CYCLOPHOSPHAMIDE
.
DESCRIPTION
Lyophilized ENDOXAN-ASTA for Injection (cyclophosphamide for injection, USP) is a
sterile white lyophilized cake or partially broken cake, containing 75 mg
mannitol per 100 mg cyclophosphamide (anhydrous). ENDOXAN-ASTA Tablets
(cyclophosphamide tablets, USP) are for oral use and contain 25 mg or 50 mg
cyclophosphamide (anhydrous). Inactive ingredients in ENDOXAN-ASTA tablets are:
acacia, FD&C Blue No. 1, D&C Yellow No. 10 Aluminum Lake, lactose, magnesium
stearate, starch, stearic acid, and talc. Cyclophosphamide is a synthetic
antineoplastic drug chemically related to the nitrogen mustards.
Cyclophosphamide is a white crystalline powder with the molecular formula of
C7H15Cl2N2O2P*H2O and a molecular weight of 279.1. The chemical name for
cyclophosphamide is 2-(bis(2-chloroethyl)amino)tetrahydro-2H- 1,3,2-
oxazaphosphorine 2-oxide monohydrate. Cyclophosphamide is soluble in water,
saline, or ethanol and has the following structural formula:
ACTIONS/CLINICAL PHARMACOLOGY:
ENDOXAN-ASTA (cyclophosphamide, USP) is biotransformed principally in the liver to
active alkylating metabolites by a mixed function microsomal oxidase system.
These metabolites interfere with the growth of susceptible rapidly proliferating
malignant cells. The mechanism of action is thought to involve cross-linking of
tumor cell DNA.
ENDOXAN-ASTA is well absorbed after oral administration with a bioavailability
greater than 75%. The unchanged drug has an elimination half-life of 3 to 12
hours. It is eliminated primarily in the form of metabolites, but from 5 to 25%
of the dose is excreted in urine as unchanged drug. Several cytotoxic and
noncytotoxic metabolites have been identified in urine and in plasma.
Concentrations of metabolites reach a maximum in plasma 2 to 3 hours after an
intravenous dose. Plasma protein binding of unchanged drug is low but some
metabolites are bound to an extent greater than 60%. It has not been
demonstrated that any single metabolite is responsible for either the
therapeutic or toxic effects of cyclophosphamide. Although elevated levels of
metabolites of cyclophosphamide have been observed in patients with renal
failure, increased clinical toxicity in such patients has not been demonstrated.
INDICATIONS AND USAGE:
MALIGNANT DISEASES
-ENDOXAN-ASTA, although effective alone in susceptible malignancies, is more
frequently used concurrently or sequentially with other antineoplastic drugs.
The following malignancies are often susceptible to ENDOXAN-ASTA treatment:
1. Malignant lymphomas (Stages III and IV of the Ann Arbor staging system),
Hodgkin's disease, lymphocytic lymphoma (nodular or diffuse), mixed- cell type
lymphoma, histiocytic lymphoma, Burkitt's lymphoma. 2. Multiple myeloma. 3.
Leukemias: Chronic lymphocytic leukemia, chronic granulocytic leukemia (it is
usually ineffective in acute blastic crisis), acute myelogenous and monocytic
leukemia, acute lymphoblastic (stem- cell) leukemia in children (ENDOXAN-ASTA given
during remission is effective in prolonging its duration). 4. Mycosis fungoides
(advanced disease). 5. Neuroblastoma (disseminated disease). 6. Adenocarcinoma
of the ovary. 7. Retinoblastoma. 8. Carcinoma of the breast.
NONMALIGNANT DISEASE: BIOPSY PROVEN "MINIMAL CHANGE" NEPHROTIC SYNDROME IN
CHILDREN-
ENDOXAN-ASTA is useful in carefully selected cases of biopsy proven "minimal change"
nephrotic syndrome in children but should not be used as primary therapy. In
children whose disease fails to respond adequately to appropriate
adrenocorticosteroid therapy or in whom the adrenocorticosteroid therapy
produces or threatens to produce intolerable side effects, ENDOXAN-ASTA may induce a
remission. ENDOXAN-ASTA is not indicated for the nephrotic syndrome in adults or for
any other renal disease.
CONTRAINDICATIONS:
Continued use of cyclophosphamide is contraindicated in patients with severely
depressed bone marrow function. Cyclophosphamide is contraindicated in patients
who have demonstrated a previous hypersensitivity to it. (See " WARNINGS" and
"PRECAUTIONS" sections.)
WARNINGS:
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
-Second malignancies have developed in some patients treated with
cyclophosphamide used alone or in association with other antineoplastic drugs
and/or modalities. Most frequently, they have been urinary bladder,
myeloproliferative, or lymphoproliferative malignancies. Second malignancies
most frequently were detected in patients treated for primary myeloproliferative
or lymphoproliferative malignancies or nonmalignant disease in which immune
processes are believed to be involved pathologically. In some cases, the second
malignancy developed several years after cyclophosphamide treatment had been
discontinued. In a single breast cancer trial utilizing two to four times the
standard dose of cyclophosphamide, in conjunction with doxorubicin, a small
number of cases of secondary acute myeloid leukemia occurred within two years of
treatment initiation. Urinary bladder malignancies generally have occurred in
patients who previously had hemorrhagic cystitis. In patients treated with
cyclophosphamide-containing regimens for a variety of solid tumors, isolated
case reports of secondary malignancies have been published. One case of
carcinoma of the renal pelvis was reported in a patient receiving long- term
cyclophosphamide therapy for cerebral vasculitis. The possibility of
cyclophosphamide- induced malignancy should be considered in any benefit-to-risk
assessment for use of the drug.
Cyclophosphamide can cause fetal harm when administered to a pregnant woman and
such abnormalities have been reported following cyclophosphamide therapy in
pregnant women. Abnormalities were found in two infants and a 6-month-old fetus
born to women treated with cyclophosphamide. Ectrodactylia was found in two of
the three cases. Normal infants have also been born to women treated with
cyclophos phamide during pregnancy, including the first trimester. If this drug
is used during pregnancy, or if the patient becomes pregnant while taking
(receiving) this drug, the patient should be apprised of the potential hazard to
the fetus. Women of childbearing potential should be advised to avoid becoming
pregnant.
Cyclophosphamide interferes with oogenesis and spermatogenesis. It may cause
sterility in both sexes. Development of sterility appears to depend on the dose
of cyclophosphamide, duration of therapy, and the state of gonadal function at
the time of treatment. Cyclophosphamide-induced sterility may be irreversible in
some patients.
Amenorrhea associated with decreased estrogen and increased gonadotropin
secretion develops in a significant proportion of women treated with
cyclophosphamide. Affected patients generally resume regular menses within a few
months after cessation of therapy. Girls treated with cyclophosphamide during
prepubescence generally develop secondary sexual characteristics normally and
have regular menses. Ovarian fibrosis with apparently complete loss of germ
cells after prolonged cyclophosphamide treatment in late prepubescence has been
reported. Girls treated with cyclophosphamide during prepubescence subsequently
have conceived.
Men treated with cyclophosphamide may develop oligospermia or azoospermia
associated with increased gonadotropin but normal testosterone secretion. Sexual
potency and libido are unimpaired in these patients. Boys treated with
cyclophosphamide during prepubescence develop secondary sexual characteristics
normally, but may have oligospermia or azoospermia and increased gonadotropin
secretion. Some degree of testicular atrophy may occur.
Cyclophosphamide-induced azoospermia is reversible in some patients, though the
reversibility may not occur for several years after cessation of therapy. Men
temporarily rendered sterile by cyclophosphamide have subsequently fathered
normal children.
URINARY SYSTEM
-Hemorrhagic cystitis may develop in patients treated with cyclophosphamide.
Rarely, this condition can be severe and even fatal. Fibrosis of the urinary
bladder, sometimes extensive, also may develop with or without accompanying
cystitis. Atypical urinary bladder epithelial cells may appear in the urine.
These adverse effects appear to depend on the dose of cyclophosphamide and the
duration of therapy. Such bladder injury is thought to be due to
cyclophosphamide metabolites excreted in the urine. Forced fluid intake helps to
assure an ample output of urine, necessitates frequent voiding, and reduces the
time the drug remains in the bladder. This helps to prevent cystitis. Hematuria
usually resolves in a few days after cyclophosphamide treatment is stopped, but
it may persist. Medical and/or surgical supportive treatment may be required,
rarely, to treat protracted cases of severe hemorrhagic cystitis. It is usually
necessary to discontinue cyclophosphamide therapy in instances of severe
hemorrhagic cystitis.
CARDIAC TOXICITY
-Although a few instances of cardiac dysfunction have been reported following
use of recommended doses of cyclophosphamide, no causal relationship has been
established. Acute cardiac toxicity has been reported with doses as low as 2.4
g/m(squared) to as high as 26 g/m(squared), usually as a portion of an intensive
antineoplastic multidrug regimen or in conjunction with transplantation
procedures. In a few instances with high doses of cyclophosphamide, severe, and
sometimes fatal, congestive heart failure has occurred after the first
cyclophosphamide dose. Histopathologic examination has primarily shown
hemorrhagic myocarditis. Hemopericardium has occurred secondary to hemorrhagic
myocarditis and myocardial necrosis. Pericarditis has been reported independent
of any hemopericardium.
No residual cardiac abnormalities, as evidenced by electrocardiogram or
echocardiogram appear to be present in patients surviving episodes of apparent
cardiac toxicity associated with high doses of cyclophosphamide.
Cyclophosphamide has been reported to potentiate doxorubicin-induced
cardiotoxicity.
INFECTIONS
-Treatment with cyclophosphamide may cause significant suppression of immune
responses. Serious, sometimes fatal, infections may develop in severely
immunosuppressed patients. Cyclophosphamide treatment may not be indicated or
should be interrupted or the dose reduced in patients who have or who develop
viral, bacterial, fungal, protozoan, or helminthic infections.
OTHER
-Rare instances of anaphylactic reaction including one death have been reported.
One instance of possible cross-sensitivity with other alkylating agents has been
reported.
PRECAUTIONS:
GENERAL
-Special attention to the possible development of toxicity should be exercised
in patients being treated with cyclophosphamide if any of the following
conditions are present.
1. Leukopenia 2. Thrombocytopenia 3. Tumor cell infiltration of bone marrow 4.
Previous X-ray therapy 5. Previous therapy with other cytotoxic agents 6.
Impaired hepatic function 7. Impaired renal function
LABORATORY TESTS
-During treatment, the patient's hematologic profile (particularly neutrophils
and platelets) should be monitored regularly to determine the degree of
hematopoietic suppression. Urine should also be examined regularly for red cells
which may precede hemorrhagic cystitis.
DRUG INTERACTIONS
-The rate of metabolism and the leukopenic activity of cyclophosphamide
reportedly are increased by chronic administration of high doses of
phenobarbital.
The physician should be alert for possible combined drug actions, desirable or
undesirable, involving cyclophosphamide even though cyclophosphamide has been
used successfully concurrently with other drugs, including other cytotoxic
drugs.
Cyclophosphamide treatment, which causes a marked and persistent inhibition of
cholinesterase activity, potentiates the effect of succinylcholine chloride.
If a patient has been treated with cyclophosphamide within 10 days of general
anesthesia, the anesthesiologist should be alerted.
ADRENALECTOMY
-Since cyclophosphamide has been reported to be more toxic in adrenalectomized
dogs, adjustment of the doses of both replacement steroids and cyclophosphamide
may be necessary for the adrenalectomized patient.
WOUND HEALING
-Cyclophosphamide may interfere with normal wound healing.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
-See "WARNINGS" section for information on carcinogenesis, mutagenesis, and
impairment of fertility.
PREGNANCY
- Pregnancy "Category D". (See "WARNINGS" section.)
NURSING MOTHERS
-Cyclophosphamide is excreted in breast milk. Because of the potential for
serious adverse reactions and the potential for tumorigenicity shown for
cyclophosphamide in humans, a decision should be made whether to discontinue
nursing or to discontinue the drug, taking into account the importance of the
drug to the mother.
DRUG INTERACTIONS:
-The rate of metabolism and the leukopenic activity of cyclophosphamide
reportedly are increased by chronic administration of high doses of
phenobarbital.
The physician should be alert for possible combined drug actions, desirable or
undesirable, involving cyclophosphamide even though cyclophosphamide has been
used successfully concurrently with other drugs, including other cytotoxic
drugs.
Cyclophosphamide treatment, which causes a marked and persistent inhibition of
cholinesterase activity, potentiates the effect of succinylcholine chloride.
If a patient has been treated with cyclophosphamide within 10 days of general
anesthesia, the anesthesiologist should be alerted.
(See also PRECAUTIONS.)
ADVERSE REACTIONS:
Information on adverse reactions associated with the use of ENDOXAN-ASTA
(cyclophosphamide, USP) is arranged according to body system affected or type of
reaction. The adverse reactions are listed in order of decreasing incidence. The
most serious adverse reactions are described in the "WARNINGS" section.
REPRODUCTIVE SYSTEM
-See " WARNINGS" section for information on impairment of fertility.
DIGESTIVE SYSTEM
-Nausea and vomiting commonly occur with cyclophosphamide therapy. Anorexia and,
less frequently, abdominal discomfort or pain and diarrhea may occur. There are
isolated reports of hemorrhagic colitis, oral mucosal ulceration and jaundice
occurring during therapy. These adverse drug effects generally remit when
cyclophosphamide treatment is stopped.
SKIN AND ITS STRUCTURES
-Alopecia occurs commonly in patients treated with cyclophosphamide. The hair
can be expected to grow back after treatment with the drug or even during
continued drug treatment, though it may be different in texture or color. Skin
rash occurs occasionally in patients receiving the drug. Pigmentation of the
skin and changes in nails can occur.
HEMATOPOIETIC SYSTEM
-Leukopenia occurs in patients treated with cyclophosphamide, is related to the
dose of drug, and can be used as a dosage guide. Leukopenia of less than 2000
cells/mm(raised to the power of 3) develops commonly in patients treated with an
initial loading dose of the drug, and less frequently in patients maintained on
smaller doses. The degree of neutropenia is particularly important because it
correlates with a reduction in resistance to infections. Fever without
documented infection has been reported in neutropenic patients.
Thrombocytopenia or anemia develop occasionally in patients treated with
ENDOXAN-ASTA. These hematologic effects usually can be reversed by reducing the drug
dose or by interrupting treatment. Recovery from leukopenia usually begins in 7
to 10 days after cessation of therapy.
URINARY SYSTEM
-See "WARNINGS" section for information on cystitis and urinary bladder
fibrosis.
Hemorrhagic ureteritis and renal tubular necrosis have been reported to occur in
patients treated with cyclophosphamide. Such lesions usually resolve following
cessation of therapy.
INFECTIONS
-See "WARNINGS" section for information on reduced host resistance to
infections.
CARCINOGENESIS
-See " WARNINGS" section for information on carcinogenesis.
RESPIRATORY SYSTEM
-Interstitial pulmonary fibrosis has been reported in patients receiving high
doses of cyclophosphamide over a prolonged period.
OTHER
-Rare instances of anaphylactic reaction including one death have been reported.
One instance of possible cross-sensitivity with other alkylating agents has been
reported. SIADH (syndrome of inappropriate ADH secretion) has been reported with
the use of cyclophosphamide.
OVERDOSAGE:
No specific antidote for cyclophosphamide is known. Overdosage should be managed
with supportive measures, including appropriate treatment for any concurrent
infection, myelosuppression, or cardiac toxicity should it occur.
DOSAGE AND ADMINISTRATION:
TREATMENT OF MALIGNANT DISEASES: ADULTS AND CHILDREN
-When used as the only oncolytic drug therapy, the initial course of ENDOXAN-ASTA
(cyclophosphamide, USP) for patients with no hematologic deficiency usually
consists of 40 to 50 mg/kg given intravenously in divided doses over a period of
2 to 5 days. Other intravenous regimens include 10 to 15 mg/kg given every 7 to
10 days or 3 to 5 mg/kg twice weekly.
Oral ENDOXAN-ASTA dosing is usually in the range of 1 to 5 mg/kg/day for both initial
and maintenance dosing.
Many other regimens of intravenous and oral ENDOXAN-ASTA have been reported. Dosages
must be adjusted in accord with evidence of antitumor activity and/or
leukopenia. The total leukocyte count is a good, objective guide for regulating
dosage. Transient decreases in the total white blood cell count to 2000
cells/mm(raised to the power of 3) (following short courses) or more persistent
reduction to 3000 cells/mm(raised to the power of 3) (with continuing therapy)
are tolerated without serious risk of infection if there is no marked
granulocytopenia.
When ENDOXAN-ASTA is included in combined cytotoxic regimens, it may be necessary to
reduce the dose of ENDOXAN-ASTA as well as that of the other drugs.
ENDOXAN-ASTA and its metabolites are dialyzable although there are probably
quantitative differences depending upon the dialysis system being used. Patients
with compromised renal function may show some measurable changes in
pharmacokinetic parameters of ENDOXAN-ASTA metabolism, but there is no consistent
evidence indicating a need for ENDOXAN-ASTA dosage modification in patients with
renal function impairment.
TREATMENT OF NONMALIGNANT DISEASES: BIOPSY PROVEN "MINIMAL CHANGE" NEPHROTIC
SYNDROME IN CHILDREN
-An oral dose of 2.5 to 3 mg/kg daily for a period of 60 to 90 days is
recommended. In males, the incidence of oligospermia and azoospermia increases
if the duration of ENDOXAN-ASTA treatment exceeds 60 days. Treatment beyond 90 days
increases the probability of sterility. Adrenocorticosteroid therapy may be
tapered and discontinued during the course of ENDOXAN-ASTA therapy. See "PRECAUTIONS"
section concerning hematologic monitoring.
PREPARATION AND HANDLING OF SOLUTIONS
-Parenteral drug products should be inspected visually for particulate matter
and discoloration prior to administration, whenever solution and container
permit.
Lyophilized ENDOXAN-ASTA for Injection should be prepared for parenteral use by
adding Sterile Water for Injection, USP to the vial and shaking to dissolve. Use
the quantity of diluent shown below to reconstitute the product.
LYOPHILIZED ENDOXAN-ASTA
FOR INJECTION
Double Strength Quantity of Diluent
100 mg 5 mL
200 mg 10 mL
500 mg 20-25 mL
1 g 50 mL
2 g 80-100 mL
Solutions of Lyophilized ENDOXAN-ASTA for Injection may be injected intravenously,
intramuscularly, intraperitoneally, or intrapleurally or it may be infused
intravenously in the following:
Dextrose Injection, USP (5% dextrose)
Dextrose and Sodium Chloride Injection, USP
(5% dextrose and 0.9% sodium chloride)
5% Dextrose and Ringer's Injection
Lactated Ringer's Injection, USP
Sodium Chloride Injection, USP (0.45% sodium chloride)
Sodium Lactate Injection, USP (1/6 molar sodium lactate)
Reconstituted Lyophilized ENDOXAN-ASTA for Injection is chemically and physically
stable for 24 hours at room temperature or for 6 days in the refrigerator; it
does not contain any antimicrobial preservative and thus care must be taken to
assure the sterility of prepared solutions.
The osmolarities of solutions of Lyophilized ENDOXAN-ASTA for Injection, and normal
saline are found in the following table:
Lyophilized ENDOXAN-ASTA for Injection m0sm/L
4 mL diluent per 100 mg cyclophosphamide 219
5 mL diluent per 100 mg cyclophosphamide 172
Lyophilized ENDOXAN-ASTA for Injection is slightly hypotonic.
Extemporaneous liquid preparations of ENDOXAN-ASTA for oral administration may be
prepared by dissolving Lyophilized ENDOXAN-ASTA for Injection in Aromatic Elixir,
N.F. Such preparations should be stored under refrigeration in glass containers
and used within 14 days.
REFERENCES:
1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH
Publication No. 83-2621. For sale by the Superintendent of Documents, US
Government Printing Office, Washington, DC 20402.
2. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA
1985; 253 (11):1590-1592.
3. National Study Commission on Cytotoxic Exposure-Re-commendations for Handling
Cytotoxic Agents. Available from Louis P. Jeffrey, ScD, Chairman, National Study
Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied
Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.
4. Clinical Oncological Society of Australia. Guidelines and Recommendations for
Safe Handling of Antineoplastic Agents. Med J Australia 1983; 1:426-428.
5. Jones RB, et al: Safe Handling of Chemotherapeutic Agents: A Report from the
Mount Sinai Medical Center. CA-A Cancer Journal for Clinicians 1983;
(Sept/Oct)258-263.
6. American Society of Hospital Pharmacists Technical Assistance Bulletin on
Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm 1990; 47:1033-1049.
7. OSHA Work-Practice Guidelines for Personnel Dealing with Cytotoxic
(Antineoplastic) Drugs. Am J Hosp Pharm 1986; 43:1193-1204.
MEADJOHNSON
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