cyclophosphamide: a comprehensive review as an …

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Wani et al. World Journal of Pharmacy and Pharmaceutical Sciences

CYCLOPHOSPHAMIDE: A COMPREHENSIVE REVIEW AS AN

ANTICANCER

*Rashmi Wani, Shivaji Sumbhe, Akanksha Singh and Bhagyashree

Assistant Professor, Ideal College of Pharmacy and Research, Kalyan,

Maharashtra, India.

ABSTRACT

Cyclophosphamide (CP), also known as Cytophosphane among other,

is a medication used as chemotherapy and to suppress the immune

system. Cyclophosphamide is classified as Alkylating agent are most

active in the resting phase of the cell. These drugs are cell-cycle non

specific. Cyclophosphamide is used to treat several forms of cancer

including leukemias, lymphomas and breast cancer. and autoimmune

diseases. Due to its toxicity, it is replaced as soon as possible by less

toxic drugs. It is used to treat a certain type of kidney disease in children

after other treatments have not worked. Cyclophosphamide therapy is

associated with minor transient serum enzyme elevations and has been

linked to rare cases of acute liver injury. In addition, when given in high doses as a part of a

myeloablative therapy, Cyclophosphamide can cause acute sinusoidal obstruction syndrome.

Cyclophosphamide is used alone or in combination with other medications to treat Hodgkin's

lymphoma and non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Multiple myeloma

and certain types of leukemia including chronic lymphocytic leukemia (CLL), chronic

myelogenous leukemia (CML), acute myeloid leukemia (AML, ANLL), and acute

lymphoblastic leukemia (ALL). It is also used to treat retinoblastoma (cancer in the eye),

neuroblastoma (a cancer that begins in nerve cells and occurs mainly in children), ovarian

cancer (cancer that begins in the female reproductive organs where eggs are formed), and

breast cancer. Cyclophosphamide is also used to treat nephrotic syndrome.

INTRODUCTION[1-4]

Cancer is the uncontrolled growth of abnormal cells anywhere in a body. There are over 200

types of cancer. Anything that may cause a normal body cell to develop abnormally

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.421

Volume 7, Issue 6, 322-340 Review Article ISSN 2278 – 4357

*Corresponding Author

Rashmi Wani

Assistant Professor, Ideal

College of Pharmacy and

Research, Kalyan,

Maharashtra, India.

Article Received on

26 March 2018,

Revised on 16 April 2018,

Accepted on 06 May 2018,

DOI: 10.20959/wjpps20186-11685

https://en.wikipedia.org/wiki/Chemotherapy

https://en.wikipedia.org/wiki/Immunosuppressant

https://en.wikipedia.org/wiki/Immunosuppressant

https://en.wikipedia.org/wiki/Autoimmune_disease

https://en.wikipedia.org/wiki/Autoimmune_disease

https://www.webmd.com/a-to-z-guides/understanding-kidney-disease-basic-information

https://www.medicinenet.com/cancer_quiz/quiz.htm


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potentially can cause cancer; general categories of cancer-related or causative agents are as

follows: chemical or toxic compound exposures, ionizing radiation, some pathogens, and

human genetics. Cancer symptoms and signs depend on the specific type and grade of cancer;

although general signs and symptoms are not very specific the following can be found in

patients with different cancers: fatigue, weight loss, pain, skin changes, change in bowel or

bladder function, unusual bleeding, persistent cough or voice change, fever, lumps, or tissue

masses. Although there are many tests to screen and presumptively diagnose cancer, the

definite diagnosis is made by examination of a biopsy sample of suspected cancer tissue.

Cancer staging is often determined by biopsy results and helps determine the cancer type and

the extent of cancer spread; staging also helps caregivers determine treatment protocols.

In general, in most staging methods, the higher the number assigned, the more aggressive the

cancer type or more widespread is the cancer in the body. Staging methods differ from cancer

to cancer and need to be individually discussed with your health care provider. Treatment

protocols vary according to the type and stage of the cancer. Most treatment protocols are

designed to fit the individual patient's disease. However, most treatments include at least one

of the following and may include all: surgery, chemotherapy, and radiation therapy.

In the most basic terms, cancer refers to cells that grow out-of-control and invade other

tissues. Cells become cancerous due to the accumulation of defects, or mutations, in their

DNA.

Certain

Inherited genetic defects (for example, BRCA1 and BRCA2 mutations),

Infections,

Environmental factors (for example, air pollution), and

Poor lifestyle choices -- such as smoking and heavy alcohol use -- can also damage DNA

and lead to cancer.

Most of the time, cells are able to detect and repair DNA damage. If a cell is severely

damaged and cannot repair itself it undergoes so-called programmed cell death or apoptosis.

Cancer occurs when damaged cells grow, divide, and spread abnormally instead of self-

destructing as they should.

a. Change in bowel or bladder habits

b. A sore throat that does not heal

https://www.medicinenet.com/radiation_therapy/article.htm

https://www.medicinenet.com/cancer_101_pictures_slideshow/article.htm

https://www.medicinenet.com/fatigue/article.htm

https://www.medicinenet.com/weight_loss/article.htm

https://www.medicinenet.com/chronic_cough/article.htm

https://www.medicinenet.com/aches_pain_fever/article.htm

https://www.medicinenet.com/chemotherapy/article.htm

https://www.medicinenet.com/radiation_therapy/article.htm

https://www.medicinenet.com/sore_throat_pharyngitis/article.htm


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c. Unusual bleeding or discharge (for example, nipple secretions or a "sore" that will not

heal that oozes material)

d. Thickening or lump in the breast, testicles, or elsewhere

e. Indigestion (usually chronic) or difficulty swallowing

f. Obvious change in the size, color, shape, or thickness of a wart or mole

g. Nagging cough or hoarseness

Fig. No 1: Anticancer drug classification.

Cytoxan is a synthetic antineoplastic drug chemically related to the nitrogen mustards.

The chemical name for Cyclophosphamide is 2-[bis(2-chloroethyl)amino]tetrahydro-2H-

1,3,2-oxazaphosphorine 2-oxide monohydrate or N,N-bis(2-chloroethyl)-2-oxo-1,3,2$l^{5}-

oxazaphosphinan-2-amine.[5]

Fig. No 2: Structure of Cyclophosphamide.

https://www.medicinenet.com/breast_anatomy/article.htm

https://www.medicinenet.com/dyspepsia/article.htm

https://www.medicinenet.com/swallowing/article.htm

https://www.medicinenet.com/cold_flu_cough_relief_pictures_slideshow/article.htm

https://www.medicinenet.com/hoarseness/article.htm


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Cyclophosphamide has a molecular formula of (C7H15Cl2N2O2P•H2O) and a molecular

weight of 279.1.Physiochemical property:-Cyclophosphamide is soluble in water, saline, or

ethanol.

Pharmacokinetics[6-7]

Absorption: The Cyclophosphamide has Bioavailability of 75% and Onset of action 2-3

hours. The Peak plasma time for Cyclophosphamide is 1 hour and for metabolites 2-3 hours.

Distribution: Protein bound of Cyclophosphamide is low and metabolites are >60% protein

bound. Volume of Distribution: 0.48-0.71 L/kg.

Metabolism: The Cyclophosphamide is metabolized by liver and metabolites are 4-

hydroperoxycyclophosphamide, 4-aldophosphamide.

Elimination: The Cyclophosphamide has Half-life of 3-12 hour and excreted via Urine.

MECHANISM OF ACTION[7-10]

Cyclophosphamide is a chiral prodrug antineoplastic agent requiring activation by metabolic

and non-metabolic processes. It is activated by cytochrome P-450 (CYP450) enzyme in the

liver followed by the release of activated phosphoramide mustard and acrolein. The initial

metabolic step is mediated primarily by CYP2B6 and involves regioselective hydroxylation

at C4 of the Oxazaphosphorine ring to generate a Carbinolamine. This hydroxylation reaction

must occur before the molecule will be transported into cells and approximately 90% of drugs

get converted. CYP3A4 and CYP2B6 stereospecifically catalyze an inactivating N-

dechloroethylation reaction on the R ans S isomers yields highly nephrotoxic and neurotoxic

chloracetaldehyde. The CYP generated Carbinolamine undergoes non-enzymatic hydrolysis

to provide the Aldophophamide either in the blood stream or inside the cells. If this

hydrolysis occurs extracellularly, the aldophosphamide is still able to penetrate cell

membranes to reach the intracellular space. Once inside the cell, Acrolein is cleaved via

spontaneous β-elimination generating Phosphoramide mustard with pKa 4.75.

Phosphoramide mustard is the final alkylating agent responsible for cross-linking the

interstranded DNA at guanine N-7 position. Acrolein is highly cytotoxic to cultured tumor

cells but is not responsible for the cytotoxicity of Cyclophosphamide. It is in fact responsible

for hemorrhagic cystitis which is a life threatening side effect associated with

Cyclophosphamide.


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Fig. No 3: Mechanism of Action of Cyclophosphamide.

Fig. No 4: Sulfhydral Alkylation of Acrolein.


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Fig. No 5: Metabolites of of Cyclophosphamide.

SIDE EFFECTS:[10-13]

Cyclophosphamide is a cancer medication used to treat several types

of cancer. Cytoxan is also used to treat certain cases of nephrotic syndrome (kidney disease)

in children. Common side effects of Cytoxan include.

1. Nausea or vomiting (may be severe),

2. Loss of appetite,

3. Stomach pain or upset,

4. Diarrhea,

5. Temporary hair loss,

6. A wound that will not heal,

7. Missed menstrual periods,

8. Changes in skin color (darkening), or

9. Changes in nails.

10. Pink/bloody urine,

11. Unusual decrease in the amount of urine,

12. Mouth sores,

13. Unusual tiredness or weakness,

14. Joint pain, or


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15. Easy bruising or bleeding.

Cyclophosphamide may be administered either intravenously (approximately once a month)

or orally (once a day, typically in a smaller dose). To some degree, the side–effects of

Cyclophosphamide differ according to the way the drug is administered.

Infection

Bone marrow suppression

Cancer

Bladder problems

Infertility

Infection

Cyclophosphamide increases the risk of ―opportunistic‖ infections, i.e. infections that a

person’s intact immune system would normally be able to fight off. Thus, Cyclophosphamide

does not enhance a patient’s susceptibility to the common cold; it does heighten the risk of

more serious infections, including tuberculosis, fungal infections, and serious viral infections.

Several specific infections frequently associated with Cyclophosphamide uses (or the use of

immunosuppressive drugs in general) are described below.

“Thrush” — Thrush is a fungal infection of the mouth caused by Candida. It generally

appears as white spots on the inside of the mouth and is easily treatable with the use of anti–

fungal mouthwash or troches. Sometimes Candida infections also involve the esophagus (the

―food tube‖ leading from the mouth to the stomach). This condition, called ―Candida

esophagitis‖, often results in pain on swallowing, and must be treated with potent anti–fungal

medications such as fluconazole.

“Shingles” or Herpes zoster: ―Shingles‖ results from reactivation of the virus that causes

chickenpox (Varicella zoster). Most probably the child greater than 5 yr had chickenpox at

one time, generally as a child. Normally, even after the rash and other symptoms of

chickenpox subside, the virus that caused the sickness continues to reside in the body in a

―dormant‖ state, hiding in the root of one of the nerves along the spine. Decades later, as the

immune system wanes slightly with age (a normal part of the aging process) or when the

immune system is suppressed (by medications such as Cyclophosphamide), the virus become

active again. When it reactivates, Varicella zoster usually causes a painful rash in the

distribution of a single nerve, such as over one side of the face or down one arm. The rash is

https://www.hopkinsvasculitis.org/vasculitis-treatments/cyclophosphamide-cytoxan/#infection

https://www.hopkinsvasculitis.org/vasculitis-treatments/cyclophosphamide-cytoxan/#bone

https://www.hopkinsvasculitis.org/vasculitis-treatments/cyclophosphamide-cytoxan/#cancer

https://www.hopkinsvasculitis.org/vasculitis-treatments/cyclophosphamide-cytoxan/#bladder

https://www.hopkinsvasculitis.org/vasculitis-treatments/cyclophosphamide-cytoxan/#infertility


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characterized by groups of small vesicles (blisters) sitting on a base of reddened skin, and

may be extremely painful. ―Shingles‖ is treatable with anti–viral medicines such as acyclovir

or famcyclovir. These should be instituted as soon as possible. Narcotic pain medicines may

also be necessary for several weeks. In a small minority of cases, ―shingles‖ results in pain

that can last for months. This condition is called ―post–herpetic neuralgia‖.

Pneumocystis carinii pneumonia (“PCP”) — Pneumocystis carinii is a fungus that resides

within the lungs of most people. People with intact immune systems have no trouble keeping

the organism at bay. In patients who are immunosuppressed, the organism can cause a serious

type of pneumonia: PCP. A few years ago, PCP was the most common cause of serious lung

infections in patients with AIDS. Because of advances in the treatment and prevention of this

condition, PCP is now a much rarer problem in AIDS. Similarly, PCP may also be prevented

in patients with vasculitis by having patients take certain types of antibiotics daily or every

other day. The antibiotics most commonly used for this purpose are Trimethoprim–

Sulfamethoxazole (Bactrim, Septra) or, in patients who are allergic to sulfa medications,

dapsone.

Bone Marrow Suppression

The bone marrow is the organ of the body that makes red blood cells (which carry oxygen),

white blood cells (which fight infection), and platelets (which help the blood clot). Nearly all

patients treated with Cyclophosphamide experience some suppression of the bone marrow’s

ability to produce these vital blood elements. Thus, careful monitoring of blood counts is

essential during Cyclophosphamide therapy. Suppression of the bone marrow by

Cyclophosphamide is usually transient — i.e. responsive to a decrease in dose or

discontinuation of the medicine — but dangerously low levels of any of these three cell lines

(or even permanent bone marrow failure) may occur.

The white blood cells are the cell line that is usually most sensitive to the effects of

Cyclophosphamide. When Cyclophosphamide is given intravenously, the white blood cell

count tends to reach its low point (―nadir‖) between 7 and 14 days after administration.

Therefore, blood cell counts should be measured approximately 10 days after the

administration of Cyclophosphamide, and repeated as often as needed to insure that the

counts do not go too low. This normally means checking blood counts every 2–4 weeks.

When Cyclophosphamide is given orally, blood counts should be checked about 7 days after

starting treatment and once every 3 weeks. At some centers experienced in the care of


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patients with Vasculitis and the use of Cyclophosphamide, blood counts are checked every 2

weeks.

Cancer

Many of the side–effects of Cyclophosphamide are most likely to occur while the patient is

taking the medication. With those side–effects, the risk of their occurrence diminishes greatly

after discontinuation of the drug. In contrast, the risk of cancer associated with

Cyclophosphamide use may continue for many years, even after patients stop the medication.

The risk of cancer appears to be dependent upon the length of time patients have taken the

medication and the cumulative dosage of the drug. Patients who have taken

Cyclophosphamide have an increased risk for at least two primary types of malignancy:

leukemia/lymphoma and bladder cancer. There may also be increased risks for other kinds of

cancer, but the risks are less high.

Leukemia/lymphoma — One of the long–term side–effects of Cyclophosphamide use is a

significant increase in the risk of bone marrow and lymph node cancers (known as leukemia

and lymphoma, respectively). Physicians are currently unable to predict which patients will

be at risk for these complications. The best means of avoiding these types of cancer is to use

Cyclophosphamide judiciously: the lowest possible dose of the medicine for the shortest

length of time necessary to control the disease.

Bladder cancer — Cyclophosphamide has a tendency to damage the bladder (see Bladder

problems, below). This damage predisposes patients to the development of bladder cancer.

The risk of bladder cancer (and of other bladder complications) is greater when

Cyclophosphamide is administered in the oral daily form. Among patients with Wegener’s

granulomatosis treated with oral daily Cyclophosphamide at the National Institutes of Health,

the risk of bladder cancer was 6%. Among patients followed for up to 15 years, the projected

incidence of bladder cancer was as high as 16%. Therefore, patients who have been treated

with Cyclophosphamide need to be followed indefinitely for the possibility of bladder

complications of the treatment. The best method of screening for this complication is to

check for red blood cells in the urine by performing a urinalysis, followed by cystoscopy if

red blood cells are present. Patients shown to have bladder damage by Cyclophoshamide, i.e.

to have drug-induced cystitis, should undergo surveillance cystoscopies at regualar intervals

determined by their urologists.


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When cyclophosphamide is administered intravenously, a bladder-protective medicine called

MESNA may be given at the same time. MESNA appears to neutralize the toxic metabolite

of Cyclophosphamide (acrolein) that is thought to be responsible for the bladder

complications. Additional strategies for decreasing the bladder toxicity of Cyclophosphamide

include: 1) giving intravenous hydration prior to cyclophosphamide; 2) taking all of the

medicine in a single morning dose and washing it down with a large amount of fluid; and 3)

drinking ample quantities of fluid throughout the day (eight 8–ounce glasses of water) to

maintain a brisk urine output.

Bladder Problems

In addition to cancer, Cyclophosphamide may cause a variable amount of bleeding from the

bladder, a complication known as ―hemorrhagic cystitis‖. This bleeding may range from a

few red blood cells in the urine (invisible to the naked eye; only detectable by examining the

urine under the microscope) to life–threatening hemorrhage from the bladder. If any bleeding

from the bladder is discovered while a patient is taking Cyclophosphamide, the medicine

should be stopped until the bladder can be evaluated by cystoscopy.

Infertility

Cyclophosphamide may cause infertility in both men and women who are treated with the

medication. As with many of Cyclophosphamide’s side–effects, the risk of infertility appears

to be related to the length of time a patient receives the drug (and probably the cumulative

dose, as well). A woman’s age may also affect her risk of infertility, with the occurrence of

early menopause higher in women over the age of 30 at the time treatment is begun.

In a long-term study of the effectiveness of Cyclophosphamide in treating lupus, the risk of

infertility among women of childbearing potential was 57%.

DRUG-DRUG INTERACTION[15-17]

Adenovirus types 4 and 7 live, oral Cyclophosphamide decreases effects of adenovirus

types 4 and 7 live, oral by pharmacodynamic antagonism. Avoid or Use Alternate Drug.

Immunosuppressive may diminish therapeutic effects of vaccines and increase risk of

adverse effects (increased risk of infection). Live-attenuated vaccines should be avoided

for at least 3mo after cessation of immunosuppressive therapy.


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Hydrochlorothiazide: Hydrochlorothiazide increases toxicity of Cyclophosphamide by

decreasing renal clearance. Avoid or Use Alternate Drug. Increased myelo-suppressive

effects can be seen.

Argatroban: Cyclophosphamide increases effects of Argatroban by unknown mechanism.

Use Caution/Monitor. Additive risk of bleeding may be seen in thrombocytopenic

patients receiving antineoplastic agents in combination with Argatroban because these

agents can decrease platelet counts.

Bivalirudin: Cyclophosphamide increases effects of Bivalirudin by unknown mechanism.

Additive risk of bleeding may be seen in thrombocytopenic patients receiving

antineoplastic agents in combination with anticoagulants such as bivalirudin.

Cholera Vaccine: Cyclophosphamide decreases effects of cholera vaccine by

immunosuppressive effects; risk of infection. Modify Therapy/Monitor Closely.

Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents,

cytotoxic drugs and corticosteroids (used in greater than physiologic doses), may reduce

the immune response to cholera vaccine.

Digoxin: Cyclophosphamide decreases levels of digoxin by inhibition of GI absorption.

Doxorubicin: Doxorubicin increases toxicity of Cyclophosphamide by unspecified

interaction mechanism. Increased risk of hemorrhagic cystitis is associated with this.

Heparin: Cyclophosphamide increases effects of heparin by unknown mechanism. Use

Caution/Monitor. Due to potential thrombocytopenic effects of Cyclophosphamide, an

additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.

Hydroxyurea: Cyclophosphamide, hydroxyurea Combination may increase risk of

myelosuppression

Pentobarbital & Phenobarbital: Pentobarbital will decrease the level or effect of

Cyclophosphamide by affecting hepatic enzyme CYP2B6 metabolism.

Warfarin: Cyclophosphamide increases effects of Warfarin by unknown mechanism.

Anticoagulant effect is increased. Monitor coagulation parameters during and after

Cyclophosphamide therapy. Adjust the Warfarin dose as needed.

Dosage Forms & Strengths:[18-20]

Powder for injection: 500mg, 1g, 2g Tablet: 25mg,

50mg.


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Fig. No 6: Cyclophosphamide for Injection 1gm.

Fig. No 7: Cyclophosphamide for Injection 2 gm.

Fig. No 8: Cyclophosphamide for Injection 500 mg.


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Fig. No 9: Cyclophosphamide Capsule 25 mg.

1. Malignant Diseases

IV (intermittent therapy): 40-50 mg/kg (400-1800 mg/m²) divided over 2-5 days; may be

repeated at intervals of 2-4 weeks

IV (continuous daily therapy): 60-120 mg/m²/day (1-2.5 mg/kg/day)

PO (intermittent therapy): 400-1000 mg/m² divided over 4-5 days

PO (continuous daily therapy): 50-100 mg/m²/day or 1-5 mg/kg/day

2. Nephrotic Syndrome

2-3 mg/kg/day for up to 12 weeks when corticosteroids unsuccessful.

3. Non-Hodgkin Lymphoma

600-1500 mg/m² IV with other antineoplastics (part of CHOP regimen).

4. Breast Cancer

600 mg/m² IV with other antineoplastics; dose intensification possible.

5. Burkitt’s Lymphoma

High doses of IV (1-4 gm per square body surface area) in combination with other

chemotherapeutic agents as Vincristine, Methotrexate, Doxorubicin and Cytarabine

6. Chronic Lymphocytic Leukemia

IV with 250 mg per square body surface area on days 2-4 on cycle 1 and on days 1-3 in

subsequent cycles.

javascript:openCalc('/calculator/dosing/weight-dosing','Malignant%20Diseases','Adult','IV%20(intermittent%20therapy):%2040-50%20mg/kg%20(400-1800%20mg/m%C2%B2)%20divided%20over%202-5%20days;%20may%20be%20repeated%20at%20intervals%20of%202-4%20weeks%C2%A0');


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7. Breast Cancer

Tablet 100 mg per square body surface area on days 1-14 given every 28 days, or IV 600 mg

per square body surface area given every 21 days as a part of CMF (Cyclophosphamide,

Methotrexate and Fluorouracil) regimen.

8. Systemic Lupus Erythematosus

IV dose is 7-25 mg per square body weight every month for 6 cycles. Oral dose is 1.5-3 mg

per square body weight per day.

9. Multiple Scelrosis

IV dose is 700 mg per square body surface area monthly.

10. Mononeuritis Muyltiplex

Oral dose 2 mg per kg body weight per day.

11. Pemphigus Vulgaris

Tablet 1-2 mg per kg body weight per day.

12. Bullous Pemphigoid

Tablet 1-2 mg per kg body weight per day.

13. Wegener’s Granulomatosis, Churg-Strauss Syndrome and Microscopic Polyangiitis:

Cyclophosphamide is an effective therapy for the treatment of this vasculitis. It is given in

doses of 2 mg per kg body weight per day orally together with glucocorticoid. After the

induction of complete remission (complete disappearance of detectable disease), patients are

maintained on Cyclophosphamide therapy for upto a year to minimize the risk of relapse and

gradually tapered and discontinued thereafter.

14. Goodpasture’s Syndrome

Usual dose is oral Cyclophosphamide 2 mg per kg body weight per day together with

Prednisolone for 2 weeks.

15. Bone Marrow Transplantation

Usual dose is 60 mg per kg body weight IV for 2 days.


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16. Autoimmune Hemolytic Anemia

Usually Prednisolone is used to prevent Hemolysis (breakdown of red blood cells) in

autoimmune hemolytic anemia. If the hemolysis fais to respond to Prednisolone, repeated

cycles of Cyclophosphamide at a dose of 50 mg per kg body weight per day for 4 days may

be considered.

17. Ovarian Cancer

Usual Adult Dose for For use in the treatment of epithelial ovarian cancer:

600 mg/m2 intravenously on day one in combination with Carboplatin or Cisplatin

Repeat cycle every 28 days.

Usual Adult Dose for Multiple Myeloma: In combination with other chemotherapeutic

agents as a part of the M2 protocol 10 mg/kg IV on day 1.

Administration[21-22]

1. Give dose early in day

2. Patients should drink plenty of fluids with PO doses

3. Patients should empty bladder frequently to prevent hemorrhagic cystitis

4. Sometimes, mesna is used concomitantly as prophylaxis against hemorrhagic cystitis

5. Monitor blood counts during therapy (WBC count may decrease to 2000-3000/μL without

serious risk of infection)

6. May be administered IM, intraperitoneally, intrapleurally, by IV piggy-back, or by

continuous IV infusion

7. IV Incompatibilities

8. Y-site: Amphotericin B cholesteryl sulfate

9. Cisplatin/etoposide, fluorouracil, hydroxyzine, methotrexate, methotrexate/fluorouracil,

mitoxantrone, ondansetron

10. Syringe: Bleomycin, cisplatin, doxapram, doxorubicin, droperidol, furosemide, heparin,

leucovorin, methotrexate, metoclopramide, mitomycin, vinblastine, vincristine

11. Y-site (partial list): Allopurinol, amifostine, bleomycin, most cephalosporins, cisplatin,

diphenhydramine, doxorubicin, doxorubicin liposomal, filgrastim, fluorouracil,

furosemide, gemcitabine, linezolid, lorazepam, mitomycin, morphine, paclitaxel,

prochlorperazine, propofol, sodium bicarbonate, trimethoprim/sulfamethoxazole,

vancomycin, vinblastine, vincristine


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IV Preparation[23]

Maximum concentration of Cyclophosphamide is limited to 20 mg/mL because of solubility

IV push: Reconstitute with NS (do not use SWI, because it is hypotonic).

Infusion: Reconstitute with SWI to concentration of 20 mg/Ml.

It may be diluted further with D5W, NS, lactated Ringer solution or other compatible fluids.

Combination Therapy[24-25]

Ewing’s sarcoma: It is one type of malignant bone tumor. Intravenous Cyclophosphamide

500 -1200 mg per square body surface area is used as chemotherapy in Ewing’s sarcoma in

combination with other chemotherapeutic agents such as doxorubicin, etoposide, vincristine

and dactinomycin.

Wegener’s granulomatosis: All are small vessel vasculitis. Cyclophosphamide is an

effective therapy for the treatment of this vasculitis. It is given in doses of 2 mg per kg body

weight per day orally together with glucocorticoids.

Chronic lymphocytic leukemia (CLL): Usual dose is intravenous Cyclophosphamide 250

mg per square body surface area on days 2-4 on cycle 1 and on days 1-3 in subsequent cycles,

as part of Cyclophosphamide, rituximab and fludarabine regimen.

Burkitt’s lymphoma: Usually higher doses of intravenous Cyclophosphamide (1 to 4 gm per

square body surface area) are used in Burkitt’s lymphoma in combination with other

chemotherapeutic agents such as Vincristine, Methotrexate, Doxorubicin and Cytarabine.

CONTRAINDICATIONS

Hypersensitivity Reaction:[26]

Cyclophosphamide is contraindicated in patients who have a history of severe

hypersensitivity reactions to it, any of its metabolites, or to other components of the product.

Anaphylactic reactions including death have been reported with Cyclophosphamide. Possible

cross-sensitivity with other alkylating agents can occur.

Urinary Outflow Obstruction

Cyclophosphamide is contraindicated in patients with urinary outflow obstruction.

Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria have been reported with

Cyclophosphamide.


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Cardiotoxicity:[27]

The risk of cardiotoxicity may be increased with high doses of Cyclophosphamide, in patients

with advanced age, and in patients with previous radiation treatment to the cardiac region

and/or previous or concomitant treatment with other cardiotoxic agents.

Pulmonary Toxicity:[28]

Pneumonitis, pulmonary fibrosis, pulmonary veno-occlusive disease and other forms of

pulmonary toxicity leading to respiratory failure have been reported during and following

treatment with Cyclophosphamide.

Infertility:[29]

Male and female reproductive function and fertility may be impaired in patients being treated

with Cyclophosphamide. 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.

Herbal Preparation[30-33]

Amla

Cyclophosphamide (CP) is one of the most popular alkylating anticancer drugs in spite of its

toxic side effects including immunotoxicity, hematotoxicity, mutagenicity and a host of

others. The present study was undertaken to assess the protective effects of total aqueous

extract of a medicinal plant, Indian gooseberry (Emblica officinalis Gaertn.) in mice treated

with CP. These protective effects were studied on immunological parameters and kidney and

liver antioxidants. Plant extract treatment at a dose of 100 mg/kg body weight per os (p.o.)

for 10 days resulted in the modulation of these parameters in normal as well as CP (50

mg/kg)-treated animals. Plant extract in particular was very effective in reducing CP-induced

suppression of humoral immunity. Plant extract treatment in normal animals modulated

certain antioxidants of kidney and liver. In CP-exposed animals, plant pretreatment provided

protection to antioxidants of kidney. Not only were the reduced glutathione levels

significantly (p<0.001) increased but plant extract treatment resulted in restoration of

antioxidant enzymes in CP-treated animals. It is suggested that E. officinalis or its medicinal

preparations may prove to be useful as a component of combination therapy in cancer

patients under CP treatment regime Protective effects of Emblica Officinalis Gaertn In

cyclophosphamide-treated mice.


339


CONCLUSION

Cyclophosphamide is used alone to treat Hodgkin's lymphoma, non-Hodgkin's lymphoma,

Burkitt’s Lymphoma, Goodpasture’s Syndrome, Wegener’s Granulomatosis and Multipple

Sclerosis. Cyclophosphamide-related hepatotoxicity is rare but can occur. Cyclophosphamide

can be used in combination with other medicaments to treat Ewing’s sarcoma, chronic

lymphocytic leukemia and Burkitt’s lymphoma like disorders and diseases.

Cyclophosphamide also can be used with herbal drug Amla to reduce Cyclophosphamide

iduced suppression of immunity. Cyclophosphamide is used to treat variety of Cancer hence

we can say that it has proves as a magical drug due to its multidirectional efficacy.

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