Cyclophosphamide
500mg /1g /2g Injection

What Cyclophosphamide is and what it is used for

Cyclophosphamide is a cytotoxic drug or anti-cancer drug. It works by killing cancer cells, this is sometimes called ‘chemotherapy’.

It is used to treat lots of different cancers. Cyclophosphamide is often used together with other anti-cancer drugs or radiotherapy. Occasionally, some doctors may prescribe Cyclophosphamide for other conditions not related to cancer, your doctor will tell you if this applies to you.

Before you are given Cyclophosphamide

• you have ever had an allergic reaction to Cyclophosphamide. An allergic reaction can include shortness of breath, wheezing, rash, itching or swelling of the face and lips
• your bone marrow is not working properly (especially if you have previously had chemotherapy or radiotherapy). You will have blood tests to check how well your bone marrow is working
• you have a urinary tract infection, which can be recognised as pain when passing urine (cystitis)
• you currently have any infections
• you have ever had kidney or bladder problems as a result of previous chemotherapy or radiotherapy
• you have a condition which decreases your ability to urinate (Urinary outflow obstruction).

• you are already having, or have recently had, radiotherapy or chemotherapy
• you have diabetes
• you have liver or kidney problems. Your doctor will check how well your liver and kidneys are working by doing a blood test
• you have had your adrenal glands removed
• you have heart problems or have had radiotherapy in the area of your heart
• you have poor general health or are frail
• you are elderly.

Cyclophosphamide can have effects on your blood and immune system.
Blood cells are made in your bone marrow. Three different types of blood cell are made:

• red blood cells, which carry oxygen around your body
• white blood cells, which fight infection, and
• latelets, which help your blood to clot.

After taking Cyclophosphamide, your blood count of the three types of cells will drop. This is an unavoidable side effect of Cyclophosphamide. Your blood count will reach its lowest level about 5 to 10 days after you start taking Cyclophosphamide and will stay low until a few days after you finish the course. Most people recover to a normal blood count within 21 to 28 days. If you have had a lot of chemotherapy in the past, it may take a little longer to return to normal.

You may be more likely to get infections when your blood count drops. Try to avoid close contact with people who have coughs, colds and other infections. Your doctor will treat you with appropriate medicine if they think you have, or are at risk, of an infection.

Your doctor will check that the number of red blood cells, white blood cells and platelets is high enough before and during your treatment with Cyclophosphamide. They may need to reduce the amount you are given or delay your next dose.

Cyclophosphamide can affect wound healing. Keep any cuts clean and dry, and check they are healing normally.

It is important to keep your gums healthy, as mouth ulcers and infections can occur. Ask your doctor about this if you are unsure.

Cyclophosphamide can damage the lining of your bladder, causing bleeding into your urine and pain on urination. Your doctor knows this can happen and, if necessary, he or she will give you a medicine called Mesna which will protect your bladder.

Mesna can either be given to you as a short injection, or mixed into the drip solution with your Cyclophosphamide, or as tablets.

More information on Mesna can be found in the Patient Information Leaflet for Mesna Injection and Mesna tablets.

Most people having Cyclophosphamide with Mesna do not develop any problems with their bladder, but your doctor may want to test your urine for the presence of blood using a ‘dipstick’ or microscope.

If you notice that you have blood in the urine, you must tell your doctor straight away as they may need to stop giving you Cyclophosphamide.

Cancer medicines and radiation therapy can increase the risk of you developing other cancers; this can be a number of years after your treatment has stopped. Cyclophosphamide has an increased risk of causing cancer in the area of your bladder.

Cyclophosphamide can cause damage to your heart or affect the rhythm of it beating. This increases with higher doses of Cyclophosphamide, if you are being treated with radiation or other chemotherapy medicines or if you are elderly. Your doctor will monitor your heart closely during treatment.

Cyclophosphamide can cause inflammation or scarring in your lungs. This can occur more than six months after your treatment. If you start having difficulty breathing tell your doctor straight away.

Cyclophosphamide can have life threatening effects on your liver.
If you have sudden weight gain, liver pain and jaundice tell your doctor straight away.

Hair thinning or baldness can occur. Your hair should grow back normally though it may be different in texture or colour.

Cyclophosphamide can make you feel sick or be sick. This can last for about 24 hours after taking Cyclophosphamide. You may need to be given medicines to stop feeling or being sick. Ask your doctor about this.

Tell your doctor or nurse if you are taking or have recently taken any other medicines, including medicines you have bought yourself. In particular, tell them about the following medicines or treatments as they may not work well with Cyclophosphamide:

The following medicines can reduce how effective Cyclophosphamide is:

• aprepitant (used to prevent being sick)
• bupropion (an anti-depressant)
• busulfan, thiotepa (used to treat cancer)
• ciprofloxacin, chloramphenicol (used to treat bacterial infections)
• fluconazole, itraconazole (used to treat fungal infections)
• Prasugrel (used to thin the blood)
• Sulfonamides, such as sulfadiazine, sulfasalazine, sulfamethoxazole (used to treat bacterial infections).

The following medicines can increase the toxicity of Cyclophosphamide:

• allopurinol (used to treat gout)
• azathioprine (used to reduce the activity of the immune system)
• chloral hydrate (used to treat insomnia)
• cimetidine (used to reduce stomach acid)
• disulfiram (used to treat alcoholism)
• glyceraldehyde (used to treat warts)
• protease inhibitors (used to treat viruses)
• ondansetron (used to prevent being sick)
• medicines that increase liver enzymes such as:
  • rifampicin (used to treat bacterial infections)
  • carbamazepine, phenobarbital, phenytoin (used to treat epilepsy)
  • St. John’s wort (a herbal remedy for mild depression)
  • Corticosteroids (used to treat inflammation)
• medicines that can increase the toxic effects on your blood cells and immunity
  • ACE inhibitors (used to treat high blood pressure).
  • natalizumab (used to treat multiple sclerosis)
  • paclitaxel (used to treat cancer)
  • thiazide diuretics such as hydrochlorothiazide or chlortalidone (used to treat high blood pressure or water retention)
  • zidovudine (used to treat viruses)
  • Clozapine (used to treat symptoms of some psychiatric disorders)
• medicines that can increase the toxic effects on your heart
  • anthracyclines such as bleomycin, doxorubicin, epirubicin, mitomycin (used to treat cancer)
  • cytarabine, pentostatin, trastuzumab (used to treat cancer)
  • radiation in the area of your heart
• medicines that can increase the toxic effects on your lungs
  • amiodarone (used to treat irregular heart beat)
  • G-CSF, GM-CSF hormones (used to increase white blood cell numbers after chemotherapy)
• medicines that can increase the toxic effects on your kidneys
  • amphotericin B (used to treat fungal infections)
  • Indomethacin (used to treat pain and inflammation).
  • Other medicines that can affect or be affected by Cyclophosphamide include:
    • etanercept (used to treat rheumatoid arthritis)
    • metronidazole (used to treat bacterial or protozoal infections)
    • tamoxifen (used to treat breast cancer)
    • bupropion (used to help stop smoking)
    • coumarins such as warfarin (used to thin the blood)
    • cyclosporine (used to reduce the activity of the immune system)
    • succinylcholine (used to relax muscles during medical procedures)
    • digoxin, ß-acetyldigoxin (used to treat heart conditions)
    • vaccines
    • verapamil (used to treat high blood pressure, angina or irregular heart beat).

Drinking alcohol can increase the nausea and vomiting caused by Cyclophosphamide.

Do not become pregnant while taking Cyclophosphamide. This is because it can cause miscarriage or damage your unborn baby. Tell your doctor if you are pregnant, think you might be pregnant or are trying to become pregnant.

• Men or women should not try to have a child during or for at least 6 to 12 months after treatment. You should use an effective contraceptive. Ask your doctor for advice.
• Cyclophosphamide can affect your ability to have children in the future. Talk to your doctor about freezing sperm samples or eggs before your treatment starts.

Do not breast-feed while being treated with Cyclophosphamide. Ask your doctor for advice.

Some of the side effects of treatment with Cyclophosphamide might affect your ability to drive and use machines safely. Your doctor will decide if it is safe for you to do so.

If you see any other doctor or have to go to hospital for any reason, tell them what medicines you are taking. Do not take any other medicines unless your doctor knows you are taking Cyclophosphamide.

How Cyclophosphamide is given

Cyclophosphamide will be given to you by a doctor or nurse.

It can be given as an injection or by mouth.

When Cyclophosphamide is given as an injection, it will normally be added to a large bag of fluid and will be slowly injected (infused) directly into your vein. The vein can be in your arm, the back of your hand or a large vein under your collar bone. Depending on your dose, it will usually take between a few minutes to an hour to be given.

When Cyclophosphamide is given by mouth, it will usually be made in to a solution with some flavourings (called an ‘elixir’) which will make it taste pleasant and easier to swallow.

Cyclophosphamide is often given with other anti-cancer drugs or radiotherapy.

The usual dose

• Your doctor will decide how much of the medicine you need and when you should be given it.
• The amount of Cyclophosphamide you will be given depends on:
  • the type of illness you have
  • how big you are (a combination of your height and weight)
  • your general health
  • whether you are being given other anti-cancer drugs or having radiotherapy.

Cyclophosphamide is usually given as a series of courses of treatment. After each course there is a break (a period when no Cyclophosphamide is given) before the next course.

Your doctor may need to change the amount of medicine you are given and monitor you more closely if you:

• have problems with your liver or kidneys
• you are elderly.

In the event of an overdose, or if a child swallows any of your tablets, talk to your doctor or local hospital emergency department immediately. Hospital admission for special treatment may be needed.

Possible side effects

Like all medicines, Cyclophosphamide can cause side effects, although not everybody gets them. Side effects can sometimes occur after ending the treatment. The following side effects may happen with this medicine.

Tell your doctor straight away, if you notice any of the following serious side effects:

allergic reactions, signs of this would be shortness of breath, wheezing, rash, itching or swelling of the face and lips

getting bruises without knocking yourself, or bleeding from your gums. This may be a sign that the platelet levels in your blood are getting too low

a lowering of your white blood cell count, your doctor will check this during your treatment. It will not cause any signs, but you will be more likely to get infections. If you think you have an infection (a high temperature, feeling cold and shivery, or hot and sweaty, or any signs of infection such as a cough, or stinging on passing water) you may need antibiotics to fight infections because your blood count is lower than usual

very pale, lethargic and tired. This may be a sign of low red blood cells (anaemia). Usually, no treatment is required, your body will eventually replace the red blood cells. If you are very anaemic, you may need a blood transfusion

blood in your urine, pain while passing urine, or less urine being passed.

Immune system and Infections
allergic reactions, signs of this would be shortness of breath, wheezing, rash, itching or swelling of the face and lips (hypersensitivity). Severe allergic reactions could lead to difficulty in breathing or shock, with a possible fatal outcome (anaphylactic shock, anaphylactic/anaphylactoid reaction)

reduction in the effectiveness of your immune system (immunosuppression)

increased risk and severity of bacterial, fungal, viral, protozoal or parasitic infections due to the effect of cyclophosphamide on your immune system

reactivation of infections you have had before (latent infections)

severe infection spreading through the blood which may lead to a dangerous drop in blood pressure with a possible fatal outcome (sepsis, shock).

Cancers

• cancer of your blood (leukaemia)
• cancer of the bone marrow (myelodysplastic syndrome)
• cancer of the lymphatic system (Non-Hodgkin’s lymphoma)
• secondary tumours in various parts of the body, often in the area of the bladder
• changes to your metabolism caused by the breakdown of the dying cancer cells (Tumour lysis syndrome).

Blood and Lymphatic System

• decrease in the activity of your bone marrow (myelosuppression). This can cause a decrease in the number of cells in your blood:
  • white cells – which fight infection (leucopenia, agranulocytosis, granulocytopenia, lymphopenia, neutropenia). This may be associated with fever (febrile neutropenia)
  • platelets – which help your blood clot (thrombocytopenia)
  • red cells – which carry oxygen around the body (anaemia). This may be associated with a decrease in their ability to carry oxygen (decreased haemoglobin)
  • red cells, white cells and platelets at the same time (pancytopenia)
• formation of small blood clots in your blood vessels disrupting the normal blood flow around your body (disseminated intravascular coagulation)
• haemolytic uremic syndrome – a condition causing abnormal break down of the red blood cells, decreased numbers of platelets in the blood and kidney failure.

Endocrine System

• swelling of the brain due to too much water in your blood (water intoxication). Signs of this can be headache, changes in personality or behaviour, confusion, drowsiness
• increase in the release of antidiuretic hormone from the pituitary gland. This affects the kidneys causing the low levels of sodium in your blood (hypernatremia) and water retention.
• Metabolism and Nutrition
• low blood levels of sodium which can cause tiredness and confusion, muscle twitching, fits and coma (hyponatremia)
• accumulation of fluid in the body (water retention), which may been seen as fluid beneath the skin or swelling in you limbs
• high blood sugar levels which can cause thirst, tiredness and irritability (hyperglycaemia)
• low blood sugar levels which can cause confusion and sweating (hypoglycaemia)
• loss of appetite (anorexia)
• dehydration.

How to store Cyclophosphamide

Because Cyclophosphamide is usually given in hospital it will be stored safely and correctly by the hospital staff. If you do need the storage conditions they are given below:

• Keep out of the reach and sight of children.
• Do not use Cyclophosphamide after the expiry date which is stated on the label after EXP. The expiry date refers to the last day of that month.
• Do not store above 25ºC. Store in the original container.

Cyclophosphamide
500mg /1g /2g Injection

DESCRIPTION

Cyclophosphamide for Injection, USP is a sterile white powder containing cyclophosphamide monohydrate. Cyclophosphamide is a synthetic antineoplastic drug chemically related to the nitrogen mustards. Cyclophosphamide is a white crystalline powder with the molecular formula C7H15CI2N2O2P•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:

CLINICAL PHARMACOLOGY

Cyclophosphamide 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.

Cyclophosphamide 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.

INDICATION AND USAGE

Cyclophosphamide, although effective alone in susceptible malignancies, is more frequently used concurrently or sequentially with other antineoplastic drugs. The following malignancies are often susceptible to cyclophosphamide treatment:

• 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.
• Multiple myeloma.
• 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 (cyclophosphamide given during remission is effective in prolonging its duration).
• Mycosis fungoides (advanced disease).
• Neuroblastoma (disseminated disease).
• Adenocarcinoma of the ovary.
• Retinoblastoma.
• Carcinoma of the breast.

Biopsy Proven “Minimal Change” Nephrotic Syndrome in Children:
Cyclophosphamide 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, cyclophosphamide may induce a remission. Cyclophosphamide 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.

WARNINGS

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 six-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 cyclophosphamide 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.

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.

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/m2 to as high as 26 g/m2, usually as a portion of an intensive antineoplastic multi-drug 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.

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.

Anaphylactic reactions have been reported; death has also been reported in association with this event. Possible cross-sensitivity with other alkylating agents has been reported.

PRECAUTIONS

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.

• Leukopenia
• Thrombocytopenia
• Tumor cell infiltration of bone marrow
• Previous X-ray therapy
• Previous therapy with other cytotoxic agents
• Impaired hepatic function
• Impaired renal function

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.

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.

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.

Cyclophosphamide may interfere with normal wound healing.

See WARNINGS section for information on carcinogenesis, mutagenesis, and impairment of fertility.

Pregnancy Category D—See WARNINGS section.

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.

The safety profile of cyclophosphamide in pediatric patients is similar to that of the adult population.

Insufficient data from clinical studies of cyclophosphamide for malignant lymphoma, multiple myeloma, leukemia, mycosis fungoides, neuroblastoma, retinoblastoma, and breast carcinoma are available for patients 65 years of age and older to determine whether they respond differently than younger patients. In two clinical trials in which cyclophosphamide was compared with paclitaxel, each in combination with cisplatin, for the treatment of advanced ovarian carcinoma, 154 (28%) of 552 patients who received cyclophosphamide plus cisplatin were 65 years or older. Subset analyses (<65 versus >65 years) from these trials, published reports of clinical trials of cyclophosphamide-containing regimens in breast cancer and non-Hodgkin’s lymphoma, and postmarketing experience suggest that elderly patients may be more susceptible to cyclophosphamide toxicities. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range and adjusting as necessary based on patient response.

ADVERSE REACTIONS

Information on adverse reactions associated with the use of cyclophosphamide 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.

See WARNINGS section for information on impairment of fertility.

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.

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. Very rare reports of Stevens-Johnson syndrome and toxic epidermal necrolysis have been received during postmarketing surveillance; due to the nature of spontaneous adverse event reporting, a definitive causal relationship to cyclophosphamide has not been established.

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/mm3 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 cyclophosphamide. 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.

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.

See WARNINGS section for information on reduced host resistance to infections.

See WARNINGS section for information on carcinogenesis.

Interstitial pneumonitis has been reported as part of the postmarketing experience. Interstitial pulmonary fibrosis has been reported in patients receiving high doses of cyclophosphamide over a prolonged period.

Anaphylactic reactions have been reported; death has also been reported in association with this event. Possible cross-sensitivity with other alkylating agents has been reported. SIADH (syndrome of inappropriate ADH secretion) has been reported with the use of cyclophosphamide. Malaise and asthenia have been reported as part of the postmarketing experience.

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

Adults and Children
sWhen used as the only oncolytic drug therapy, the initial course of cyclophosphamide 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 cyclophosphamide 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 cyclophosphamide 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/mm3 (following short courses) or more persistent reduction to 3000 cells/mm3 (with continuing therapy) are tolerated without serious risk of infection if there is no marked granulocytopenia.

When cyclophosphamide is included in combined cytotoxic regimens, it may be necessary to reduce the dose of cyclophosphamide as well as that of the other drugs.

Cyclophosphamide 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 cyclophosphamide metabolism, but there is no consistent evidence indicating a need for cyclophosphamide dosage modification in patients with renal function impairment.

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 cyclophosphamide treatment exceeds 60 days. Treatment beyond 90 days increases the probability of sterility. Adrenocorticosteroid therapy may be tapered and discontinued during the course of cyclophosphamide therapy. See PRECAUTIONS section concerning hematologic monitoring.

Preparation and Handling of Solutions
Intravenous administration
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Cyclophosphamide does not contain any antimicrobial preservative and thus care must be taken to assure the sterility of prepared solutions. USE ASEPTIC TECHNIQUE.

Cyclophosphamide may be prepared for intravenous administration using 0.9% Sterile Sodium Chloride Injection, USP or Sterile Water for Injection, USP with the following methods. Add the diluent to the vial and shake it vigorously to dissolve. If the powder fails to dissolve immediately and completely, it is advisable to allow the vial to stand for a few minutes. Use the quantity of diluent shown below to reconstitute the product:

For Direct Intravenous Injection
Cyclophosphamide reconstituted to 2% concentration in 0.9% Sterile Sodium Chloride Injection, USP can be injected directly.

Cyclophosphamide reconstituted to 2% concentration in Sterile Water for Injection, USP is hypotonic and should not be injected directly.

For Intravenous Infusion
Cyclophosphamide should first be reconstituted in 0.9% Sterile Sodium Chloride Injection, USP or Sterile Water for Injection, USP to a 2% concentration (20 mg per mL) and then further diluted for infusion to a minimum concentration of 0.2% (2 mg per mL) with any of the following diluents:

• Dextrose Injection, USP (5% dextrose)
• Dextrose and Sodium Chloride Injection, USP (5% dextrose and 0.9% Sterile Sodium Chloride Injection, USP)
• Sodium Chloride Injection, USP (0.45% Sterile Sodium Chloride Injection, USP)

Storage
Unopened vials of cyclophosphamide are stable until the date indicated on the package when stored at or below 25°C (77°F).

If not used immediately, for microbiological integrity, cyclophosphamide solutions should be stored as follows:

Cyclophosphamide (prepared for intravenous administration) is chemically and physically stable for the period of time as shown in the above table.

Liquid preparations of cyclophosphamide for oral administration may be prepared by dissolving cyclophosphamide for injection in Aromatic Elixir, N.F. Such preparations should be stored under refrigeration in glass containers and used within 14 days.

HOW SUPPLIED

Cyclophosphamide for Injection, USP contains cyclophosphamide monohydrate and is supplied in vials for single dose use.

Cyclophosphamide for Injection, USP

500 mg vial, carton of 1
1g vial, carton of 1
2g vial, carton of 1

Store vials at or below 25°C (77°F). During transport or storage of cyclophosphamide vials, temperature influences can lead to melting of the active ingredient, cyclophosphamide. Vials containing melted substance can be visually differentiated. Melted cyclophosphamide is a clear or yellowish viscous liquid usually found as a connected phase or in droplets in the affected vials. Do not use cyclophosphamide vials if there are signs of melting.

Caution should be exercised when handling and preparing the cyclophosphamide sterile powder for injection. The handling and preparation of cyclophosphamide should always be in accordance with current guidelines1-4 on safe handling of cytotoxic agents. To minimize the risk of dermal exposure, always wear gloves when handling vials containing cyclophosphamide sterile powder for injection. More information is available in the references listed below.

REFERENCES:

1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.
2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999.
   http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:1172-1193.
4. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.