CYCLOPHOSPHAMIDE injection

CYCLOPHOSPHAMIDE injection

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CYCLOPHOSPHAMIDE injection

Cyclophosphamide 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.

Cyclophosphamide has a molecular formula of C7H15Cl2N2O2P•H2O and a molecular weight of 279.1. Cyclophosphamide is soluble in water, saline, or ethanol.

Cyclophosphamide Injection is a 200 mg/mL sterile clear colorless solution available as 500 mg and 1 g strength vials.

  • 500 mg vial contains 534.5 mg cyclophosphamide monohydrate equivalent to 500 mg cyclophosphamide, 1.55 g Ethanol, 0.085 g Propylene Glycol, 0.085 g Polyethylene glycol 400 and 0.345 mg Monothioglycerol.
  • 1 g vial contains 1069.0 mg cyclophosphamide monohydrate equivalent to 1 g cyclophosphamide, 3.1 g Ethanol, 0.17 g Propylene Glycol, 0.17 g Polyethylene glycol 400 and 0.69 mg Monothioglycerol.

Indications and usage

Cyclophosphamide is an alkylating drug indicated for treatment of: Malignant Diseases:

  • Cyclophosphamide is indicated for the treatment of:
  • 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 (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

Cyclophosphamide, although effective alone in susceptible malignancies, is more frequently used concurrently or sequentially with other antineoplastic drugs.

Mechanism of Action

The mechanism of action is thought to involve cross-linking of tumor cell DNA.

Pharmacodynamics

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.

Dosage and administration

During or immediately after the administration, adequate amounts of fluid should be ingested or infused to force diuresis in order to reduce the risk of urinary tract toxicity. Therefore, cyclophosphamide should be administered in the morning.

Intravenous: When used as the only oncolytic drug therapy, the initial course of cyclophosphamide for patients with no hematologic deficiency usually consists of 40 mg per kg to 50 mg per kg given intravenously in divided doses over a period of 2 to 5 days. Other intravenous regimens include 10 mg per kg to 15 mg per kg given every 7 to 10 days or 3 mg per kg to 5 mg per kg twice weekly.

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.

Contraindications

  • Hypersensitivity: 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

Warnings and precautions

Myelosuppression, Immunosuppression, Bone Marrow Failure and Infections

Cyclophosphamide can cause myelosuppression (leukopenia, neutropenia, thrombocytopenia and anemia), bone marrow failure, and severe immunosuppression which may lead to serious and sometimes fatal infections, including sepsis and septic shock. Latent infections can be reactivated

Antimicrobial prophylaxis may be indicated in certain cases of neutropenia at the discretion of the managing physician. In case of neutropenic fever, antibiotic therapy is indicated. Antimycotics and/or antivirals may also be indicated.

Urinary Tract and Renal Toxicity: Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria have been reported with cyclophosphamide. Medical and/or surgical supportive treatment may be required to treat protracted cases of severe hemorrhagic cystitis. Discontinue cyclophosphamide therapy in case of severe hemorrhagic cystitis. Urotoxicity (bladder ulceration, necrosis, fibrosis, contracture and secondary cancer) may require interruption of cyclophosphamide treatment or cystectomy. Urotoxicity can be fatal. Urotoxicity can occur with short-term or long-term use of cyclophosphamide.

Cardiotoxicity: Myocarditis, myopericarditis, pericardial effusion including cardiac tamponade, and congestive heart failure, which may be fatal, have been reported with cyclophosphamide therapy.

Supraventricular arrhythmias (including atrial fibrillation and flutter) and ventricular arrhythmias (including severe QT prolongation associated with ventricular tachyarrhythmia) have been reported after treatment with regimens that included cyclophosphamide.

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: 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. Late onset pneumonitis (greater than 6 months after start of cyclophosphamide) appears to be associated with increased mortality. Pneumonitis may develop years after treatment with cyclophosphamide.

Secondary Malignancies: Cyclophosphamide is genotoxic. Secondary malignancies (urinary tract cancer, myelodysplasia, acute leukemias, lymphomas, thyroid cancer, and sarcomas) have been reported in patients treated with cyclophosphamide-containing regimens. The risk of bladder cancer may be reduced by prevention of hemorrhagic cystitis.

Veno-occlusive Liver Disease: Veno-occlusive liver disease (VOD) including fatal outcome has been reported in patients receiving cyclophosphamide-containing regimens. A cytoreductive regimen in preparation for bone marrow transplantation that consists of cyclophosphamide in combination with whole-body irradiation, busulfan, or other agents has been identified as a major risk factor. VOD has also been reported to develop gradually in patients receiving long-term low-dose immunosuppressive doses of cyclophosphamide. Other risk factors predisposing to the development of VOD include preexisting disturbances of hepatic function, previous radiation therapy of the abdomen, and a low performance status.

Alcohol Content: The alcohol content in a dose of Cyclophosphamide Injection may affect the central nervous system and should be taken into account for patients in whom alcohol intake should be avoided or minimized. Consideration should be given to the alcohol content in Cyclophosphamide Injection on the ability to drive or use machines immediately after the infusion. Each administration of Cyclophosphamide Injection at 50 mg per kg delivers 0.155 g/kg of ethanol. For a 75 kg patient this would deliver 11.625 grams of ethanol. Other cyclophosphamide products may have a different amount of alcohol or no alcohol.

Embryo-Fetal Toxicity: Based on its mechanism of action and published reports of effects in pregnant patients or animals, Cyclophosphamide Injection can cause fetal harm when administered to a pregnant woman. Exposure to cyclophosphamide during pregnancy may cause birth defects, miscarriage, fetal growth retardation, and fetotoxic effects in the newborn. Cyclophosphamide is teratogenic and embryo-fetal toxic in mice, rats, rabbits and monkeys.

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Infertility: Male and female reproductive function and fertility may be impaired in patients being treated with Cyclophosphamide Injection. 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. Advise patients on the potential risks for infertility

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 (syndrome of inappropriate secretion of antidiuretic hormone), which may be fatal, has been reported.

Adverse reactions

Adverse reactions reported most often include neutropenia, febrile neutropenia, fever, alopecia, nausea, vomiting, and diarrhea

Drug interactions

Cyclophosphamide is a pro-drug that is activated by cytochrome P450s. An increase of the concentration of cytotoxic metabolites may occur with:

  • Protease inhibitors: Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites. Use of protease inhibitor-based regimens was found to be associated with a higher Incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen.

Combined or sequential use of cyclophosphamide and other agents with similar toxicities can potentiate toxicities.

Increased hematotoxicity and/or immunosuppression may result from a combined effect of cyclophosphamide and, for example:

  • ACE inhibitors: ACE inhibitors can cause leukopenia.
  • Natalizumab
  • Paclitaxel: Increased hematotoxicity has been reported when cyclophosphamide was administered after paclitaxel infusion.
  • Thiazide diuretics
  • Zidovudine

Increased cardiotoxicity may result from a combined effect of cyclophosphamide and, for example:

  • Anthracyclines
  • Cytarabine
  • Pentostatin
  • Radiation therapy of the cardiac region
  • Trastuzumab

Increased pulmonary toxicity may result from a combined effect of cyclophosphamide and, for example:

  • Amiodarone
  • G-CSF, GM-CSF (granulocyte colony-stimulating factor, granulocyte macrophage colonystimulating factor): Reports suggest an increased risk of pulmonary toxicity in patients treated with cytotoxic chemotherapy that includes cyclophosphamide and G-CSF or GMCSF.

Increased nephrotoxicity may result from a combined effect of cyclophosphamide and, for example:

  • Amphotericin B
  • Indomethacin: Acute water intoxication has been reported with concomitant use of indomethacin

Increase in other toxicities:

  • Azathioprine: Increased risk of hepatotoxicity (liver necrosis)
  • Busulfan: Increased incidence of hepatic veno-occlusive disease and mucositis has been reported.
  • Protease inhibitors: Increased incidence of mucositis
  • Increased risk of hemorrhagic cystitis may result from a combined effect of cyclophosphamide and past or concomitant radiation treatment.

Etanercept: In patients with Wegener’s granulomatosis, the addition of etanercept to standard treatment, including cyclophosphamide, was associated with a higher incidence of non-cutaneous malignant solid tumors.

Metronidazole: Acute encephalopathy has been reported in a patient receiving cyclophosphamide and metronidazole. Causal association is unclear. In an animal study, the combination of cyclophosphamide with metronidazole was associated with increased cyclophosphamide toxicity.

Tamoxifen: Concomitant use of tamoxifen and chemotherapy may increase the risk of thromboembolic complications.

Coumarins: Both increased and decreased warfarin effect have been reported in patients receiving warfarin and cyclophosphamide.

Cyclosporine: Lower serum concentrations of cyclosporine have been observed in patients receiving a combination of cyclophosphamide and cyclosporine than in patients receiving only cyclosporine. This interaction may result in an increased incidence of graft-versus-host disease.

Depolarizing muscle relaxants: Cyclophosphamide treatment causes a marked and persistent inhibition of cholinesterase activity. Prolonged apnea may occur with concurrent depolarizing muscle relaxants (e.g., succinylcholine). If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, alert the anesthesiologist.

Use in specific populations

Pregnancy: Based on its mechanism of action and published reports of effects in pregnant patients or animals, Cyclophosphamide Injection can cause fetal harm when administered to a pregnant woman. Exposure to cyclophosphamide during pregnancy may cause fetal malformations, miscarriage, fetal growth retardation, and toxic effects in the newborn. Cyclophosphamide is teratogenic and embryo-fetal toxic in mice, rats, rabbits and monkeys. Advise pregnant women and females of reproductive potential of the potential risk to the fetus.

Lactation: Cyclophosphamide is present in breast milk. Neutropenia, thrombocytopenia, low hemoglobin, and diarrhea have been reported in infants breast fed by women treated with cyclophosphamide. Because of the potential for serious adverse reactions in a breastfed child from Cyclophosphamide Injection, advise lactating women not to breastfeed during the treatment and for 1 week after the last dose.

Pediatric Use: Pre-pubescent girls treated with cyclophosphamide 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 pre-pubescence has been reported. Girls treated with cyclophosphamide who have retained ovarian function after completing treatment are at increased risk of developing premature menopause.

Pre-pubescent boys treated with cyclophosphamide 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.

Geriatric Use: There is insufficient data from clinical studies of cyclophosphamide available for patients 65 years of age and older to determine whether they respond differently than younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac functioning, and of concomitant disease or other drug therapy.

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.

Serious consequences of overdosage include manifestations of dose dependent toxicities such as myelosuppression, urotoxicity, cardiotoxicity (including cardiac failure), veno-occlusive hepatic disease, and stomatitis.

Patients who received an overdose should be closely monitored for the development of toxicities, and hematologic toxicity in particular.

Cyclophosphamide and its metabolites are dialyzable. Therefore, rapid hemodialysis is indicated when treating any suicidal or accidental overdose or intoxication.

Cystitis prophylaxis with mesna may be helpful in preventing or limiting urotoxic effects with cyclophosphamide overdose.

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