CYCLOPHOSPHAMIDE Drug Interactions: What You Need to Know

INTERACTIONS

7.1 Effect of Other Drugs on Cyclophosphamide Exposure 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.

7.2 Drugs That Potentiate Cyclophosphamide Toxicities 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: Myelosuppression and/or immunosuppression <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> Nephrotoxicity including hemorrhagic cystitis <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span> Cardiotoxicity <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span> Pulmonary toxicity <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span> Secondary malignancies <span class="opacity-50 text-xs">[see Warnings and Precautions (5.5) ]</span> Hepatotoxicity including liver necrosis and VOD <span class="opacity-50 text-xs">[see Warnings and Precautions(5.6) ]</span>

7.3 Effect of Cyclophosphamide on Other Drugs 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).

7.1 Effect of Other Drugs on Cyclophosphamide Exposure 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.

7.2 Drugs That Potentiate Cyclophosphamide Toxicities 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: Myelosuppression and/or immunosuppression <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> Nephrotoxicity including hemorrhagic cystitis <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span> Cardiotoxicity <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span> Pulmonary toxicity <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span> Secondary malignancies <span class="opacity-50 text-xs">[see Warnings and Precautions (5.5) ]</span> Hepatotoxicity including liver necrosis and VOD <span class="opacity-50 text-xs">[see Warnings and Precautions(5.6) ]</span>

7.3 Effect of Cyclophosphamide on Other Drugs 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).

Severe Hypersensitivity Cyclophosphamide Injection is contraindicated in patients who have 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.

Urinary Outflow Obstruction Cyclophosphamide

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

• Severe hypersensitivity to cyclophosphamide ( 4 )
• Urinary outflow obstruction ( 4 )

AND PRECAUTIONS

• Myelosuppression, Immunosuppression, Bone Marrow Failure, and Infections: Severe immunosuppression may lead to serious and sometimes fatal infections. Close hematological monitoring is required. ( 5.1 )
• Urinary Tract and Renal Toxicity: Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria can occur. Urotoxicity can be fatal. Exclude or correct any urinary tract obstructions prior to treatment. ( 5.2 )
• Cardiotoxicity: Myocarditis, myopericarditis, pericardial effusion, arrythmias and congestive heart failure, which may be fatal, have been reported. Monitor patients, especially those with risk factors for cardiotoxicity or pre-existing cardiac disease. ( 5.3 )
• Pulmonary Toxicity: Pneumonitis, pulmonary fibrosis and pulmonary veno-occlusive disease leading to respiratory failure may occur. Monitor patients for signs and symptoms of pulmonary toxicity. ( 5.4 )
• Secondary Malignancies: Have been reported in patients treated with cyclophosphamide containing regimens. ( 5.5 )
• Veno-occlusive Liver Disease: Fatal outcome can occur. ( 5.6 )
• Alcohol Content: This product is not indicated for use in pediatric patients. The alcohol content in a dose of Cyclophosphamide Injection may affect the central nervous system. This may include impairment of a patient's ability to drive or use machines immediately after infusion. ( 5.7 )
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. Advise males with female partners of reproductive potential to use effective contraception ( 5.8 , 8.1 , 8.3 )

5.1 Myelosuppression, Immunosuppression, Bone Marrow Failure and Infections Cyclophosphamide can cause myelosuppression (leukopenia, neutropenia, thrombocytopenia and anemia), bone marrow failure, and severe immunosuppression which may lead to serious and sometimes fatal infections, including sepsis and septic shock. Latent infections can be reactivated <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span>. 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

Injection should not be administered to patients with neutrophils ≤1,500/mm3 and platelets < 50,000/mm 3 .

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.

5.2 Urinary Tract and Renal Toxicity Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria have been reported with cyclophosphamide. Medical and/or surgical supportive treatment may be required to treat protracted cases of severe hemorrhagic cystitis.

Discontinue Cyclophosphamide

Injection 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

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.

5.3 Cardiotoxicity Myocarditis, myopericarditis, pericardial effusion including cardiac tamponade, and congestive heart failure, which may be fatal, have been reported with cyclophosphamide therapy. Supraventricular arrhythmias (including atrial fibrillation and flutter) and ventricular arrhythmias (including severe QT prolongation associated with ventricular tachyarrhythmia) have been reported after treatment with regimens that included cyclophosphamide. The risk of cardiotoxicity may be increased with high doses of cyclophosphamide, in patients with advanced age, and in patients with previous radiation treatment to the cardiac region and/or previous or concomitant treatment with other cardiotoxic agents. 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.

5.4 Pulmonary Toxicity Pneumonitis, pulmonary fibrosis, pulmonary veno-occlusive disease and other forms of pulmonary toxicity leading to respiratory failure have been reported during and following treatment with cyclophosphamide. Late onset pneumonitis (greater than 6 months after start of cyclophosphamide) appears to be associated with increased mortality. Pneumonitis may develop years after treatment with cyclophosphamide. Monitor patients for signs and symptoms of pulmonary toxicity.

5.5 Secondary Malignancies Cyclophosphamide is genotoxic <span class="opacity-50 text-xs">[see Nonclinical Toxicology ( 13.1 )]</span> . 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.

5.6 Veno-occlusive Liver Disease Veno-occlusive liver disease (VOD) including fatal outcome has been reported in patients receiving cyclophosphamide-containing regimens. A cytoreductive regimen in preparation for bone marrow transplantation that consists of Cyclophosphamide Injection 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.

5.7 Alcohol Content Due to the alcohol and propylene glycol content of this product, this cyclophosphamide product is not indicated for use in pediatric patients <span class="opacity-50 text-xs">[see Indications and Usage ( 1 ) and Use in Specific Populations ( 8.4 )]</span> . If treatment with cyclophosphamide is indicated for a pediatric patient, use a different cyclophosphamide product. 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 this cyclophosphamide product at 25 mg/kg/day delivers 146.2 mg/kg of ethanol. For a patient with a BSA of 70 kg, this would deliver 10.23 grams of ethanol. Other cyclophosphamide products may have a different amount of alcohol or no alcohol. Monitor patients for signs of alcohol intoxication during and after treatment. Counsel patients about the possible effects of the alcohol content in this cyclophosphamide product, including possible effects on the central nervous system.

5.8 Embryo-Fetal Toxicity Based on its mechanism of action and published reports of effects in pregnant patients or animals, Cyclophosphamide Injection can cause fetal harm when administered to a pregnant woman <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 ), Clinical Pharmacology ( 12.1 ), and Nonclinical Toxicology ( 13.1 )]</span> . 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 )]</span>. 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 )]</span> .

5.9 Infertility Male and female reproductive function and fertility may be impaired in patients being treated with Cyclophosphamide Injection. Cyclophosphamide interferes with oogenesis and spermatogenesis. It may cause sterility in both sexes. Development of sterility appears to depend on the dose of cyclophosphamide, duration of therapy, and the state of gonadal function at the time of treatment. Cyclophosphamide-induced sterility may be irreversible in some patients. Advise patients on the potential risks for infertility <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.3 , 8.4 )]</span> .

5.10 Impairment of Wound Healing Cyclophosphamide may interfere with normal wound healing.

5.11 Hyponatremia Hyponatremia associated with increased total body water, acute water intoxication, and a syndrome resembling SIADH (syndrome of inappropriate secretion of antidiuretic hormone), which may be fatal, has been reported.