Alkylating Agents Includes-

Mechlorethamine ,Chlorambucil, Melphalan, Ifosamide,Cyclophosphamide, Urasil Mustard,
Lomustine, Carmustine, Streptozocin, Thiotepa, Busulfan, Pipobroman, Cisplatin, Carboplatin 

Interacting drugs- summary

+  cyclophosphamide-

Chloramphenicol
Cyclophosphmide  half-life  increased, metabolite conc decreased

Thiazide diuretics
 antineoplastic-induced leukopenia    prolonged

Allopurinol
myelosuppressive  effects of cyclophosphamide may be enhanced, possibly increasing the risk of bleeding or infection

Chloramphenicol + Cyclophosphamide
 decreased or delayed activation of cyclophosphamide may occur, although it is 
 unclear if a significant decrease in its effects would occur.

Doxorubicin
exacerbation of cyclophosphamide -induced hemorrhagic cystitis and      
 enhancement of 6-mercaptopurine have occurred.

Cyclophosphamide +

Digoxin
Digoxin serum level reduced

Succinyl choline
 neuromuscular blockade  prolonged

Anticoagulants
May increase the anticoagulant efect of warfarin or anisindione
 The risk of bleeding is increased. The mechanism of action
  is unknown or complicated.
 
                

Alkylating Agents Includes-  Mechlorethamine ,Chlorambucil, Melphalan, Ifosamide,Cyclophosphamide, Urasil Mustard, Lomustine, Carmustine, Streptozocin, Thiotepa, Busulfan, Pipobroman, Cisplatin, Carboplatin 

Leukemias. 

Secondary neoplasia- has developed  with cyclophosphamide alone or with other neoplastic drugs
or radiation therapy.

GU- acute hemorrhagic cystitis occurs in 7% to 12% of patients and may occur in upto 40%.

Hematologic- leukopenia is an expected effect and is used a guide to dosage. Leukopenia of < 200
cells/mm2 develops commonly in patients treated with an initial loading dose of the drug.and less
 frequently in patients maintained on smaller doses.
Thrombocytopenia or anemia develop occassionally.These effects are usually reversible when
 therapy is interrupted.

GI- anorexia, nausea, vomiting, diarrhea, stomatitis, abdominal discomfort or pain. There are reports
of hemorrhagic colitis, oral mucosal ulceration and jaundice.

Dermatologic- alopecia, is frequent, regrowth of hair can be expected, although it may be of a
different color. or texture. Skin rash occurs occassionally in patients receiving the drug.
 Pigmentation of the skin and changes in nails can occur.

Pulmonary- interstitial pulmonary fibrosis with prolonged high dosagehas occured., although dose,
 duration or schedule dependency is not established

Cardiovascular- cardiotoxicity (hemorrhagic cardiac necrosis, transmural hemorrhages, coronary
artery vaculitis) has occured with massive doses (120 to 240mg/kg)

Bladder haemorrhage, pregnancy, leucopenia, thrombocytopenia.

Special precautions:
W.B.C. counts to be maintained at 3000-4000,infection,breastfeeding within 36 hours of the drug to
be avoided.

Monitoring- during treatment, monitor the patients hematologic profile (particularly neutrophils and
 platelets) regularly to determine  thedegree of hematopoietic suppresion. Examine urine regularly
 for red cells which may precede hemorrhagic cystitis.

Give cautiously to patients - to patients with leukopenia, thrombocytopenia, tumor or cell infiltration
 of bone marrow,previous radiation therapy, previous cytotoxic therapy.

Imunosuppression- treatment with cyclophophamide may cause significant suppression of immune
responses, Serious sometimes fatal , infections may develop in some severely immunosuppressed
 patients. 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.

Renal effects- a syndrome of inapprpropiate antidiuretic hormone (SIADH) has occured with IV
 doses > 50mg/kg.
It is both renal tubular necrosis have occured. Such lesions usually resolve following cessation of
 therapy.

Warnings-
Cardiac toxicity- although a few instances of cardiac dysfunction have occured following use of
 recommended doses of cyclophosphamide,  no casuaul  relationship has not been established.
 Cardiotoxicity has been observed in some patients receiving high doses of cyclophosphamide
ranging from 120 to 270mg/kg administred over a period of few days.

Adrenalecttomy- adjustment of doses of both replacement steroids and cyclophophamide may be
necessary for the adrenalectomized patient.

Wound healing- cyclophosphamide may interfer with normal wound healing.

GU- acute hemorrhagic cystitis occurs in 7% to 12% of patients, although some report an occurrence
 of up to 40%.
Hemorrhagic cyctitis can be severe, even fatal, and is probably due to urinary metabolites.

Hypersensitivity- reactions have ocurred , mediated through increased B-cell activity and production
 of IgE.

Renal function impairment- use cautiously .Patients with compromised renal function may show
measurable changes in pharmacokinetic parameters of cyclophosphamide metabolism, but there
 is no evidence indicating a need for modified dosage in these patients.

Carcinogenesis- secondary neoplasma has developed with cyclophosphamide  alone or with
 antineoplastic drugs or radiation therapy. These most frequently have been urinary bladder,
myeloproliferative and lymphoproliferative malignacies. Consider the posssibility of secondary
 malignancy in any benefit-to-risk assessment for use of the drug.

Pregnancy- both normal and malformed newborns have been reported following the use of
cyclophophamide in pregnancy

Lactation- because of the potential for serious adverse reactions, and the potential for tumorigenicity
decide whether to discontinue the drug taking into account the importance of the drug to the mother. 

Indications:

Used concurrently with other anti-neoplatics in malignancies. Leukemias.

Dosage:

Take tablets preferably in an empty stomach. If GI upset is severe then take with food. Oral- 1 to 5mg/kg/day for both initial and maintenance dosing. Overdosage- No specific antidote is known Use general supportive measures

Missed dose-

 1. If you miss a dose of this medicine, take it as soon as possible.

2. However, if it is almost time for next dose, skip the missed dose and go back to your regular dosing schedule.

3. Do not double doses.

Hemorrhagic Cystisis

Drugs causing adverse reactions-
1. Cyclophophamide

1. Take tables preferably on an empty stomach.
2. If GI upset is very severe take with food.
3. Notify your doctor of unusual bleeding, or bruising, fever, chills, sore throat, cough, shortness of
  breath, seizures,  lack of mentrul flow, unusuallumps or masses , flank or stomach pain, joint pain,
  sores in the mouth or on the lips, or   yellow discoloration of the skin or the eyes
4. Contraceptive measures are recommended during therapy for both men and women.

5. Allergies- Tell your doctor if you have ever had any unusual or allergic raections to
   cyclophosphamide or other  related medicines. Also tell your doctor if youn are allergic to any
   other substances such as foods, preservatives or dyes.

6. Pregnancy-  this medicine can cause several different defects if either male oe female taking at
   the time of  conception. Sterilty occurs commonly with cyclophosphamide, but usually it is only
   temporary.  
   
7. Breast feeding- because this medicine may cause serious side efects breast feeding is generally
    not recommended  while you are taking it.
       
8. Children- not reported to cause different side effects or problems in children than adults
   
9. Elderly- not expected to cause differnt side effects or problems in older people than it does in
   younger adults.

10. Other medicines- tell your doctor if you are taking any of the following-
   
    Amphotericin B by injection or
    Antithyroid agents or
      Azathioprine or
      Chloramphenicol or
      Colchicine or
      Flucytosine or
      Ganciclovir or
      Interferon or
      Pilacamycin  or
      Zidovudine or
      If you have been treated with radiation or cancer medicines or radiation therapy on the blood
   
      Azathioprine or
      Chlorambutil or
      Corticosteroids or
      Cyclosporine or  
      Mercaptopurine or
      Muromonab CD3 - (monoclonal antibody) there may increased risk of infection and development
      of cancer   because cyclophosphamide reduces the bodys ability to fight them
 
     Probenecid or
     Sulfinpyrazone - cyclophosphamide may increase the amount of uric acid in the blood . Since these
      medicines are used to lower uric acid levels, they may not work in patients taking
      cyclophosphamide     
   
11. Other medical problems- tell your doctor if you have any other medical problems-
   
      Chickenpox or
      Herpes zoster -risk of severe disease afecting other parts of the body
      Gout or
      Kidney stones - cyclophosphamide may increase levels of uric acid in the body which can cause
      gout or  kidney stones

      Infection- cyclophosphamide can decrease your bodys ability tofight infection.
    
      Kidney disease- effects of cyclophosphamide may be increased because of slower removal from
      the body.

      Liver disease - effects of cyclophosphamide may be decreased.
   

11. Missed dose-
    If you miss a dose of this medicine take it as soon as possible. However if it is almost time for your
     next dose go back to your regular dosing schedule.
    Do not double doses.

Pharmacology:

Cyclophosphamide is a synthetic antineoplastic agent chemically related to the nitrogen mustards. Cyclophosphamide is first hydrolysed by hepatic mixed functions oxidase to the intermediate metabolite 4-hydroxycyclophosphamide and aldophosphamide. Cyclophosphamide has immunosuppresive activity that may be partly explained by a marked sensitivity of presuppressor cells for B-cell function to low concentration of drug metabolites.

Pharmacokinetics:

Cyclophosphamide is well absorbed after oral administration with a bioavailability of more than 75%. Concentrations of metabolite reach a maximum in plasma in 3 to 12 hours. 5% of the dose is excreted as unchanged cyclphosphamide which has an elimination half-life of 3 to 12 hours.

Preferably taken on empty stomach , but may be taken with meals to minimise GI irritation

Avoid Grape Fruit juice

Pregnancy-

Both normal and malformed newborns have been reported following the use of cyclophophamide in pregnancy

Lactation-

Because of the potential for serious adverse reactions, and the potential for tumorigenicity decide whether to discontinue the drug taking into account the importance of the drug to the mother.