Cyclophosphamide

Use is not recommended in patients receiving concurrent cyclophosphamide therapy.

Cyclophosphamide causes marked and persistent inhibition of cholinesterase activity. Prolonged apnea may occur with concurrent depolarizing muscle relaxants within 10 days of treatment.

Increases bone marrow suppression in patients with neoplastic disease (except leukemia). Blood count monitoring recommended.

Increased pulmonary toxicity may result from combined effect with cyclophosphamide.

Increased nephrotoxicity may result from combined effect with cyclophosphamide.

Increased hematotoxicity and immunosuppression may result from combined effect with cyclophosphamide.

Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine Monoamine Oxidase Inhibitors, Nonselective Beta-Adrenergic Antagonists, or Tricyclic Antidepressants: May produce severe, prolonged hypertension ( 7 ) Phenothiazines and Butyrophenones: May reduce or reverse the pressor effect of epinephrine ( 7 )

Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: Table 5: Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, ropivacaine, procaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate, Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine Monoamine Oxidase Inhibitors, Nonselective Beta-adrenergic Antagonists, or Tricyclic Antidepressants : May produce severe, prolonged hypertension ( 7 ) Phenothiazines and butyrophenones : May reduce or reverse the pressor effect of epinephrine ( 7 )

Increased risk of hepatotoxicity including liver necrosis with concomitant use.

Increased risk of methemoglobinemia when concurrently exposed to this antineoplastic oxidizing agent with local anesthetics.

Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, isofamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine (e.g., Bupivacaine Hydrochloride and Epinephrine Injection) are used in patients during or following the administration of potent inhalation anesthetics [see Warnings and Precautions (5.13) ] .

Increased risk of methemoglobinemia when local anesthetics are used concomitantly with antineoplastic agents.

Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine (e.g., Bupivacaine Hydrochloride and Epinephrine Injection) are used in patients during or following the administration of potent inhalation anesthetics [see Warnings and Precautions (5.13) ] .

Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine (e.g., MARCAINE WITH EPINEPHRINE) are used in patients during or following the administration of potent inhalation anesthetics [see Warnings and Precautions (5.13) ] .

Increased incidence of hepatic veno-occlusive disease and mucositis has been reported.

Cyclophosphamide may decrease serum concentrations of cyclosporine, resulting in increased incidence of graft-versus-host disease.

Increased cardiotoxicity may result from combined effect with cyclophosphamide.

Concurrent use may result in increased cardiotoxicity when used with daunorubicin hydrochloride.

Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, isofamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine (e.g., Bupivacaine Hydrochloride and Epinephrine Injection) are used in patients during or following the administration of potent inhalation anesthetics [see Warnings and Precautions (5.13) ] .

Reports suggest increased risk of pulmonary toxicity in patients treated with cyclophosphamide and G-CSF.

Reports suggest increased risk of pulmonary toxicity in patients treated with cyclophosphamide and GM-CSF.

Increased nephrotoxicity; acute water intoxication has been reported with concomitant use of indomethacin and cyclophosphamide.

Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, isofamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine (e.g., Bupivacaine Hydrochloride and Epinephrine Injection) are used in patients during or following the administration of potent inhalation anesthetics [see Warnings and Precautions (5.13) ] .

Increased risk of methemoglobinemia when used concurrently with lidocaine.

Antineoplastic agent that may cause methemoglobinemia when used concomitantly with lidocaine patch 5%.

Antineoplastic agent that increases risk of methemoglobinemia when used concurrently with lidocaine and capsaicin patch.

Antineoplastic agent; increased risk of methemoglobinemia when concurrently exposed.

7.5 Drugs Associated with Methemoglobinemia Patients that are administered local anesthetics may be at increased risk of developing methemoglobinemia when concurrently exposed to the following oxidizing agents: Class Examples Nitrates/Nitrites nitroglycerin, nitroprusside, nitric oxide, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, rasburicase, ifosfamide, hydroxyurea Antibiotics dapsone, sulfonamides, nitrofurantoin, para‑aminosalicylic acid Antimalarials chloroquine, primaquine Anticonvulsants phenytoin, sodium valproate, phenobarbital Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if lidocaine solutions containing epinephrine are used in patients during or following the administration of potent inhalation anesthetics [see Warnings and Precautions (5.11) ] .

Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, isofamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing epinephrine are used in patients during or following the administration of potent inhalation anesthetics [see Warnings and Precautions (5.10) ] .

Increased risk of methemoglobinemia when local anesthetic is concurrently exposed to antineoplastic agents.

Concurrent exposure increases risk of methemoglobinemia in patients administered local anesthetics.

Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, isofamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine (e.g., Bupivacaine Hydrochloride and Epinephrine Injection) are used in patients during or following the administration of potent inhalation anesthetics [see Warnings and Precautions (5.13) ] .

Increased risk of methemoglobinemia; antineoplastic agents associated with methemoglobinemia when used with local anesthetics.

Increased risk of methemoglobinemia when used with lidocaine.

Increased risk of methemoglobinemia when lidocaine is concurrently exposed to antineoplastic agents.

Increased risk of methemoglobinemia when local anesthetics are concurrently exposed to antineoplastic agents.

Increased hematotoxicity and immunosuppression may result from combined effect; ACE inhibitors can cause leukopenia.

Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine are used in patients during or following the administration of potent inhalation anesthetics.

Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine are used in patients during or following the administration of potent inhalation anesthetics.

Concurrent exposure increases risk of methemoglobinemia in patients administered mepivacaine.

Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, isofamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine (e.g., Bupivacaine Hydrochloride and Epinephrine Injection) are used in patients during or following the administration of potent inhalation anesthetics [see Warnings and Precautions (5.13) ] .

Acute encephalopathy has been reported in a patient receiving cyclophosphamide and metronidazole.

Cyclophosphamide causes marked and persistent inhibition of cholinesterase activity, which may result in prolonged apnea if used within 10 days of general anesthesia.

Increased hematotoxicity and immunosuppression may result from combined effect with cyclophosphamide.

Increased hematotoxicity has been reported when cyclophosphamide was administered after paclitaxel infusion.

Increased cardiotoxicity may result from combined effect with cyclophosphamide.

Clinically Significant Drug Interactions Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: EXAMPLES OF DRUGS ASSOCIATED WITH METHEMOGLOBINEMIA: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic Agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine The administration of local anesthetic injections containing epinephrine or norepinephrine to patients receiving monoamine oxidase inhibitors, tricyclic antidepressants or phenothiazines may produce severe, prolonged hypotension or hypertension.

Clinically Significant Drug Interactions Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: EXAMPLES OF DRUGS ASSOCIATED WITH METHEMOGLOBINEMIA: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic Agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants Phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine Concurrent administration of vasopressor drugs and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents.

Concomitant use may increase concentration of cytotoxic metabolites and enhance toxicities of cyclophosphamide, including higher incidence of infections, neutropenia, and mucositis.

Increased risk of developing methemoglobinemia when concurrently exposed to cyclophosphamide.

Concomitant use may increase the risk of thromboembolic complications when used with cyclophosphamide-containing chemotherapy regimen.

Increased cardiotoxicity may result from combined effect with cyclophosphamide.

Combined use intensifies toxicity rather than enhancing therapeutic response. If sequential use is necessary, recovery from first agent must be complete before starting second.

Increased cardiotoxicity may result from combined effect with cyclophosphamide.

Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine are used in patients during or following the administration of potent inhalation anesthetics.

Increased risk of methemoglobinemia when used concurrently with triethanolamine salicylate.

Increased risk of methemoglobinemia when used with Trubrexa Transdermal Patch.

Increased hematotoxicity and immunosuppression may result from combined effect with cyclophosphamide.

Patients who are administered local anesthetics, including bupivacaine liposome injectable suspension, may be at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants Phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine Bupivacaine Bupivacaine HCl administered together with bupivacaine liposome injectable suspension may impact the pharmacokinetic and/or physicochemical properties of bupivacaine liposome injectable suspension, and this effect is concentration dependent.

Increased risk of developing methemoglobinemia when concurrently exposed.

DRUG 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. 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 [ see Warnings and Precautions ( 5.1 ) ] • Nephrotoxicity including hemorrhagic cystitis [ see Warnings and Precautions ( 5.2 ) ] • Cardiotoxicity [ see Warnings and Precautions ( 5.3 ) ] • Pulmonary toxicity [ see Warnings and Precautions ( 5.4 ) ] • Secondary malignancies [ see Warnings and Precautions ( 5.5 ) ] • Hepatotoxicity including liver necrosis and VOD [ see Warnings and Precautions ( 5.6 ) ] 7.3 Effect of Cyclophosphamide on Other Drugs Metronidazole Acute encephalopathy has been reported in a patient receiving cyclophosphamide and metronidazole.

May increase glucose-lowering effect of glimepiride, increasing susceptibility to and/or intensity of hypoglycemia.

7.3 Drugs That May Cause Methemoglobinemia When Used with PLIAGLIS Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine

Chemotherapy agent metabolized by CYP3A4; systemic exposure can increase with AKYNZEO; caution and monitoring advised.

Both increased and decreased warfarin effects have been reported in patients receiving warfarin and cyclophosphamide.

Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitroglycerin, nitroprusside, nitric oxide, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine

Suspected of causing SIADH; may increase pressor and antidiuretic effects of vasopressin. Hemodynamic monitoring recommended.

May cause SIADH, increasing pressor and antidiuretic effects of vasopressin. Hemodynamic monitoring recommended; adjust vasopressin dose as needed.

Both increased and decreased warfarin effect have been reported in patients receiving warfarin and cyclophosphamide. Anticoagulant activity should be monitored closely.

Administered concomitantly in clinical trials without evidence of clinically meaningful effect on belimumab pharmacokinetics.

Rituximab did not alter systemic exposure to cyclophosphamide in patients with CLL, and concomitant administration did not alter rituximab pharmacokinetics in RA patients.

Cyclophosphamide is a prodrug , metabolized by CYP450 including CYP3A to an active metabolite. The metabolism of cyclophosphamide may be inhibited by amiodarone.

Antineoplastic agents (e.g., cyclophosphamide, methotrexate): Concomitant use of thiazide diuretics may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects.

Therefore, the potential exists for a drug interaction between bupropion and drugs that are substrates or inhibitors of the CYP2B6 isoenzyme (e.g., orphenadrine, thiotepa, and cyclophosphamide).

cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.

Other Drug Interactions Cyclophosphamide is an inactive prodrug and is converted to its active metabolite in part by CYP3A. The rate of metabolism and the leukopenic activity of cyclophosphamide are reportedly increased by chronic coadministration of CYP3A4 inducers. There is a potential for increased cyclophosphamide toxicity when coadministered with carbamazepine.

Plasma cholinesterase activity may be decreased by chronic administration of certain monoamine oxidase inhibitors, oral contraceptives, glucocorticoids, antimyasthenics (neostigmine), cyclophosphamide, and possibly thiotepa.

7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on Cyclophosphamide Exposure Protease Inhibitors Cyclophosphamide is a pro-drug that is activated by cytochrome P450s [see Clinical Pharmacology (12.3) ]. Use of protease inhibitor-based regimens was found to be associated with a higher Incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. 7.2 Drugs that Can Potentiate Cyclophosphamide Toxicities Combined or sequential use of Cyclophosphamide Injection and other drugs or agents with similar toxicities to Cyclophosphamide Injection and can potentiate these effects and are listed in Table 2 .

) Cyclophosphamide : Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine.

Cancer Chemotherapy: Cyclophosphamide Plasma concentrations may be decreased.

Palonosetron did not inhibit the antitumor activity of the five chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C) in murine tumor models.

The following are examples of medications that may increase the glucose-lowering effect of sulfonylureas including glimepiride, a component of pioglitazone and glimepiride tablets, increasing the susceptibility to and/or intensity of hypoglycemia: oral anti-diabetic medications, pramlintide acetate, insulin, angiotensin converting enzyme (ACE) inhibitors, H2 receptor antagonists, fibrates, propoxyphene, pentoxifylline, somatostatin analogs, anabolic steroids and androgens, cyclophosphamide, phenyramidol, guanethidine, fluconazole, sulfinpyrazone, tetracyclines, clarithromycin, disopyramide, quinolones, and those drugs that are highly protein-bound, such as fluoxetine, nonsteroidal anti-inflammatory drugs, salicylates, sulfonamides, chloramphenicol, coumarins, probenecid and monoamine oxidase inhibitors.

Prasugrel is not anticipated to have significant effect on the pharmacokinetics of drugs that are primarily metabolized by CYP2B6, such as halothane, cyclophosphamide, propofol, and nevirapine.

Rasburicase does not metabolize allopurinol, cytarabine, methylprednisolone, methotrexate, 6-mercaptopurine, thioguanine, etoposide, daunorubicin, cyclophosphamide or vincristine in vitro.

In patients with CLL, RITUXAN did not alter systemic exposure to fludarabine or cyclophosphamide. In clinical trials of patients with RA, concomitant administration of methotrexate or cyclophosphamide did not alter the pharmacokinetics of rituximab.

In patients with CLL, rituximab did not alter systemic exposure to fludarabine or cyclophosphamide. In clinical trials of patients with RA, concomitant administration of methotrexate or cyclophosphamide did not alter the pharmacokinetics of rituximab.

In patients with CLL, rituximab did not alter systemic exposure to fludarabine or cyclophosphamide. In clinical trials of patients with RA, concomitant administration of methotrexate or cyclophosphamide did not alter the pharmacokinetics of rituximab.

The effect of tamoxifen on metabolism and excretion of other antineoplastic drugs, such as cyclophosphamide and other drugs that require mixed function oxidases for activation, is not known.

Antineoplastic Agents (e.g., Cyclophosphamide, Methotrexate) Concomitant use of thiazide diuretics may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects.

The absorption of verapamil can be reduced by the cyclophosphamide, oncovin, procarbazine, prednisone (COPP) and the vindesine, adriamycin, cisplatin (VAC) cytotoxic drug regimens.