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

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{ "type": "ul", "children": [ "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" ], "text": "" }

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

{ "type": "p", "children": [], "text": "Cyclophosphamide, although effective alone in susceptible malignancies, is more frequently used concurrently or sequentially with other antineoplastic drugs." }

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 Injection should be administered in the morning.

Adults and Pediatric Patients

Intravenous Use

When used as the only oncolytic drug therapy, the initial course of Cyclophosphamide Injection 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.

Dosages may also be adjusted based on antitumor activity and/or leukopenia. The total leukocyte count may be used to manage dosage.

When cyclophosphamide is included in combined cytotoxic regimens, it may be necessary to reduce the dose of Cyclophosphamide Injection as well as that of the other drugs.

Cyclophosphamide Injection is a hazardous drug. Follow applicable special handling and disposal procedures. 1Caution should be exercised when handling and preparing Cyclophosphamide Injection. To minimize the risk of dermal exposure, always wear gloves when handling vials containing Cyclophosphamide Injection. Cyclophosphamide Injection Intravenous Administration Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use cyclophosphamide vials if there are visible particulate matter or discoloration of the solution. Cyclophosphamide does not contain any antimicrobial preservative and thus care must be taken to assure the sterility of prepared solutions. Use aseptic technique. For Direct Intravenous Injection Aseptically withdraw the prescribed dose from the vial. Dilute the prescribed dose of Cyclophosphamide Injection to a concentration of 20 mg per mL by using any of the following diluents:    •    0.9% Sodium Chloride Injection, USP     •    0.45% Sodium Chloride Injection, USP     •    5% Dextrose Injection, USP    •    5% Dextrose and 0.9% Sodium Chloride Injection, USP Do not use Sterile Water for Injection, USP because it results in a hypotonic solution and should not be injected directly. For Intravenous Infusion Aseptically withdraw the prescribed dose from the vial. Dilute the prescribed dose of Cyclophosphamide Injection to a concentration of 2 mg per mL by using any of the following diluents:    •    0.9% Sodium Chloride Injection, USP     •    0.45% Sodium Chloride Injection, USP     •    5% Dextrose Injection, USP     •    5% Dextrose and 0.9% Sodium Chloride Injection, USP To reduce the likelihood of adverse reactions that appear to be administration rate-dependent (e.g., facial swelling, headache, nasal congestion, scalp burning), Cyclophosphamide Injection should be injected or infused very slowly. Duration of the infusion also should be appropriate for the volume and type of diluted solution to be infused. Storage of Diluted Cyclophosphamide Injection Solution If not used immediately, for microbiological integrity, Cyclophosphamide Injection solutions should be stored as described in Table 1:

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 1: Storage of Diluted Cyclophosphamide Injection Solutions </span> </caption> <colgroup> <col width="55.78%"/> <col width="23.08%"/> <col width="21.14%"/> </colgroup> <thead> <tr class="First"> <th align="left" class="Lrule Rrule Toprule" rowspan="2"><span class="Bold">Diluent</span> <br/> </th><th align="left" class="Lrule Rrule Toprule" colspan="2"><span class="Bold">Storage </span> <br/> </th> </tr> <tr class="Last"> <th align="left" class="Lrule Rrule Toprule"><span class="Bold">Room Temperature </span> <br/> </th><th align="left" class="Lrule Rrule Toprule"><span class="Bold">Refrigerated </span> <br/> </th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Diluted Solutions (20 mg/mL) </span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">0.9% Sodium Chloride Injection, USP<br/> </td><td align="left" class="Rrule" valign="top">up to 48 hrs<br/> </td><td align="left" class="Rrule" valign="top">up to 12 days<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">0.45% Sodium Chloride Injection, USP<br/> </td><td align="left" class="Rrule" valign="top">up to 48 hrs<br/> </td><td align="left" class="Rrule" valign="top">up to 12 days<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">5% Dextrose Injection, USP<br/> </td><td align="left" class="Rrule" valign="top">up to 48 hrs<br/> </td><td align="left" class="Rrule" valign="top">up to 12 days<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">5% Dextrose and 0.9% Sodium Chloride Injection, USP<br/> </td><td align="left" class="Rrule" valign="top">up to 48 hrs<br/> </td><td align="left" class="Rrule" valign="top">up to 12 days<br/> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Diluted</span><span class="Bold"> Solutions (2 mg/mL) </span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">0.9% Sodium Chloride Injection, USP<br/> </td><td align="left" class="Rrule" valign="top">up to 48 hrs<br/> </td><td align="left" class="Rrule" valign="top">up to 12 days<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">0.45% Sodium Chloride Injection, USP<br/> </td><td align="left" class="Rrule" valign="top">up to 48 hrs<br/> </td><td align="left" class="Rrule" valign="top">up to 12 days<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">5% Dextrose Injection, USP<br/> </td><td align="left" class="Rrule" valign="top">up to 48 hrs<br/> </td><td align="left" class="Rrule" valign="top">up to 12 days<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">5% Dextrose and 0.9% Sodium Chloride Injection, USP<br/> </td><td align="left" class="Rrule" valign="top">up to 48 hrs<br/> </td><td align="left" class="Rrule" valign="top">up to 12 days<br/> </td> </tr> </tbody> </table></div>

Storage of Undiluted Cyclophosphamide Solution: After first use, store partially used multiple-dose vial in the original carton at 2°C to 8°C (36°F to 46°F) for up to 28 days. Discard unused portion after 28 days.

Cyclophosphamide Injection is a sterile, colorless to slightly yellow clear solution in multiple-dose vials containing:

{ "type": "p", "children": [], "text": "Cyclophosphamide Injection is a sterile, colorless to slightly yellow clear solution in multiple-dose vials containing:" }

{ "type": "ul", "children": [ "500 mg/2.5 mL (200 mg/mL)", " 1 g/5 mL (200 mg/mL)", "2 g/10 mL (200 mg/mL)" ], "text": "" }

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.

{ "type": "p", "children": [], "text": "\nHypersensitivity\nCyclophosphamide 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)].

{ "type": "p", "children": [], "text": "\nUrinary Outflow Obstruction\n Cyclophosphamide Injection is contraindicated in patients with urinary outflow obstruction [see Warnings and Precautions (5.2)].\n" }

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 [see Adverse Reactions (6.1)]. Antimicrobial prophylaxis may be indicated in certain cases of neutropenia at the discretion of the managing healthcare provider. In case of neutropenic fever, antibiotic therapy is indicated. Antimycotics and/or antivirals may also be indicated. Monitoring of complete blood counts is essential during cyclophosphamide treatment so that the dose can be adjusted, if needed. Cyclophosphamide Injection should not be administered to patients with neutrophils ≤1,500/mm3 and platelets < 50,000/mm3. Cyclophosphamide Injection treatment may not be indicated, or should be interrupted, or the dose reduced, in patients who have or who develop a serious infection. G-CSF may be administered to reduce the risks of neutropenia complications associated with cyclophosphamide use. Primary and secondary prophylaxis with G-CSF should be considered in all patients considered to be at increased risk for neutropenia complications. The nadirs of the reduction in leukocyte count and thrombocyte count are   usually reached in weeks 1 and 2 of treatment. Peripheral blood cell counts are expected to normalize after approximately 20 days. Bone marrow failure has been reported. Severe myelosuppression may be expected particularly in patients pretreated with and/or receiving concomitant chemotherapy and/or radiation therapy.

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 Injection therapy in case of severe hemorrhagic cystitis. Urotoxicity (bladder ulceration, necrosis, fibrosis, contracture and secondary cancer) may require interruption of Cyclophosphamide Injection treatment or cystectomy. Urotoxicity can be fatal. Urotoxicity can occur with short-term or long-term use of cyclophosphamide. Before starting treatment, exclude or correct any urinary tract obstructions [see Contraindications (4)]. Urinary sediment should be checked regularly for the presence of erythrocytes and other signs of urotoxicity and/or nephrotoxicity. Cyclophosphamide Injection should be used with caution, if at all, in patients with active urinary tract infections. Aggressive hydration with forced diuresis and frequent bladder emptying can reduce the frequency and severity of bladder toxicity. Mesna has been used to prevent severe bladder toxicity.

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. Particular caution is necessary in patients with risk factors for cardiotoxicity and in patients with pre­-existing cardiac disease. Monitor patients with risk factors for cardiotoxicity and with pre-existing cardiac disease.

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. Monitor patients for signs and symptoms of pulmonary toxicity.

Cyclophosphamide is genotoxic [see Nonclinical Toxicology (13.1)]. 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 (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.

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 0.17 g/kg of ethanol. For a 75 kg patient this would deliver 12.7 grams of ethanol [see Description (11)]. Other cyclophosphamide products may have a different amount of alcohol or no alcohol.

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 [see Use in Specific Populations (8.1), Clinical Pharmacology  (12.1), and Nonclinical Toxicology  (13.1)]. 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.

Advise pregnant women and females of reproductive potential of the potential risk to the fetus [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with Cyclophosphamide Injection and for up to 1 year after completion of therapy. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Cyclophosphamide Injection and for 4 months after completion of therapy [see Use in Specific Populations (8.1, 8.3)].

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 [see Use in Specific Populations (8.3, 8.4)].

Cyclophosphamide may interfere with normal wound healing.

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.

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.

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.

Drugs or agents with similar toxicities to Cyclophosphamide Injection and can potentiate these effects are listed in Table 2.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 2:  Drugs that Potentiate Cyclophosphamide Toxicities </span> </caption> <colgroup> <col width="26.66%"/> <col width="73.34%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="top"><span class="Bold">Toxicity</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Drugs </span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Increased hematotoxicity and/or immunosuppression<br/> </td><td class="Rrule" valign="top"> <ul class="Disc"> <li>ACE inhibitors: ACE inhibitors can cause leukopenia.</li> <li>Natalizumab</li> <li>Paclitaxel: Increased hematotoxicity has been reported when cyclophosphamide was administered after paclitaxel infusion.</li> <li>Thiazide diuretics</li> <li>Zidovudine</li> </ul> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Increased cardiotoxicity<br/> </td><td class="Rrule" valign="top"> <ul class="Disc"> <li>Anthracyclines</li> <li>Cytarabine</li> <li>Pentostatin</li> <li>Radiation therapy of the cardiac region</li> <li>Trastuzumab</li> </ul> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Increased pulmonary toxicity<br/> </td><td class="Rrule" valign="top"> <ul class="Disc"> <li>Amiodarone</li> <li>G-CSF, GM-CSF (granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor)</li> </ul> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Increased nephrotoxicity<br/> </td><td class="Rrule" valign="top"> <ul class="Disc"> <li>Amphotericin B</li> <li>Indomethacin: Acute water intoxication has been reported with concomitant use of indomethacin</li> </ul> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Increase in other toxicities:<br/> </td><td class="Rrule" valign="top"> <ul class="Disc"> <li>Azathioprine: Increased risk of hepatotoxicity (liver necrosis)</li> <li>Busulfan: Increased incidence of hepatic veno-occlusive disease and mucositis has been reported.</li> <li>Protease inhibitors: Increased incidence of mucositis</li> </ul> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">Increased risk of hemorrhagic cystitis<br/> </td><td class="Rrule" valign="top"> <ul class="Disc"> <li>Radiation treatment: Increased risk of hemorrhagic cystitis may result from a combined effect of cyclophosphamide and past or concomitant radiation treatment.</li> </ul> </td> </tr> </tbody> </table></div>

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).

Risk Summary 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 [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)]. Exposure to cyclophosphamide during pregnancy may cause fetal malformations, miscarriage, fetal growth retardation, and toxic effects in the newborn [see Data]. Cyclophosphamide is teratogenic and embryo-fetal toxic in mice, rats, rabbits and monkeys [see Data]. Advise pregnant women and females of reproductive potential of the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies. Data Human Data Malformations of the skeleton, palate, limbs and eyes as well as miscarriage have been reported after exposure to cyclophosphamide in the first trimester. Fetal growth retardation and toxic effects manifesting in the newborn, including leukopenia, anemia, pancytopenia, severe bone marrow hypoplasia, and gastroenteritis have been reported after exposure to cyclophosphamide. Animal Data Administration of cyclophosphamide to pregnant mice, rats, rabbits and monkeys during the period of organogenesis at doses at or below the dose in patients based on body surface area resulted in various malformations, which included neural tube defects, limb and digit defects and other skeletal anomalies, cleft lip and palate, and reduced skeletal ossification.

Risk Summary 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, advise lactating women not to breastfeed during treatment with Cyclophosphamide Injection and for 1 week after the last dose.

Cyclophosphamide Injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to the initiation of Cyclophosphamide Injection [see Use in Specific Populations (8.1)]. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with Cyclophosphamide Injection and for up to 1 year after completion of therapy [see Use in Specific Populations (8.1)]. Males Based on findings in genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment with Cyclophosphamide Injection and for 4 months after completion of therapy [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.1)]. Infertility Females Amenorrhea, transient or permanent, associated with decreased estrogen and increased gonadotropin secretion develops in a proportion of women treated with cyclophosphamide. Affected patients generally resume regular menses within a few months after cessation of therapy. The risk of premature menopause with cyclophosphamide increases with age. Oligomenorrhea has also been reported in association with cyclophosphamide treatment. Animal data suggest an increased risk of failed pregnancy and malformations may persist after discontinuation of cyclophosphamide as long as oocytes/follicles exist that were exposed to cyclophosphamide during any of their maturation phases. The exact duration of follicular development in humans is not known but may be longer than 12 months [see Nonclinical Toxicology (13.1)]. Males Men treated with cyclophosphamide may develop oligospermia or azoospermia which are normally associated with increased gonadotropin but normal testosterone secretion.

The safety and effectiveness of cyclophosphamide have been established in pediatric patients and information on this use is discussed throughout the labeling.

The alcohol content of Cyclophosphamide Injection should be taken into account when given to pediatric patients [see Warnings and Precautions (5.7)].

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.

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.

In patients with severe renal impairment, decreased renal excretion may result in increased plasma levels of cyclophosphamide and its metabolites. This may result in increased toxicity [see Clinical Pharmacology (12.3)]. Monitor patients with severe renal impairment (CrCl =10 mL/min to 24 mL/min) for signs and symptoms of toxicity. Cyclophosphamide and its metabolites are dialyzable although there are probably quantitative differences depending upon the dialysis system being used. In patients requiring dialysis, use of a consistent interval between cyclophosphamide administration and dialysis should be considered.

Patients with severe hepatic impairment have reduced conversion of cyclophosphamide to the active 4­-hydroxyl metabolite, potentially reducing efficacy [see Clinical Pharmacology (12.3)]. The alcohol content of Cyclophosphamide Injection should be taken into account when given to patients with hepatic impairment [see Warnings and Precautions (5.7)].

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 [see Warnings and Precautions (5.1, 5.2, 5.3, and 5.6)]. 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.

{ "type": "p", "children": [], "text": "No specific antidote for cyclophosphamide is known.\n Overdosage should be managed with supportive measures, including appropriate treatment for any concurrent infection, myelosuppression, or cardiac toxicity should it occur.\n Serious consequences of overdosage include manifestations of dose dependent toxicities such as myelosuppression, urotoxicity, cardiotoxicity (including cardiac failure), veno-occlusive hepatic disease, and stomatitis [see Warnings and Precautions (5.1, 5.2, 5.3, and 5.6)].\n Patients who received an overdose should be closely monitored for the development of toxicities, and hematologic toxicity in particular.\n Cyclophosphamide and its metabolites are dialyzable. Therefore, rapid hemodialysis is indicated when treating any suicidal or accidental overdose or intoxication.\n Cystitis prophylaxis with mesna may be helpful in preventing or limiting urotoxic effects with cyclophosphamide overdose." }

Cyclophosphamide is an alkylating drug. It is an 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, and has the following structural formula:

{ "type": "p", "children": [], "text": "Cyclophosphamide is an alkylating drug. It is an 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, and has the following structural formula:" }

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 sterile, colorless to slightly yellow clear solution available in clear glass vials for multiple-dose use. Vials of Cyclophosphamide Injection are available in three presentations:

{ "type": "p", "children": [], "text": " Cyclophosphamide has a molecular formula of C7H15Cl2N2O2P•H2O and a molecular weight of 279.1. Cyclophosphamide is soluble in water, saline, or ethanol.\n Cyclophosphamide Injection is a sterile, colorless to slightly yellow clear solution available in clear glass vials for multiple-dose use. Vials of Cyclophosphamide Injection are available in three presentations:" }

{ "type": "ul", "children": [ "500 mg per 2.5 mL vial contains 500 mg anhydrous cyclophosphamide (equivalent to 534 mg cyclophosphamide monohydrate) and 10 mg citric acid dissolved in dehydrated alcohol (1.69 grams).", "1 g per 5 mL vial contains 1 gram anhydrous cyclophosphamide (equivalent to 1.07 g cyclophosphamide monohydrate) and 20 mg citric acid dissolved in dehydrated alcohol (3.38 grams).", "2 g per 10 mL vial contains 2 gram anhydrous cyclophosphamide (equivalent to 2.14 g cyclophosphamide monohydrate) and 40 mg citric acid dissolved in dehydrated alcohol (6.76 grams)." ], "text": "" }

The mechanism of action has not been fully characterized. However, cross-linking of tumor cell DNA may be involved.

The active alkylating metabolites of cyclophosphamide interfere with the growth of susceptible rapidly proliferating malignant cells.

Cyclophosphamide exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized.

Cyclophosphamide is a prodrug. Cyclophosphamide pharmacokinetics are linear over the approved recommended dose range.

Distribution

Cyclophosphamide volume of distribution approximates total body water (30 to 50 L). Cyclophosphamide is approximately 20% protein bound, with no dose dependent changes.  Some metabolites are greater than 60% protein bound. 

Elimination

The cyclophosphamide elimination half-life ranges from 3 to 12 hours with total body clearance (CL) values of 4 to 5.6 L/h following IV administration. Cyclophosphamide appears to induce its own metabolism. This auto-induction results in an increase in the total clearance, increased formation of active 4-hydroxyl metabolites and shortened elimination half-life values following repeated administration at 12- to 24-hour interval.

Cyclophosphamide and its metabolites are eliminated by both a hepatic pathway and a renal pathway. When cyclophosphamide was administered at 4.0 g/m2 (approximately 2 times the approved recommended dosage) over a 90-minutes infusion, saturable elimination in parallel with first-order renal elimination describe the kinetics of the drug.

Metabolism

The liver is the major site of cyclophosphamide activation. Approximately 75% of the administered dose of cyclophosphamide is activated by hepatic microsomal cytochrome P450s including CYP2A6, 2B6, 3A4, 3A5, 2C9, 2C18 and 2C19, with 2B6 displaying the highest 4-hydroxylase activity. Cyclophosphamide is activated to form 4-hydroxycyclophosphamide, which is in equilibrium with its ring-open tautomer aldophosphamide. 4-hydroxycyclophosphamide and aldophosphamide can undergo oxidation by aldehyde dehydrogenases to form the inactive metabolites 4-ketocyclophosphamide and carboxyphosphamide, respectively. Aldophosphamide can undergo β-elimination to form active metabolites phosphoramide mustard and acrolein. This spontaneous conversion can be catalyzed by albumin and other proteins. Less than 5% of cyclophosphamide may be directly detoxified by side chain oxidation, leading to the formation of inactive metabolites 2-dechloroethylcyclophosphamide. At high doses, the fraction of parent compound cleared by 4-hydroxylation is reduced resulting in non-linear elimination of cyclophosphamide in patients.

Excretion

Cyclophosphamide is primarily excreted as metabolites. 10 to 20% is excreted unchanged in the urine and 4% is excreted in the bile following IV administration.

Specific Populations

Renal Impairment

Cyclophosphamide exposure increased following one-hour intravenous infusion to renally impaired patients. Mean dose-corrected cyclophosphamide AUC increased by 38% in the moderate renal group, (Creatinine clearance (CrCl of 25 to 50 mL/min), by 64% in the severe renal group (CrCl of 10 to 24 mL/min) and by 23% in the hemodialysis group (CrCl of < 10mL/min) compared to the control group.

Cyclophosphamide is dialyzable.  Dialysis clearance averaged 104 mL/min (calculated by arterial-venous difference and actual drug recovery in dialysate), which is in the range of the metabolic clearance of 95 mL/min for the drug. A mean of 37% of the administered dose of cyclophosphamide was removed during hemodialysis. The elimination half-life (t1/2) was 3.3 hours in patients during hemodialysis, a 49% reduction of the 6.5 hours to t1/2 was reported in uremic patients.

Hepatic Impairment

Cyclophosphamide total body clearance (CL) is decreased by 40% in patients with severe hepatic impairment and elimination half-life (t½) is prolonged by 64%. Mean CL and t½ were 45 ± 8.6 L/kg and 12.5 ± 1.0 hours respectively, in patients with severe hepatic impairment.

Cyclophosphamide administered by different routes, including intravenous, subcutaneous or intraperitoneal injection, or in drinking water, caused tumors in both mice and rats. In addition to leukemia and lymphoma, benign and malignant tumors were found at various tissue sites, including urinary bladder, mammary gland, lung, liver, and injection site [see Warnings and Precautions (5.5)]. Cyclophosphamide was mutagenic and clastogenic in multiple in vitro and in vivo genetic toxicology studies. Cyclophosphamide is genotoxic in male and female germ cells. Animal data indicate that exposure of oocytes to cyclophosphamide during follicular development may result in a decreased rate of implantations and viable pregnancies, and in an increased risk of malformations. Male mice and rats treated with cyclophosphamide show alterations in male reproductive organs (e.g., decreased weights, atrophy, changes in spermatogenesis), and decreases in reproductive potential (e.g., decreased implantations and increased post-implantation loss) and increases in fetal malformations when mated with untreated females [see Use in Specific Populations (8.3)].

1. “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

{ "type": "p", "children": [], "text": "1. “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html" }

Cyclophosphamide Injection is a colorless to slightly yellow clear solution supplied in multiple-dose vial. Cyclophosphamide Injection: NDC 55150-270-99                 500 mg/2.5 mL (200 mg/mL), carton of 1 vial

{ "type": "p", "children": [], "text": "Cyclophosphamide Injection is a colorless to slightly yellow clear solution supplied in multiple-dose vial.\n Cyclophosphamide Injection:\n NDC 55150-270-99                 500 mg/2.5 mL (200 mg/mL), carton of 1 vial" }

NDC 55150-271-99                 1 g/5 mL (200 mg/mL), carton of 1 vial

{ "type": "p", "children": [], "text": " NDC 55150-271-99                 1 g/5 mL (200 mg/mL), carton of 1 vial " }

NDC 55150-272-01                 2 g/10 mL (200 mg/mL), carton of 1 vial Storage: Store vials refrigerated at 2°C to 8°C (36°F to 46°F). Cyclophosphamide is a hazardous drug. Follow special handling and disposal procedures.1 The vial stopper is not made with natural rubber latex.

{ "type": "p", "children": [], "text": " NDC 55150-272-01                 2 g/10 mL (200 mg/mL), carton of 1 vial\n Storage:\n Store vials refrigerated at 2°C to 8°C (36°F to 46°F).\n Cyclophosphamide is a hazardous drug. Follow special handling and disposal procedures.1\n\n The vial stopper is not made with natural rubber latex." }

Advise the patient of the following: Myelosuppression, Immunosuppression, Bone Marrow Failure, and Infections

{ "type": "p", "children": [], "text": "Advise the patient of the following:\n\n\nMyelosuppression, Immunosuppression, Bone Marrow Failure, and Infections\n" }

{ "type": "ul", "children": [ "Inform patients of the possibility of myelosuppression, immunosuppression, bone marrow failure, and infections. Explain the need for routine blood cell counts. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever [see Warnings and Precautions (5.1)].\n" ], "text": "" }

Urinary Tract and Renal Toxicity

{ "type": "p", "children": [], "text": "\nUrinary Tract and Renal Toxicity\n" }

{ "type": "ul", "children": [ "Advise the patient to report urinary symptoms (patients should report if their urine has turned a pink or red color) and the need for increasing fluid intake and frequent voiding [see Warnings and Precautions (5.2)].\n" ], "text": "" }

Cardiotoxicity

{ "type": "p", "children": [], "text": "\nCardiotoxicity\n" }

{ "type": "ul", "children": [ "Advise patients to contact a health care professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness [see Warnings and Precautions (5.3)]." ], "text": "" }

Pulmonary Toxicity

{ "type": "p", "children": [], "text": "\nPulmonary Toxicity\n" }

{ "type": "ul", "children": [ "Warn patients of the possibility of developing non-infectious pneumonitis. Advise patients to report promptly any new or worsening respiratory symptoms [see Warnings and Precautions (5.4)]." ], "text": "" }

Alcohol Content

{ "type": "p", "children": [], "text": "\nAlcohol Content\n" }

{ "type": "ul", "children": [ "Explain to patients the possible effects of the alcohol content in Cyclophosphamide Injection, including possible effects on the central nervous system. Patients in whom alcohol should be avoided or minimized should consider the alcohol content of Cyclophosphamide Injection. Alcohol could impair their ability to drive or use machines immediately after infusion [see Warnings and Precautions (5.7)]." ], "text": "" }

Embryo-Fetal Toxicity

{ "type": "p", "children": [], "text": "\nEmbryo-Fetal Toxicity\n" }

{ "type": "ul", "children": [ "Inform female patients of the risk to a fetus and potential loss of the pregnancy. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)].", "Advise females of reproductive potential to use effective contraception during treatment and for up to 1 year after completion of therapy [See Warning and Precautions (5.8) and Use in Specific Population (8.1, 8.3)]. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 4 months after completion of therapy [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1, 8.3)].\n" ], "text": "" }

Lactation

{ "type": "p", "children": [], "text": "\nLactation\n" }

{ "type": "ul", "children": [ "Advise lactating women not to breastfeed during treatment and for 1 week after the last dose of Cyclophosphamide Injection [see Use in Specific Populations (8.2)].\n" ], "text": "" }

Infertility

{ "type": "p", "children": [], "text": "\nInfertility\n" }

{ "type": "ul", "children": [ "Advise males and females of reproductive potential that Cyclophosphamide Injection may impair fertility [see Warnings and Precautions (5.9) and Use in Specific Populations (8.3, 8.4)].\n" ], "text": "" }

Common Adverse Reactions

{ "type": "p", "children": [], "text": "\nCommon Adverse Reactions\n" }

{ "type": "ul", "children": [ "Explain to patients that side effects such as nausea, vomiting, stomatitis, impaired wound healing, amenorrhea, premature menopause, sterility and hair loss may be associated with cyclophosphamide administration. Other undesirable effects (including, e.g., dizziness, blurred vision, visual impairment) could affect the ability to drive or use machines [see Adverse Reactions (6)]." ], "text": "" }

Distributed by: Eugia US LLC 279 Princeton-Hightstown Rd.E. Windsor, NJ 08520 

{ "type": "p", "children": [], "text": "\n Distributed by:\nEugia US LLC\n279 Princeton-Hightstown Rd.E. Windsor, NJ 08520 " }

Manufactured by: Eugia Pharma Specialities Limited Hyderabad - 500032 India

{ "type": "p", "children": [], "text": "Manufactured by:\nEugia Pharma Specialities Limited\nHyderabad - 500032 India" }

Rx only                   NDC 55150-270-99 Cyclophosphamide Injection 500 mg per 2.5 mL (200 mg per mL) For Intravenous Use After Dilution

{ "type": "p", "children": [], "text": "\nRx only                   NDC 55150-270-99\nCyclophosphamide\nInjection\n500 mg per 2.5 mL\n\n(200 mg per mL)\n\nFor Intravenous Use After Dilution\n" }

HAZARDOUS AGENT   Multiple-Dose Vial

{ "type": "p", "children": [], "text": "\nHAZARDOUS AGENT   Multiple-Dose Vial\n\n\n\n" }

Rx only                   NDC 55150-270-99 Cyclophosphamide Injection 500 mg per 2.5 mL (200 mg per mL) HAZARDOUS AGENT For Intravenous Use After Dilution One 2.5 mL Multiple-Dose Vialeugia

{ "type": "p", "children": [], "text": "\nRx only                   NDC 55150-270-99\nCyclophosphamide\nInjection\n500 mg per 2.5 mL\n\n(200 mg per mL)\n\nHAZARDOUS AGENT\n\nFor Intravenous Use\n\nAfter Dilution\nOne 2.5 mL Multiple-Dose Vialeugia" }

Rx only                   NDC 55150-271-99 Cyclophosphamide Injection 1 g per 5 mL (200 mg per mL) For Intravenous Use After Dilution  HAZARDOUS AGENT Multiple-Dose Vial

{ "type": "p", "children": [], "text": "\nRx only                   NDC 55150-271-99\nCyclophosphamide\nInjection\n1 g per 5 mL\n\n(200 mg per mL)\n\nFor Intravenous Use\n\nAfter Dilution \n\nHAZARDOUS AGENT\nMultiple-Dose Vial" }

Rx only                   NDC 55150-271-99 Cyclophosphamide Injection 1 g per 5 mL (200 mg per mL) HAZARDOUS AGENT For Intravenous Use After Dilution One 5 mL Multiple-Dose Vialeugia

{ "type": "p", "children": [], "text": "\nRx only                   NDC 55150-271-99\nCyclophosphamide\nInjection\n1 g per 5 mL\n\n(200 mg per mL)\n\nHAZARDOUS AGENT\n\nFor Intravenous Use\n\nAfter Dilution\nOne 5 mL Multiple-Dose Vialeugia" }

Rx only                   NDC 55150-272-01 Cyclophosphamide Injection  2 g per 10 mL (200 mg per mL) For Intravenous Use After Dilution  HAZARDOUS AGENT Multiple-Dose Vial

{ "type": "p", "children": [], "text": "\nRx only                   NDC 55150-272-01\nCyclophosphamide\nInjection \n2 g per 10 mL\n\n(200 mg per mL)\n\nFor Intravenous Use\n\nAfter Dilution \n\nHAZARDOUS AGENT\nMultiple-Dose Vial" }

Rx only                   NDC 55150-272-01 Cyclophosphamide Injection  2 g per 10 mL (200 mg per mL) HAZARDOUS AGENT For Intravenous Use After Dilution One 10 mL Multiple-Dose Vialeugia

{ "type": "p", "children": [], "text": "\nRx only                   NDC 55150-272-01\nCyclophosphamide\nInjection \n2 g per 10 mL\n\n(200 mg per mL)\n\nHAZARDOUS AGENT\n\nFor Intravenous Use\n\nAfter Dilution\nOne 10 mL Multiple-Dose Vialeugia" }

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

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

Cyclophosphamide for Injection is indicated for the treatment of biopsy proven minimal change nephrotic syndrome in pediatric patients who failed to adequately respond to or are unable to tolerate adrenocorticosteroid therapy.

Limitations of Use: The safety and effectiveness of Cyclophosphamide for Injection for the treatment of nephrotic syndrome in adults or other renal disease has not been established.

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

Adults and Pediatric Patients Intravenous UseWhen used as the only oncolytic drug therapy, the recommended dosage for the initial course of Cyclophosphamide for Injection for patients with no hematologic deficiency is 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.

Oral UseThe recommended dosage for oral cyclophosphamide is 1 mg per kg per day to 5 mg per kg per day for both initial and maintenance dosing.

Adjust the dosage of Cyclophosphamide for Injection based on the specific regimen administered, response to treatment, myelosuppression or other adverse reactions, and patient risk factors [see Warnings and Precautions (5)].

The recommended dosage is 2 mg per kg orally once daily for 8 to 12 weeks (maximum cumulative dose 168 mg per kg) is recommended. Treatment beyond 90 days increases the probability of sterility in males [see Use in Specific Populations (8.4)].

Cyclophosphamide for Injection is a hazardous drug. Follow applicable special handling and disposal procedures1. Caution should be exercised when handling and preparing Cyclophosphamide for Injection. To minimize the risk of dermal exposure, always wear gloves when handling vials containing Cyclophosphamide for Injection.

Cyclophosphamide for Injection

Intravenous Administration

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use cyclophosphamide vials if there are signs of melting. Melted cyclophosphamide is a clear or yellowish viscous liquid usually found as a connected phase or in droplets in the affected vials.

Cyclophosphamide does not contain any antimicrobial preservative and thus care must be taken to assure the sterility of prepared solutions. Use aseptic technique.

For Direct Intravenous Injection

Reconstitute Cyclophosphamide with 0.9% Sodium Chloride Injection, USP only, using the volumes listed below in Table 1. Shake the vial vigorously to dissolve the drug completely. Do not use Sterile Water for Injection, USP because it results in a hypotonic solution and should not be injected directly. Discard unused solution.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 1: Reconstitution for Direct Intravenous Injection</span> </caption> <col width="10%"/> <col width="38%"/> <col width="20%"/> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Strength</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Volume of<br/>0.9% Sodium Chloride Injection, USP</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Cyclophosphamide<br/>Concentration</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">500 mg</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">25 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="3" valign="middle"> <p class="First">20 mg per mL</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1 g</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">50 mL</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2 g</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">100 mL</p> </td> </tr> </tbody> </table></div>

For Intravenous Infusion

Reconstitution of Cyclophosphamide:Reconstitute Cyclophosphamide using 0.9% Sodium Chloride Injection, USP or Sterile Water for Injection, USP with the volume of diluent listed below in Table 2. Add the diluent to the vial and shake the vial vigorously to dissolve the drug completely. Discard unused solution.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 2: Reconstitution in preparation for Intravenous Infusion</span> </caption> <col width="10%"/> <col width="12%"/> <col width="20%"/> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Strength</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Volume of<br/>Diluent</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Cyclophosphamide<br/>Concentration</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">500 mg</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">25 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="3" valign="middle"> <p class="First">20 mg per mL</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1 g</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">50 mL</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2 g</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">100 mL</p> </td> </tr> </tbody> </table></div>

Dilution of Reconstituted Cyclophosphamide:Further dilute the reconstituted Cyclophosphamide solution to a minimum concentration of 2 mg per mL with any of the following diluents:

0.45% Sodium Chloride Injection, USP

5% Dextrose Injection, USP

5% Dextrose and 0.9% Sodium Chloride Injection, USP

To reduce the likelihood of adverse reactions that appear to be administration rate-dependent (e.g., facial swelling, headache, nasal congestion, scalp burning), cyclophosphamide should be injected or infused very slowly. Duration of the infusion also should be appropriate for the volume and type of carrier fluid to be infused.

Storage of Reconstituted and Diluted Cyclophosphamide Solution

If not used immediately, for microbiological integrity, cyclophosphamide solutions should be stored as described in Table 3:

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 3: Storage of Cyclophosphamide Solutions</span> </caption> <col width="54%"/> <col width="20%"/> <col width="16%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Storage time is the total time cyclophosphamide is in solution including the time it is reconstituted in 0.9% Sterile Sodium Chloride Injection, USP or Sterile Water for Injection, USP.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Diluent</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First">Storage</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Room Temperature</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Refrigerated</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Reconstituted Solution</span> (<span class="Bold">Without Further Dilution</span>)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">0.9% Sodium Chloride Injection, USP</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">up to 24 hours</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">up to 6 days</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Sterile Water for Injection, USP</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First">Do not store; use immediately</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Diluted Solutions</span><a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">0.45% Sodium Chloride Injection, USP</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">up to 24 hours</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">up to 6 days</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">5% Dextrose Injection, USP</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">up to 24 hours</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">up to 36 hours</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5% Dextrose and 0.9% Sodium Chloride Injection, USP</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">up to 24 hours</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">up to 36 hours</p> </td> </tr> </tbody> </table></div>

Reconstituted Solution for Oral Administration

Liquid preparations of cyclophosphamide for oral administration may be prepared by dissolving Cyclophosphamide for Injection in Aromatic Elixir, National Formulary (NF).

Store preparations under refrigeration in glass containers and use within 14 days. See the prescribing information for cyclophosphamide for oral use for additional dosage information.

Cyclophosphamide for Injection, USP is a sterile white powder available in single-dose vials

{ "type": "p", "children": [], "text": "Cyclophosphamide for Injection, USP is a sterile white powder available in single-dose vials " }

{ "type": "", "children": [], "text": "" }

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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 [see Adverse Reactions (6.1)].

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.

Monitoring of complete blood counts is essential during cyclophosphamide treatment so that the dose can be adjusted, if needed. Cyclophosphamide should not be administered to patients with neutrophils ≤1,500/mm3 and platelets < 50,000/mm3. Cyclophosphamide treatment may not be indicated, or should be interrupted, or the dose reduced, in patients who have or who develop a serious infection. G-CSF may be administered to reduce the risks of neutropenia complications associated with cyclophosphamide use. Primary and secondary prophylaxis with G-CSF should be considered in all patients considered to be at increased risk for neutropenia complications. The nadirs of the reduction in leukocyte count and thrombocyte count are usually reached in weeks 1 and 2 of treatment. Peripheral blood cell counts are expected to normalize after approximately 20 days. Bone marrow failure has been reported. Severe myelosuppression may be expected particularly in patients pretreated with and/or receiving concomitant chemotherapy and/or radiation therapy.

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.

Before starting treatment, exclude or correct any urinary tract obstructions [see Contraindications (4)]. Urinary sediment should be checked regularly for the presence of erythrocytes and other signs of urotoxicity and/or nephrotoxicity. Cyclophosphamide should be used with caution, if at all, in patients with active urinary tract infections. Aggressive hydration with forced diuresis and frequent bladder emptying can reduce the frequency and severity of bladder toxicity. Mesna has been used to prevent severe bladder toxicity.

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.

Particular caution is necessary in patients with risk factors for cardiotoxicity and in patients with pre-existing cardiac disease.

Monitor patients with risk factors for cardiotoxicity and with pre-existing cardiac disease.

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.

Monitor patients for signs and symptoms of pulmonary toxicity.

Cyclophosphamide is genotoxic [see Nonclinical Toxicology (13.1)]. 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 (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.

Based on its mechanism of action and published reports of effects in pregnant patients or animals, Cyclophosphamide for Injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1), Clinical Pharmacology (12.1), and Nonclinical Toxicology (13.1)]. 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.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with Cyclophosphamide for Injection and for up to 1 year after completion of therapy. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Cyclophosphamide for Injection and for 4 months after completion of therapy [see Use in Specific Populations (8.1, 8.3)].

Male and female reproductive function and fertility may be impaired in patients being treated with Cyclophosphamide for 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 [see Use in Specific Populations (8.3, 8.4)].

Cyclophosphamide may interfere with normal wound healing.

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.

The following adverse reactions associated with the use of cyclophosphamide were identified in clinical studies or post-marketing 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.

Protease Inhibitors

Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites and may enhance the toxicities of cyclophosphamide, including higher incidence of infections, neutropenia, and mucositis. Monitor for increased toxicities in patients receiving protease inhibitors.

Radiation therapy or drugs with similar toxicities to Cyclophosphamide for Injection can potentiate toxicities for cyclophosphamide. Monitor for increased toxicities in patients receiving radiation therapy or drugs known to cause:

Metronidazole

Acute encephalopathy has been reported in a patient receiving cyclophosphamide and metronidazole. Monitor for neurologic toxicities in patients receiving metronidazole.

Tamoxifen

Concomitant use of tamoxifen and a cyclophosphamide-containing chemotherapy regimen may increase the risk of thromboembolic complications. Monitor for signs and symptoms of thromboembolic events in patients receiving tamoxifen.

Coumarins

Both increased and decreased warfarin effect have been reported in patients receiving warfarin and cyclophosphamide. Monitor anticoagulant activity closely in patients receiving warfarin or other coumarins.

Cyclosporine

Concomitant administration of cyclophosphamide may decrease serum concentrations of cyclosporine. This interaction may result in an increased incidence of graft-versus-host disease. Monitor for signs and symptoms of graft-versus-host disease in patients receiving cyclosporine.

Depolarizing muscle relaxants

If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, alert the anesthesiologist.

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

Risk Summary Based on its mechanism of action and published reports of effects in pregnant patients or animals, Cyclophosphamide for Injection can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)]. Exposure to cyclophosphamide during pregnancy may cause fetal malformations, miscarriage, fetal growth retardation, and toxic effects in the newborn [see Data]. Cyclophosphamide is teratogenic and embryo-fetal toxic in mice, rats, rabbits and monkeys [see Data]. Advise pregnant women and females of reproductive potential of the potential risk to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and miscarriage is 15% to 20% of clinically recognized pregnancies.

Data

Human Data Malformations of the skeleton, palate, limbs and eyes as well as miscarriage have been reported after exposure to cyclophosphamide in the first trimester. Fetal growth retardation and toxic effects manifesting in the newborn, including leukopenia, anemia, pancytopenia, severe bone marrow hypoplasia, and gastroenteritis have been reported after exposure to cyclophosphamide.

Animal Data Administration of cyclophosphamide to pregnant mice, rats, rabbits and monkeys during the period of organogenesis at doses at or below the dose in patients based on body surface area resulted in various malformations, which included neural tube defects, limb and digit defects and other skeletal anomalies, cleft lip and palate, and reduced skeletal ossification.

Risk summary

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, advise lactating women not to breastfeed during treatment with Cyclophosphamide for Injection and for 1 week after the last dose.

Cyclophosphamide for Injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to the initiation of Cyclophosphamide for Injection.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with Cyclophosphamide for Injection and for up to 1 year after completion of therapy.

Males

Based on findings in genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment with Cyclophosphamide for Injection and for 4 months after completion of therapy [see Nonclinical Toxicology (13.1)].

Infertility

Females

Amenorrhea, transient or permanent, associated with decreased estrogen and increased gonadotropin secretion develops in a proportion of women treated with cyclophosphamide. Affected patients generally resume regular menses within a few months after cessation of therapy. The risk of premature menopause with cyclophosphamide increases with age. Oligomenorrhea has also been reported in association with cyclophosphamide treatment.

Animal data suggest an increased risk of failed pregnancy and malformations may persist after discontinuation of cyclophosphamide as long as oocytes/follicles exist that were exposed to cyclophosphamide during any of their maturation phases. The exact duration of follicular development in humans is not known, but may be longer than 12 months [see Nonclinical Toxicology (13.1)].

Males

Men treated with cyclophosphamide may develop oligospermia or azoospermia which are normally associated with increased gonadotropin but normal testosterone secretion.

The safety and effectiveness of cyclophosphamide have been established in pediatric patients and information on this use is discussed throughout the labeling.

Pre-pubescent females who receive cyclophosphamide generally develop secondary sexual characteristics normally and have regular menses. Ovarian fibrosis with apparently complete loss of germ cells after prolonged administration of cyclophosphamide in late pre-pubescence has been reported. Females who received cyclophosphamide who have retained ovarian function after completing treatment are at increased risk of developing premature menopause.

Pre-pubescent males who receive 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.

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.

In patients with severe renal impairment, decreased renal excretion may result in increased plasma levels of cyclophosphamide and its metabolites, which may increase toxicity [see Clinical Pharmacology (12.3)]. Monitor patients with severe renal impairment (creatinine clearance (CLcr)=10 mL/min to 24 mL/min) for signs and symptoms of toxicity.

Cyclophosphamide and its metabolites are dialyzable although there are probably quantitative differences depending upon the dialysis system. In patients requiring dialysis, consider using a consistent interval between cyclophosphamide administration and dialysis.

Patients with severe hepatic impairment have reduced conversion of cyclophosphamide to the active 4-hydroxyl metabolite, potentially reducing efficacy [see Clinical Pharmacology (12.3)]. Monitor patients with severe hepatic impairment (total bilirubin > 3 x ULN and any aspartate aminotransferase (AST)) for reduced effectiveness of cyclophosphamide.

No specific antidote for cyclophosphamide is known.

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Overdosage should be managed with supportive measures, including appropriate treatment for any concurrent infection, myelosuppression, or cardiac toxicity should it occur.

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Serious consequences of overdosage include manifestations of dose dependent toxicities such as myelosuppression, urotoxicity, cardiotoxicity (including cardiac failure), veno-occlusive hepatic disease, and stomatitis [see Warnings and Precautions (5.1, 5.2, 5.3, and 5.6)].

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

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Cyclophosphamide and its metabolites are dialyzable. Therefore, rapid hemodialysis is indicated when treating any suicidal or accidental overdose or intoxication [see Clinical Pharmacology (12.3)].

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

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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, and has the following structural formula:

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Cyclophosphamide is a white crystalline powder with the molecular formula C7H15Cl2N2O2P•H2O and a molecular weight of 279.1. Cyclophosphamide is soluble in water, saline, or ethanol.

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Cyclophosphamide for Injection, USP is a sterile white powder available as 500 mg, 1 g, and 2 g strength single-dose vials.

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The mechanism of action has not been fully characterized. However, cross-linking of tumor cell DNA may be involved.

The active alkylating metabolites of cyclophosphamide interfere with the growth of susceptible rapidly proliferating malignant cells.

Cyclophosphamide exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized.

Cyclophosphamide is a prodrug. Cyclophosphamide pharmacokinetics are linear over the approved recommended dose range.

Distribution The volume of distribution of cyclophosphamide is 30 to 50 L. Cyclophosphamide is approximately 20% protein bound, with no dose dependent changes. Some metabolites are greater than 60% protein bound.

Elimination

The elimination half-life (t½) of cyclophosphamide ranges from 3 to 12 hours, and clearance (CL) ranges from 4 to 5.6 L/h.

When cyclophosphamide was administered at 4 g/m2 (approximately 2 times the approved recommended dosage) over a 90-minute infusion, concentration-time data demonstrate saturable elimination in parallel with first-order renal elimination.

Metabolism

Cyclophosphamide is metabolized by cytochrome P450s including CYP2A6, 2B6, 3A, 2C9, and 2C19. Cyclophosphamide is activated to form 4-hydroxycyclophosphamide, which is in equilibrium with its ring-open tautomer aldophosphamide. 4-hydroxycyclophosphamide and aldophosphamide can undergo oxidation by aldehyde dehydrogenases to form the inactive metabolites 4-ketocyclophosphamide and carboxyphosphamide, respectively. Aldophosphamide can undergo β-elimination to form active metabolites phosphoramide mustard and acrolein. This spontaneous conversion can be catalyzed by albumin and other proteins. At high doses, the fraction of parent compound cleared by 4-hydroxylation is reduced resulting in non-linear elimination of cyclophosphamide.

Cyclophosphamide appears to induce its own metabolism. This auto-induction results in an increase in CL, increased formation of active 4-hydroxycyclophosphamide and shortened t1/2following multiple doses administered at 12- to 24-hour interval.

Excretion

Cyclophosphamide and its metabolites are eliminated by hepatic and renal pathways. Cyclophosphamide is primarily excreted as metabolites. Ten to 20% is excreted unchanged in the urine. A small percentage of cyclophosphamide may be eliminated unchanged in bile.

Specific Populations

Renal Impairment Following one-hour intravenous infusion, cyclophosphamide AUC increased by 38% in patients with CLcr of 25 to 50 mL/min, by 77% in patients with CLcr of 10 to 24 mL/min and by 23% in the hemodialysis group (CLcr of < 10 mL/min) compared to the control group (CLcr≥ 80 mL/min).

Cyclophosphamide is dialyzable. Dialysis clearance averaged 104 mL/min, which is similar to the metabolic clearance of 95 mL/min for cyclophosphamide. A mean of 37% of the administered dose of cyclophosphamide was removed during a 4-hour hemodialysis period. The t½ was 3.3 hours in patients during hemodialysis, a 49% reduction compared to t½ of 6.5 hours in uremic patients.

Hepatic Impairment Cyclophosphamide CL is decreased by 40% (45 ± 8.6 L/kg) and t½ is prolonged by 64% (12.5 ± 1 hours) in patients with hepatic impairment with a mean bilirubin 3.5 mg/dL and mean AST 90 IU/L compared to patients with normal hepatic function (mean bilirubin 0.5 mg/dL, mean AST 10 IU/L).

Cyclophosphamide administered by different routes, including intravenous, subcutaneous or intraperitoneal injection, or in drinking water, caused tumors in both mice and rats. In addition to leukemia and lymphoma, benign and malignant tumors were found at various tissue sites, including urinary bladder, mammary gland, lung, liver, and injection site [see Warnings and Precautions (5.5)].

Cyclophosphamide was mutagenic and clastogenic in multiple in vitro and in vivo genetic toxicology studies.

Cyclophosphamide is genotoxic in male and female germ cells. Animal data indicate that exposure of oocytes to cyclophosphamide during follicular development may result in a decreased rate of implantations and viable pregnancies, and in an increased risk of malformations. Male mice and rats treated with cyclophosphamide show alterations in male reproductive organs (e.g., decreased weights, atrophy, changes in spermatogenesis), and decreases in reproductive potential (e.g., decreased implantations and increased post-implantation loss) and increases in fetal malformations when mated with untreated females [see Use in Specific Populations (8.3)].

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Cyclophosphamide for Injection, USP is a sterile white powder containing cyclophosphamide and is supplied in single-dose vials.

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Cyclophosphamide for Injection, USP

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Store vials at or below 25°C (77°F). During transport or storage of cyclophosphamide vials, temperature influences can lead to melting of the active ingredient, cyclophosphamide [see Dosage and Administration (2.4)].

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Cyclophosphamide is a hazardous product. Follow special handling and disposal procedures.1

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Advise the patient of the following:

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Myelosuppression, Immunosuppression and Infections

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Urinary Tract and Renal Toxicity

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Cardiotoxicity

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Pulmonary Toxicity

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Secondary Malignancies

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Embryo-Fetal Toxicity

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Lactation

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Infertility

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Common Adverse Reactions

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Hydration and Important Administration Instructions

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Manufactured by: Baxter Healthcare Corporation Deerfield, IL 60015 USA

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Product Made in Germany

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For Product Inquiry 1 800 ANA DRUG (1-800-262-3784)

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Baxter is a registered trademark of Baxter International Inc.

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NovaPlus Logo Novaplus is a registered trademark of Vizient, Inc.

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HA-30-02-400

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Revised January 2025

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Container Label

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LOT/EXP:

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NDC 10019-938-25

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Cyclophosphamide for Injection, USP

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500 mg/vial

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HAZARDOUS DRUGFOR INTRAVENOUS USE.SINGLE-DOSE VIAL. DISCARD UNUSEDPORTION. STERILE, NON-PYROGENIC.

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Rx only

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Manufactured by Baxter Healthcare CorporationDeerfield, IL 60015 USA

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NOVAPLUS Logo

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Made in Germany

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460-629-01

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Each vial contains 500 mg cyclophosphamide. For IV Infusion Use: Add 25 mL Sterile Water for Injection, USP, and shakevigorously to dissolve the drug.

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For Direct Injection Use: Add 25 mL0.9% Sodium Chloride Injection, USP, andshake vigorously to dissolve the drug.

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Usual Dosage: See prescribing informationfor complete Dosage and Administrationinstructions. Store vial at or below 25°C (77°F)[see USP Controlled Room Temperature].

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Bar Code

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Bar Code(01)00310019938257

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USA HA-65-02-296 C 845

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Carton Label

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Cyclophosphamide for Injection, USP

{ "type": "p", "children": [], "text": "\nCyclophosphamide\nfor Injection, USP" }

500 mg/vial

{ "type": "p", "children": [], "text": "\n500 mg/vial\n" }

Bar Code

{ "type": "p", "children": [], "text": "Bar Code" }

NDC 10019-938-01

{ "type": "p", "children": [], "text": "NDC 10019-938-01" }

Cyclophosphamide for Injection, USP

{ "type": "p", "children": [], "text": "Cyclophosphamide\nfor Injection, USP" }

500 mg/vial

{ "type": "p", "children": [], "text": "\n500 mg/vial\n" }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

HAZARDOUS DRUG

{ "type": "p", "children": [], "text": "\nHAZARDOUS DRUG\n" }

MUST BE DILUTEDFOR INTRAVENOUS INFUSIONOR DIRECT INJECTION USE

{ "type": "p", "children": [], "text": "\nMUST BE DILUTEDFOR INTRAVENOUS INFUSIONOR DIRECT INJECTION USE\n" }

1 Single-Dose VialDiscard Unused Portion.

{ "type": "p", "children": [], "text": "1 Single-Dose VialDiscard Unused Portion." }

Manufactured by Baxter Healthcare CorporationDeerfield, IL 60015 USA

{ "type": "p", "children": [], "text": "Manufactured by Baxter Healthcare CorporationDeerfield, IL 60015 USA" }

Novaplus is a registered trademark ofVizient, Inc.

{ "type": "p", "children": [], "text": "Novaplus is a registered trademark ofVizient, Inc." }

NOVAPLUS Logo Made in Germany

{ "type": "p", "children": [], "text": "\nNOVAPLUS Logo\nMade in Germany" }

HA-80-03-627US

{ "type": "p", "children": [], "text": "HA-80-03-627US" }

Each vial contains 500 mg cyclophosphamide.

{ "type": "p", "children": [], "text": "Each vial contains 500 mg cyclophosphamide." }

For Intravenous Infusion Use: Add 25 mLSterile Water for Injection, USP, and shakevigorously to dissolve the drug.

{ "type": "p", "children": [], "text": "\nFor Intravenous Infusion Use: Add 25 mLSterile Water for Injection, USP, and shakevigorously to dissolve the drug." }

For Direct Injection Use: Add 25 mL0.9% Sodium Chloride Injection, USP,and shake vigorously to dissolve the drug.

{ "type": "p", "children": [], "text": "\nFor Direct Injection Use: Add 25 mL0.9% Sodium Chloride Injection, USP,and shake vigorously to dissolve the drug." }

Store vial at or below 25°C (77°F) [see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "\nStore vial at or below 25°C (77°F)\n[see USP Controlled Room Temperature]." }

Usual Dosage: See prescribing information for complete Dosage and Administrationinstructions. Should not be prescribed without thorough knowledge of dose, indications andtoxicity as contained in accompanyingliterature.

{ "type": "p", "children": [], "text": "\nUsual Dosage: See prescribing information for complete Dosage and Administrationinstructions. Should not be prescribed without thorough knowledge of dose, indications andtoxicity as contained in accompanyingliterature. " }

HAZARDOUS DRUG

{ "type": "p", "children": [], "text": "\nHAZARDOUS DRUG\n" }

SINGLE-DOSE VIALSTERILE, NON-PYROGENICFOR PARENTERAL USE

{ "type": "p", "children": [], "text": "\nSINGLE-DOSE VIALSTERILE, NON-PYROGENICFOR PARENTERAL USE\n" }

Discard unused portion.

{ "type": "p", "children": [], "text": "Discard unused portion." }

C728

{ "type": "p", "children": [], "text": "C728" }

NDC 10019-938-01

{ "type": "p", "children": [], "text": "NDC 10019-938-01" }

Cyclophosphamide for Injection, USP

{ "type": "p", "children": [], "text": "Cyclophosphamide\nfor Injection, USP" }

500 mg/vial

{ "type": "p", "children": [], "text": "\n500 mg/vial\n" }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

HAZARDOUS DRUG

{ "type": "p", "children": [], "text": "\nHAZARDOUS DRUG\n" }

MUST BE DILUTEDFOR INTRAVENOUS INFUSIONOR DIRECT INJECTION USE

{ "type": "p", "children": [], "text": "\nMUST BE DILUTEDFOR INTRAVENOUS INFUSIONOR DIRECT INJECTION USE\n" }

1 Single-Dose VialDiscard unused portion.

{ "type": "p", "children": [], "text": "1 Single-Dose VialDiscard unused portion." }

Manufactured by Baxter Healthcare CorporationDeerfield, IL 60015 USA

{ "type": "p", "children": [], "text": "Manufactured by Baxter Healthcare CorporationDeerfield, IL 60015 USA" }

NOVAPLUS Logo Made in Germany

{ "type": "p", "children": [], "text": "\nNOVAPLUS Logo\nMade in Germany" }

LOT/EXP

{ "type": "p", "children": [], "text": "LOT/EXP" }

2638B5147

{ "type": "p", "children": [], "text": "2638B5147" }

Bar Code

{ "type": "p", "children": [], "text": "Bar Code" }

NDC 10019-938-01

{ "type": "p", "children": [], "text": "NDC 10019-938-01" }

Cyclophosphamide for Injection, USP

{ "type": "p", "children": [], "text": "Cyclophosphamide\nfor Injection, USP" }

500 mg/vial

{ "type": "p", "children": [], "text": "\n500 mg/vial\n" }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

HAZARDOUS DRUG

{ "type": "p", "children": [], "text": "\nHAZARDOUS DRUG\n" }

MUST BE DILUTEDFOR INTRAVENOUS INFUSIONOR DIRECT INJECTION USE

{ "type": "p", "children": [], "text": "\nMUST BE DILUTEDFOR INTRAVENOUS INFUSIONOR DIRECT INJECTION USE\n" }

1 Single Dose VialDiscard unused portion.

{ "type": "p", "children": [], "text": "1 Single Dose VialDiscard unused portion." }

Manufactured by Baxter Healthcare CorporationDeerfield, IL 60015 USA

{ "type": "p", "children": [], "text": "Manufactured by Baxter Healthcare CorporationDeerfield, IL 60015 USA" }

NOVAPLUS Logo Made in Germany

{ "type": "p", "children": [], "text": "\nNOVAPLUS Logo\nMade in Germany" }

Container Label

{ "type": "p", "children": [], "text": "Container Label" }

LOT/EXP:

{ "type": "p", "children": [], "text": "LOT/EXP:" }

NDC 10019-939-50

{ "type": "p", "children": [], "text": "NDC 10019-939-50" }

Cyclophosphamide for Injection, USP

{ "type": "p", "children": [], "text": "Cyclophosphamide\nfor Injection, USP" }

1 gram/vial

{ "type": "p", "children": [], "text": "\n1 gram/vial\n" }

HAZARDOUS DRUGFOR INTRAVENOUS USE.SINGLE-DOSE VIAL. DISCARD UNUSEDPORTION. STERILE, NON-PYROGENIC

{ "type": "p", "children": [], "text": "\nHAZARDOUS DRUGFOR INTRAVENOUS USE.SINGLE-DOSE VIAL. DISCARD UNUSEDPORTION. STERILE, NON-PYROGENIC\n" }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

Manufactured by Baxter Healthcare CorporationDeerfield, IL 60015 USA

{ "type": "p", "children": [], "text": "Manufactured by Baxter Healthcare CorporationDeerfield, IL 60015 USA" }

NOVAPLUS Logo Made in Germany

{ "type": "p", "children": [], "text": "\nNOVAPLUS Logo\nMade in Germany" }

460-631-01

{ "type": "p", "children": [], "text": "460-631-01" }

Each vial contains 1g cyclophosphamide.

{ "type": "p", "children": [], "text": "Each vial contains 1g cyclophosphamide." }

For IV Infusion Use: Add 50 mLSterile Water for Injection, USP, and shakevigorously to dissolve the drug.

{ "type": "p", "children": [], "text": "\nFor IV Infusion Use: Add 50 mLSterile Water for Injection, USP, and shakevigorously to dissolve the drug." }

For Direct Injection Use: Add 50 mL0.9% Sodium Chloride Injection, USP, andshake vigorously to dissolve the drug.

{ "type": "p", "children": [], "text": "\nFor Direct Injection Use: Add 50 mL0.9% Sodium Chloride Injection, USP, andshake vigorously to dissolve the drug." }

Usual Dosage: See prescribing informationfor complete Dosage and Administrationinstructions. Store vial at or below 25°C (77°F)[see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "Usual Dosage: See prescribing informationfor complete Dosage and Administrationinstructions. Store vial at or below 25°C (77°F)[see USP Controlled Room Temperature].\n" }

Bar Code

{ "type": "p", "children": [], "text": "Bar Code" }

Bar Code(01)00310019939506

{ "type": "p", "children": [], "text": "Bar Code(01)00310019939506" }

USA HA-65-02-297 C 848

{ "type": "p", "children": [], "text": "\nUSA HA-65-02-297 C 848" }

Carton Label

{ "type": "p", "children": [], "text": "Carton Label" }

Cyclophosphamide for Injection, USP

{ "type": "p", "children": [], "text": "\nCyclophosphamide\nfor Injection, USP" }

1 gram/vial

{ "type": "p", "children": [], "text": "\n1 gram/vial\n" }

Bar Code

{ "type": "p", "children": [], "text": "Bar Code" }

NDC 10019-939-01

{ "type": "p", "children": [], "text": "NDC 10019-939-01" }

Cyclophosphamide for Injection, USP

{ "type": "p", "children": [], "text": "Cyclophosphamide\nfor Injection, USP" }

1 gram/vial

{ "type": "p", "children": [], "text": "\n1 gram/vial\n" }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

HAZARDOUS DRUG

{ "type": "p", "children": [], "text": "\nHAZARDOUS DRUG\n" }

MUST BE DILUTEDFOR INTRAVENOUS INFUSIONOR DIRECT INJECTION USE

{ "type": "p", "children": [], "text": "\nMUST BE DILUTEDFOR INTRAVENOUS INFUSIONOR DIRECT INJECTION USE\n" }

1 Single-Dose VialDiscard Unused Portion.

{ "type": "p", "children": [], "text": "1 Single-Dose VialDiscard Unused Portion." }

Manufactured by Baxter Healthcare CorporationDeerfield, IL 60015 USA

{ "type": "p", "children": [], "text": "Manufactured by Baxter Healthcare CorporationDeerfield, IL 60015 USA" }

Novaplus is a registered trademark ofVizient, Inc.

{ "type": "p", "children": [], "text": "Novaplus is a registered trademark ofVizient, Inc." }

NOVAPLUS Logo Made in Germany

{ "type": "p", "children": [], "text": "\nNOVAPLUS Logo\nMade in Germany" }

HA-80-03-628US

{ "type": "p", "children": [], "text": "HA-80-03-628US" }

Each vial contains 1 g cyclophosphamide.

{ "type": "p", "children": [], "text": "Each vial contains 1 g cyclophosphamide." }

For Intravenous Infusion Use: Add 50 mLSterile Water for Injection, USP, and shakevigorously to dissolve the drug.

{ "type": "p", "children": [], "text": "\nFor Intravenous Infusion Use: Add 50 mLSterile Water for Injection, USP, and shakevigorously to dissolve the drug." }

For Direct Injection Use: Add 50 mL0.9% Sodium Chloride Injection, USP,and shake vigorously to dissolve the drug.

{ "type": "p", "children": [], "text": "\nFor Direct Injection Use: Add 50 mL0.9% Sodium Chloride Injection, USP,and shake vigorously to dissolve the drug." }

Store vial at or below 25°C (77°F) [see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "\nStore vial at or below 25°C (77°F)\n[see USP Controlled Room Temperature]." }

Usual Dosage: See prescribing information for complete Dosage and Administration instructions.Should not be prescribed without thoroughknowledge of dose, indications and toxicity ascontained in accompanying literature.

{ "type": "p", "children": [], "text": "\nUsual Dosage: See prescribing information for complete Dosage and Administration instructions.Should not be prescribed without thoroughknowledge of dose, indications and toxicity ascontained in accompanying literature. " }

HAZARDOUS DRUG

{ "type": "p", "children": [], "text": "\nHAZARDOUS DRUG\n" }

SINGLE-DOSE VIALSTERILE, NON-PYROGENICFOR PARENTERAL USE

{ "type": "p", "children": [], "text": "\nSINGLE-DOSE VIALSTERILE, NON-PYROGENICFOR PARENTERAL USE\n" }

Discard unused portion.

{ "type": "p", "children": [], "text": "Discard unused portion." }

C760

{ "type": "p", "children": [], "text": "C760" }

NDC 10019-939-01

{ "type": "p", "children": [], "text": "NDC 10019-939-01" }

Cyclophosphamide for Injection, USP

{ "type": "p", "children": [], "text": "Cyclophosphamide\nfor Injection, USP" }

1 gram/vial

{ "type": "p", "children": [], "text": "\n1 gram/vial\n" }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

HAZARDOUS DRUG

{ "type": "p", "children": [], "text": "\nHAZARDOUS DRUG\n" }

MUST BE DILUTEDFOR INTRAVENOUS INFUSIONOR DIRECT INJECTION USE

{ "type": "p", "children": [], "text": "\nMUST BE DILUTEDFOR INTRAVENOUS INFUSIONOR DIRECT INJECTION USE\n" }

1 Single Dose VialDiscard unused portion.

{ "type": "p", "children": [], "text": "1 Single Dose VialDiscard unused portion." }

Manufactured by Baxter Healthcare CorporationDeerfield, IL 60015 USA

{ "type": "p", "children": [], "text": "Manufactured by Baxter Healthcare CorporationDeerfield, IL 60015 USA" }

NOVAPLUS Logo Made in Germany

{ "type": "p", "children": [], "text": "\nNOVAPLUS Logo\nMade in Germany" }

LOT/EXP:

{ "type": "p", "children": [], "text": "LOT/EXP:" }

2638B5149

{ "type": "p", "children": [], "text": "2638B5149" }

Bar Code

{ "type": "p", "children": [], "text": "Bar Code" }

NDC 10019-939-01

{ "type": "p", "children": [], "text": "NDC 10019-939-01" }

Cyclophosphamide for Injection, USP

{ "type": "p", "children": [], "text": "Cyclophosphamide\nfor Injection, USP" }

1 gram/vial

{ "type": "p", "children": [], "text": "\n1 gram/vial\n" }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

HAZARDOUS DRUG

{ "type": "p", "children": [], "text": "\nHAZARDOUS DRUG\n" }

MUST BE DILUTEDFOR INTRAVENOUS INFUSIONOR DIRECT INJECTION USE

{ "type": "p", "children": [], "text": "\nMUST BE DILUTEDFOR INTRAVENOUS INFUSIONOR DIRECT INJECTION USE\n" }

1 Single-Dose VialDiscard unused portion.

{ "type": "p", "children": [], "text": "1 Single-Dose VialDiscard unused portion." }

Manufactured by Baxter Healthcare CorporationDeerfield, IL 60015 USA

{ "type": "p", "children": [], "text": "Manufactured by Baxter Healthcare CorporationDeerfield, IL 60015 USA" }

NOVAPLUS Logo Made in Germany

{ "type": "p", "children": [], "text": "\nNOVAPLUS Logo\nMade in Germany" }

Container Label

{ "type": "p", "children": [], "text": "Container Label" }

LOT/EXP:

{ "type": "p", "children": [], "text": "LOT/EXP:" }

NDC 10019-942-10

{ "type": "p", "children": [], "text": "NDC 10019-942-10" }

Cyclophosphamide for Injection, USP

{ "type": "p", "children": [], "text": "Cyclophosphamide\nfor Injection, USP" }

2 gram/vial

{ "type": "p", "children": [], "text": "\n2 gram/vial\n" }

HAZARDOUS DRUGFOR INTRAVENOUS USE.SINGLE-DOSE VIAL. DISCARD UNUSEDPORTION. STERILE, NON-PYROGENIC.

{ "type": "p", "children": [], "text": "\nHAZARDOUS DRUGFOR INTRAVENOUS USE.SINGLE-DOSE VIAL. DISCARD UNUSEDPORTION. STERILE, NON-PYROGENIC.\n" }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

Manufactured by Baxter Healthcare CorporationDeerfield, IL 60015 USA

{ "type": "p", "children": [], "text": "Manufactured by Baxter Healthcare CorporationDeerfield, IL 60015 USA" }

NOVAPLUS Logo Made in Germany

{ "type": "p", "children": [], "text": "\nNOVAPLUS Logo\nMade in Germany" }

460-633-01

{ "type": "p", "children": [], "text": "460-633-01" }

Each vial contains 2 g cyclophosphamide.

{ "type": "p", "children": [], "text": "Each vial contains 2 g cyclophosphamide." }

For IV Infusion Use: Add 100 mL Sterile Water for Injection, USP, and shakevigorously to dissolve the drug.

{ "type": "p", "children": [], "text": "\nFor IV Infusion Use: Add 100 mL Sterile Water for Injection, USP, and shakevigorously to dissolve the drug." }

For Direct Injection Use: Add 100 mL0.9% Sodium Chloride Injection, USP, andshake vigorously to dissolve the drug.

{ "type": "p", "children": [], "text": "\nFor Direct Injection Use: Add 100 mL0.9% Sodium Chloride Injection, USP, andshake vigorously to dissolve the drug." }

Usual Dosage: See prescribing informationfor complete Dosage and Administrationinstructions. Store vial at or below 25°C (77°F)[see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "Usual Dosage: See prescribing informationfor complete Dosage and Administrationinstructions. Store vial at or below 25°C (77°F)[see USP Controlled Room Temperature].\n" }

Bar Code

{ "type": "p", "children": [], "text": "Bar Code" }

Bar Code(01)00310019942100

{ "type": "p", "children": [], "text": "Bar Code(01)00310019942100" }

USA HA-65-02-298 C 849

{ "type": "p", "children": [], "text": "USA HA-65-02-298 C 849" }

Carton Label

{ "type": "p", "children": [], "text": "Carton Label" }

Cyclophosphamide for Injection, USP

{ "type": "p", "children": [], "text": "\nCyclophosphamide\nfor Injection, USP" }

2 gram/vial

{ "type": "p", "children": [], "text": "\n2 gram/vial\n" }

Bar Code

{ "type": "p", "children": [], "text": "Bar Code" }

NDC 10019-942-01

{ "type": "p", "children": [], "text": "NDC 10019-942-01" }

Cyclophosphamide for Injection, USP

{ "type": "p", "children": [], "text": "Cyclophosphamide\nfor Injection, USP" }

2 gram/vial

{ "type": "p", "children": [], "text": "\n2 gram/vial\n" }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

HAZARDOUS DRUG

{ "type": "p", "children": [], "text": "\nHAZARDOUS DRUG\n" }

MUST BE DILUTEDFOR INTRAVENOUS INFUSIONOR DIRECT INJECTION USE

{ "type": "p", "children": [], "text": "\nMUST BE DILUTEDFOR INTRAVENOUS INFUSIONOR DIRECT INJECTION USE\n" }

1 Single-Dose VialDiscard Unused Portion.

{ "type": "p", "children": [], "text": "1 Single-Dose VialDiscard Unused Portion." }

Manufactured by Baxter Healthcare CorporationDeerfield, IL 60015 USA

{ "type": "p", "children": [], "text": "Manufactured by Baxter Healthcare CorporationDeerfield, IL 60015 USA" }

Novaplus is a registered trademark ofVizient, Inc.

{ "type": "p", "children": [], "text": "Novaplus is a registered trademark ofVizient, Inc." }

NOVAPLUS Logo Made in Germany

{ "type": "p", "children": [], "text": "\nNOVAPLUS Logo\nMade in Germany" }

HA-80-03-629US

{ "type": "p", "children": [], "text": "HA-80-03-629US" }

Each vial contains 2 g cyclophosphamide.

{ "type": "p", "children": [], "text": "Each vial contains 2 g cyclophosphamide." }

For Intravenous Infusion Use: Add 100 mLSterile Water for Injection, USP, and shakevigorously to dissolve the drug.

{ "type": "p", "children": [], "text": "\nFor Intravenous Infusion Use: Add 100 mLSterile Water for Injection, USP, and shakevigorously to dissolve the drug." }

For Direct Injection Use: Add 100 mL0.9% Sodium Chloride Injection, USP,and shake vigorously to dissolve the drug.

{ "type": "p", "children": [], "text": "\nFor Direct Injection Use: Add 100 mL0.9% Sodium Chloride Injection, USP,and shake vigorously to dissolve the drug." }

Store vial at or below 25°C (77°F) [see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "\nStore vial at or below 25°C (77°F)\n[see USP Controlled Room Temperature]." }

Usual Dosage: See prescribing information for complete Dosage and Administrationinstructions. Should not be prescribed withoutthorough knowledge of dose, indications andtoxicity as contained in accompanying literature.

{ "type": "p", "children": [], "text": "\nUsual Dosage: See prescribing information for complete Dosage and Administrationinstructions. Should not be prescribed withoutthorough knowledge of dose, indications andtoxicity as contained in accompanying literature. " }

HAZARDOUS DRUG

{ "type": "p", "children": [], "text": "\nHAZARDOUS DRUG\n" }

SINGLE-DOSE VIALSTERILE, NON-PYROGENICFOR PARENTERAL USE

{ "type": "p", "children": [], "text": "\nSINGLE-DOSE VIALSTERILE, NON-PYROGENICFOR PARENTERAL USE\n" }

Discard unused portion.

{ "type": "p", "children": [], "text": "Discard unused portion." }

C786

{ "type": "p", "children": [], "text": "C786" }

NDC 10019-942-01

{ "type": "p", "children": [], "text": "NDC 10019-942-01" }

Cyclophosphamide for Injection, USP

{ "type": "p", "children": [], "text": "Cyclophosphamide\nfor Injection, USP" }

2 gram/vial

{ "type": "p", "children": [], "text": "\n2 gram/vial\n" }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

HAZARDOUS DRUG

{ "type": "p", "children": [], "text": "\nHAZARDOUS DRUG\n" }

MUST BE DILUTEDFOR INTRAVENOUS INFUSIONOR DIRECT INJECTION USE

{ "type": "p", "children": [], "text": "\nMUST BE DILUTEDFOR INTRAVENOUS INFUSIONOR DIRECT INJECTION USE\n" }

1 Single Dose VialDiscard unused portion.

{ "type": "p", "children": [], "text": "1 Single Dose VialDiscard unused portion." }

Manufactured by Baxter Healthcare CorporationDeerfield, IL 60015 USA

{ "type": "p", "children": [], "text": "Manufactured by Baxter Healthcare CorporationDeerfield, IL 60015 USA" }

NOVAPLUS Logo Made in Germany

{ "type": "p", "children": [], "text": "\nNOVAPLUS Logo\nMade in Germany" }

LOT/EXP:

{ "type": "p", "children": [], "text": "LOT/EXP:" }

2638B5151

{ "type": "p", "children": [], "text": "2638B5151" }

Bar Code

{ "type": "p", "children": [], "text": "Bar Code" }

NDC 10019-942-01

{ "type": "p", "children": [], "text": "NDC 10019-942-01" }

Cyclophosphamide for Injection, USP

{ "type": "p", "children": [], "text": "Cyclophosphamide\nfor Injection, USP" }

2 gram/vial

{ "type": "p", "children": [], "text": "\n2 gram/vial\n" }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

HAZARDOUS DRUG

{ "type": "p", "children": [], "text": "\nHAZARDOUS DRUG\n" }

MUST BE DILUTEDFOR INTRAVENOUS INFUSIONOR DIRECT INJECTION USE

{ "type": "p", "children": [], "text": "\nMUST BE DILUTEDFOR INTRAVENOUS INFUSIONOR DIRECT INJECTION USE\n" }

1 Single-Dose VialDiscard unused portion.

{ "type": "p", "children": [], "text": "1 Single-Dose VialDiscard unused portion." }

Manufactured by Baxter Healthcare CorporationDeerfield, IL 60015 USA

{ "type": "p", "children": [], "text": "Manufactured by Baxter Healthcare CorporationDeerfield, IL 60015 USA" }

NOVAPLUS Logo Made in Germany

{ "type": "p", "children": [], "text": "\nNOVAPLUS Logo\nMade in Germany" }

Cyclophosphamide Capsules are indicated for the treatment of:

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

Cyclophosphamide Capsules are indicated for the treatment of biopsy proven minimal change nephrotic syndrome in pediatric patients who failed to adequately respond to or are unable to tolerate adrenocorticosteroid therapy.

Limitations of Use: The safety and effectiveness of Cyclophosphamide Capsules for the treatment of nephrotic syndrome in adults or other renal disease has not been established.

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

Cyclophosphamide Capsules should be swallowed whole. The capsules should not be opened, chewed, or crushed.

Cyclophosphamide Capsules is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1Exposure to broken capsules should be avoided. If contact with broken capsules occurs, wash hands immediately and thoroughly.

Adults and Pediatric Patients

The recommended dosage of Cyclophosphamide Capsules is in the range of 1 mg per kg to 5 mg per kg orally once daily for both initial and maintenance dosing.

Other regimens of intravenous and oral cyclophosphamide have been reported. Dosages should be adjusted based on evidence of antitumor activity, myelosuppression, or other severe adverse reactions [ see WARNINGS and PRECAUTIONS ( 5) ].

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.

The recommended dosage of Cyclophosphamide Capsules is 2 mg per kg orally once daily for 8 to 12 weeks (maximum cumulative dose 168 mg per kg). Treatment beyond 90 days increases the probability of sterility in males [see USE IN SPECIFIC POPULATIONS ( 8.4)] .

Capsules:

{ "type": "p", "children": [], "text": "Capsules:" }

{ "type": "ul", "children": [ "25 mg capsule for oral administration contains 25 mg of cyclophosphamide USP. It is a blue/blue opaque capsule with NSP 25 printed in black ink on the cap and body, containing a white to off-white powder.", "50 mg capsule for oral administration contains 50 mg of cyclophosphamide USP. It is a blue/blue opaque capsule with NSP 50 printed in black ink on the cap and body, containing a white to off-white powder." ], "text": "" }

Cyclophosphamide Capsules are contraindicated in patients with:

{ "type": "p", "children": [], "text": "Cyclophosphamide Capsules are contraindicated in patients with:" }

{ "type": "ul", "children": [ "A history of severe hypersensitivity reactions to cyclophosphamide, any of its metabolites, or to other components of the product. Anaphylactic reactions including death have been reported with cyclophosphamide. Cross-sensitivity with other alkylating agents can occur.", "In patients with urinary outflow obstruction\n \n [see WARNINGS AND PRECAUTIONS (\n \n 5.2)]\n \n .\n \n " ], "text": "" }

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 [see ADVERSE REACTIONS ( 6.2)] .

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.

Monitoring of complete blood counts is essential during cyclophosphamide treatment so that the dose can be adjusted, if needed. Cyclophosphamide should not be administered to patients with neutrophils ≤1,500/mm 3and platelets <50,000/mm 3. Cyclophosphamide treatment may not be indicated, or should be interrupted, or the dose reduced, in patients who have or who develop a serious infection. G-CSF may be administered to reduce the risks of neutropenia complications associated with cyclophosphamide use. Primary and secondary prophylaxis with G-CSF should be considered in all patients considered to be at increased risk for neutropenia complications. The nadirs of the reduction in leukocyte count and thrombocyte count are usually reached in weeks 1 and 2 of treatment. Peripheral blood cell counts are expected to normalize after approximately 20 days. Bone marrow failure has been reported. Severe myelosuppression may be expected particularly in patients pretreated with and/or receiving concomitant chemotherapy and/or radiation therapy.

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.

Before starting treatment, exclude or correct any urinary tract obstructions [see CONTRAINDICATIONS ( 4)] . Urinary sediment should be checked regularly for the presence of erythrocytes and other signs of urotoxicity and/or nephrotoxicity. Cyclophosphamide should be used with caution, if at all, in patients with active urinary tract infections. Aggressive hydration with forced diuresis and frequent bladder emptying can reduce the frequency and severity of bladder toxicity. Mesna has been used to prevent severe bladder toxicity.

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.

Particular caution is necessary in patients with risk factors for cardiotoxicity and in patients with pre-existing cardiac disease.

Monitor patients with risk factors for cardiotoxicity and with pre-existing cardiac disease.

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.

Monitor patients for signs and symptoms of pulmonary toxicity.

Cyclophosphamide is genotoxic [see NONCLINICAL TOXICOLOGY ( 13.1)] . 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 (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.

Based on its mechanism of action and published reports of effects in pregnant patients or animals, Cyclophosphamide Capsules can cause fetal harm when administered to a pregnant woman [see USE IN SPECIFIC POPULATIONS ( 8.1), CLINICAL PHARMACOLOGY ( 12.1) and NONCLINICAL TOXICOLOGY ( 13.1)] . 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.

Advise pregnant women and female patients of reproductive potential of the potential risk to the fetus [see USE IN SPECIFIC POPULATIONS ( 8.1)] . Verify the pregnancy status of females of reproductive potential prior to initiation of Cyclophosphamide Capsules. Advise females of reproductive potential to use effective contraception during treatment with Cyclophosphamide Capsules and for up to 1 year after completion of therapy. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Cyclophosphamide Capsules and for 4 months after completion of therapy [see USE IN SPECIFIC POPULATIONS ( 8.1, 8.3)] .

Male and female reproductive function and fertility may be impaired in patients being treated with Cyclophosphamide Capsules. 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 [see USE IN SPECIFIC POPULATIONS ( 8.3) and ( 8.4)] .

Cyclophosphamide may interfere with normal wound healing.

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.

Hematopoietic system

Neutropenia occurs in patients treated with cyclophosphamide. The degree of neutropenia is particularly important because it correlates with a reduction in resistance to infections. Fever without documented infection has been reported in neutropenic patients.

Gastrointestinal system

Nausea and vomiting occur with cyclophosphamide therapy. Anorexia and, less frequently, abdominal discomfort or pain and diarrhea may occur. There are isolated reports of hemorrhagic colitis, oral mucosal ulceration and jaundice occurring during therapy.

Skin and its structures

Alopecia occurs in patients treated with cyclophosphamide. Skin rash occurs occasionally in patients receiving the drug. Pigmentation of the skin and changes in nails can occur.

The following adverse reactions have been identified from clinical trials or post-marketing surveillance. Because they are reported from a population from unknown size, precise estimates of frequency cannot be made.

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.

General Disorders and Administrative Site Conditions:multiorgan failure, general physical deterioration, influenza-like illness, pyrexia, edema, chest pain, mucosal inflammation, asthenia, pain, chills, fatigue, malaise, headache.

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.

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 is a pro-drug that is activated by cytochrome P450s [see CLINICAL PHARMACOLOGY ( 12.3)] .

{ "type": "p", "children": [], "text": "Cyclophosphamide is a pro-drug that is activated by cytochrome P450s\n \n [see CLINICAL PHARMACOLOGY (\n \n 12.3)]\n \n .\n\n " }

An increase of the concentration of cytotoxic metabolites may occur with:

{ "type": "p", "children": [], "text": "An increase of the concentration of cytotoxic metabolites may occur with:" }

{ "type": "ul", "children": [ "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." ], "text": "" }

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

{ "type": "p", "children": [], "text": "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:

{ "type": "p", "children": [], "text": "• Increased hematotoxicity and/or immunosuppression may result from a combined effect of cyclophosphamide and, for example:" }

{ "type": "ul", "children": [ "ACE inhibitors: ACE inhibitors can cause leukopenia.", "Natalizumab", "Paclitaxel: Increased hematotoxicity has been reported when cyclophosphamide was administered after paclitaxel infusion.", "Thiazide diuretics", "Zidovudine" ], "text": "" }

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

{ "type": "p", "children": [], "text": "• Increased cardiotoxicity may result from a combined effect of cyclophosphamide and, for example:" }

{ "type": "ul", "children": [ "Anthracyclines" ], "text": "" }

• Cytarabine

{ "type": "p", "children": [], "text": "• Cytarabine" }

• Pentostatin

{ "type": "p", "children": [], "text": "• Pentostatin" }

• Radiation therapy of the cardiac region

{ "type": "p", "children": [], "text": "• Radiation therapy of the cardiac region" }

• Trastuzumab

{ "type": "p", "children": [], "text": "• Trastuzumab" }

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

{ "type": "p", "children": [], "text": "• Increased pulmonary toxicity may result from a combined effect of cyclophosphamide and, for example:" }

{ "type": "ul", "children": [ "Amiodarone", "G-CSF, GM-CSF (granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor): Reports suggest an increased risk of pulmonary toxicity in patients treated with cytotoxic chemotherapy that includes cyclophosphamide and G-CSF or GMCSF." ], "text": "" }

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

{ "type": "p", "children": [], "text": "• Increased nephrotoxicity may result from a combined effect of cyclophosphamide and, for example:" }

{ "type": "ul", "children": [ "Amphotericin B", "Indomethacin: Acute water intoxication has been reported with concomitant use of indomethacin" ], "text": "" }

• Increase in other toxicities:

{ "type": "p", "children": [], "text": "• Increase in other toxicities:" }

{ "type": "ul", "children": [ "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" ], "text": "" }

• Increased risk of hemorrhagic cystitis may result from a combined effect of cyclophosphamide and past or concomitant radiation treatment.

{ "type": "p", "children": [], "text": "• 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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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." }

Risk Summary

Based on its mechanism of action and published reports of effects in pregnant patients or animals, Cyclophosphamide Capsules can cause fetal harm when administered to a pregnant woman [see CLINICAL PHARMACOLOGY ( 12.1) and NONCLINICAL TOXICOLOGY ( 13.1)] . Exposure to cyclophosphamide during pregnancy may cause fetal malformations, miscarriage, fetal growth retardation, and toxic effects in the newborn [see Data]. Cyclophosphamide is teratogenic and embryo-fetal toxic in mice, rats, rabbits and monkeys [see Data]. Advise pregnant women and females of reproductive potential of the potential risk to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies.

Data

Human Data

Malformations of the skeleton, palate, limbs and eyes as well as miscarriage have been reported after exposure to cyclophosphamide in the first trimester. Fetal growth retardation and toxic effects manifesting in the newborn, including leukopenia, anemia, pancytopenia, severe bone marrow hypoplasia, and gastroenteritis have been reported after exposure to cyclophosphamide.

Animal Data

Administration of cyclophosphamide to pregnant mice, rats, rabbits and monkeys during the period of organogenesis at doses at or below the dose in patients based on body surface area resulted in various malformations, which included neural tube defects, limb and digit defects and other skeletal anomalies, cleft lip and palate, and reduced skeletal ossification.

Risk Summary

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 Capsules, advise lactating women not to breastfeed during the treatment and for 1 week after the last dose.

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to the initiation of Cyclophosphamide Capsules [see USE IN SPECIFIC POPULATIONS ( 8.1)] .

Contraception

Females

Cyclophosphamide Capsules can cause fetal harm. Advise females of reproductive potential to use effective contraception during treatment with Cyclophosphamide Capsules for up to 1 year after completion of therapy [see USE IN SPECIFIC POPULATIONS ( 8.1)] .

Males

Based on findings in genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment with Cyclophosphamide Capsules and for 4 months after completion of therapy [see USE IN SPECIFIC POPULATIONS ( 8.1) and NONCLINICAL TOXICOLOGY ( 13.1)] .

Infertility

Females

Amenorrhea, transient or permanent, associated with decreased estrogen and increased gonadotropin secretion develops in a proportion of women treated with cyclophosphamide. Affected patients generally resume regular menses within a few months after cessation of therapy. The risk of premature menopause with cyclophosphamide increases with age. Oligomenorrhea has also been reported in association with cyclophosphamide treatment.

Animal data suggest an increased risk of failed pregnancy and malformations may persist after discontinuation of cyclophosphamide as long as oocytes/follicles exist that were exposed to cyclophosphamide during any of their maturation phases. The exact duration of follicular development in humans is not known, but may be longer than 12 months [see NONCLINICAL TOXICOLOGY ( 13.1)] .

Males

Men treated with cyclophosphamide may develop oligospermia or azoospermia which are normally associated with increased gonadotropin but normal testosterone secretion.

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.

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.

In patients with severe renal impairment, decreased renal excretion may result in increased plasma levels of cyclophosphamide and its metabolites. This may result in increased toxicity [see CLINICAL PHARMACOLOGY ( 12.3)] .

Monitor patients with severe renal impairment (CrCl =10 mL/min to 24 mL/min) for signs and symptoms of toxicity.

Cyclophosphamide and its metabolites are dialyzable although there are probably quantitative differences depending upon the dialysis system being used. In patients requiring dialysis, use of a consistent interval between cyclophosphamide administration and dialysis should be considered.

Patients with severe hepatic impairment have reduced conversion of cyclophosphamide to the active 4-hydroxyl metabolite, potentially reducing efficacy [see CLINICAL PHARMACOLOGY ( 12.3)] .

No specific antidote for cyclophosphamide is known.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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 [see WARNINGS AND PRECAUTIONS ( 5.1, 5.2, 5.3, and 5.6)] .

{ "type": "p", "children": [], "text": "Serious consequences of overdosage include manifestations of dose dependent toxicities such as myelosuppression, urotoxicity, cardiotoxicity (including cardiac failure), veno-occlusive hepatic disease, and stomatitis\n \n [see WARNINGS AND PRECAUTIONS (\n \n 5.1,\n \n 5.2,\n \n 5.3, and\n \n 5.6)]\n \n .\n\n " }

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

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "Cystitis prophylaxis with mesna may be helpful in preventing or limiting urotoxic effects with cyclophosphamide overdose." }

Cyclophosphamide, USP 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, and has the following structural formula:

{ "type": "p", "children": [], "text": "Cyclophosphamide, USP 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, and has the following structural formula:" }

Cyclophosphamide has a molecular formula C 7H 15Cl 2N 2O 2P • H 2O and a molecular weight of 279.1. Cyclophosphamide is soluble in water, saline and ethanol.

{ "type": "p", "children": [], "text": "Cyclophosphamide has a molecular formula C\n \n 7H\n \n 15Cl\n \n 2N\n \n 2O\n \n 2P • H\n \n 2O and a molecular weight of 279.1. Cyclophosphamide is soluble in water, saline and ethanol.\n\n " }

Each capsule for oral administration contains 25 mg or 50 mg cyclophosphamide (anhydrous, USP) and the following inactive ingredients: Starch 1500 and sodium stearyl fumarate.

{ "type": "p", "children": [], "text": "Each capsule for oral administration contains 25 mg or 50 mg cyclophosphamide (anhydrous, USP) and the following inactive ingredients: Starch 1500 and sodium stearyl fumarate." }

Each gelatin capsule shell contains FD&C Blue #1, FD&C Red #3, gelatin and titanium dioxide.

{ "type": "p", "children": [], "text": "Each gelatin capsule shell contains FD&C Blue #1, FD&C Red #3, gelatin and titanium dioxide." }

In addition to the ingredients listed above, each capsule contains Opacode (Black) monogramming ink. Opacode (Black) contains Ferrosoferric oxide-black, propylene glycol and shellac.

{ "type": "p", "children": [], "text": "In addition to the ingredients listed above, each capsule contains Opacode (Black) monogramming ink. Opacode (Black) contains Ferrosoferric oxide-black, propylene glycol and shellac." }

FDA approved dissolution test method differs from USP.

{ "type": "p", "children": [], "text": "FDA approved dissolution test method differs from USP." }

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

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.

Following IV administration, elimination half-life (t ½) ranges from 3 to 12 hours with total body clearance (CL) values of 4 to 5.6 L/h. Pharmacokinetics are linear over the dose range used clinically. When cyclophosphamide was administered at 4.0 g/m 2over a 90 minutes infusion, saturable elimination in parallel with first-order renal elimination describe the kinetics of the drug.

Absorption

After oral administration, peak concentrations of cyclophosphamide occurred at one hour. Area under the curve ratio for the drug after oral and IV administration (AUC po: AUC iv) ranged from 0.87 to 0.96.

Distribution

Approximately 20% of cyclophosphamide is protein bound, with no dose dependent changes. Some metabolites are protein bound to an extent greater than 60%. Volume of distribution approximates total body water (30 to 50 L).

Metabolism

The liver is the major site of cyclophosphamide activation. Approximately 75% of the administered dose of cyclophosphamide is activated by hepatic microsomal cytochrome P450s including CYP2A6, 2B6, 3A4, 3A5, 2C9, 2C18 and 2C19, with 2B6 displaying the highest 4-hydroxylase activity. Cyclophosphamide is activated to form 4-hydroxycyclophosphamide, which is in equilibrium with its ring-open tautomer aldophosphamide. 4 hydroxycyclophosphamide and aldophosphamide can undergo oxidation by aldehyde dehydrogenases to form the inactive metabolites 4 ketocyclophosphamide and carboxyphosphamide, respectively. Aldophosphamide can undergo β-elimination to form active metabolites phosphoramide mustard and acrolein. This spontaneous conversion can be catalyzed by albumin and other proteins. Less than 5% of cyclophosphamide may be directly detoxified by side chain oxidation, leading to the formation of inactive metabolites 2-dechloroethylcyclophosphamide. At high doses, the fraction of parent compound cleared by 4-hydroxylation is reduced resulting in non-linear elimination of cyclophosphamide in patients. Cyclophosphamide appears to induce its own metabolism. Auto-induction results in an increase in the total clearance, increased formation of 4-hydroxyl metabolites and shortened t ½values following repeated administration at 12- to 24-hour interval.

Elimination

Cyclophosphamide is primarily excreted as metabolites. 10 to 20% is excreted unchanged in the urine and 4% is excreted in the bile following IV administration.

Special Populations

Renal Impairment

The pharmacokinetics of cyclophosphamide were determined following one-hour intravenous infusion to renally impaired patients. The results demonstrated that the systemic exposure to cyclophosphamide increased as the renal function decreased. Mean dose-corrected AUC increased by 38% in the moderate renal group, (Creatinine clearance CrCl of 25 to 50 mL/min), by 64% in the severe renal group (CrCl of 10 to 24 mL/min) and by 23% in the hemodialysis group (CrCl of <10 mL/min) compared to the control group. The increase in exposure was significant in the severe group (p>0.05); thus, patients with severe renal impairment should be closely monitored for toxicity [see USE IN SPECIFIC POPULATIONS ( 8.6)] .

The dialyzability of cyclophosphamide was investigated in four patients on long-term hemodialysis. Dialysis clearance calculated by arterial-venous difference and actual drug recovery in dialysate averaged 104 mL/min, which is in the range of the metabolic clearance of 95 mL/min for the drug. A mean of 37% of the administered dose of cyclophosphamide was removed during hemodialysis. The elimination half-life (t½) was 3.3 hours in patients during hemodialysis, a 49% reduction of the 6.5 hours to t½ reported in uremic patients. Reduction in t½, larger dialysis clearance than metabolic clearance, high extraction efficiency, and significant drug removal during dialysis, suggest that cyclophosphamide is dialyzable.

Hepatic Impairment

Total body clearance (CL) of cyclophosphamide is decreased by 40% in patients with severe hepatic impairment and elimination half-life (t ½) is prolonged by 64%. Mean CL and t ½were 45 ± 8.6 L/kg and 12.5 ± 1.0 hours respectively, in patients with severe hepatic impairment and 63 ± 7.6 L/kg and 7.6 ± 1.4 hours respectively in the control group [see USE IN SPECIFIC POPULATIONS ( 8.7)] .

Cyclophosphamide administered by different routes, including intravenous, subcutaneous or intraperitoneal injection, or in drinking water, caused tumors in both mice and rats. In addition to leukemia and lymphoma, benign and malignant tumors were found at various tissue sites, including urinary bladder, mammary gland, lung, liver, and injection site [see WARNINGS AND PRECAUTIONS ( 5.5)] .

Cyclophosphamide was mutagenic and clastogenic in multiple in vitroand in vivogenetic toxicology studies.

Cyclophosphamide is genotoxic in male and female germ cells. Animal data indicate that exposure of oocytes to cyclophosphamide during follicular development may result in a decreased rate of implantations and viable pregnancies, and in an increased risk of malformations. Male mice and rats treated with cyclophosphamide show alterations in male reproductive organs (e.g., decreased weights, atrophy, changes in spermatogenesis), and decreases in reproductive potential (e.g., decreased implantations and increased post-implantation loss) and increases in fetal malformations when mated with untreated females [see USE IN SPECIFIC POPULATIONS ( 8.3)] .

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Storage

Store at 20°C to 25°C (68°F to 77°F); with excursions permitted between 15ºC to 30ºC (59°F to 86°F). [See USP Controlled Room Temperature.]

Cyclophosphamide is an antineoplastic product. Follow special handling and disposal procedures. 1

Advise the patient of the following:

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Myelosuppression, Immunosuppression, and Infections

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Urinary Tract and Renal Toxicity

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Cardiotoxicity

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Pulmonary Toxicity

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Embryo-Fetal Toxicity

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Lactation

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Infertility

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Common Adverse Reactions

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Hydration and Important Administration Instructions

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Manufactured by: Eirgen Pharma Ltd. Waterford, Ireland

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Distr. by: NextSource Pharma, Pompano Beach, FL 33069, USA

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Revised: 11/2024

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NDC 58181-4102-5

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Cyclophosphamide

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Capsules, USP

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25 mg

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CYTOTOXIC AGENT

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Wear gloves when handling container and capsules.

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Rx Only 100 Capsules

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NEXTSOURCE PHARMA

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Each capsule contains 25mg of Cyclophosphamide USP (Calculated as anhydrous)

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USUAL DOSAGE:See Package insert for Complete Prescribing Informaiton.

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Swallow capsules whole. Do not open, chew, or crush capsules.

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Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]

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This package is child-resistant.

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Dispense in a tight container as defined in the USP/NF.

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Distr. by:

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NextSource Pharma,

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Pompano Beach, FL 33069, USA.

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NDC 58181-4115-0

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Cyclophosphamide

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Capsules, USP

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50 mg

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CYTOTOXIC AGENT

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Wear gloves when handling container and capsules.

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Rx Only 100 Capsules

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NEXTSOURCE PHARMA

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Each capsule contains 50mg of Cyclophosphamide USP (Calculated as anhydrous)

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USUAL DOSAGE:See Package insert for Complete Prescribing Informaiton.

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Swallow capsules whole. Do not open, chew, or crush capsules.

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Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]

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This package is child-resistant.

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Dispense in a tight container as defined in the USP/NF.

{ "type": "p", "children": [], "text": "Dispense in a tight container as defined in the USP/NF." }

Distr. by:

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NextSource Pharma,

{ "type": "p", "children": [], "text": "\nNextSource Pharma,\n" }

Pompano Beach, FL 33069, USA.

{ "type": "p", "children": [], "text": "\nPompano Beach, FL 33069, USA.\n" }

Cyclophosphamide Tablets is indicated for the treatment of:

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

Cyclophosphamide Tablets is indicated for the treatment of biopsy proven minimal change nephrotic syndrome in pediatric patients who failed to adequately respond to or are unable to tolerate adrenocorticosteroid therapy.

Limitations of Use:

The safety and effectiveness of Cyclophosphamide Tablets for the treatment of nephrotic syndrome in adults or other renal disease has not been established.

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

Cyclophosphamide Tablets should be taken in the morning.

Cyclophosphamide Tablets should be swallowed whole. The tablets should not be chewed or crushed.

Cyclophosphamide Tablets is a cytotoxic drug. Follow applicable special handling and disposal procedures.1 Exposure to broken tablets should be avoided. If contact with broken tablets occurs, wash hands immediately and thoroughly.

Adults and Pediatric Patients

The recommended dose of Cyclophosphamide Tablets is in the range of 1 mg per kg to 5 mg per kg orally once daily for both initial and maintenance dosing.

Other regimens of oral cyclophosphamide have been reported. Dosages should be adjusted based on evidence of antitumor activity, myelosuppression, or other severe adverse reactions [see Warnings and Precautions (5)].

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.

The recommended dosage of Cyclophosphamide Tablets is 2 mg per kg once daily for 8 to 12 weeks (maximum cumulative dose 168 mg per kg). Treatment beyond 90 days increases the probability of sterility in males [see Use in Specific Populations (8.4)].

Tablets:

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Cyclophosphamide Tablets are contraindicated in patients with:

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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 [see Adverse Reactions (6.2)].

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.

Monitoring of complete blood counts is essential during cyclophosphamide treatment so that the dose can be adjusted, if needed. Cyclophosphamide should not be administered to patients with neutrophils ≤1,500/mm3 and platelets < 50,000/mm3. Cyclophosphamide treatment may not be indicated, or should be interrupted, or the dose reduced, in patients who have or who develop a serious infection. G-CSF may be administered to reduce the risks of neutropenia complications associated with cyclophosphamide use. Primary and secondary prophylaxis with G-CSF should be considered in all patients considered to be at increased risk for neutropenia complications. The nadirs of the reduction in leukocyte count and thrombocyte count are usually reached in weeks 1 and 2 of treatment. Peripheral blood cell counts are expected to normalize after approximately 20 days. Bone marrow failure has been reported. Severe myelosuppression may be expected particularly in patients pretreated with and/or receiving concomitant chemotherapy and/or radiation therapy.

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.

Before starting treatment, exclude or correct any urinary tract obstructions [see Contraindications (4)]. Urinary sediment should be checked regularly for the presence of erythrocytes and other signs of urotoxicity and/or nephrotoxicity. Cyclophosphamide should be used with caution, if at all, in patients with active urinary tract infections. Aggressive hydration with forced diuresis and frequent bladder emptying can reduce the frequency and severity of bladder toxicity. Mesna has been used to prevent severe bladder toxicity.

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.

Particular caution is necessary in patients with risk factors for cardiotoxicity and in patients with pre-existing cardiac disease.

Monitor patients with risk factors for cardiotoxicity and with pre-existing cardiac disease.

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.

Monitor patients for signs and symptoms of pulmonary toxicity.

Cyclophosphamide is genotoxic [see Nonclinical Toxicology (13.1)]. 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 (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.

Based on its mechanism of action and published reports of effects in pregnant patients or animals, Cyclophosphamide Tablets can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1), Clinical Pharmacology (12.1), and Nonclinical Toxicology (13.1)]. 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.

Advise pregnant women and females of reproductive potential of the potential risk to the fetus [see Use in Specific Populations (8.1)]. Verify the pregnancy status of females of reproductive potential prior to initiation of Cyclophosphamide Tablets. Advise females of reproductive potential to use effective contraception during treatment with Cyclophosphamide Tablets and for up to 1 year after completion of therapy. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Cyclophosphamide Tablets and for 4 months after completion of therapy [see Use in Specific Populations (8.1, 8.3)].

Male and female reproductive function and fertility may be impaired in patients being treated with Cyclophosphamide Tablets. 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 [see Use in Specific Populations (8.3, 8.4)].

Cyclophosphamide may interfere with normal wound healing.

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.

Hematopoietic system: Neutropenia occurs in patients treated with cyclophosphamide. The degree of neutropenia is particularly important because it correlates with a reduction in resistance to infections. Fever without documented infection has been reported in neutropenic patients.

Gastrointestinal system: Nausea and vomiting occur with cyclophosphamide therapy. Anorexia and, less frequently, abdominal discomfort or pain and diarrhea may occur. There are isolated reports of hemorrhagic colitis, oral mucosal ulceration and jaundice occurring during therapy.

Skin and its structures: Alopecia occurs in patients treated with cyclophosphamide. Skin rash occurs occasionally in patients receiving the drug. Pigmentation of the skin and changes in nails can occur.

The following adverse reactions have been identified from clinical trials or post-marketing surveillance. Because they are reported from a population from unknown size, precise estimates of frequency cannot be made.

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.

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.

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.

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

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An increase of the concentration of cytotoxic metabolites may occur with:

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

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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.

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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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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." }

Risk Summary Based on its mechanism of action and published reports of effects in pregnant patients or animals, Cyclophosphamide Tablets can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)]. Exposure to cyclophosphamide during pregnancy may cause fetal malformations, miscarriage, fetal growth retardation, and toxic effects in the newborn [see Data]. 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.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies.

Data Human Data Malformations of the skeleton, palate, limbs and eyes as well as miscarriage have been reported after exposure to cyclophosphamide in the first trimester. Fetal growth retardation and toxic effects manifesting in the newborn, including leukopenia, anemia, pancytopenia, severe bone marrow hypoplasia, and gastroenteritis have been reported after exposure to cyclophosphamide.

Animal Data Administration of cyclophosphamide to pregnant mice, rats, rabbits and monkeys during the period of organogenesis at doses at or below the dose in patients based on body surface area resulted in various malformations, which included neural tube defects, limb and digit defects and other skeletal anomalies, cleft lip and palate, and reduced skeletal ossification.

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

Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to the initiation of Cyclophosphamide Tablets [see Use in Specific Populations (8.1)].

Contraception Females Cyclophosphamide can cause fetal harm. Advise females of reproductive potential to use effective contraception during treatment with Cyclophosphamide Tablets and for up to 1 year after completion of therapy [see Use in Specific Populations (8.1)].

Males Based on findings in genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment with Cyclophosphamide Tablets and for at least 4 months after completion of therapy [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.1)].

Infertility Females Amenorrhea, transient or permanent, associated with decreased estrogen and increased gonadotropin secretion develops in a proportion of women treated with cyclophosphamide. Affected patients generally resume regular menses within a few months after cessation of therapy. The risk of premature menopause with cyclophosphamide increases with age. Oligomenorrhea has also been reported in association with cyclophosphamide treatment.

Animal data suggest an increased risk of failed pregnancy and malformations may persist after discontinuation of cyclophosphamide as long as oocytes/follicles exist that were exposed to cyclophosphamide during any of their maturation phases. The exact duration of follicular development in humans is not known, but may be longer than 12 months [see Nonclinical Toxicology (13.1)].

Males Men treated with cyclophosphamide may develop oligospermia or azoospermia which are normally associated with increased gonadotropin but normal testosterone secretion.

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.

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.

In patients with severe renal impairment, decreased renal excretion may result in increased plasma levels of cyclophosphamide and its metabolites. This may result in increased toxicity [see Clinical Pharmacology (12.3)]. Monitor patients with severe renal impairment (CrCl =10 mL/min to 24 mL/min) for signs and symptoms of toxicity.

Cyclophosphamide and its metabolites are dialyzable although there are probably quantitative differences depending upon the dialysis system being used. In patients requiring dialysis, use of a consistent interval between cyclophosphamide administration and dialysis should be considered.

Patients with severe hepatic impairment have reduced conversion of cyclophosphamide to the active 4-hydroxyl metabolite, potentially reducing efficacy [see Clinical Pharmacology (12.3)].

No specific antidote for cyclophosphamide is known.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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 [see Warnings and Precautions (5.1, 5.2, 5.3, and 5.6)].

{ "type": "p", "children": [], "text": "Serious consequences of overdosage include manifestations of dose dependent toxicities such as myelosuppression, urotoxicity, cardiotoxicity (including cardiac failure), veno-occlusive hepatic disease, and stomatitis [see Warnings and Precautions (5.1, 5.2, 5.3, and 5.6)].\n" }

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

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "Cystitis prophylaxis with mesna may be helpful in preventing or limiting urotoxic effects with cyclophosphamide overdose." }

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, and has the following structural formula:

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

{ "type": "p", "children": [], "text": "Cyclophosphamide has a molecular formula of C7H15Cl2N2O2P•H2O and a molecular weight of 279.1. Cyclophosphamide is soluble in water, saline, or ethanol." }

Cyclophosphamide Tablets, USP are for oral use and contain 25 mg or 50 mg cyclophosphamide (anhydrous). Inactive ingredients in Cyclophosphamide Tablets are: acacia, FD&C Blue No. 1, D&C Yellow No. 10 Aluminum Lake, lactose, magnesium stearate, starch, stearic acid and talc.

{ "type": "p", "children": [], "text": "Cyclophosphamide Tablets, USP are for oral use and contain 25 mg or 50 mg cyclophosphamide (anhydrous). Inactive ingredients in Cyclophosphamide Tablets are: acacia, FD&C Blue No. 1, D&C Yellow No. 10 Aluminum Lake, lactose, magnesium stearate, starch, stearic acid and talc." }

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

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.

Absorption After oral administration, peak concentrations of cyclophosphamide occurred at one hour. Area under the curve ratio for the drug after oral and IV administration (AUCpo : AUCiv) ranged from 0.87 to 0.96.

Distribution Approximately 20% of cyclophosphamide is protein bound, with no dose dependent changes. Some metabolites are protein bound to an extent greater than 60%. Volume of distribution approximates total body water (30 to 50 L).

Metabolism The liver is the major site of cyclophosphamide activation. Approximately 75% of the administered dose of cyclophosphamide is activated by hepatic microsomal cytochrome P450s including CYP2A6, 2B6, 3A4, 3A5, 2C9, 2C18 and 2C19, with 2B6 displaying the highest 4-hydroxylase activity. Cyclophosphamide is activated to form 4-hydroxycyclophosphamide, which is in equilibrium with its ring-open tautomer aldophosphamide. 4-hydroxycyclophosphamide and aldophosphamide can undergo oxidation by aldehyde dehydrogenases to form the inactive metabolites 4-ketocyclophosphamide and carboxyphosphamide, respectively. Aldophosphamide can undergo β-elimination to form active metabolites phosphoramide mustard and acrolein. This spontaneous conversion can be catalyzed by albumin and other proteins. Less than 5% of cyclophosphamide may be directly detoxified by side chain oxidation, leading to the formation of inactive metabolites 2-dechloroethylcyclophosphamide. At high doses, the fraction of parent compound cleared by 4-hydroxylation is reduced resulting in non-linear elimination of cyclophosphamide in patients. Cyclophosphamide appears to induce its own metabolism. Auto-induction results in an increase in the total clearance, increased formation of 4-hydroxyl metabolites and shortened t1/2 values following repeated administration at 12- to 24-hour interval.

Elimination Cyclophosphamide is primarily excreted as metabolites. 10 to 20% is excreted unchanged in the urine and 4% is excreted in the bile following IV administration.

Special Populations

Renal Impairment The pharmacokinetics of cyclophosphamide were determined following one-hour intravenous infusion to renally impaired patients. The results demonstrated that the systemic exposure to cyclophosphamide increased as the renal function decreased. Mean dose-corrected AUC increased by 38% in the moderate renal group, (Creatinine clearance (CrCl of 25 to 50 mL/min), by 64% in the severe renal group (CrCl of 10 to 24 mL/min) and by 23% in the hemodialysis group (CrCl of < 10 mL/min) compared to the control group. The increase in exposure was significant in the severe group (p>0.05); thus, patients with severe renal impairment should be closely monitored for toxicity [see Use in Specific Populations (8.6)].

The dialyzability of cyclophosphamide was investigated in four patients on long-term hemodialysis. Dialysis clearance calculated by arterial-venous difference and actual drug recovery in dialysate averaged 104 mL/min, which is in the range of the metabolic clearance of 95 mL/min for the drug. A mean of 37% of the administered dose of cyclophosphamide was removed during hemodialysis. The elimination half-life (t1/2) was 3.3 hours in patients during hemodialysis, a 49% reduction of the 6.5 hours to t1/2 reported in uremic patients. Reduction in t1/2, larger dialysis clearance than metabolic clearance, high extraction efficiency, and significant drug removal during dialysis, suggest that cyclophosphamide is dialyzable.

Hepatic Impairment Total body clearance (CL) of cyclophosphamide is decreased by 40% in patients with severe hepatic impairment and elimination half-life (t1/2) is prolonged by 64%. Mean CL and t1/2 were 45 ± 8.6 L/kg and 12.5 ± 1.0 hours respectively, in patients with severe hepatic impairment and 63 ± 7.6 L/kg and 7.6 ± 1.4 hours respectively in the control group [see Use in Specific Populations (8.7)].

Cyclophosphamide administered by different routes, including intravenous, subcutaneous or intraperitoneal injection, or in drinking water, caused tumors in both mice and rats. In addition to leukemia and lymphoma, benign and malignant tumors were found at various tissue sites, including urinary bladder, mammary gland, lung, liver, and injection site [see Warnings and Precautions (5.5)].

Cyclophosphamide was mutagenic and clastogenic in multiple in vitro and in vivo genetic toxicology studies.

Cyclophosphamide is genotoxic in male and female germ cells. Animal data indicate that exposure of oocytes to cyclophosphamide during follicular development may result in a decreased rate of implantations and viable pregnancies, and in an increased risk of malformations. Male mice and rats treated with cyclophosphamide show alterations in male reproductive organs (e.g., decreased weights, atrophy, changes in spermatogenesis), and decreases in reproductive potential (e.g., decreased implantations and increased post-implantation loss) and increases in fetal malformations when mated with untreated females [see Use in Specific Populations (8.3)].

1. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

{ "type": "p", "children": [], "text": "1. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html." }

Tablets:

{ "type": "p", "children": [], "text": "Tablets:" }

{ "type": "", "children": [], "text": "" }

Store tablets at 20°C to 25°C (68°F to77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "Store tablets at 20°C to 25°C (68°F to77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].\n" }

Cyclophosphamide is an antineoplastic product. Follow special handling and disposal procedures.1

{ "type": "p", "children": [], "text": "Cyclophosphamide is an antineoplastic product. Follow special handling and disposal procedures.1\n" }

Advise the patient of the following:

{ "type": "p", "children": [], "text": "Advise the patient of the following:" }

Myelosuppression, Immunosuppression, and Infections

{ "type": "p", "children": [], "text": "\nMyelosuppression, Immunosuppression, and Infections\n" }

{ "type": "", "children": [], "text": "" }

Urinary Tract and Renal Toxicity

{ "type": "p", "children": [], "text": "\nUrinary Tract and Renal Toxicity\n" }

{ "type": "", "children": [], "text": "" }

Cardiotoxicity

{ "type": "p", "children": [], "text": "\nCardiotoxicity\n" }

{ "type": "", "children": [], "text": "" }

Pulmonary Toxicity

{ "type": "p", "children": [], "text": "\nPulmonary Toxicity\n" }

{ "type": "", "children": [], "text": "" }

Embryo-Fetal Toxicity

{ "type": "p", "children": [], "text": "\nEmbryo-Fetal Toxicity\n" }

{ "type": "", "children": [], "text": "" }

Lactation

{ "type": "p", "children": [], "text": "\nLactation\n" }

{ "type": "", "children": [], "text": "" }

Infertility

{ "type": "p", "children": [], "text": "\nInfertility\n" }

{ "type": "", "children": [], "text": "" }

Common Adverse Reactions

{ "type": "p", "children": [], "text": "\nCommon Adverse Reactions\n" }

{ "type": "", "children": [], "text": "" }

Hydration and Important Administration Instructions

{ "type": "p", "children": [], "text": "\nHydration and Important Administration Instructions\n" }

{ "type": "", "children": [], "text": "" }

Baxter

{ "type": "p", "children": [], "text": "\nBaxter\n" }

Manufactured forBaxter Healthcare CorporationDeerfield, IL 60015 USAMade in ItalyProduct of Germany

{ "type": "p", "children": [], "text": "Manufactured forBaxter Healthcare CorporationDeerfield, IL 60015 USAMade in ItalyProduct of Germany" }

Baxter is a registered trademark of Baxter International Inc.

{ "type": "p", "children": [], "text": "Baxter is a registered trademark of Baxter International Inc." }

HA-30-01-863

{ "type": "p", "children": [], "text": "HA-30-01-863" }

Revised August 2020

{ "type": "p", "children": [], "text": "Revised August 2020" }

{ "type": "", "children": [], "text": "" }

Barcode

{ "type": "p", "children": [], "text": "\nBarcode\n" }

100 Tablets NDC 10019-982-09

{ "type": "p", "children": [], "text": "100 Tablets NDC 10019-982-09" }

Cyclophosphamidetablets, USP 25 mg

{ "type": "p", "children": [], "text": "\nCyclophosphamidetablets, USP 25 mg \n" }

CYTOTOXIC AGENT Wear gloves when handling container and tablets

{ "type": "p", "children": [], "text": "\nCYTOTOXIC AGENT\nWear gloves when handling container and tablets" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

Baxter Logo Manufactured for Baxter Healthcare Corporation Deerfield, IL 60015 USAMade in ItalyProduct of Germany

{ "type": "p", "children": [], "text": "\nBaxter Logo\nManufactured for\nBaxter Healthcare Corporation\nDeerfield, IL 60015 USAMade in ItalyProduct of Germany" }

Each tablet contains 25 mgof cyclophosphamide, USP.

{ "type": "p", "children": [], "text": "Each tablet contains 25 mgof cyclophosphamide, USP." }

Recommended Dosage:See prescribing information.

{ "type": "p", "children": [], "text": "Recommended Dosage:See prescribing information." }

Swallow tablets whole.Do not cut, chew, or crush tablets.

{ "type": "p", "children": [], "text": "\nSwallow tablets whole.Do not cut, chew, or crush tablets.\n" }

Dispense in a tight containeras defined in the USP.

{ "type": "p", "children": [], "text": "Dispense in a tight containeras defined in the USP." }

Store at or below 25°C (77°F)[see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "\nStore at or below 25°C (77°F)[see USP Controlled Room Temperature].\n" }

GS1-1D Barcodefor position only(01) GTIN

{ "type": "p", "children": [], "text": "GS1-1D Barcodefor position only(01) GTIN" }

USA HA-65-01-7443001068

{ "type": "p", "children": [], "text": "USA HA-65-01-7443001068" }

LotExp.YYYY-MM

{ "type": "p", "children": [], "text": "LotExp.YYYY-MM" }

{ "type": "", "children": [], "text": "" }

GTIN:S/N:LOT:EXP.:YYYY-MM

{ "type": "p", "children": [], "text": "GTIN:S/N:LOT:EXP.:YYYY-MM" }

GS1-2DBarcodefor positiononly

{ "type": "p", "children": [], "text": "GS1-2DBarcodefor positiononly" }

(01) GTIN

{ "type": "p", "children": [], "text": "(01) GTIN" }

Barcode

{ "type": "p", "children": [], "text": "Barcode" }

NDC 10019-982-01

{ "type": "p", "children": [], "text": "NDC 10019-982-01" }

Cyclophosphamidetablets, USP 25 mg

{ "type": "p", "children": [], "text": "\nCyclophosphamidetablets, USP 25 mg \n" }

CYTOTOXIC AGENT Wear gloves when handlingcontainer and tablets

{ "type": "p", "children": [], "text": "\nCYTOTOXIC AGENT\nWear gloves when handlingcontainer and tablets" }

100 tabletsRx only

{ "type": "p", "children": [], "text": "100 tabletsRx only" }

Baxter Logo Manufactured for Baxter Healthcare Corporation Deerfield, IL 60015 USAMade in ItalyProduct of Germany

{ "type": "p", "children": [], "text": "\nBaxter Logo\nManufactured for\nBaxter Healthcare Corporation\nDeerfield, IL 60015 USAMade in ItalyProduct of Germany" }

3001067

{ "type": "p", "children": [], "text": "3001067" }

CYTOTOXIC AGENT

{ "type": "p", "children": [], "text": "\nCYTOTOXIC AGENT\n" }

Each tablet contains 25 mgof cyclophosphamide, USP.

{ "type": "p", "children": [], "text": "Each tablet contains 25 mgof cyclophosphamide, USP." }

Recommended Dosage:See prescribing information.

{ "type": "p", "children": [], "text": "Recommended Dosage:See prescribing information." }

Swallow tablets whole. Do not cut, chew, or crush tablets.

{ "type": "p", "children": [], "text": "\nSwallow tablets whole. Do not cut, chew, or crush tablets.\n" }

Dispense in a tight container as defined in the USP.

{ "type": "p", "children": [], "text": "Dispense in a tight container as defined in the USP." }

Store at 20°C to 25°C (68°F to 77°) [see USP Controlled Room Temperature]

{ "type": "p", "children": [], "text": "Store at 20°C to 25°C (68°F to 77°) [see USP Controlled Room Temperature]" }

HA-80-02-730 USA

{ "type": "p", "children": [], "text": "HA-80-02-730\nUSA\n" }

NDC 10019-982-01

{ "type": "p", "children": [], "text": "NDC 10019-982-01" }

Cyclophosphamidetablets, USP 25 mg

{ "type": "p", "children": [], "text": "\nCyclophosphamidetablets, USP 25 mg \n" }

CYTOTOXIC AGENT Wear gloves when handlingcontainer and tablets

{ "type": "p", "children": [], "text": "\nCYTOTOXIC AGENT\nWear gloves when handlingcontainer and tablets" }

100 tabletsRx only

{ "type": "p", "children": [], "text": "100 tabletsRx only" }

Baxter Logo Manufactured for Baxter Healthcare Corporation Deerfield, IL 60015 USAMade in ItalyProduct of Germany

{ "type": "p", "children": [], "text": "\nBaxter Logo\nManufactured for\nBaxter Healthcare Corporation\nDeerfield, IL 60015 USAMade in ItalyProduct of Germany" }

NDC 10019-982-01

{ "type": "p", "children": [], "text": "NDC 10019-982-01" }

Cyclophosphamidetablets, USP 25 mg

{ "type": "p", "children": [], "text": "\nCyclophosphamidetablets, USP 25 mg \n" }

100 tablets

{ "type": "p", "children": [], "text": "100 tablets" }

Barcode

{ "type": "p", "children": [], "text": "Barcode" }

AB14

{ "type": "p", "children": [], "text": "AB14" }

NDC 10019-982-01

{ "type": "p", "children": [], "text": "NDC 10019-982-01" }

Cyclophosphamidetablets, USP 25 mg

{ "type": "p", "children": [], "text": "\nCyclophosphamidetablets, USP 25 mg \n" }

CYTOTOXIC AGENT Wear gloves when handlingcontainer and tablets

{ "type": "p", "children": [], "text": "\nCYTOTOXIC AGENT\nWear gloves when handlingcontainer and tablets" }

100 tablets Rx only

{ "type": "p", "children": [], "text": "100 tablets Rx only" }

2638B6200

{ "type": "p", "children": [], "text": "2638B6200" }

{ "type": "", "children": [], "text": "" }

Barcode

{ "type": "p", "children": [], "text": "Barcode" }

100 TABLETS NDC 10019-984-09

{ "type": "p", "children": [], "text": "100 TABLETS NDC 10019-984-09" }

Cyclophosphamidetablets, USP 50 mg

{ "type": "p", "children": [], "text": "\nCyclophosphamidetablets, USP 50 mg \n" }

CYTOTOXIC AGENT Wear gloves when handling container and tablets

{ "type": "p", "children": [], "text": "\nCYTOTOXIC AGENT\nWear gloves when handling container and tablets" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

Baxter Logo Manufactured for Baxter Healthcare Corporation Deerfield, IL 60015 USAMade in ItalyProduct of Germany

{ "type": "p", "children": [], "text": "\nBaxter Logo\nManufactured for\nBaxter Healthcare Corporation\nDeerfield, IL 60015 USAMade in ItalyProduct of Germany" }

Each tablet contains 50 mgof cyclophosphamide, USP.

{ "type": "p", "children": [], "text": "Each tablet contains 50 mgof cyclophosphamide, USP." }

Recommended Dosage:See prescribing information.

{ "type": "p", "children": [], "text": "Recommended Dosage:See prescribing information." }

Swallow tablets whole.Do not cut, chew, or crush tablets.

{ "type": "p", "children": [], "text": "\nSwallow tablets whole.Do not cut, chew, or crush tablets.\n" }

Dispense in a tight containeras defined in the USP.

{ "type": "p", "children": [], "text": "Dispense in a tight containeras defined in the USP." }

Store at or below 25°C (77°F)[see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "\nStore at or below 25°C (77°F)[see USP Controlled Room Temperature].\n" }

GS1-1D Barcodefor position only(01) GTIN

{ "type": "p", "children": [], "text": "GS1-1D Barcodefor position only(01) GTIN" }

USA HA-65-01-7453001069

{ "type": "p", "children": [], "text": "USA HA-65-01-7453001069" }

LotExp.YYYY-MM

{ "type": "p", "children": [], "text": "LotExp.YYYY-MM" }

{ "type": "", "children": [], "text": "" }

GTIN:S/N:LOT:EXP.:YYYY-MM

{ "type": "p", "children": [], "text": "GTIN:S/N:LOT:EXP.:YYYY-MM" }

GS1-2DBarcodefor positiononly(01) GTIN

{ "type": "p", "children": [], "text": "GS1-2DBarcodefor positiononly(01) GTIN" }

Barcode

{ "type": "p", "children": [], "text": "Barcode" }

NDC 10019-984-01

{ "type": "p", "children": [], "text": "NDC 10019-984-01" }

Cyclophosphamidetablets, USP 50 mg

{ "type": "p", "children": [], "text": "\nCyclophosphamidetablets, USP 50 mg\n" }

CYTOTOXIC AGENT Wear gloves when handling containerand tablets

{ "type": "p", "children": [], "text": "\nCYTOTOXIC AGENT\nWear gloves when handling containerand tablets" }

100 tabletsRx only

{ "type": "p", "children": [], "text": "100 tabletsRx only" }

Baxter Logo Manufactured for Baxter Healthcare Corporation Deerfield, IL 60015 USAMade in ItalyProduct of Germany

{ "type": "p", "children": [], "text": "\nBaxter Logo\nManufactured for\nBaxter Healthcare Corporation\nDeerfield, IL 60015 USAMade in ItalyProduct of Germany" }

3001066

{ "type": "p", "children": [], "text": "\n3001066\n" }

CYTOTOXIC AGENT

{ "type": "p", "children": [], "text": "\nCYTOTOXIC AGENT\n" }

Each tablet contains 50 mg ofcyclophosphamide, USP.

{ "type": "p", "children": [], "text": "Each tablet contains 50 mg ofcyclophosphamide, USP." }

Recommended Dosage:See prescribing information.

{ "type": "p", "children": [], "text": "Recommended Dosage:See prescribing information." }

Swallow tablets whole.Do not cut, chew, or crush tablets.

{ "type": "p", "children": [], "text": "\nSwallow tablets whole.Do not cut, chew, or crush tablets.\n" }

Dispense in a tight container asdefined in the USP.

{ "type": "p", "children": [], "text": "Dispense in a tight container asdefined in the USP." }

Store at 20°C to 25°C (68°F to 77°) [see USP Controlled RoomTemperature]

{ "type": "p", "children": [], "text": "Store at 20°C to 25°C (68°F to 77°) [see USP Controlled RoomTemperature]" }

HA-80-02-731USA

{ "type": "p", "children": [], "text": "\nHA-80-02-731USA\n" }

NDC 10019-984-01

{ "type": "p", "children": [], "text": "NDC 10019-984-01" }

Cyclophosphamidetablets, USP 50 mg

{ "type": "p", "children": [], "text": "\nCyclophosphamidetablets, USP 50 mg\n" }

CYTOTOXIC AGENT Wear gloves when handling containerand tablets

{ "type": "p", "children": [], "text": "\nCYTOTOXIC AGENT\nWear gloves when handling containerand tablets" }

100 tabletsRx only

{ "type": "p", "children": [], "text": "100 tabletsRx only" }

Baxter Logo Manufactured for Baxter Healthcare Corporation Deerfield, IL 60015 USAMade in ItalyProduct of Germany

{ "type": "p", "children": [], "text": "\nBaxter Logo\nManufactured for\nBaxter Healthcare Corporation\nDeerfield, IL 60015 USAMade in ItalyProduct of Germany" }

NDC 10019-984-01

{ "type": "p", "children": [], "text": "NDC 10019-984-01" }

Cyclophosphamidetablets, USP 50 mg

{ "type": "p", "children": [], "text": "\nCyclophosphamidetablets, USP 50 mg\n" }

100 tablets

{ "type": "p", "children": [], "text": "100 tablets" }

Barcode

{ "type": "p", "children": [], "text": "Barcode" }

F4

{ "type": "p", "children": [], "text": "F4" }

NDC 10019-984-01

{ "type": "p", "children": [], "text": "NDC 10019-984-01" }

Cyclophosphamidetablets, USP 50 mg

{ "type": "p", "children": [], "text": "\nCyclophosphamidetablets, USP 50 mg\n" }

CYTOTOXIC AGENT Wear gloves when handling containerand tablets

{ "type": "p", "children": [], "text": "\nCYTOTOXIC AGENT\nWear gloves when handling containerand tablets" }

100 tabletsRx only

{ "type": "p", "children": [], "text": "100 tabletsRx only" }

2638B6201

{ "type": "p", "children": [], "text": "2638B6201" }