Cyclophosphamide

CYCLOPHOSPHAMIDE

Complete information including dosage, side effects, interactions and pregnancy & breast feeding warnings for patient and professional use.

Overview and uses

Cyclophosphamide is an alkylating agent used for the treatment of cancer.

Indication (uses)

  • Malignant diseases:
    • Malignant lymphomas (stage 3 and 4 of Ann Arbor staging system)
    • Hodgkin’s disease
    • Lymphocytic lymphoma (nodular or diffuse)
    • Mixed-cell type lymphoma
    • Histiocytic lymphoma
    • Burkitt’s lymphoma
    • Multiple myeloma
    • Leukemia – lymphocytic leukemia, chronic granulocytic leukemia, acute myelogenous and monocytic leukemia, acute lymphoblastic leukemia.
    • Mycosis fungoides
    • Neuroblastoma
    • Adenocarcinoma of the ovary
    • Retinoblastoma
    • Carcinoma of the breast
  • Minimal change nephrotic syndrome in pediatric patients.

Pharmacological classification

Alkylating agent used for the treatment of cancer.

Brand names

Endoxan, Cytoxan, Neosar, Procytox

Dosage form

  • Available as 25 mg and 50 mg tablets.
  • Available in vials containing 500 mg, 1 gm and 2 gm injection.

Mechanism of action

Alkylating agents produce highly reactive carbonium ion intermediates which transfer alkyl groups to cellular macromolecules by forming covalent bonds. These intermediates may react with carboxyl, hydroxyl, amino, sulfhydryl and phosphate groups of bio macromolecules. Alkylation results in cross linking/abnormal base pairing/scission of DNA strand. Cross linking of nucleic acids with proteins can also take place.

Dosage

During the administration or after the administration, adequate amounts of fluids should be ingested or infused to force diuresis in order to reduce the risk of toxicity of urinary tract.

  • Dosing guidelines for malignant diseases
  • Intravenous dose for adults and children
    • When cyclophosphamide is used as a single drug therapy, dose for patients with no hematologic deficiency should be 40 mg/kg to 50 mg/kg in divided doses over a period of 2 to 5 days.
    • Alternatively, 10 mg/kg to 15 mg/kg every 7 to 10 days or 3 mg/kg to 5 mg/kg twice weekly.
  • Oral dose
    • 1 mg/kg per day to 5 mg/kg per day for initial and maintenance dose.
    • Dosage must be adjusted according to anti-tumor activity, leukopenia and total leukocyte count.

When cyclophosphamide is used in combination with other drugs, it is necessary to reduce the dose of cyclophosphamide and the other drug as well.

  • Dosing guidelines for minimal change nephrotic syndrome in pediatric patients
    • Oral dose of 2 mg/kg daily for 8 to 12 weeks (maximum cumulative dose 168 mg/kg) is recommended.
    • Treatment beyond 90 days increases the risk of sterility in males.

Hepatic dose adjustment

  • Patients with severe hepatic impairment have reduced conversion of Cyclophosphamide to its active metabolite, thus potentially reducing the efficacy.

Renal dose adjustments

  • Patients with severe renal impairment have decreased renal excretion which may lead to increased plasma levels of Cyclophosphamide and its metabolites leading to increased toxicity.
  • Patients with Creatinine clearance equal to 10 mL/min to less than 24 mL/min may show signs and symptoms of toxicity.

Geriatric dose adjustments

  • Data not available.

Overdosage

  • No specific antidote is known.
  • General supportive measures should be given.
  • Appropriate treatment for any concurrent infection, Myelosuppression and cardiac toxicity should be considered.
  • Myelosuppression, urotoxicity, cardiotoxicity, veno-occlusive hepatic disease and stomatitis are dose dependent.
  • Patient should be monitored for all the toxicities mentioned above as well as for hematologic toxicity.
  • Rapid hemodialysis is beneficial in removing Cyclophosphamide and its metabolites.

Side effects or adverse effects

  • Local side effects
    • Thrombophlebitis and thrombosis at the site of injection.
  • Hypersensitivity reactions
    • Anaphylaxis has been reported with Mechlorethamine use.
    • Pain in chest or abdomen, skin rash, difficulty in breathing, rapid breathing, shortness of breath, dizziness, fainting, low blood pressure are some of the symptoms.
    • Consult your doctor as soon as possible.
  • Other systemic side effects
    • Jaundice
    • Vertigo
    • Tinnitus
    • Diminished hearing
    • Occurrence/precipitation of hemolytic anemia
  • Bone marrow depression
    • Bone marrow depression is the most serious side effect/toxicity. It is also a limiting factor for the dose. Infections and bleeding are the common complications.
    • Bone marrow depression results in granulocytopenia, agranulocytosis, thrombocytopenia and aplastic anemia.
    • Consult your doctor as soon as possible if you observe any of the below mentioned symptoms:
      • Sore throat
      • Chills
      • Sudden fever
      • Weakness in limbs
      • Mouth ulcers
      • Bleeding gums
      • Sore mouth
      • Fast heart rate
      • Low blood pressure
      • Sore gums
      • Skin abscesses
      • Rapid breathing
      • Rapid progression of infection of any organ
      • Rapid progression of Septicemia
    • Gastrointestinal side effects
      • Nausea and vomiting are commonly observed with anti-cancer medicines.
      • Mucositis – painful inflammation and ulceration of mucus membrane lining the digestive tract.
      • Diarrhea, shredding of mucosa and haemorrhage due to decreased rate of renewal of gastrointestinal mucosa lining.
    • Skin
      • Alopecia or hair loss.
      • Dermatitis
      • Pigmentation of the skin and changes in the nail colour.
    • Oral side effects
      • Breaches during chewing.
      • Depression of immunity due to reduction in number of WBCs largely increases the risk of oral infections.
      • Bleeding gums
      • Rapid progression of dental caries.
    • Gonadal side effects
      • Infertility due to Oligozoospermia in males.
      • Impotence in males.
      • Loss or reduces sex drive.
      • Inhibition of ovulation in females
      • Amenorrhea in females.
      • Damage to germinal cells may lead to mutagenesis.
    • Lymphoreticular tissue
      • Lymphocytopenia (reduced number of lymphocytes)
      • Inhibition of lymphocyte function.
      • Suppression of immunity due to bone marrow depression and reduced lymphocyte function highly increases the risk of opportunistic infections like:
        • Candida and other infections causing deep mycosis.
        • Cytomegalo virus
        • Herpes zoster
        • Pneumocystis jiroveci
        • Toxoplasma
      • Pulmonary toxicity
        • Pneumonitis
        • Pulmonary fibrosis
        • Pulmonary veno-occlusive disease
      • Impairment of wound healing
        • Cyclophosphamide may interfere with normal wound healing.
      • Hyponatremia
        • Hyponatremia associated with increased total body water, acute water intoxication and a syndrome resembling SIADH.
      • Secondary malignancies
        • Urinary tract cancer
        • Myelodysplasia
        • Acute leukemias
        • Lymphomas
        • Thyroid cancer
        • Sarcomas
      • Cardiac side effects
        • Congestive heart failure
        • Myocarditis
        • Myopericarditis
        • Pericardial effusion including cardiac tamponade
        • Supraventricular arrhythmias
        • Ventricular arrythmias
      • Fetal side effects
        • Use of anti-cancer medicines in pregnant women may cause fetal damage leading to:
          • Fetal death
          • Abortion
          • Teratogenesis
        • Renal side effects
          • Renal failure, Gout and Urate stones may develop in urinary tract.
          • Hemorrhagic cystitis, pyelitis, ureteritis and hematuria.
        • Hyperuricemia
          • An elevated level of uric acid is common in leukemia and bulky lymphomas.

Please note: The side effects mentioned above are from the reported cases. However, side effects are not limited to above mentioned conditions and symptoms. Consult your doctor as soon as possible if you feel or observe any symptoms that you relate to your treatment.

Warnings & Precautions

  • Contra-indicated in patients with known hypersensitivity to cyclophosphamide.
  • Contra-indicated in patients with known infectious disease.
  • Hematologic status of the patient must be determined before starting cyclophosphamide therapy.
  • Anti-microbial prophylaxis may be needed in certain cases of neutropenia.

Pregnancy & breast feeding warnings

  • Pregnancy
    • Category D, which means there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.
  • Nursing:
    • Cyclophosphamide is excreted in human breast milk.
    • Neutropenia, thrombocytopenia, low hemoglobin and diarrhea have been reported in infants’ breast fed by mothers on Cyclophosphamide therapy. Because of the potential for side effects in nursing infants, a decision should be made whether to discontinue drug or to discontinue nursing.

Interactions

Drug – drug interactions

  • Concomitant use of cyclophosphamide with protease inhibitors may increase the concentration of cytotoxic metabolites which may be associated with higher incidence of infections, mucositis and neutropenia.
  • Increased risk of thromboembolic complications with concomitant use of Tamoxifen and Cyclophosphamide.
  • Concomitant use of cyclophosphamide with following drugs may cause increased cardiac toxicity.
    • Anthracyclines
    • Cytarabine
    • Pentostatin
    • Trastuzumab
    • Radiotherapy of cardiac region
  • Increased pulmonary toxicity may result from concomitant use of cyclophosphamide with Amiodarone.
  • Concomitant use of cyclophosphamide with azathioprine increases the risk of hepatotoxicity.
  • Acute encephalopathy has been reported in patients concomitantly receiving cyclophosphamide and metronidazole.
  • Concomitant use of cyclophosphamide with busulfan increases the incidence of hepatic veno-occlusive disease and mucositis.
  • Cyclophosphamide reduces the serum concentrations of cyclosporine.
  • Both increased and decreased effect of Warfarin has been reported with concomitant use of cyclophosphamide.
  • Increased nephrotoxicity may result due to concomitant administration of cyclophosphamide with following drugs:
    • Amphoterecin B
    • Indomethacin – acute water intoxication has been reported with concomitant use.
  • Depolarizing muscle relaxants – cyclophosphamide causes a marked and persistent inhibition of cholinesterase activity. Alert the anesthesiologist if the patient has been treated with cyclophosphamide within 10 days of general anesthesia.
  • Concomitant use of Cyclophosphamide with following drugs/medicines should be strictly avoided.
    • ACE inhibitors can cause leukopenia.
    • Thiazide diuretics
    • Zidovudine
    • Paclitaxel causes increased hematotoxicity.
    • Leflunomide as it increases the risk of infections.
    • Adalimumab as it increases the risk of infections.
    • Teriflunomide as it increases the risk of infections.
    • Certolizumab as it increases the risk of infections.
    • Clozapine as it may lower the WBC count.
    • Deferiprone as it may lower the WBC count.
    • Etanercept as it increases the risk of infections.
    • Fingolimod as it increases the risk of infections.
    • Golimumab as it increases the risk of infections.
    • Infliximab as it increases the risk of infections.
    • Talimogene as it increases the risk of herpes infections.
    • Nalidixic acid as the combination may cause unusual bruising or bleeding, nausea, stomach pain, unusual weakness, low fever and loss of appetite.
    • Natalizumab as it increases the risk of infections.
    • Tofacitinib as it increases the risk of infections.

Click here to go to cyclophosphamide forums.

Reference

  • “Product information. Procytox (cyclophosphamide).” Baxter healthcare corporation, IL, USA.

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About the Author:

B. Pharm (K.L.E. society's S.V.V. Patil College of Pharmacy, Bengaluru) M. Pharm (Maharishi Arvind Institute of Pharmacy, Jaipur)

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