Medroxyprogesterone Acetate (medroxyprogesterone acetate)

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Medroxyprogesterone acetate (alone or in fixed combination with estrogens (i.e., conjugated estrogens, estradiol cypionate)) is administered orally, subcutaneously, or IM. When used as a contraceptive in females, medroxyprogesterone acetate is administered subcutaneously or IM; the drug is administered subcutaneously for the management of pain associated with endometriosis. Medroxyprogesterone acetate is administered IM in the treatment of cancer or male sexual deviance+ (paraphilia). Because of the prolonged action, parenteral administration of the drug is not recommended for the treatment of secondary amenorrhea or abnormal uterine bleeding.

Medroxyprogesterone acetate injectable suspension (containing medroxyprogesterone acetate alone or in fixed combination with estradiol cypionate) must be vigorously shaken immediately before each use to ensure complete suspension of the drug(s). IM injection of medroxyprogesterone acetate alone (Depo-Provera(R) Contraceptive, Depo-Provera(R), Medroxyprogesterone Acetate Contraceptive) or in combination with estradiol cypionate (Lunelle(R) Monthly Contraceptive) should be made deep into the gluteal, deltoid, or anterior thigh muscle. Subcutaneous injection of medroxyprogesterone acetate (depo-subQ provera 104(R)) is made into the anterior thigh or abdomen; the preparation for subcutaneous administration should not be administered IM.

Oral dosage preparations containing medroxyprogesterone acetate in combination with conjugated estrogens as monophasic or biphasic regimens are commercially available in a mnemonic dispensing package that is designed to aid the user in complying with the prescribed dosage schedule. The monophasic combination (Prempro(R)) is available in a 28-day dosage preparation that contains 28 tablets of conjugated estrogens (0.625 mg) in fixed combination with medroxyprogesterone acetate (2.5 or 5 mg). The monophasic combination (Prempro(R)) also is available in a 28-day dosage preparation that contains 28 tablets of conjugated estrogens USP (0.3 or 0.45 mg) in fixed combination with medroxyprogesterone acetate (1.5 mg). The biphasic combination (Premphase(R)) also is available in a 28-day dosage preparation that contains 14 tablets of conjugated estrogens (0.625 mg) and 14 tablets of conjugated estrogens (0.625 mg) in fixed combination with medroxyprogesterone acetate (5 mg).

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There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Progestin Replacement Therapy/Ulipristal

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Ulipristal is a progesterone receptor modulator and binds to the progesterone receptor with high affinity.(1)(2)

CLINICAL EFFECTS: Concurrent use of ulipristal may make progesterone products ineffective.(1,2) These agents may also make ulipristal ineffective.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Products containing progestin should not be used within 12 days of ulipristal discontinuation.(3)

DISCUSSION: Ulipristal is a progesterone receptor modulator and binds to the progesterone receptor with high affinity, thus it may interfere with the efficacy of progestin products.(1-3) These products may also make ulipristal ineffective.(3)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Medroxyprogesterone; Megestrol/Coumarin Anticoagulants

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism of this interaction is unknown but may involve inhibition of anticoagulant metabolism by medroxyprogesterone and megestrol.(1,2)

CLINICAL EFFECTS: The concurrent use of medroxyprogesterone or megestrol and coumarin anticoagulants may increase international normalized ratio (INR) and result in an increased risk for bleeding.(1,2)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with medroxyprogesterone or megestrol and a coumarin anticoagulant (e.g. warfarin) should have their INR closely monitored.(1) When concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: A study of four patients on high-dose progestins (two patients on medroxyprogesterone 500 mg twice daily and two patients on megestrol 160 mg once daily) and warfarin found that the progestins decreased the clearance of warfarin by 34.8% (from 2.3 to 1.5 mL/h*kg BW) and increased the half-life of warfarin by 71.4% (from 43.4 to 74.4 hours).(2)

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• Carcinoma of breast
• Porphyria

• Acute myocardial infarction
• Bed-ridden
• Cerebrovascular accident
• Coronary artery disease
• Deep venous thrombosis
• Disease of liver
• Migraine
• Neoplasm of liver
• Obesity
• Predisposition to thrombosis
• Pulmonary thromboembolism
• Retinal thrombosis
• Thromboembolic disorder
• Thrombophlebitis
• Tobacco smoker

• Diabetes mellitus
• Edema
• Hyperlipidemia
• Hypertension

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More Frequent

• Abdominal distension
• Abnormal vaginal bleeding
• Irregular menstrual periods

Less Frequent

• Endometrial hyperplasia

Rare or Very Rare

• Abnormal hepatic function tests
• Acute myocardial infarction
• Anaphylaxis
• Angioedema
• Depression
• Ectopic pregnancy
• Erythema multiforme
• Erythema nodosum
• Galactorrhea not associated with childbirth
• Hypersensitivity drug reaction
• Hypertension
• Malignant neoplasm of the ovary
• Menorrhagia
• Obstructive hyperbilirubinemia
• Optic neuritis
• Ovarian cyst
• Pancreatitis
• Pruritus of skin
• Pulmonary thromboembolism
• Retinal thrombosis
• Thromboembolic disorder
• Thrombophlebitis

More Frequent

• Back pain
• Edema
• Fatigue
• Headache disorder
• Myalgia
• Vaginitis
• Weight loss

Less Frequent

• Dizziness
• Dyspepsia
• Ectropion of cervix
• Hypertonia
• Palpitations
• Vaginal discharge

Rare or Very Rare

• Acne vulgaris
• Alopecia
• Amenorrhea
• Body fluid retention
• Cervical discharge
• Chloasma
• Constipation
• Cystitis
• Drowsy
• Fever
• Fibrocystic breast disease
• Hirsutism
• Hyperglycemia
• Insomnia
• Irritability
• Mastalgia
• Migraine
• Nausea
• Nervousness
• Pain in extremities
• Skin rash
• Urinary incontinence
• Urticaria
• Weight gain

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Although progestins have been used beginning in the first trimester of pregnancy to prevent habitual abortion or to treat threatened abortion, there is no adequate evidence from well-controlled studies to substantiate the efficacy of progestins for these uses; however, there is evidence of potential adverse effects on the fetus when these drugs are administered within the first 4 months of pregnancy. In addition, in most women, the cause of abortion is a defective ovum, which progestins could not be expected to influence. Because of their uterine-relaxant effects, progestins may delay spontaneous abortion of fertilized defective ova. Masculinization of the female fetus has reportedly occurred when progestins were used during pregnancy. Clitoral hypertrophy and fusion of the labia have been reported in a few female neonates born to women who had received medroxyprogesterone during pregnancy; hypospadias in male neonates born to women receiving progestational agents occurs at approximately twice the rate of occurrence in male neonates born to women not receiving the drugs. Postpartum bleeding, postabortal bleeding, and missed abortion have been reported in women who received the drug during pregnancy. An association between intrauterine exposure to female sex hormones and congenital anomalies, including cardiovascular and limb defects, has been suggested. (See Cautions: Pregnancy, Fertility, and Lactation, in Estrogen-Progestin Combinations 68:12.) Use of progestins, including medroxyprogesterone, is not recommended during the first 4 months of pregnancy. If a woman becomes pregnant while receiving medroxyprogesterone or is inadvertently exposed to the drug during the first 4 months of pregnancy, she should be advised of the potential risks to the fetus. To increase ensurance that the drug is not administered inadvertently to a pregnant woman, it is important that use of the drug be initiated only during the first 5 days after onset of normal menses, within 5 days postpartum if the woman is not lactating, or at the sixth postpartum week if she is. If more than 13-14 weeks has elapsed since the last dose of medroxyprogesterone, appropriate assessment should be performed to ensure that the woman is not pregnant prior to administering a dose.

When medroxyprogesterone is used as a contraceptive, unintended pregnancies that occur within 1-2 months after IM injection of the drug may be characterized by impaired fetal growth as evidenced by low birthweights, which theoretically could result in an increased risk of neonatal death. However, the attributable risk of this adverse effect is low because such pregnancies are unlikely. The risk of low birthweight was particularly evident when conception was estimated to occur within 4 weeks of medroxyprogesterone injection. While an increase in polysyndactyly, particularly among offspring of women younger than 30 years of age, and chromosomal anomalies also have been observed in neonates born to women who received IM medroxyprogesterone contraception, the unrelated nature of these effects, the lack of confirmation from other studies, the prolonged period of time between use of the drug and conception in many cases, and chance effects resulting from the multiple statistical comparisons applied make an association between these effects and the drug unlikely.

The possibility of ectopic pregnancy should be considered in any women using medroxyprogesterone contraception if pregnancy occurs or the woman develops complaints of severe abdominal pain.

Medroxyprogesterone should not be used to induce withdrawal bleeding as a test for pregnancy.

Progestins reportedly are distributed into milk, and detectable amounts of medroxyprogesterone have been identified in milk of lactating women receiving the drug IM. Milk composition, quality, and volume are not affected adversely by medroxyprogesterone use. While the manufacturers warn that the possible effects of progestins in milk on nursing infants have not been determined, study of infants exposed to the drug via breast milk has revealed no evidence of adverse developmental or behavioral effects through puberty.

The effects of combined medroxyprogesterone acetate and estradiol cypionate therapy on lactation and nursing infants have not been established. However, because adverse effects such as jaundice and breast enlargement have been reported in nursing infants of women receiving estrogen-progestin combination oral contraceptives, the usual cautions and precautions associated with estrogens must be considered in lactating women receiving IM medroxyprogesterone acetate in fixed combination with estradiol cypionate. The manufacturer states that use of estrogen-progestin combination contraceptives should be deferred until 6 weeks postpartum. For additional information, see Cautions: Pregnancy, Fertility, and Lactation, in Estrogen-Progestin Combinations 68:12.

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