FDA

Cyclophosphamide

Approved 25 Aug 2021IntravenousSolution

The FDA lists this product in 60 strengths and forms.

Indications

Malignant Diseases Cyclophosphamide Injection is indicated for the treatment of adult and pediatric patients with: 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.

Cyclophosphamide Injection is an alkylating drug indicated for treatment of adult and pediatric patients with: Malignant Diseases : malignant lymphomas: Hodgkin’s disease, lymphocytic lymphoma, mixed-cell type lymphoma, histiocytic lymphoma, Burkitt’s lymphoma; multiple myeloma, leukemias, mycosis fungoides, neuroblastoma, adenocarcinoma of ovary, retinoblastoma, breast carcinoma ( 1 )

Contraindications

Hypersensitivity Cyclophosphamide Injection 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 Injection is contraindicated in patients with urinary outflow obstruction [see Warnings and Precautions (5.2) ].

Hypersensitivity to cyclophosphamide ( 4 ) Urinary outflow obstruction ( 4 )

Warnings and precautions

Myelosuppression, Immunosuppression, Bone Marrow Failure and Infections – Severe immunosuppression may lead to serious and sometimes fatal infections. Close hematological monitoring is required. ( 5.1 ) Urinary Tract and Renal Toxicity – Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria can occur. Exclude or correct any urinary tract obstructions prior to treatment. ( 5.2 ) Cardiotoxicity – Myocarditis, myopericarditis, pericardial effusion, arrythmias and congestive heart failure, which may be fatal, have been reported.

At a glance

Brand name: Cyclophosphamide
Route: Intravenous
Dosage form: Solution
Applicant: Eugia Pharma Speclts
Status: Prescription
FDA approval: 25 Aug 2021
Application: NDA210735-002

Indications

Contraindications

Hypersensitivity to cyclophosphamide ( 4 ) Urinary outflow obstruction ( 4 )

Warnings and precautions

Interactions

7.1Effect of Other Drugs on Cyclophosphamide Exposure Protease Inhibitors

Cyclophosphamide is a pro-drug that is activated by cytochrome P450s [see Clinical Pharmacology (12.3) ] . 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.

7.2 Drugs that potentiate Cyclophosphamide Toxicities Drugs or agents with similar toxicities to Cyclophosphamide Injection and can potentiate these effects are listed in Table 2. Table 2: Drugs that Potentiate Cyclophosphamide Toxicities Toxicity Drugs Increased hematotoxicity and/or immunosuppression 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 Anthracyclines Cytarabine Pentostatin Radiation therapy of the cardiac region Trastuzumab Increased pulmonary toxicity Amiodarone G-CSF, GM-CSF (granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor) Increased nephrotoxicity 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 Radiation treatment: Increased risk of hemorrhagic cystitis may result from a combined effect of cyclophosphamide and past or concomitant radiation treatment.

7.3Effect of Cyclophosphamide on Other Drugs Etanercept

A higher incidence of non-cutaneous malignant solid tumors in patients with Wegener’s granulomatosis occurred with the addition of etanercept to cyclophosphamide treatment. Metronidazole Acute encephalopathy has been reported in a patient receiving cyclophosphamide and metronidazole. 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 If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, alert the anesthesiologist.

Cyclophosphamide treatment causes a marked and persistent inhibition of cholinesterase activity. Prolonged apnea may occur with concurrent depolarizing muscle relaxants (e.g., succinylcholine).

Adverse reactions

The following adverse reactions are discussed in more detail in other sections of the labeling. Hypersensitivity [see Contraindications (4) ] Myelosuppression, Immunosuppression, Bone Marrow Failure, and Infections [see Warnings and Precautions (5.1) ] Urinary Tract and Renal Toxicity [see Warnings and Precautions (5.2) ] Cardiotoxicity [see Warnings and Precautions (5.3) ] Pulmonary Toxicity [see Warnings and Precautions (5.4) ] Secondary Malignancies [see Warnings and Precautions (5.5) ] Veno-Occlusive Liver Disease [see Warnings and Precautions (5.6) ] Alcohol Content [see Warnings and Precautions (5.7) ] Infertility [see Warnings and Precautions (5.9) and Use in Specific Populations (8.3 and 8.4) ] Impaired Wound Healing [see Warnings and Precautions (5.10) ] Hyponatremia [see Warnings and Precautions (5.11) ] Common adverse reactions are neutropenia, febrile neutropenia, fever, alopecia, nausea, vomiting, and diarrhea.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eugia US LLC at 1-888-238-7880 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials and Postmarketing Experience

The following adverse reactions associated with the use of cyclophosphamide were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The most common adverse reactions were neutropenia, febrile neutropenia, fever, alopecia, nausea, vomiting, and diarrhea.

Cardiac: cardiac arrest, ventricular fibrillation, ventricular tachycardia, cardiogenic shock, pericardial effusion (progressing to cardiac tamponade), myocardial hemorrhage, myocardial infarction, cardiac failure (including fatal outcomes), cardiomyopathy, myocarditis, pericarditis, carditis, atrial fibrillation, supraventricular arrhythmia, ventricular arrhythmia, bradycardia, tachycardia, palpitations, QT prolongation.

Congenital, Familial and Genetic : intra-uterine death, fetal malformation, fetal growth retardation, fetal toxicity (including myelosuppression, gastroenteritis). Ear and Labyrinth: deafness, hearing impaired, tinnitus. Endocrine: water intoxication. Eye: visual impairment, conjunctivitis, lacrimation. Gastrointestinal: gastrointestinal hemorrhage, acute pancreatitis, colitis, enteritis, cecitis, stomatitis, constipation, parotid gland inflammation, nausea, vomiting, diarrhea.

General Disorders and Administrative Site Conditions: multiorgan failure, general physical deterioration, influenza-like illness, injection/infusion site reactions (thrombosis, necrosis, phlebitis, inflammation, pain, swelling, erythema), pyrexia, edema, chest pain, mucosal inflammation, asthenia, pain, chills, fatigue, malaise, headache, febrile neutropenia. Hematologic: myelosuppression, bone marrow failure, disseminated intravascular coagulation and hemolytic uremic syndrome (with thrombotic microangiopathy).

Hepatic: veno-occlusive liver disease, cholestatic hepatitis, cytolytic hepatitis, hepatitis, cholestasis; hepatotoxicity with hepatic failure, hepatic encephalopathy, ascites, hepatomegaly, blood bilirubin increased, hepatic function abnormal, hepatic enzymes increased. Immune: immunosuppression, anaphylactic shock and hypersensitivity reaction. Infections: The following manifestations have been associated with myelosuppression and immunosuppression caused by cyclophosphamide: increased risk for and severity of pneumonias (including fatal outcomes), other bacterial, fungal, viral, protozoal and, parasitic infections; reactivation of latent infections, (including viral hepatitis, tuberculosis), Pneumocystis jiroveci , herpes zoster, Strongyloides , sepsis and septic shock.

Investigations: blood lactate dehydrogenase increased, C-reactive protein increased. Metabolism and Nutrition: hyponatremia, fluid retention, blood glucose increased, blood glucose decreased. Musculoskeletal and Connective Tissue : rhabdomyolysis, scleroderma, muscle spasms, myalgia, arthralgia. Neoplasms: acute leukemia, myelodysplastic syndrome, lymphoma, sarcomas, renal cell carcinoma, renal pelvis cancer, bladder cancer, ureteric cancer, thyroid cancer.

Nervous System: encephalopathy, convulsion, dizziness, neurotoxicity has been reported and manifested as reversible posterior leukoencephalopathy syndrome, myelopathy, peripheral neuropathy, polyneuropathy, neuralgia, dysesthesia, hypoesthesia, paresthesia, tremor, dysgeusia, hypogeusia, parosmia. Pregnancy: premature labor. Psychiatric: confusional state. Renal and Urinary: renal failure, renal tubular disorder, renal impairment, nephropathy toxic, hemorrhagic cystitis, bladder necrosis, cystitis ulcerative, bladder contracture, hematuria, nephrogenic diabetes insipidus, atypical urinary bladder epithelial cells.

Reproductive System: infertility, ovarian failure, ovarian disorder, amenorrhea, oligomenorrhea, testicular atrophy, azoospermia, oligospermia. Respiratory: pulmonary veno-occlusive disease, acute respiratory distress syndrome, interstitial lung disease as manifested by respiratory failure (including fatal outcomes), obliterative bronchiolitis, organizing pneumonia, alveolitis allergic, pneumonitis, pulmonary hemorrhage; respiratory distress, pulmonary hypertension, pulmonary edema, pleural effusion, bronchospasm, dyspnea, hypoxia, cough, nasal congestion, nasal discomfort, oropharyngeal pain, rhinorrhea.

Skin and Subcutaneous Tissue: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, palmar-plantar erythrodysesthesia syndrome, radiation recall dermatitis, toxic skin eruption, urticaria, dermatitis, blister, pruritus, erythema, nail disorder, facial swelling, hyperhidrosis, alopecia. Tumor lysis syndrome : like other cytotoxic drugs, cyclophosphamide may induce tumor-lysis syndrome and hyperuricemia in patients with rapidly growing tumors.

Vascular: pulmonary embolism, venous thrombosis, vasculitis, peripheral ischemia, hypertension, hypotension, flushing, hot flush.

Cyclophosphamide

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

Cyclophosphamide

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

5.1Myelosuppression, Immunosuppression, Bone Marrow Failure and Infections

5.2Urinary Tract and Renal Toxicity

5.3Cardiotoxicity

5.4Pulmonary Toxicity

5.5Secondary Malignancies

5.6Veno-Occlusive Liver Disease

5.7Alcohol Content

5.8Embryo-Fetal Toxicity Based

Interactions

7.1Effect of Other Drugs on Cyclophosphamide Exposure Protease Inhibitors

7.3Effect of Cyclophosphamide on Other Drugs Etanercept

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary Based

Adverse reactions

6.1Clinical Trials and Postmarketing Experience

Composition

Strengths and forms

Official product information