PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Cytostatic Estrogens
    Other Alkylating Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Oral nitrogen mustard antineoplastic agent; linked to an estradiol molecule; used primarily for hormone-refractory prostate CA; used off-label for breast CA and malignant glioma.

    COMMON BRAND NAMES

    Emcyt

    HOW SUPPLIED

    Emcyt Oral Cap: 140mg

    DOSAGE & INDICATIONS

    For the treatment of metastatic prostate cancer.
    For the treatment of hormone-refractory, metastatic prostate cancer in combination with docetaxel†.
    Oral dosage
    Adult males

    280 mg orally three times daily on days 1, 2, 3, 4, and 5, in combination with docetaxel 60 mg/m2 IV on day 2, repeated every 21 days until disease progression or unacceptable toxicity. The night before docetaxel administration (day 1), begin administration of dexamethasone 60 mg PO in 3 divided doses (i.e., 20 mg orally every 12 hours for 3 doses). In a randomized, phase 3 clinical trial in patients with androgen-independent prostate cancer (n = 674), administration of docetaxel/estramustine/dexamethasone significantly improved overall survival compared with mitoxantrone/prednisone (17.5 vs. 15.6 months; p = 0.02). In addition, the median time to progression was improved in the docetaxel/estramustine/dexamethasone arm (6.3 vs. 3.2 months; p < 0.001).

    For the palliative treatment of metastatic and/or progressive prostate cancer.
    Oral dosage
    Adult males

    14 mg/kg per day orally in 3 to 4 divided doses; most patients in studies in the United States have been treated at a dose range of 10 to 16 mg/kg per day. After 30 to 90 days of treatment, response should be evaluated. Continue as long as a favorable response lasts. Some patients have been maintained on therapy for more than 3 years at a dose up to 10 to 16 mg/kg per day.

    MAXIMUM DOSAGE

    Adults

    16 mg/kg per day.

    Geriatric

    16 mg/kg per day.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. Estramustine may be poorly metabolized in patients with hepatic disease, so it should be administered with caution in such patients.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration

    Estramustine should be swallowed with water on an empty stomach (i.e., at least one hour prior to or two hours after a meal). Do not administer with milk products, or calcium-containing foods or drugs.

    STORAGE

    Emcyt:
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Estramustine is contraindicated for use in patients with estradiol hypersensitivity or nitrogen mustard hypersensitivity.

    Cardiac disease, cerebrovascular disease, coronary artery disease, hypertension, myocardial infarction, stroke, thromboembolic disease, thrombophlebitis

    Estramustine is contraindicated for use in patients with active thromboembolic disease, stroke or thrombophlebitis, except in rare cases where the actual tumor mass is the cause of the thromboembolic disease and the benefits of therapy outweigh the risks. In patients with a history of thromboembolic disease or disorder, estramustine should be given with extreme caution, especially if these disorders were associated with estrogen therapy. There is an increased risk of thrombosis, including fatal myocardial infarction, in men who take estrogen and estrogen-like compounds such as estramustine for prostate cancer. Estramustine should be administered with caution to men with a history of cerebrovascular disease, or cardiac disease, including coronary artery disease or hypertension. Blood pressure should be monitored periodically in patients receiving estramustine.

    Heart failure, hypercalcemia, hypocalcemia, migraine, peripheral edema, renal failure, renal impairment, seizure disorder

    Patients with congestive heart failure or preexisting peripheral edema may experience exacerbations of these conditions during treatment with estramustine. Other conditions that may be affected by estramustine-induced fluid retention include seizure disorder, migraine, or renal failure. In addition, estramustine may influence the metabolism of calcium and phosphorus. Therefore, estramustine should be used with caution in patients with metabolic bone diseases that are associated with hypercalcemia, or in patients with known renal impairment. Patients with prostate cancer and osteoblastic metastasis are at risk for hypocalcemia; monitor serum calcium concentrations.

    Herpes infection, varicella, viral infection

    Patients with a history of varicella, other herpes infection (e.g., herpes zoster), or other viral infection are at risk for reactivation of prior infections when treated with estramustine or other chemotherapy.

    Diabetes mellitus

    Estramustine may decrease glucose tolerance, so patients with diabetes mellitus should be carefully observed.

    Hepatic disease, jaundice

    Estramustine may be poorly metabolized in patients with hepatic disease, so it should be administered with caution in such patients or in patients with jaundice.

    Male-mediated teratogenicity, pregnancy

    Although testing has failed to demonstrate mutagenicity for estramustine phosphate, it is known that both estradiol (FDA pregnancy risk category X) and nitrogen mustard are mutagenic (FDA pregnancy risk category D). In addition, some male patients who had been impotent while on estrogen therapy have regained potency while taking estramustine. As estramustine may cause male-mediated teratogenicity, both males and females should use effective contraception while receiving estramustine therapy.

    Breast-feeding

    Estramustine should not be given to a woman who is breast-feeding her infant due to potential toxicities to the infant. It is not known if estramustine is excreted in breast milk. However, a metabolite of estramustine (i.e., estradiol) has been reported to interfere with milk production and duration of lactation in some women. Less than 10% of a dose passes into breast milk.

    Children

    The safety and efficacy of estramustine in children have not been established.

    Vaccination

    Vaccination during chemotherapy, such as estramustine, or radiation therapy should be avoided because the antibody response is suboptimal. When chemotherapy is being planned, vaccination should precede the initiation of chemotherapy by >= 2 weeks. The administration of live vaccines to immunocompromised patients should be avoided. Those undergoing chemotherapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Measles-mumps-rubella (MMR) vaccination is not contraindicated for the close contacts, including health care professionals, of immunocompromised patients. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of, or in addition to, vaccination. When exposed to a vaccine-preventable disease such as measles, severely immunocompromised children should be considered susceptible regardless of their vaccination history.

    ADVERSE REACTIONS

    Severe

    myocardial infarction / Delayed / 3.0-3.0
    heart failure / Delayed / 3.0-3.0
    stroke / Early / 2.0-2.0
    pulmonary embolism / Delayed / 2.0-2.0
    GI bleeding / Delayed / 1.0-1.0
    thromboembolism / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known

    Moderate

    elevated hepatic enzymes / Delayed / 31.0-31.0
    edema / Delayed / 19.0-19.0
    dyspnea / Early / 11.0-11.0
    gynecomastia / Delayed / 10.0-10.0
    leukopenia / Delayed / 4.0-4.0
    phlebitis / Rapid / 3.0-3.0
    thrombocytopenia / Delayed / 1.0-1.0
    chest pain (unspecified) / Early / 1.0-1.0
    hyperbilirubinemia / Delayed / 1.0-1.0
    impotence (erectile dysfunction) / Delayed / Incidence not known
    peripheral edema / Delayed / Incidence not known
    fluid retention / Delayed / Incidence not known

    Mild

    mastalgia / Delayed / 66.0-66.0
    nausea / Early / 15.0-15.0
    diarrhea / Early / 12.0-12.0
    dyspepsia / Early / 11.0-11.0
    muscle cramps / Delayed / 8.0-8.0
    anorexia / Delayed / 4.0-4.0
    lethargy / Early / 4.0-4.0
    ecchymosis / Delayed / 3.0-3.0
    insomnia / Early / 3.0-3.0
    flatulence / Early / 2.0-2.0
    pruritus / Rapid / 2.0-2.0
    xerosis / Delayed / 2.0-2.0
    emotional lability / Early / 2.0-2.0
    polydipsia / Early / 1.0-1.0
    vomiting / Early / 1.0-1.0
    hoarseness / Early / 1.0-1.0
    flushing / Rapid / 1.0-1.0
    rash / Early / 1.0-1.0
    anxiety / Delayed / 1.0-1.0
    headache / Early / 1.0-1.0
    lacrimation / Early / 1.0-1.0

    DRUG INTERACTIONS

    Abciximab: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as estramustine.
    Acarbose: (Moderate) Estramustine may decrease glucose tolerance leading to hyperglycemia. Patients receiving antidiabetic agents should monitor their blood glucose levels frequently due to this potential pharmacodynamic interaction.
    Alogliptin; Metformin: (Minor) Estramustine should be used cautiously in patients receiving metformin. Patients should routinely monitor their blood glucose as indicated. Estramustine may decrease glucose tolerance leading to hyperglycemia.
    Alogliptin; Pioglitazone: (Moderate) Estramustine may decrease glucose tolerance leading to hyperglycemia. Patients receiving antidiabetic agents should monitor their blood glucose levels frequently due to this potential pharmacodynamic interaction.
    Alpha interferons: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Alpha-glucosidase Inhibitors: (Moderate) Estramustine may decrease glucose tolerance leading to hyperglycemia. Patients receiving antidiabetic agents should monitor their blood glucose levels frequently due to this potential pharmacodynamic interaction.
    Alteplase: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Anagrelide: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as estramustine.
    Anticoagulants: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Antithrombin III: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Antithymocyte Globulin: (Moderate) Because antithymocyte globulin is an immunosuppressant, additive affects may be seen with other immunosuppressives or antineoplastic agents. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk of infection or other side effects.
    Apixaban: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Argatroban: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Aspirin, ASA; Dipyridamole: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as estramustine.
    Azelastine; Fluticasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Bacillus Calmette-Guerin Vaccine, BCG: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Beclomethasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Betamethasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Betrixaban: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Bivalirudin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Budesonide: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Budesonide; Formoterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Calcium: (Major) Administration of estramustine with calcium impairs the oral absorption of estramustine significantly, due to formation of a calcium-phosphate complex. Calcium-containing drugs must not be taken simultaneously with estramustine. Patients should be instructed to take estramustine with water at least 1 hour before or 2 hours after calcium supplements.
    Canagliflozin; Metformin: (Minor) Estramustine should be used cautiously in patients receiving metformin. Patients should routinely monitor their blood glucose as indicated. Estramustine may decrease glucose tolerance leading to hyperglycemia.
    Carbamazepine: (Moderate) Myelosuppressive antineoplastic agents and radiation therapy possess hematologic toxicities similar to carbamazepine, and should be used concomitantly with caution. Dosage adjustments may be necessary. Monitor patient closely.
    Ciclesonide: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Cilostazol: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as estramustine.
    Clobazam: (Major) Concurrent administration of clobazam, a weak CYP3A4 inducer, with estrogens, may increase the elimination of these hormones. Patients may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy.
    Clopidogrel: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as estramustine.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Corticosteroids: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Corticotropin, ACTH: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Cortisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Dabigatran: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Dalteparin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Danaparoid: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Dapagliflozin; Metformin: (Minor) Estramustine should be used cautiously in patients receiving metformin. Patients should routinely monitor their blood glucose as indicated. Estramustine may decrease glucose tolerance leading to hyperglycemia.
    Deflazacort: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Desirudin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Dexamethasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Diclofenac: (Minor) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Diclofenac; Misoprostol: (Minor) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Diphenhydramine; Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Diphenhydramine; Naproxen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Dipyridamole: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as estramustine.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Edoxaban: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Empagliflozin; Metformin: (Minor) Estramustine should be used cautiously in patients receiving metformin. Patients should routinely monitor their blood glucose as indicated. Estramustine may decrease glucose tolerance leading to hyperglycemia.
    Enoxaparin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Eptifibatide: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as estramustine.
    Ertugliflozin; Metformin: (Minor) Estramustine should be used cautiously in patients receiving metformin. Patients should routinely monitor their blood glucose as indicated. Estramustine may decrease glucose tolerance leading to hyperglycemia.
    Esomeprazole; Naproxen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ethotoin: (Moderate) Estrogens are metabolized by CYP3A4. Concurrent administration of hepatic enzyme inducers with estrogens, including hydantoin anticonvulsants, may increase the elimination of estrogen.
    Etodolac: (Minor) An increased risk of bleeding may occur when NSAIDs, such as etodolac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Famotidine; Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
    Fenoprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as fenoprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Filgrastim, G-CSF: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Fludrocortisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Flunisolide: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Flurbiprofen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as flurbiprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Fluticasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fluticasone; Salmeterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fluticasone; Umeclidinium; Vilanterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fluticasone; Vilanterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fondaparinux: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Food: (Major) Milk, milk products, and calcium-rich foods must not be taken simultaneously with estramustine. Patients should be instructed to take estramustine with water at least 1 hour before or 2 hours after meals.
    Formoterol; Mometasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fosphenytoin: (Moderate) Estrogens are metabolized by CYP3A4. Concurrent administration of hepatic enzyme inducers with estrogens, including hydantoin anticonvulsants, may increase the elimination of estrogen.
    Glimepiride; Pioglitazone: (Moderate) Estramustine may decrease glucose tolerance leading to hyperglycemia. Patients receiving antidiabetic agents should monitor their blood glucose levels frequently due to this potential pharmacodynamic interaction.
    Glimepiride; Rosiglitazone: (Moderate) Estramustine may decrease glucose tolerance leading to hyperglycemia. Patients receiving antidiabetic agents should monitor their blood glucose levels frequently due to this potential pharmacodynamic interaction.
    Glipizide; Metformin: (Minor) Estramustine should be used cautiously in patients receiving metformin. Patients should routinely monitor their blood glucose as indicated. Estramustine may decrease glucose tolerance leading to hyperglycemia.
    Glyburide; Metformin: (Minor) Estramustine should be used cautiously in patients receiving metformin. Patients should routinely monitor their blood glucose as indicated. Estramustine may decrease glucose tolerance leading to hyperglycemia.
    Heparin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Hydantoins: (Moderate) Estrogens are metabolized by CYP3A4. Concurrent administration of hepatic enzyme inducers with estrogens, including hydantoin anticonvulsants, may increase the elimination of estrogen.
    Hydrocodone; Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Hydrocortisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ibuprofen; Oxycodone: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ibuprofen; Pseudoephedrine: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Indomethacin: (Major) An increased risk of bleeding may occur when NSAIDs, such as indomethacin, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Insulins: (Moderate) Estramustine may decrease glucose tolerance leading to hyperglycemia. Patients receiving antidiabetic agents should monitor their blood glucose levels frequently due to this potential pharmacodynamic interaction.
    Interferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-2b; Ribavirin: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfacon-1: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-n3: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Intranasal Influenza Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Ketoprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ketoprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ketorolac: (Major) An increased risk of bleeding may occur when NSAIDs, such as ketorolac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Lansoprazole; Naproxen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Lepirudin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Linagliptin; Metformin: (Minor) Estramustine should be used cautiously in patients receiving metformin. Patients should routinely monitor their blood glucose as indicated. Estramustine may decrease glucose tolerance leading to hyperglycemia.
    Live Vaccines: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles/Mumps/Rubella Vaccines, MMR: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Meclofenamate Sodium: (Major) An increased risk of bleeding may occur when NSAIDs, such as meclofenamate sodium, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Mefenamic Acid: (Major) An increased risk of bleeding may occur when NSAIDs, such as mefenamic acid, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Meglitinides: (Moderate) Estramustine may decrease glucose tolerance leading to hyperglycemia. Patients receiving antidiabetic agents should monitor their blood glucose levels frequently due to this potential pharmacodynamic interaction.
    Meloxicam: (Minor) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. However, meloxicam may be associated with less risk than other NSAIDs due to its relative minimal platelet inhibitory effects and gastric ulceration or hemorrhagic potential. Monitor closely for bleeding.
    Metformin: (Minor) Estramustine should be used cautiously in patients receiving metformin. Patients should routinely monitor their blood glucose as indicated. Estramustine may decrease glucose tolerance leading to hyperglycemia.
    Metformin; Pioglitazone: (Moderate) Estramustine may decrease glucose tolerance leading to hyperglycemia. Patients receiving antidiabetic agents should monitor their blood glucose levels frequently due to this potential pharmacodynamic interaction. (Minor) Estramustine should be used cautiously in patients receiving metformin. Patients should routinely monitor their blood glucose as indicated. Estramustine may decrease glucose tolerance leading to hyperglycemia.
    Metformin; Repaglinide: (Moderate) Estramustine may decrease glucose tolerance leading to hyperglycemia. Patients receiving antidiabetic agents should monitor their blood glucose levels frequently due to this potential pharmacodynamic interaction. (Minor) Estramustine should be used cautiously in patients receiving metformin. Patients should routinely monitor their blood glucose as indicated. Estramustine may decrease glucose tolerance leading to hyperglycemia.
    Metformin; Rosiglitazone: (Moderate) Estramustine may decrease glucose tolerance leading to hyperglycemia. Patients receiving antidiabetic agents should monitor their blood glucose levels frequently due to this potential pharmacodynamic interaction. (Minor) Estramustine should be used cautiously in patients receiving metformin. Patients should routinely monitor their blood glucose as indicated. Estramustine may decrease glucose tolerance leading to hyperglycemia.
    Metformin; Saxagliptin: (Minor) Estramustine should be used cautiously in patients receiving metformin. Patients should routinely monitor their blood glucose as indicated. Estramustine may decrease glucose tolerance leading to hyperglycemia.
    Metformin; Sitagliptin: (Minor) Estramustine should be used cautiously in patients receiving metformin. Patients should routinely monitor their blood glucose as indicated. Estramustine may decrease glucose tolerance leading to hyperglycemia.
    Methylprednisolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Miglitol: (Moderate) Estramustine may decrease glucose tolerance leading to hyperglycemia. Patients receiving antidiabetic agents should monitor their blood glucose levels frequently due to this potential pharmacodynamic interaction.
    Mometasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Nabumetone: (Minor) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. However, nabumetone may be associated with less risk than other NSAIDs due to its relative minimal platelet inhibitory effects and gastric ulceration or hemorrhagic potential. Monitor closely for bleeding.
    Naproxen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Naproxen; Pseudoephedrine: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Naproxen; Sumatriptan: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Nateglinide: (Moderate) Estramustine may decrease glucose tolerance leading to hyperglycemia. Patients receiving antidiabetic agents should monitor their blood glucose levels frequently due to this potential pharmacodynamic interaction.
    Nefazodone: (Moderate) It is not known if nefazodone interacts with estrasmustine, but the interaction seems theoretically possible since estramustine contains an estradiol molecule linked to nornitrogen mustard and nefazodone inhibits the hepatic CYP3A4 isoenzyme which is responsible for the metabolism of estrogens. Until more data are available, monitor for potential estrogen-related side effects, such as increased nausea and fluid-retention.
    Oxaprozin: (Minor) An increased risk of bleeding may occur when NSAIDs, such as oxaprozin, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Peginterferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Peginterferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pentosan: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Phenytoin: (Moderate) Estrogens are metabolized by CYP3A4. Concurrent administration of hepatic enzyme inducers with estrogens, including hydantoin anticonvulsants, may increase the elimination of estrogen.
    Pioglitazone: (Moderate) Estramustine may decrease glucose tolerance leading to hyperglycemia. Patients receiving antidiabetic agents should monitor their blood glucose levels frequently due to this potential pharmacodynamic interaction.
    Piroxicam: (Minor) An increased risk of bleeding may occur when NSAIDs, such as piroxicam, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Platelet Inhibitors: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as estramustine.
    Polycarbophil: (Major) Administration of estramustine with calcium polycarbophil can impair the oral absorption of estramustine significantly, due to formation of a calcium-phosphate complex. Each 625 mg of calcium polycarbophil contains a substantial amount of calcium (approximately 125 mg) and must not be taken simultaneously with estramustine. Patients should be instructed to take estramustine with water at least 1 hour before or 2 hours after meals.
    Prasugrel: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as estramustine.
    Prednisolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Prednisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Repaglinide: (Moderate) Estramustine may decrease glucose tolerance leading to hyperglycemia. Patients receiving antidiabetic agents should monitor their blood glucose levels frequently due to this potential pharmacodynamic interaction.
    Reteplase, r-PA: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Rivaroxaban: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Rosiglitazone: (Moderate) Estramustine may decrease glucose tolerance leading to hyperglycemia. Patients receiving antidiabetic agents should monitor their blood glucose levels frequently due to this potential pharmacodynamic interaction.
    Rotavirus Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Rubella Virus Vaccine Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Smallpox Vaccine, Vaccinia Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Streptokinase: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Sulindac: (Minor) An increased risk of bleeding may occur when NSAIDs, such as sulindac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Tbo-Filgrastim: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Tenecteplase: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Thiazolidinediones: (Moderate) Estramustine may decrease glucose tolerance leading to hyperglycemia. Patients receiving antidiabetic agents should monitor their blood glucose levels frequently due to this potential pharmacodynamic interaction.
    Thrombolytic Agents: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Ticagrelor: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as estramustine.
    Ticlopidine: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as estramustine.
    Tinzaparin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Tirofiban: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as estramustine.
    Tolmetin: (Minor) An increased risk of bleeding may occur when NSAIDs, such as tolmetin, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Triamcinolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Typhoid Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Urokinase: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Varicella-Zoster Virus Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Vorapaxar: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as estramustine.
    Warfarin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Yellow Fever Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.

    PREGNANCY AND LACTATION

    Pregnancy

    Estramustine should not be given to a woman who is breast-feeding her infant due to potential toxicities to the infant. It is not known if estramustine is excreted in breast milk. However, a metabolite of estramustine (i.e., estradiol) has been reported to interfere with milk production and duration of lactation in some women. Less than 10% of a dose passes into breast milk.

    MECHANISM OF ACTION

    Estramustine is classified as an alkylating agent, but its mechanism of action is probably due to antimicrotubule activity. Estramustine possesses several unique pharmacologic actions. The estradiol portion of estramustine was originally designed to facilitate uptake by steroid receptors in malignant cells, to be followed by a release of the nitrogen mustard alkylating moiety. Prolonged treatment with estramustine produces elevated levels of estradiol similar to levels seen with conventional estrogen therapy for prostate cancer. Estrogenic effects as demonstrated by changes in circulating levels of steroids and pituitary hormones, are similar in patients treated with either estramustine or conventional estradiol therapy. The selective uptake and incorporation of estramustine in tumor tissues is probably due to the presence of estramustine-binding protein (EMBP), which is found in prostatate carcinoma, glioma, melanoma, and breast carcinoma. Estramustine binds to high molecular weight microtubule associated proteins and/or tubulin which results in the microtubule disassembly and arrest of cell division in the G2/M phase of the cell cycle. In addition to antimicrotubule activity, estramustine causes rapid and dose-related DNA strand breaks, and may inhibit DNA synthesis. Estramustine resistant cells exhibit no cross-resistance to other antimicrotubule agents and natural products, in which resistance is conferred by the (multidrug resistance) MDR phenotype. The phosphate moiety of orally administered estramustine may bind calcium, especially in patients with metabolic bone diseases that are associated with hypercalcemia, or in patients with renal insufficiency.
     
    Estramustine may also have cytotoxic effects through the production of apoptosis, or programmed cell death, which has been demonstrated in glioma cells in a rat model in vitro, and in vivo. Estramustine may not be totally active through hormonal mechanisms, since it is active in cell lines that lack estrogen receptors. The combination of estramustine and other microtubule agents, such as vinblastine and paclitaxel, may produce synergistic cytotoxicity in vitro.

    PHARMACOKINETICS

    Estramustine is administered orally. The metabolites in plasma are estramustine, estromustine, estradiol and estrone. Estromustine (17-keto analog) is the major metabolite. Estramustine is excreted as metabolites of both the alkylating and estrogenic moieties in the bile, urine and feces. Nonrenal excretion is considered the main route of elimination. Elimination half-life is 20—24 hours.

    Oral Route

    Approximately 44—75% of orally administered estramustine phosphate is absorbed from the gastrointestinal tract. Estramustine phosphate is readily dephosphorylated during absorption, and peak plasma concentrations are achieved in 2—3 hours.