
erythemia nodosum
hemorrhagic eruption
itching

In view of these observations, patients on progestin therapy should be carefully observed.

The following laboratory results may be altered by the use of estrogen-progestin combination drugs:
Increased sulfobromophthalein retention and other hepatic function tests.
Coagulation tests: increase in prothrombin factors VII, VIII, IX, and X.
Metyrapone test.
Pregnanediol determination.
Thyroid function: increase in PBI, and butanol extractable protein bound iodine and decreases in T₃ uptake values.

Top of page

DOSAGE AND ADMINISTRATION

SECONDARY AMENORRHEA- Cycrin (medroxyprogesterone acetate tablets) may be given in dosages of 5 mg to 10 mg daily for from 5 to 10 days. A dose for inducing an optimum secretory transformation of an endometrium that has been adequately primed with either endogenous or erogenous estrogen is 10 mg of Cycrin daily for 10 days. In cases of secondary amenorrhea, therapy may be started at any time. Progestin withdrawal bleeding usually occurs within 3 to 7 days after discontinuing Cycrin therapy.

ABNORMAL UTERINE BLEEDING DUE TO HORMONAL IMBALANCE IN THE ABSENCE OF ORGANIC PATHOLOGY: Beginning on the calculated 16th or 21st day of the menstrual cycle, 5 to 10 mg of medroxyprogesterone acetate may be given daily for from 5 to 10 days. To produce an optimum secretary transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen, 10 mg of medroxyprogesterone acetate daily for 1 0 days beginning on the 16th day of the cycle is suggested. Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing therapy with Cycrin. Patients with a past history of recurrent episodes of abnormal uterine bleeding may benefit from planned menstrual cycling with Cycrin.

Top of page

HOW SUPPLIED

Cycrin® (medroxyprogesterone acetate tablets, USP) is available for oral administration in the following dosage strengths:

2.5 mg, white, oval tablet with a score debossed on one side and opposing "C"s debossed on the reverse, in bottles of 100 (NDC 59911-5898-1) and bottles of 1,000 (NDC 59911-5898-3).

5 mg, light-purple, oval tablet with "CYCRIN" and a score debossed on one side and opposing "C"s debossed on the reverse, in bottles of 100 (NDC 59911-5897-1) and bottles of 1,000 (NDC 59911-5897-3). 10 mg, peach, oval tablet with "CYCRIN" and a score debossed on one side and opposing "C"s debossed on the reverse, in bottles of 100 (NDC 59911-5897-1) and bottles of 1,000 (NDC 59911-5897-3).

10 mg, peach, oval tablet with "CYCRIN" and a score debossed on one side and opposing "C"s debossed on the reverse, in bottles of 1 00 (NDC 59911-5896-1) and bottles of 1000 (NDC 59911-5896-3).

The appearance of these tablets is a registered trademark.

Store at controlled room temperature, 20^o-25^oC (68^o-77^oF).
Dispense in a well-closed container as defined in the USP.

Caution: Federal law prohibits dispensing without prescription.

References

1. Royal College of General Practitioners: Oral contraception and thromboembolic disease. J Coll Gen Pract 1967- 13:267-279.
2. Inman WHW, Vessey MP: Investigation of deaths from pulmonary, coronary, and cerebral thrombosis and embolism in women of childbearing age. Br Med J 1968; 2:193-199.
3. Vessey MP, Doll R: Investigation of relation between use of oral contraceptives and thromboembolic disease. A further report. Br Med J 1 969; 2:65 657.
4. Sartwell PE, Masi AT, Arthes FG, et al: Thromboembolism and oral contraceptives: An epidemiological case-control study. Am J Epidemiol 1969; 90:365-380.

PATIENT INFORMATION Cycrin tablets contain medroxyprogesterone acetate, a progesterone. The information below is that which the U.S. Food and Drug Administration requires be provided for all patients taking progesterones. The information below relates only to the risk to the unborn child associated with use of progesterone during pregnancy. For further information on the use, side-effects, and other risks associated with this product, ask your doctor.

Warning for Women
Progesterone or progesterone-like drugs have been used to prevent miscarriage in the first few months of pregnancy. No adequate evidence is available to show that they are effective for this purpose. Furthermore, most cases of early miscarriage are due to causes which could not be helped by these drugs.

There is an increased risk of minor birth defects in children whose mothers take this drug during the first four months of pregnancy. Several reports suggest an association between mothers who take these drugs in the first trimester of pregnancy and genital abnormalities in male and female babies. The risk to the male baby is the possibility of being born with a condition in which the opening of the penis is on the underside rather than the tip of the penis (hypospadias). Hypospadias occurs in about 5 to 8 per 1,000 male births and is about doubled with exposure to these drugs. There is not enough information to quantify the risk to exposed female fetuses, but enlargement of the clitoris and fusion of the labia may occur, although rarely.

Therefore, since drugs of this type may induce mild masculinization of the external genitalia of the female fetus, as well as hypospadias in the male fetus, it is wise to avoid using the drug during the first trimester of pregnancy. These drugs have been used as a test for pregnancy, but such use is no longer considered safe because of possible damage to a developing baby. Also, more rapid methods for testing for pregnancy are now available.

If you take Cycrin (medroxyprogesterone acetate tablets, USP) and later find you were pregnant when you took it, be sure to discuss this with your doctor as soon as possible.

Cl 4163-4
Revised January 20, 1995
Printed in USA