Medication Guide App

Cyproterone (Systemic)



USAN:
Cyproterone acetate{04}
VA CLASSIFICATION
Primary: AN500

Commonly used brand name(s): Androcur®; Androcur® Depot.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.



Category:


Antineoplastic—

Indications

Accepted

Carcinoma, prostatic (treatment, palliative)—Cyproterone is indicated for the palliative treatment of patients with advanced prostatic carcinoma.{01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    416.9{02}

Solubility
    Cyproterone is very soluble in dichloromethane, soluble in methyl alcohol, freely soluble in acetone, sparingly soluble in dehydrated alcohol, and insoluble in water.{02}

Mechanism of action/Effect:

The direct antiandrogenic effect of cyproterone is to block the binding of dihydrotestosterone to the specific receptors in the prostatic carcinoma cell. In addition, cyproterone exerts a negative feed-back on the hypothalamo-pituitary axis, by inhibiting the secretion of LH resulting in diminished production of testicular testosterone.{01}

Absorption:

Following oral administration, cyproterone is completely absorbed.{01}

Distribution:

Cyproterone accumulates in fatty tissue. Significant amounts of the drug are released from adipose tissue for up to two weeks after therapy is discontinued.{03}

Biotransformation:

Hepatic, primarily; producing 15β-hydroxycyproterone as the principal active metabolite.{01}{02}


Half-life:


Elimination:

Following oral or intramuscular administration, the plasma half-life is 38 and 96 hours, respectively.{01}


Time to peak concentration:

Peak plasma concentrations are reached three to four hours after oral administration. Following intramuscular administration, mean peak blood concentrations are attained 3.4 days after injection.{01}

Elimination:


Biliary—
        60% in the form of glucuronidized metabolites within 72 hours.{01}



Renal—
        33% mainly in the form of unconjugated metabolites within 72 hours.{01}



Precautions to Consider

Carcinogenicity

Individual reports have described the development of hepatocellular carcinoma in patients receiving cyproterone. There is also some evidence in vitro of the formation of DNA adducts in exposed hepatocytes; however, there does not seem to be clinical evidence to support an association between the use of cyproterone and the development of liver tumors.{02}

Pregnancy/Reproduction
Fertility—
Sperm count and the volume of ejaculate are reduced at oral doses of 50 to 300 mg per day. Infertility is usual, and there may be azoospermia after eight weeks of therapy, which is associated with atrophy of seminiferous tubules. These changes have been shown to be reversible upon discontinuation of therapy. Spermatogenesis usually reverts to previous levels approximately three to five months after stopping cyproterone (occasionally up to 20 months). Production of abnormal spermatozoa during cyproterone therapy has not been observed.{01}

Pregnancy—
Studies have not been done in humans.

Studies have not been done in animals.

Breast-feeding

It is not known whether cyproterone is distributed into breast milk.

Pediatrics

No information is available on the relationship of age to the effects of cyproterone in pediatric patients. Safety and efficacy have not been established.


Geriatrics


No information is available on the relationship of age to the effects of cyproterone in geriatric patients.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Alcohol    (antiandrogenic effect may be reduced{01})


» Ethinyl estradiol    (risk for recurrence of thrombophlebitis or thromboembolism due to increased coagulation capability{01})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Adrenocortical function tests    (suppression has occurred in patients receiving high doses [100 mg per square meter of body surface area]{01})


Glucose tolerance test    (may reveal evidence of impaired carbohydrate metabolism{01})


Metyrapone test    (a reduced response to endogenous ACTH was noted{01})

With physiology/laboratory test values
» Alanine aminotransferase (ALT [SGPT]), serum and
» Aspartate aminotransferase (AST [SGOT]), serum and
» Bilirubin, blood    (values may be increased{01}; may indicate hepatotoxicity )


Calcium, blood and
Creatinine, serum and
Glucose, blood and
Sodium, blood    (concentrations may be increased{01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Cardiac disease    (cyproterone may cause fluid retention, hypercalcemia, and changes in plasma lipid profile{01})


Depressive reaction tendencies    (increased incidence of depressive mood changes, especially during the first 6 to 8 weeks of therapy)

{01}
Diabetes mellitus    (may worsen blood glucose control{01})


» Hepatic dysfunction or
» Liver disease    (risk of cyproterone hepatotoxicity is increased{01})


    (Sensitivity to cyproterone{01})


Thrombophlebitis, history of or
Thromboembolism, history of    (may increase risk of recurrence of the disease{01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Alanine aminotransferase (ALT [SGPT]) values and
» Aspartate aminotransferase (AST [SGOT]) values and
» Bilirubin, total    (recommended prior to initiation of therapy and at periodic intervals during treatment; frequency varies according to clinical state, agent, dose, and other agents being used concurrently{01})


Cortisol assay, serum    (recommended at periodic intervals during treatment)


Creatinine, serum    (recommended at periodic intervals prior to and during treatment)


Glucose, blood, fasting    (monitor carefully in all patients and particularly in all diabetics before and regularly during therapy)


Hematocrit or hemoglobin and
Red blood cell counts    (recommended at periodic intervals during treatment{01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent or rare
    
Allergic reaction (cough; difficulty swallowing ; dizziness; fast heartbeat; hives; itching; puffiness or swelling of the eyelids or around the eyes, face, lips or tongue; shortness of breath; skin rash; tightness in chest ; wheezing)
    
anemia (pale skin; unusual tiredness or weakness)
    
cerebrovascular accident ( blurred vision; headache, sudden and severe; inability to speak; seizures; slurred speech ; temporary blindness; weakness in arm and/or leg on one side of the body, sudden and severe)
    
cirrhosis of the liver
hepatomegaly
liver carcinoma
liver failure (abdominal pain or tenderness; clay colored stools; dark urine ; decreased appetite; fever; itching; loss of appetite; nausea and vomiting ; swelling of feet or lower legs; yellow eyes or skin)
    
depression ( mood or mental changes)
    
diabetes mellitus (dry mouth; fatigue; flushed, dry skin; fruit-like breath odor; increased hunger; increased thirst; increased urination; loss of consciousness; stomachache; sweating; unexplained weight loss; vomiting)
    
encephalopathy (agitation; back pain; confusion ; drowsiness; fever; hallucinations ; irritability; stiff neck; vomiting)
    
exfoliative dermatitis (blisters on skin; general feeling of discomfort or illness; red, thickened, or scaly skin; swollen and/or painful glands)
    
heart failure (chest pain; decreased urine output; dilated neck veins; extreme fatigue; irregular breathing; irregular heartbeat; swelling of face, fingers, feet, or lower legs; tightness in chest )
    
leukopenia (black, tarry stools ; painful or difficult urination; sore throat; sores, ulcers, or white spots on lips or in mouth )
    
myocardial infarction
    
pancreatitis
    
pulmonary embolism
    
renal failure (lower back/side pain; decreased frequency/amount of urine; bloody urine; increased thirst ; increased blood pressure)
    
syncope (fainting or light-headedness when getting up from a lying or sitting position; unusually fast heartbeat ; palpitations)
    
tachycardia (fast, pounding, or irregular heartbeat or pulse)
    
thrombocytopenia (black, tarry stools; chest pain; chills; fever; sore throat; swollen glands; unusual bleeding or bruising)
    
thrombosis ( severe headaches of sudden onset; sudden loss of coordination ; pains in chest, groin, or legs, especially calves of legs ; sudden onset of shortness of breath for no apparent reason ; sudden onset of slurred speech; sudden vision changes)
    
vision abnormal
{01}
Note: Adverse reactions are rarely of sufficient severity to require dosage reduction or discontinuation of treatment; however, if reactions are severe, it may be beneficial to reduce the dosage.{01}




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Galactorrhea (unexpected or excess milk flow from breasts)
    
gynecomastia (swelling of the breasts or breast soreness in both females and males)
    
impotence (loss in sexual ability, desire, drive, or performance; decreased interest in sexual intercourse; inability to have or keep an erection)
    
libido, increased (increase in sexual ability, desire, drive, or performance; increased interest in sexual intercourse)
{01}
Note: These reactions usually disappear upon discontinuation of therapy or reduction of dose.{01}


Incidence less frequent or rare
    
Abnormal gait (change in walking and balance; clumsiness or unsteadiness )
    
alopecia (hair loss; thinning of hair)
    
constipation
    
diarrhea (increase in bowel movements; loose stools; soft stools)
    
fatigue ( tiredness or weakness)
    
hemiplegia (inability to move legs or arms; paralysis of one side of the body)
    
hirsutism ( unusual increase in hair growth)
    
injection site reaction (bleeding, blistering, burning, coldness, or discoloration of skin; feeling of pressure)
    
myasthenia (loss of strength or energy; muscle pain or weakness)
    
nausea
    
photosensitivity, skin (increased sensitivity of skin to sunlight; itching; redness or other discoloration of skin ; severe sunburn; skin rash)
    
vomiting
    
weight gain or weight loss
{01}


Those not indicating need for medical attention
Incidence less frequent or rare
    
Dryness of the skin
{01}




Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

No cases of fatal overdose have been reported.{01}

Treatment of overdose
There is no known specific antidote to cyproterone. Treatment is generally symptomatic and supportive.{01}


To decrease absorption:
If oral overdosage is discovered within two to three hours, gastric lavage can safely be used if indicated.{01}



Supportive care:
Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Cyproterone (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to cyproterone



Carcinogenicity—
Risk of development of hepatocellular carcinoma
Other medications, especially alcohol or ethinyl estradiol
Other medical problems, especially hepatic dysfunction or liver disease

Proper use of this medication
Taking after food or milk

» Proper dosing
Taking as soon as possible; not taking if almost time for next scheduled dose; not doubling doses

Precautions while using this medication
» Caution if dizziness or drowsiness occurs; not driving, using machines, or doing anything else that requires alertness while taking cyproterone and for 24 hours after discontinuing it

Possible skin photosensitivity; avoiding unprotected exposure to sun; using protective clothing; using a sun block product that includes protection against both UVA-caused photosensitivity reactions and UVB-caused sunburn reactions; avoiding use of sunlamp, tanning bed, or tanning booth


Side/adverse effects
Signs of potential side effects, especially abnormal vision, allergic reaction, anemia, cerebrovascular accident, cirrhosis of the liver, hepatomegaly, liver carcinoma, liver failure, depression, diabetes mellitus, encephalopathy, exfoliative dermatitis, heart failure, leukopenia, myocardial infarction, pancreatitis, pulmonary embolism, renal failure, syncope, tachycardia, thrombocytopenia, and thrombosis


General Dosing Information
Because of their pharmacokinetic properties, oral cyproterone and intramuscular cyproterone acetate may be interchanged in the course of long-term treatment. The dosage may be reduced if side effects are intolerable but should be kept within the oral range of 100 to 300 mg per day or intramuscular injections of 300 mg every one or two weeks.{01}

Therapy with cyproterone should not be discontinued when remission or improvement occurs.{01}

Fatigue and lassitude are common in the first few weeks of therapy, but usually become much less pronounced from the third month on.{01}

For treatment of adverse effects
In the event of severe adverse effects, it may be beneficial to reduce the dosage of cyproterone.{01}


Oral Dosage Forms

CYPROTERONE TABLETS

Usual adult dose
Prostatic carcinoma (treatment, palliative)
The usual initial and maintenance dose of cyproterone is 200 to 300 mg per day divided into two to three doses and taken after meals.{01}

Note: After orchiectomy, a dose of 100 to 200 mg per day is recommended.{01}



Usual pediatric dose
Safety and efficacy have not been established.

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


50 mg (Rx) [Androcur®]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light and heat.

Auxiliary labeling:
Take after food.



Parenteral Dosage Forms

CYPROTERONE ACETATE INJECTION

Usual adult dose
Carcinoma, prostatic (treatment, palliative)
The usual initial and maintenance dose of cyproterone is 300 mg (3 mL) given intramuscularly once per week.{01}

Note: After orchiectomy, a dose of 300 mg every two weeks is recommended.{01}



Usual pediatric dose
Safety and efficacy have not been established.

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


100 mg per mL (Rx) [Androcur® Depot (castor oil)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing, light and heat.



Developed: 05/02/2000



References
  1. Product Information: Androcur®, cyproterone acetate. Berlex Canada, Lachine, Quebec (PI revised 7/1995) reviewed 4/2000.
  1. Parfitt K (ed): Martindale: The Complete Drug Reference, 32nd ed. The Pharmaceutical Press, London, England, 1999.
  1. Jungers P, Kuttenn F, Liote F et al: Hormonal modulation in systemic lupus erythematosus. Preliminary clinical and hormonal results with cyproterone acetate. Arthritis Rheum 1985; 28:1243-1250.
  1. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, Maryland: The United States Pharmacopeial Convention Inc; 1997: p. 204.
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