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Estramustine

Pronunciation

(es tra MUS teen)

Index Terms

  • Estramustine Phosphate
  • Estramustine Phosphate Sodium

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral, as phosphate sodium:

Emcyt: 140 mg

Brand Names: U.S.

  • Emcyt

Pharmacologic Category

  • Antineoplastic Agent, Alkylating Agent
  • Antineoplastic Agent, Antimicrotubular
  • Antineoplastic Agent, Hormone (Estrogen/Nitrogen Mustard)

Pharmacology

Estradiol and nornitrogen mustard carbamate-linked combination which has antiandrogen effects (due to estradiol) and antimicrotubule effects (due to nornitrogen mustard); causes a marked decrease in plasma testosterone and an increase in estrogen levels.

Absorption

Incomplete (Bergenheim, 1998)

Metabolism

Initially dephosphorylated in the GI tract, then hepatically oxidated and hydrolyzed to estramustine, estromustine (oxidized isomer of estramustine), estrone, and estradiol.

Excretion

Feces (primarily); urine (trace amounts) (Bergenheim, 1998)

Time to Peak

2-3 hours (Bergenheim, 1998)

Half-Life Elimination

Estromustine: 13.6 hours (range: 9-23 hours); Estrone: 16.5 hours (Bergenheim, 1998)

Special Populations: Hepatic Function Impairment

May be poorly metabolized in these patients.

Use: Labeled Indications

Prostate cancer: Treatment (palliative) of progressive or metastatic prostate cancer

Limitation of use: A clinical practice guideline from the American Society of Clinical Oncology (ASCO) and Cancer Care Ontario recommends that estramustine not be offered to men with metastatic castration-resistant prostate cancer due to a lack of benefit in survival or quality of life (Basch, 2014).

Contraindications

Hypersensitivity to estramustine, estradiol, nitrogen mustard, or any component of the formulation; active thrombophlebitis or thromboembolic disorders (except where tumor mass is the cause of thromboembolic disorder and the benefit may outweigh the risk)

Canadian labeling: Additional contraindications (not in the U.S. labeling): Severe hepatic or cardiac disease

Dosing: Adult

Note: Estramustine is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting.

Prostate cancer, progressive or metastatic: Males: Oral: 14 mg/kg/day (range: 10-16 mg/kg/day) in 3 or 4 divided doses

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling; use with caution.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling; use with caution (may be poorly metabolized).

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs, 2012).

Administration

Estramustine is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting.

Administer on an empty stomach, at least 1 hour before or 2 hours after eating. Administer with water; do not administer with milk, milk-based products, or calcium products.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Dietary Considerations

Should be taken at least 1 hour before or 2 hours after eating. Milk products and calcium-rich foods or supplements may impair the oral absorption of estramustine phosphate sodium.

Storage

Store refrigerated at 2°C to 8°C (36°F to 46°F).

Drug Interactions

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Calcium Salts: May decrease the absorption of Estramustine. Exceptions: Calcium Chloride. Consider therapy modification

Clodronate: May increase the serum concentration of Estramustine. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Adverse Reactions

Frequency not always defined.

>10%:

Cardiovascular: Edema (20%)

Endocrine & metabolic: Gynecomastia (75%), increased lactate dehydrogenase (2% to 33%), decreased libido

Gastrointestinal: Nausea (16%), diarrhea (13%), gastrointestinal irritation (12%)

Genitourinary: Breast tenderness (71%)

Hepatic: Increased serum AST (2% to 33%)

Respiratory: Dyspnea (12%)

1% to 10%:

Cardiovascular: Cardiac failure (3%), local thrombophlebitis (3%), myocardial infarction (3%), cerebrovascular accident (2%), pulmonary embolism (2%), chest pain (1%), flushing (1%)

Central nervous system: Lethargy (4%), insomnia (3%), emotional lability (2%), anxiety (1%), headache (1%)

Dermatologic: Pruritus (2%), xeroderma (2%), exfoliation of skin (1%), skin rash (1%), thinning hair (1%)

Endocrine & metabolic: Increased thirst (1%)

Gastrointestinal: Anorexia (4%), flatulence (2%), gastrointestinal hemorrhage (1%), sore throat (1%), vomiting (1%)

Hematologic & oncologic: Leukopenia (4%), bruise (3%), thrombocytopenia (1%)

Hepatic: Increased serum bilirubin (1% to 2%)

Neuromuscular & skeletal: Leg cramps (9%)

Ophthalmic: Lacrimation (1%)

Respiratory: Hoarseness (1%), rhinorrhea (1%)

<1% (Limited to important or life-threatening): Anemia, angina pectoris, angioedema, cerebral ischemia, confusion, depression, decreased glucose tolerance, hypercalcemia, hypocalcemia, hypersensitivity reaction, hypertension, impotence, ischemic heart disease, myasthenia, venous thrombosis

Warnings/Precautions

Concerns related to adverse effects:

• Allergic reaction: Allergic reactions and angioedema, including airway involvement, have been reported.

• Cardiovascular effects: Elevated blood pressure or congestive heart disease may occur. Estrogen treatment for prostate cancer is associated with an increased risk of thrombosis or MI (including fatalities). Use with caution in patients with a history of thrombophlebitis, thrombosis, or thromboembolic disease. Use with caution in patients with cerebrovascular disease or coronary artery disease.

• Endocrine effects: Estrogenic effects may decrease testosterone levels; may cause gynecomastia and/or impotence.

• Fluid retention: Peripheral edema (new onset or exacerbation) or congestive heart disease may occur. Use with caution in patients where fluid accumulation may be poorly tolerated, including cardiovascular disease (HF or hypertension), migraine, seizure disorder or renal dysfunction.

• Gastrointestinal toxicity: Estramustine is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting.

• Glucose tolerance: Glucose tolerance may be decreased; use with caution in patients with diabetes mellitus.

• Hepatic effects: Liver enzyme and bilirubin abnormalities may occur; monitor during and for 2 months after treatment.

• Hypertension: May cause hypertension; monitor blood pressure periodically.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment (may be metabolized poorly).

• Metabolic bone disease: Use with caution in patients with metabolic bone diseases due to the effects on calcium and phosphorus homeostasis.

• Osteoblastic metastases: Patients with osteoblastic metastases are at risk for hypocalcemia; monitor calcium regularly.

• Renal impairment: Use with caution in patients with renal impairment.

Concurrent drug therapy issues:

• Drug-drug/drug-food Interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Immunization: Avoid vaccination with live vaccines during treatment (risk of infection may be increased due to immunosuppression). Although the response to vaccines may be diminished, inactivated vaccines may be administered during treatment.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Other warnings/precautions:

• Limitation of use: A clinical practice guideline from the American Society of Clinical Oncology (ASCO) and Cancer Care Ontario recommends that estramustine not be offered to men with metastatic castration-resistant prostate cancer due to a lack of benefit in survival or quality of life (Basch, 2014).

Monitoring Parameters

Serum calcium, liver function tests (during and for 2 months following treatment); blood pressure

Pregnancy Considerations

Estramustine is not indicated for use in women. Some men who were impotent on estrogen therapy have regained potency while taking estramustine; effective contraception should be used for male patients with partners of childbearing potential.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, diarrhea, leg cramps, breast pain or soreness, enlarged breasts, or sexual dysfunction. Have patient report immediately to prescriber signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, polyuria, flushing, fast breathing, or breath that smells like fruit), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), angina, tachycardia, severe dizziness, passing out, shortness of breath, excessive weight gain, swelling of arms or legs, severe headache, coughing up blood, or vision changes (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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