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Interactions with Methotrexate

Contents
Fluconazole, Didanosine, Valproic acid, Isoniazid, Itraconazole, Ketoconazole, Pyrazinamide, Zalcitabine, Methyldopa, Fosinopril, Lovastatin, Niacin (nicotinic acid), Pravastatin, Quinapril, Tamoxifen, Ramipril, Lisinopril, Simvastatin, Dantrolene, Isotretinoin (oral), Fluvastatin, Stavudine, Nefazodone, Divalproex sodium, Moexipril, Acarbose, Lamivudine, Ritonavir, Trandolapril, Terbinafine, Nevirapine, Zafirlukast, Atorvastatin, Dacarbazine, Flutamide (oral), Propylthiouracil, Testosterone injection, Testosterone topical (patches and gel), Testosterone buccal system, Stanozolol, Oxandrolone, Clotrimazole, Lomustine, Carmustine, Thioguanine, Aldesleukin, Naltrexone (oral), Naltrexone (injection), Nilutamide, Bicalutamide, Tretinoin, Riluzole, Gemcitabine, Tizanidine, Cerivastatin, Tolcapone, Fenofibrate, Abacavir, Kava, Red yeast rice, Rosiglitazone (oral), Perindopril, Pioglitazone (oral), Tenofovir, Bosentan, Voriconazole, Atomoxetine, Rosuvastatin, Emtricitabine

If you are currently being treated with any of the following medications, you should not use Methotrexate without reading these interactions.

Palifermin

ADJUST DOSING INTERVAL: In a clinical trial, administration of palifermin within 24 hours of chemotherapy resulted in increased severity and duration of oral mucositis, presumably due to increased sensitivity of the rapidly dividing epithelial cells in the immediate post-chemotherapy period.

MANAGEMENT: Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy.

Pegfilgrastim

ADJUST DOSING INTERVAL: The safety and efficacy of granulocyte colony-stimulating factor (G-CSF) given simultaneously with cytotoxic chemotherapy have not been established. Theoretical concerns exist regarding their concomitant administration because (G-CSF) stimulates myeloid cell proliferation while cytotoxic agents primarily target rapidly dividing cells.

MANAGEMENT: Because of the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy, the manufacturer recommends that pegfilgrastim not be given from 14 days before until 24 hours after cytotoxic chemotherapy administration.

Filgrastim, Sargramostim

ADJUST DOSING INTERVAL: The safety and efficacy of hematopoietic growth factors such as colony-stimulating factors (G-CSF and GM-CSF) and stem cell factors (SCF) given simultaneously with cytotoxic chemotherapy have not been established. Theoretical concerns exist regarding their concomitant administration because hematopoietic growth factors stimulate myeloid cell proliferation while cytotoxic agents primarily target rapidly dividing cells.

MANAGEMENT: Because of the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy, hematopoietic growth factors should not be used within 24 hours before or 24 hours after cytotoxic chemotherapy administration.

Sodium bicarbonate, Potassium citrate

Alkalinization of the urine can increase the renal elimination of methotrexate. The pharmacologic effects of methotrexate may be decreased. No special clinical interventions appear to be necessary. In some cases of methotrexate toxicity, this interaction may prove beneficial.

Hydroxychloroquine

A small, single dose pharmacokinetic study has indicated that coadministration of methotrexate and chloroquine may lead to a reduced bioavailability of methotrexate. Clinical evidence of this effect has not been established. Consider monitoring the patient more closely for reduced efficacy and adjust the dose of methotrexate if needed.

Cidofovir

CONTRAINDICATED: Coadministration of cidofovir with other nephrotoxic agents may potentiate the risk of renal impairment. Dose-related nephrotoxicity is the major toxicity of cidofovir. Cases of acute renal failure resulting in dialysis and/or contributing to death have occurred with as few as one or two doses of cidofovir.

MANAGEMENT: The use of cidofovir in combination with other potentially nephrotoxic agents (e.g., aminoglycosides, polypeptide and polymyxin antibiotics, vancomycin, amphotericin B, adefovir, tenofovir, foscarnet, cisplatin, gallium nitrate, lithium, mesalamine, certain immunosuppressants, intravenous bisphosphonates, intravenous pentamidine, high intravenous dosages of methotrexate, high dosages of nonsteroidal anti-inflammatory agents) is considered contraindicated. Such agents should be discontinued for at least seven days prior to starting therapy with cidofovir. Initiation of cidofovir is also contraindicated in patients with a serum creatinine greater than 1.5 mg/dL, a calculated creatinine clearance at or below 55 mL/min, or a urine protein greater than or equal to 100 mg/dL.

Mumps virus vaccine, Yellow fever vaccine, Varicella virus (chickenpox) vaccine, Rotavirus vaccine, live (oral), Influenza virus vaccine (nasal), Zoster vaccine live

CONTRAINDICATED: The administration of live, attenuated virus or bacterial vaccines during immunosuppressant or intense antineoplastic therapy may be associated with a risk of disseminated infection due to enhanced replication of vaccine virus or bacteria in the presence of diminished immune competence. Patients may be immunosuppressed if they have recently received or are receiving alkylating agents, antimetabolites, radiation, some antirheumatic agents, high dosages of corticosteroids or adrenocorticotropic agents, or long-term topical or inhaled corticosteroids. These patients may also have increased adverse reactions and decreased or suboptimal immunologic response to vaccines.

MANAGEMENT: In general, live virus or bacterial vaccines should not be used in patients receiving immunosuppressive therapy or cancer chemotherapy. Vaccination should be deferred until after such therapy is discontinued for at least 3 months in most cases. In patients who have recently been vaccinated, such therapy should not be initiated for at least 2 weeks.

Smallpox vaccine

CONTRAINDICATED: The administration of live smallpox virus vaccine during immunosuppressant or intense antineoplastic therapy may be associated with a risk of disseminated infection due to enhanced replication of vaccine virus in the presence of diminished immune competence. Patients may be immunosuppressed if they have recently received or are receiving alkylating agents, antimetabolites, radiation, some antirheumatic agents, high dosages of corticosteroids or adrenocorticotropic agents, or long-term topical or inhaled corticosteroids. These patients may also have increased adverse reactions and decreased or suboptimal immunologic response to vaccines. Cases of generalized vaccinia and progressive vaccinia have been reported in HIV patients who received the smallpox vaccine.

MANAGEMENT: Routine, nonemergency smallpox vaccination is contraindicated in patients receiving immunosuppressive therapy or cancer chemotherapy. Vaccination should be deferred until after such therapy is discontinued for at least 3 months in most cases. In patients who have recently been vaccinated, such therapy should not be initiated for at least 2 weeks. Household contacts of immunosuppressed patients should also not be vaccinated. However, there are no absolute contraindications to vaccination if a high-risk exposure has occurred. In an outbreak emergency, smallpox vaccine is recommended for all persons, regardless of medical conditions. The risk for experiencing serious complications from the vaccine should be weighed against the risk of acquiring a potentially fatal smallpox infection.

Clozapine

CONTRAINDICATED: The use of clozapine with other potentially myelotoxic agents may increase the risk and severity of hematologic toxicity due to additive pharmacodynamic effects. Clozapine alone may cause agranulocytosis, and the risk may theoretically increase when coadministered with other myelotoxic therapy. Agents that may be significantly myelotoxic include antineoplastic drugs, some anticonvulsant and antirheumatic medications, albendazole, chloramphenicol, colchicine, dapsone, interferons, linezolid, pentamidine, procainamide, and zidovudine.

MANAGEMENT: Clozapine should not be used concomitantly with other agents having a well-known potential to cause agranulocytosis or otherwise suppress bone marrow function.

Acitretin

CONTRAINDICATED: The use of etretinate (of which acitretin is the active metabolite) in combination with methotrexate has been associated with an increased risk of hepatitis. The exact mechanism of interaction is unknown but does not appear to be pharmacokinetically related. These agents individually have been associated with the development of hepatotoxicity and may have additive effects during coadministration.

MANAGEMENT: The use of acitretin, or etretinate, in combination with methotrexate is considered contraindicated.

Dapsone topical

Folate antagonists have been reported to possibly increase the likelihood of hematologic reactions (e.g., agranulocytosis, anemia) associated with oral dapsone. The effect on topically administered dapsone is unknown. Exposure to dapsone from the recommended topical dose for acne vulgaris is about 1% of that from a 100 mg oral dose.

Charcoal

GENERALLY AVOID: Charcoal may reduce the absorption of many drugs and can absorb enterohepatically circulated drugs. Clinical utility may be the reduction either of the effects or of the toxicity of many drugs. Activated charcoal may absorb any therapeutic agents administered while it is in the gastrointestinal tract.

MANAGEMENT: The regular ingestion of charcoal should be avoided by patients requiring maintenance medications. If concomitant use is necessary, the dosage or route of administration may need to be altered.

Leflunomide (oral)

GENERALLY AVOID: Coadministration of methotrexate and leflunomide has resulted in an increased risk for hepatotoxicity. One small study reported a 2 to 3 fold elevation in liver enzymes in 16% of patients receiving this combination. Serious hepatic reactions have also been reported in patients being concurrently treated with other hepatotoxic agents, including methotrexate. The risk of additive hematologic toxicity may also be increased.

MANAGEMENT: The concurrent use of leflunomide and methotrexate is not recommended. Since the active metabolite of leflunomide may remain present in the body for up to 2 years, the cholestyramine washout procedure is recommended when changing from leflunomide to methotrexate. Liver enzyme levels should be obtained before beginning leflunomide and monthly during therapy. If ALT increases to 2 to 3 times normal, the dose should be reduced and liver enzymes should be monitored weekly. If ALT increases to more than 3 times normal, leflunomide should be discontinued and the washout procedure should be instituted.

Fluconazole, Didanosine, Valproic acid, Isoniazid, Itraconazole, Ketoconazole, Pyrazinamide, Zalcitabine, Methyldopa, Fosinopril, Lovastatin, Niacin (nicotinic acid), Pravastatin, Quinapril, Tamoxifen, Ramipril, Lisinopril, Simvastatin, Dantrolene, Isotretinoin (oral), Fluvastatin, Stavudine, Nefazodone, Divalproex sodium, Moexipril, Acarbose, Lamivudine, Ritonavir, Trandolapril, Terbinafine, Nevirapine, Zafirlukast, Atorvastatin, Dacarbazine, Flutamide (oral), Propylthiouracil, Testosterone injection, Testosterone topical (patches and gel), Testosterone buccal system, Stanozolol, Oxandrolone, Clotrimazole, Lomustine, Carmustine, Thioguanine, Aldesleukin, Naltrexone (oral), Naltrexone (injection), Nilutamide, Bicalutamide, Tretinoin, Riluzole, Gemcitabine, Tizanidine, Cerivastatin, Tolcapone, Fenofibrate, Abacavir, Kava, Red yeast rice, Rosiglitazone (oral), Perindopril, Pioglitazone (oral), Tenofovir, Bosentan, Voriconazole, Atomoxetine, Rosuvastatin, Emtricitabine

GENERALLY AVOID: Coadministration of methotrexate with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Methotrexate, especially at higher doses or with prolonged treatment, has been associated with hepatotoxicity including acute hepatitis, chronic fibrosis, necrosis, cirrhosis, and liver enzyme elevations.

MANAGEMENT: Concomitant use is generally not recommended unless the potential benefit outweighs the risk of hepatotoxicity. Baseline and regular monitoring of hepatic function is recommended.

Minocycline, Demeclocycline

GENERALLY AVOID: Concomitant use of tetracyclines may elevate serum methotrexate concentrations. The mechanism may involve displacement of methotrexate from its binding to plasma proteins. Individual cases of methotrexate toxicity have been reported with doxycycline and tetracycline.

MANAGEMENT: Concomitant use of tetracyclines should be avoided in patients on high-dose methotrexate regimens. If broad-spectrum antibiotic coverage is needed during high-dose methotrexate therapy, the use of an alternate anti-infective is recommended. If these drugs must be used together, close monitoring for evidence of serious methotrexate toxicity is recommended.

Aspirin (oral), Salsalate, Magnesium salicylate, Aspirin (rectal), Diflunisal

GENERALLY AVOID: Salicylates may interfere with the renal elimination of methotrexate and may displace it from binding sites. The pharmacologic effect and toxicity of methotrexate may be increased. Patients receiving high-dose methotrexate are at a greater risk of developing toxicity.

MANAGEMENT: If these agents must be used concomitantly, caution should be exercised and the patient should be monitored closely for signs and symptoms of bone marrow suppression and nephrotoxicity. Patients should be advised to report possible symptoms of toxicity including nausea, vomiting, diarrhea, stomatitis, sore throat, chills, fever, rash, unusual bruising or bleeding, jaundice, dark urine, swelling of the extremities, or shortness of breath to their physician. Patients should also be counseled to avoid any other over-the-counter salicylate products.

Clofarabine

GENERALLY AVOID: Since the liver is a known target organ for clofarabine toxicity (i.e., hepatomegaly, jaundice), concomitant use of agents known to induce hepatotoxicity may potentiate the risk of liver injury.

MANAGEMENT: The use of clofarabine with other agents that are potentially hepatotoxic (e.g., alcohol; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, HMG-CoA reductase inhibitors, and niacin; nucleoside reverse transcriptase inhibitors; thiazolidinediones) should be avoided if possible.

Sulfasalazine, Sulfadiazine, Sulfisoxazole

GENERALLY AVOID: Sulfonamides may decrease the renal clearance of methotrexate. Serum levels of free methotrexate and the risk of bone marrow suppression may be increased. Sulfonamides may also displace methotrexate from plasma protein binding sites, which may further increase serum methotrexate levels and the risk of toxicity. Methotrexate toxicity has also been reported in patients receiving low weekly doses.

MANAGEMENT: This combination should be avoided. If patients do receive methotrexate and a sulfonamide, the complete blood count should be monitored periodically, and the clinician should look for signs and symptoms of anemia, leukopenia, megaloblastosis, and even pancytopenia. Patients should be advised to report possible symptoms of toxicity including nausea, vomiting, diarrhea, stomatitis, sore throat, chills, fever, rash, unusual bruising or bleeding, jaundice, dark urine, swelling of the extremities, or shortness of breath to their physician.

Trimethoprim

GENERALLY AVOID: The concomitant use of methotrexate and trimethoprim may potentiate the risk of severe myelosuppression and megaloblastic anemia due to additive or synergistic effects involving folate antagonism. The interaction has been reported primarily with sulfamethoxazole-trimethoprim but has also occurred with trimethoprim alone. Most cases involve the elderly, often in association with renal impairment. In one case report, an 81-year-old woman receiving low-dose methotrexate (7.5 mg/week) for rheumatoid arthritis developed fatal pancytopenia following the addition of trimethoprim. The dosage of trimethoprim had been 100 mg/day for nearly two months but was increased to 200 mg/day due to suspected urinary tract infection one week prior to hospitalization. The patient's bone marrow failed to recover despite treatment with folinic acid and granulocyte colony stimulating factor, and she died of bronchopneumonia one week after admission.

MANAGEMENT: The concomitant use of trimethoprim and methotrexate, even at low dosages, should generally be avoided if possible. If the combination is given, close monitoring for hematologic toxicity is recommended, particularly in the elderly. Folate supplementation may be necessary in some cases. Patients should be advised to notify their physician if they experience signs and symptoms of bone marrow depression or anemia such as fever, chills, sore throat, easy bruising or bleeding, pallor, dizziness, fatigue, lethargy, sore mouth or tongue, and tingling in hands or feet.

Alefacept

GENERALLY AVOID: The use of alefacept with other immunosuppressive or myelosuppressive agents may increase the risk of infections. Agents that may be significantly myelo- or immunosuppressive include antineoplastic agents, radiation, zidovudine, linezolid, some antirheumatic agents, high dosages of corticosteroids or adrenocorticotropic agents (greater than 10 mg/day to 1 mg/kg/day, whichever is less, of prednisone or equivalent for more than 2 weeks), and long-term topical or inhaled corticosteroids.

MANAGEMENT: Patients receiving other immunosuppressive or myelosuppressive agents or phototherapy should not be treated with alefacept because of the possibility of excessive immunosuppression. The duration of the period following treatment with alefacept before one should consider starting other immunosuppressive therapy has not been evaluated.

Anakinra (injectable)

GENERALLY AVOID: The use of anakinra with other immunosuppressive or myelosuppressive agents may increase the risk of infections. Anakinra alone may cause neutropenia and serious infections due to interleukin-1 receptor blockade, and the risk may be increased when coadministered with other immunosuppressive therapy. Agents that may be significantly myelo- or immunosuppressive include antineoplastic agents, radiation, zidovudine, linezolid, some antirheumatic agents, high dosages of corticosteroids or adrenocorticotropic agents (greater than 10 mg/day to 1 mg/kg/day, whichever is less, of prednisone or equivalent for more than 2 weeks), and long-term topical or inhaled corticosteroids.

MANAGEMENT: The safety and efficacy of anakinra in immunosuppressed patients have not been established. Until more information is available, anakinra should preferably not be administered to immunosuppressed patients, or else it should be undertaken with extreme caution. Anakinra should be discontinued if neutropenia or serious infection occur.

Efalizumab

GENERALLY AVOID: The use of efalizumab with other immunosuppressive or myelosuppressive agents may increase the risk of infections. Efalizumab alone can cause serious infections requiring hospitalization, and the risk may theoretically increase when coadministered with other immunosuppressive therapy. Agents that may be significantly myelo- or immunosuppressive include antineoplastic agents, radiation, zidovudine, linezolid, some antirheumatic agents, high dosages of corticosteroids or adrenocorticotropic agents (greater than 10 mg/day to 1 mg/kg/day, whichever is less, of prednisone or equivalent for more than 2 weeks), and long-term topical or inhaled corticosteroids.

MANAGEMENT: The safety and efficacy of efalizumab in combination with other immunosuppressive agents or phototherapy have not been evaluated. Patients receiving other immunosuppressive agents should not be treated with efalizumab because of the possibility of excessive immunosuppression. The duration of the period following treatment with efalizumab before one should consider starting other immunosuppressive therapy has not been evaluated.

Ganciclovir (oral and injectable), Valganciclovir

GENERALLY AVOID: The use of ganciclovir with other potentially myelotoxic agents may increase the risk and severity of hematologic toxicity due to additive pharmacodynamic effects. Ganciclovir alone may cause severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow depression and aplastic anemia, and the risk may theoretically increase when coadministered with other myelotoxic therapy. Agents that may be significantly myelotoxic include antineoplastic drugs, some anticonvulsant and antirheumatic medications, albendazole, chloramphenicol, colchicine, dapsone, interferons, linezolid, pentamidine, procainamide, and zidovudine.

MANAGEMENT: Ganciclovir or its prodrug, valganciclovir, should generally not be combined with other myelotoxic drugs unless the benefits are anticipated to outweigh the potential risks. Extreme caution is advised if they are used in patients who have recently received or are receiving treatment with myelotoxic drugs, and vice versa. Reduced dosages of one or more of the drugs may be required, and patient should be monitored for the development of severe hematologic adverse effects both during and after discontinuation of therapy.

Natalizumab

GENERALLY AVOID: The use of natalizumab with immunosuppressant, immunomodulating, or antineoplastic agents may increase the risk of infections including progressive multifocal leukoencephalopathy (PML), a severely disabling, potentially fatal opportunistic viral infection of the brain. In clinical trials, PML occurred in two of 1869 patients with multiple sclerosis treated with natalizumab for a median of 120 weeks and one of 1043 patients with Crohn's disease after eight doses of natalizumab. Both of the MS patients were receiving concomitant interferon beta therapy, and the third patient was immunocompromised due to recent treatment with azathioprine. However, the number of cases is too few and the number of patients treated too small to reliably conclude that the risk of PML is lower with natalizumab monotherapy.

MANAGEMENT: The safety and efficacy of natalizumab in combination with immunosuppressant, immunomodulating, antineoplastic or other myelosuppressive agents have not been evaluated. Patients receiving such agents should not be treated with natalizumab because of the possibility of increased risk of infections, including PML. However, short courses of corticosteroids may be given. All patients treated with natalizumab should be monitored closely and the drug discontinued immediately at the first sign or symptom suggestive of PML, although it is not known if early detection of PML and discontinuation of natalizumab will mitigate the disease.

Procarbazine

GENERALLY AVOID: Three cases of renal impairment have been reported following the combined use of high dose methotrexate and procarbazine (despite adequate standard precautions such as hydration and alkalinization of the urine). The specific mechanism of this interaction has not been reported. However, it has been theorized that procarbazine has a transient effect on kidneys, which alters the excretion of methotrexate. If high dose methotrexate is administered before recovery from this change, methotrexate excretion is delayed and subsequent prolonged exposure of the kidneys to methotrexate may result in further impairment of renal function.

MANAGEMENT: An interval of at least 72 hours is recommended between administration of the final dose of procarbazine and the beginning of high dose methotrexate administration.

Mercaptopurine

Methotrexate inhibits the hepatic metabolism of the thiopurines. Decreased first-pass metabolism and increased bioavailability result. The clinical significance of this interaction has not been determined and is probably insignificant with standard intermittent oral doses of methotrexate. Generally the combination has beneficial effects when used in the treatment of acute lymphoblastic leukemia.

Prednisolone, Dexamethasone, Hydrocortisone, Methylprednisolone, Prednisone, Cortisone, Triamcinolone (oral and injectable), Triamcinolone inhalation, Betamethasone, Fludrocortisone, Triamcinolone acetonide injection, Budesonide inhalation, Budesonide (oral)

MONITOR: Although they are often used together in clinical practice, limited data suggest that corticosteroids may increase the risk of methotrexate toxicity. Individual cases of severe and fatal bone marrow suppression and fatal systemic moniliasis have been reported. Data have been conflicting. A pediatric study found no increased methotrexate toxicity; however, hepatic enzyme elevations were noted. The mechanism is unknown.

MANAGEMENT: Close monitoring for signs and symptoms of bone marrow suppression and nephrotoxicity is advisable during concomitant administration. Patients should be advised to report possible symptoms of toxicity including nausea, vomiting, diarrhea, stomatitis, sore throat, chills, fever, rash, unusual bruising or bleeding, jaundice, dark urine, swelling of the extremities, or shortness of breath to their physician.

Chlorothiazide, Chlorthalidone, Hydrochlorothiazide, Indapamide, Metolazone

MONITOR: Antineoplastic-induced bone marrow suppression may be prolonged with concomitant thiazide administration. The mechanism is unknown. Thiazides have been associated with blood dyscrasias.

MANAGEMENT: Alternative antihypertensive therapy may be advisable. Hematological status should be closely monitored in patients receiving this combination.

Entecavir

MONITOR: Because entecavir is primarily eliminated by renal excretion, coadministration with drugs that affect renal function may alter the plasma concentrations of entecavir and/or the coadministered drug. In patients with renal impairment, the apparent oral clearance of entecavir has been shown to decrease as the creatinine clearance decreases. In a small pilot study consisting of nine liver transplant recipients on a stable dose of cyclosporine or tacrolimus, entecavir exposure was approximately 2-fold that in healthy subjects with normal renal function. Altered renal function contributed to the increase in entecavir exposure in these patients.

MANAGEMENT: Caution is advised if entecavir is prescribed in combination with potentially nephrotoxic drugs (e.g., aminoglycosides, polypeptide and polymyxin antibiotics, vancomycin, amphotericin B, adefovir, cidofovir, tenofovir, foscarnet, cisplatin, gallium nitrate, lithium, mesalamine, certain immunosuppressants, intravenous bisphosphonates, intravenous pentamidine, high intravenous dosages of methotrexate, high dosages of nonsteroidal anti-inflammatory agents). Renal function should be evaluated prior to and during therapy with entecavir. Dosage adjustment is required in patients with renal insufficiency (creatinine clearance below 50 mL/min) at baseline or during treatment in accordance with the manufacturer's product labeling.

Telbivudine

MONITOR: Because telbivudine is primarily eliminated by renal excretion, coadministration with drugs that affect renal function may alter the plasma concentrations of telbivudine and/or the coadministered drug.

MANAGEMENT: Caution is advised if telbivudine is prescribed in combination with potentially nephrotoxic drugs (e.g., aminoglycosides, polypeptide and polymyxin antibiotics, vancomycin, amphotericin B, adefovir, cidofovir, tenofovir, foscarnet, cisplatin, gallium nitrate, lithium, mesalamine, certain immunosuppressants, intravenous bisphosphonates, intravenous pentamidine, high intravenous dosages of methotrexate, high dosages of nonsteroidal anti-inflammatory agents). Renal function should be evaluated prior to and during therapy with telbivudine. Adjustment of dosing interval is required in patients with renal insufficiency (creatinine clearance below 50 mL/min) at baseline or during treatment in accordance with the manufacturer's product labeling.

Phenytoin (oral), Mephenytoin, Ethotoin

MONITOR: Cases have been reported in which patients receiving chemotherapy have experienced markedly reduced plasma phenytoin concentrations and seizures. Other hydantoins may interact with chemotherapy in a similar manner. The mechanism of this interaction has not been clearly established. One study has shown that the absorption of phenytoin decreases significantly. Phenytoin metabolism may also increase.

MANAGEMENT: It may be necessary to increase phenytoin dosage during chemotherapy and to decrease it after or between courses of chemotherapy. Intravenous phenytoin may be less likely to interact with chemotherapy. Careful monitoring of patients for seizure activity is recommended, as is monitoring of plasma phenytoin levels.

Adefovir

MONITOR CLOSELY: Coadministration of adefovir dipivoxil with other nephrotoxic agents may increase the risk and severity of nephrotoxicity due to additive effects on the kidney. Additionally, renal impairment secondary to the use of these agents may reduce the clearance of adefovir, which is primarily eliminated by renal excretion. The use of adefovir dipivoxil has been associated with dose-related nephrotoxicity characterized by a delayed onset of gradual increases in serum creatinine and decreases in serum phosphorus. Generally, the risk is low in patients with adequate renal function receiving 10 mg/day but increases with increasing dosage and in patients with underlying renal impairment.

MANAGEMENT: Caution is advised if adefovir dipivoxil must be used in patients who have recently received or are receiving treatment with other potentially nephrotoxic agents (e.g., aminoglycosides, polypeptide and polymyxin antibiotics, vancomycin, amphotericin B, cidofovir, tenofovir, foscarnet, cisplatin, gallium nitrate, lithium, mesalamine, certain immunosuppressants, intravenous bisphosphonates, intravenous pentamidine, high intravenous dosages of methotrexate, high dosages of nonsteroidal anti-inflammatory agents). Renal function should be evaluated prior to and during therapy with adefovir dipivoxil. Patients with renal insufficiency at baseline or during treatment may require dosage adjustment in accordance with the manufacturer's product labeling.

Tacrolimus (oral), Sirolimus

MONITOR CLOSELY: Coadministration of macrolide immunosuppressants with other nephrotoxic agents may increase the risk and severity of renal impairment due to additive effects on the kidney. No formal interaction studies have been performed. However, clinical experience in coadministration with cyclosporine indicates increased renal toxicity as evidenced by increased serum creatinine and decreased glomerular filtration rate. An interaction with ibuprofen resulting in acute renal failure was suspected in two liver transplant patients who had been stabilized on tacrolimus.

MANAGEMENT: Caution is advised if macrolide immunosuppressants must be used in patients who have recently received or are receiving treatment with other potentially nephrotoxic drugs (e.g., aminoglycosides, polypeptide and polymyxin antibiotics, vancomycin, amphotericin B, adefovir, cidofovir, tenofovir, foscarnet, cisplatin, cyclosporine, gallium nitrate, lithium, mesalamine, intravenous bisphosphonates, intravenous pentamidine, high intravenous dosages of methotrexate, high dosages of nonsteroidal anti-inflammatory agents). Renal function should be closely monitored both during and after discontinuation of therapy.

Thalidomide

MONITOR CLOSELY: Coadministration of thalidomide with glucocorticoids and/or antineoplastic agents in the treatment of malignancy may potentiate the risk of thromboembolism. The exact mechanism is unknown but likely multifactorial. Thalidomide alone has been associated with the development of deep-vein thrombosis (DVT), and malignancy itself is also a common cause. In a study of 100 patients receiving induction chemotherapy (combinations of dexamethasone, vincristine, doxorubicin, cyclophosphamide, etoposide, and cisplatin) for multiple myeloma, the addition of thalidomide was associated with an increased incidence of DVT compared to chemotherapy without thalidomide (28% vs. 4%). Administration of thalidomide was safely resumed in 75% of patients after initiation of appropriate anticoagulation therapy. In another study, 9 of 21 (43%) patients with metastatic renal cell carcinoma (RCC) receiving gemcitabine, 5-FU, and thalidomide developed venous thromboembolism, including one case of fatal cardiac arrest. This rate is substantially higher than the 3% rate observed in a group of 125 patients previously treated at the same institution with similar regimens of gemcitabine and 5-FU but without thalidomide. It is also higher than the 9% rate (12 of 140 patients) the investigators found in a review of published data from five RCC trials that used thalidomide therapy without concomitant cytotoxic therapy. Another study found a significant association of DVT with exposure to doxorubicin in patients receiving thalidomide. Specifically, 31 of 192 (16%) multiple myeloma patients treated with DT-PACE (a regimen of dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide) developed DVT, while only 1 of 40 (2.5%) did so on DCEP-T (similar to DT-PACE but without doxorubicin). The time to DVT was also significantly decreased with doxorubicin exposure. In a pooled analysis of 39 prospectively monitored clinical trials involving 1784 thalidomide-treated patients, the incidence of thromboembolism was 5% when thalidomide was used as a single agent, 13% when combined with corticosteroids (8% to 26% has been reported in individual studies with dexamethasone), and 17% when combined with chemotherapy. Among thalidomide-treated patients with multiple myeloma, thromboembolism rates ranged from a low of 1/30 among those treated with concomitant cyclophosphamide, etoposide, and cisplatin to a high of about 1/3 in those treated with doxorubicin-containing regimens.

MANAGEMENT: Close monitoring for DVT is recommended in patients who require thalidomide therapy in combination with glucocorticoids and/or cytotoxic agents. Limited data suggest that prophylactic anticoagulation with low-molecular weight heparin is effective and may be appropriate if not otherwise contraindicated. Low-dose warfarin (1 mg/day) has generally failed to demonstrate a significant protective effect, although full dose anticoagulation has shown efficacy. Aspirin may also be considered. Patients should be advised to seek medical attention if they experience symptoms that could indicate thromboembolism such as chest pain, shortness of breath, sudden loss of vision, and pain, redness or swelling in an extremity.

Amoxicillin, Carbenicillin, Oxacillin, Penicillin V, Bacampicillin, Cloxacillin, Dicloxacillin, Penicillin G potassium injection, Ticarcillin

MONITOR CLOSELY: Concomitant use of large doses of penicillins may elevate serum methotrexate concentrations. The mechanism may involve competitive inhibition of renal tubular secretion of methotrexate. In one study, methotrexate clearance reductions were 35%, 40%, and 66% with penicillin, ticarcillin, and piperacillin, respectively. Serious adverse effects, primarily hematologic, have been described with concurrent penicillins and high or low-dose methotrexate regimens. Fatalities have occurred with both types of methotrexate regimens.

MANAGEMENT: If a penicillin must be used concurrently, close monitoring of methotrexate serum concentrations and of the patient for evidence of serious methotrexate toxicity are recommended. Leucovorin rescue should be available. Methotrexate dose reductions may be necessary. If broad-spectrum antibiotic coverage is needed during high-dose methotrexate therapy, use of other antimicrobials may be preferable. Patients should be advised to promptly report symptoms including fever, chills, sore throat, bruising, bleeding, stomatitis, or malaise to their physician.

Flurbiprofen, Ketorolac, Mefenamic acid, Nabumetone, Piroxicam, Diclofenac, Etodolac, Oxaprozin, Meclofenamate

MONITOR CLOSELY: Nonsteroidal anti-inflammatory agents (NSAIDs) may interfere with the renal elimination of methotrexate. Pharmacologic effect and toxicity of methotrexate may be increased. Patients who are receiving high doses of methotrexate or who have renal impairment are at greater risk of developing toxicity. Fatalities have been reported. Weekly low-dose methotrexate has been used in combination with NSAIDs to treat rheumatic inflammatory diseases.

MANAGEMENT: Caution should be exercised with concomitant use of these agents, and the patient should be monitored closely for signs and symptoms of bone marrow suppression and nephrotoxicity. Patients should be advised to report possible symptoms of toxicity including nausea, vomiting, diarrhea, stomatitis, sore throat, chills, fever, rash, unusual bruising or bleeding, jaundice, dark urine, swelling of the extremities, or shortness of breath to their physician. Patients should also be counseled to avoid any other over-the-counter NSAID products.

Infliximab, Etanercept (injectable), Adalimumab

MONITOR CLOSELY: The use of tumor necrosis factor (TNF) blockers with other immunosuppressive or myelosuppressive agents may increase the risk of infections. Serious infections and sepsis, including fatalities, have been reported with the use of TNF blockers, particularly in patients on concomitant immunosuppressive therapy. Agents that may be significantly myelo- or immunosuppressive include antineoplastic agents, radiation, zidovudine, linezolid, some antirheumatic agents, high dosages of corticosteroids or adrenocorticotropic agents (greater than 10 mg/day to 1 mg/kg/day, whichever is less, of prednisone or equivalent for more than 2 weeks), and long-term topical or inhaled corticosteroids.

MANAGEMENT: Patients receiving a TNF blocker alone or with other immunosuppressive or myelosuppressive agents should be monitored closely for the development of infections. TNF blocker therapy should be discontinued if a serious infection or sepsis occurs.

Mesalamine (oral), Olsalazine, Mesalamine (rectal), Balsalazide

MONITOR: Coadministration of 5-aminosalicylate with other nephrotoxic agents may increase the risk and severity of nephrotoxicity due to additive effects on the kidney. The use of 5-aminosalicylate or its prodrugs has been associated with rare reports of renal impairment including minimal change nephropathy and acute or chronic interstitial nephritis. Animal studies have also shown the kidney to be the major target organ of 5-aminosalicylate toxicity. Renal lesions including granular and hyaline casts, tubular degeneration, tubular dilation, renal infarct, papillary edema, papillary necrosis, tubular necrosis, interstitial fibrosis, and interstitial nephritis have been observed with large doses.

MANAGEMENT: Caution is advised if 5-aminosalicylate preparations must be used in patients who have recently received or are receiving treatment with other potentially nephrotoxic agents (e.g., aminoglycosides, polypeptide and polymyxin antibiotics, vancomycin, amphotericin B, adefovir, cidofovir, foscarnet, cisplatin, gallium nitrate, lithium, certain immunosuppressants, intravenous bisphosphonates, intravenous pentamidine, high intravenous dosages of methotrexate, high dosages of nonsteroidal anti-inflammatory agents). Renal function should be evaluated prior to and during 5-aminosalicylate therapy.

Neomycin, Paromomycin

MONITOR: Coadministration of an oral aminoglycoside and methotrexate may lead to decreased gastrointestinal absorption of methotrexate which could result in reduced efficacy of methotrexate. The proposed mechanism is a malabsorption syndrome caused by oral aminoglycosides. It has been suggested that increased absorption could occur with kanamycin.

MANAGEMENT: Patients should be closely monitored for altered efficacy and safety of methotrexate. Consider the intravenous route of administration for methotrexate to avoid the interaction.

Interferon beta-1b, Interferon beta-1a

MONITOR: Coadministration of beta interferons with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Use of beta interferons has been associated with rare cases of liver injury, including autoimmune hepatitis and severe liver damage leading to hepatic failure, some of which required transplantation. In some cases, these events have occurred in the presence of other drugs that have been associated with hepatic injury. Symptoms of liver dysfunction typically began from 1 to 6 months following the initiation of therapy. Asymptomatic elevation of hepatic transaminases (particularly SGPT) have also been reported but is common with interferon therapy.

MANAGEMENT: The risk of hepatic injury should be considered when beta interferons are used in combination with other agents that are potentially hepatotoxic (e.g., alcohol; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, HMG-CoA reductase inhibitors, and niacin; nucleoside reverse transcriptase inhibitors; thiazolidinediones). Liver function tests should be monitored at regular intervals and the interferon dosage reduced if SGPT rises above 5 times the upper limit of normal. The dosage may be gradually re-escalated when enzyme levels return to normal. Patients should be advised to notify their physician if they experience signs and symptoms of hepatotoxicity such as fever, rash, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, and jaundice. If liver injury is suspected, interferon therapy should be promptly discontinued due to the potential for rapid progression to liver failure.

Etidronate, Pamidronate, Zoledronic acid, Ibandronate

MONITOR: Coadministration of bisphosphonates with other nephrotoxic agents may increase the risk and severity of renal impairment due to additive effects on the kidney. The use of bisphosphonates has been associated with nephrotoxicity manifested as deterioration of renal function and renal failure. Cases have primarily involved intravenous formulations of the drugs such as pamidronate and zoledronic acid, especially when they are administered too rapidly. The risk of hypocalcemia may also be increased, as drug-induced renal tubular damage can lead to renal loss of calcium and other electrolytes such as magnesium. Bisphosphonates alone often cause mild, asymptomatic hypocalcemia via inhibitive effects on bone resorption and possibly chelation of blood calcium.

MANAGEMENT: Caution is advised if pamidronate, zoledronic acid, or other intravenous formulations of bisphosphonates must be used in patients who have recently received or are receiving treatment with other potentially nephrotoxic agents (e.g., aminoglycosides, polypeptide and polymyxin antibiotics, vancomycin, amphotericin B, adefovir, cidofovir, tenofovir, foscarnet, cisplatin, gallium nitrate, lithium, mesalamine, certain immunosuppressants, intravenous pentamidine, high intravenous dosages of methotrexate, high dosages of nonsteroidal anti-inflammatory agents). Renal function and serum electrolytes should be monitored. Patients should have serum creatinine assessed prior to each treatment, and treatment should be withheld for renal deterioration. In those treated for bone metastases, treatment should not be resumed until renal function returns to baseline.

Pyrimethamine

MONITOR: Coadministration of pyrimethamine with antifolate or myelosuppressive agents may increase the risk of bone marrow depression. The mechanism is additive antifolate effects.

MANAGEMENT: Periodic clinical and laboratory monitoring for folic acid deficiency and/or bone marrow depression is advisable during concurrent use.

Enoxacin, Lomefloxacin, Norfloxacin, Ofloxacin, Sparfloxacin, Levofloxacin, Grepafloxacin, Trovafloxacin, Moxifloxacin, Gatifloxacin, Gemifloxacin

MONITOR: Coadministration with ciprofloxacin or other quinolones may increase the plasma concentrations of methotrexate. The exact mechanism of interaction is unknown but may involve competitive inhibition of the renal tubular secretion of methotrexate. In a case report of two pediatric patients treated with high-dose methotrexate, coadministration of ciprofloxacin was associated with delayed elimination of methotrexate resulting in severe toxicity. Both patients tolerated the methotrexate regimen and had normal drug clearance in the absence of ciprofloxacin. Limited data also suggest that chemotherapy with antineoplastic agents may reduce the plasma concentrations of orally administered quinolones. The proposed mechanism is decreased quinolone absorption secondary to alteration of intestinal mucosa by cancer chemotherapy. In six patients with newly diagnosed hematologic malignancy, treatment with various antineoplastic agents (cyclophosphamide, cytarabine, daunorubicin, doxorubicin, mitoxantrone, prednisolone, vincristine) decreased the mean peak serum concentration (Cmax) and area under the concentration-time curve (AUC 0 to 4 hours) of ciprofloxacin by approximately 46% each. Data are not available for other quinolone antibiotics, but the possibility of a similar interaction should be considered.

MANAGEMENT: Caution is advised if quinolones must be used with methotrexate. The authors of the case report recommend that ciprofloxacin and related antibiotics not be coadministered with high-dose methotrexate. During concomitant use, patients should be monitored for altered pharmacologic effects of both drugs and the dosage(s) adjusted accordingly if necessary.

Pemetrexed

MONITOR: Coadministration with drugs that are nephrotoxic may delay and/or decrease the clearance of pemetrexed, which is primarily eliminated unchanged by the kidney via glomerular filtration and active tubular secretion.

MANAGEMENT: Caution is advised if pemetrexed is used in patients who have recently received or are receiving treatment with potentially nephrotoxic drugs (e.g., aminoglycosides, polypeptide and polymyxin antibiotics, vancomycin, amphotericin B, adefovir, cidofovir, tenofovir, foscarnet, cisplatin, gallium nitrate, lithium, mesalamine, certain immunosuppressants, intravenous bisphosphonates, intravenous pentamidine, high intravenous dosages of methotrexate, high dosages of nonsteroidal anti-inflammatory agents). The potential for increased toxicity of pemetrexed such as bone marrow suppression should be considered. Renal function should be closely monitored during therapy. Pemetrexed should not be administered to patients whose creatinine clearance is below 45 mL/min.

Omeprazole, Lansoprazole, Rabeprazole, Pantoprazole, Esomeprazole

MONITOR: Coadministration with proton pump inhibitors (PPIs) may increase the serum concentrations of methotrexate (MTX) and its potentially active 7-hydroxy metabolite. The proposed mechanism is PPI inhibition of the active tubular secretion of MTX and 7-hydroxymethotrexate via renal H+/K+ ATPase pumps. The interaction was suspected in 2 case reports involving omeprazole and high-dose MTX cycles, where elimination of MTX was significantly delayed during cycles with omeprazole but became normal during subsequent cycles after omeprazole was discontinued or substituted with ranitidine. In another case, coadministration of pantoprazole and low-dose pulse MTX (15 mg IM once a week) resulted in severe myalgia and bone pain for several days following each of five MTX injections. The symptoms subsided dramatically and eventually disappeared after pantoprazole was replaced with ranitidine. A subsequent rechallenge led to reappearance of symptoms. Although the pharmacokinetics of MTX were not affected, systemic exposure (AUC) of 7-hydroxymethotrexate was significantly increased by 70% and half-life was doubled in the presence of pantoprazole.

MANAGEMENT: Proton pump inhibitor therapy should preferably be stopped several days prior to administration of methotrexate. If concomitant use is necessary, clinicians should consider the potential for interaction and closely monitor methotrexate serum levels and toxicity. Use of an H2 antagonist may also be an appropriate alternative. It is not known if the interaction occurs with low, oral doses of methotrexate used to treat rheumatoid arthritis.

Cyclosporine

MONITOR: Concomitant administration of cyclosporine and methotrexate may be associated with an increased risk of toxicity. In rheumatoid arthritis patients (n=20), the concentrations of methotrexate were increased by 30% and concentrations of the 7-hydroxy metabolite decreased by 80%. There was no significant change in cyclosporine concentrations (n=6). The mechanism is unknown.

MANAGEMENT: Close monitoring of cyclosporine and methotrexate concentrations, renal function, and liver enzymes is recommended during concurrent therapy. Dosage adjustments may be necessary. Patients should be advised to report any nausea, vomiting, mouth sores, diarrhea, abdominal pain, dizziness, fatigue, or headache.

Vancomycin

MONITOR: Concurrent or recent exposure to systemic vancomycin may significantly prolong the clearance of methotrexate (MTX) and increase the risk of toxicity. The mechanism is impaired renal excretion of MTX due to vancomycin-induced nephrotoxicity. In two patients with osteosarcoma receiving chemotherapy containing high-dose MTX (12 g/m2), the time for serum MTX levels to fall below 0.2 mcM/L increased from within 48-96 hours to 170-231 hours following therapy with vancomycin in the preceding 10 days, and this delay was associated with development of MTX toxicity. Both patients were found to have subclinical renal impairment as indicated by impaired glomerular filtration rates (GFRs). In subsequent cycles using an unmodified schedule, MTX cleared within 72 hours in both patients, and marked improvements in their GFR were noted.

MANAGEMENT: Methotrexate, particularly in high dosages, should be administered cautiously in patients who have recently received or are receiving treatment with intravenous vancomycin, even in the absence of overt renal impairment (e.g., abnormal BUN or serum creatinine). The author of the case report recommends assessing GFR in these patients to allow for dose modification of MTX if necessary. Patients should be monitored closely for development of MTX toxicity such as myelosuppression and mucositis.

Lamotrigine

MONITOR: Lamotrigine is an inhibitor of dihydrofolate reductase and may have additive effects with other dihydrofolate reductase inhibitors on rapidly proliferating tissues such as bone marrow. The risk of megaloblastic anemia and other hematologic adverse effects may theoretically be increased.

MANAGEMENT: Clinicians should consider the potential for increased risk of hematologic toxicity when lamotrigine is prescribed with other inhibitors of dihydrofolate reductase. Folate supplementation may be appropriate in some situations.

Caffeine citrate (oral)

MONITOR: Limited data suggest that consumption of greater than 180 mg/day of caffeine may interfere with the efficacy of methotrexate (MTX) in patients with rheumatoid arthritis. The exact mechanism of interaction is unknown but may be related to the antagonistic effect of caffeine on adenosine receptors, as anti-inflammatory properties of MTX is thought to result from the accumulation of adenosine. In a study of 39 patients treated with MTX 7.5 mg/week (without folate supplementation) for 3 months, patients with high caffeine intake (more than 180 mg/day) experienced significantly less improvement in morning stiffness and joint pain from baseline than patients with low caffeine intake (more than 120 mg/day). There were no significant differences between the responses of patients with moderate caffeine intake (120 to 180 mg/day) and those of the other 2 groups. In an interview of 91 patients treated with MTX, 26% of patients who discontinued the drug were regular coffee drinkers compared to only 2% of those still receiving the drug. Because treatment failure was the reason for MTX discontinuation in 80% of patients who discontinued, the investigators suggested that caffeine may have interfered with MTX efficacy.

MANAGEMENT: Until further information is available, the potential for interaction should be considered in patients who consume substantial amounts of caffeine and caffeine-containing foods and are prescribed methotrexate for rheumatoid arthritis. It may be appropriate to limit caffeine intake if an interaction is suspected in cases of treatment failure.

Theophylline

MONITOR: Methotrexate may reduce oral theophylline clearance. Intramuscular methotrexate (15 mg/kg weekly) has been reported to lead to a 19% decrease in theophylline clearance. The mechanism has not been described. Patients who are maintained on theophylline may exhibit toxicity if methotrexate is added to the regimen.

MANAGEMENT: The clinician should observe closely for alterations in theophylline serum levels and signs of toxicity. Patients should be advised to report any signs of theophylline toxicity including nausea, vomiting, diarrhea, headache, restlessness, insomnia, or irregular heartbeat.

Digoxin (oral)

MONITOR: Some antineoplastic agents have been associated with decreased gastrointestinal absorption of digoxin. The suspected mechanism is alteration of the gastrointestinal mucosa. The risk of an interaction is expected to be less with digoxin solution in capsules because absorption occurs rapidly in the upper GI tract.

MANAGEMENT: During coadministration, the patient should be monitored for digoxin effectiveness. Serum digoxin levels should be monitored and the digoxin dosage adjusted as necessary. Also, the clinician should be aware that the risk of digoxin toxicity is increased when an antineoplastic agent is discontinued or interrupted for longer than a few days.

Rabies vaccine, Meningococcal polysaccharide vaccine, Pneumococcal polysaccharide vaccine (PPV adult, 23-valent), Haemophilus influenzae type b (Hib) vaccine, Polio vaccine (IPV), Influenza virus vaccine (injectable), Hepatitis B vaccine, Tetanus toxoid vaccine, Japanese encephalitis virus vaccine, Hepatitis A vaccine, Mixed respiratory vaccine, Pneumococcal conjugate vaccine (PCV-pediatric only), 7-valent, Pneumococcal polysaccharides vaccine (PPV), 23-valent, Hepatitis A pediatric vaccine, Hepatitis A adult vaccine, Haemophilus b conjugate (HbOC) vaccine, Haemophilus b conjugate (PRP-OMP) vaccine, Haemophilus b conjugate (PRP-T) vaccine, Meningococcal conjugate vaccine, Rabies vaccine, human diploid cell, Rabies vaccine, purified chick embryo cell, Human papillomavirus vaccine

MONITOR: The administration of inactivated, killed, or otherwise non-infectious vaccines to immunosuppressed patients is generally safe but may be associated with a diminished or suboptimal immunologic response due to antibody inhibition. Such patients may include those who have recently received or are receiving immunosuppressive agents, antilymphocyte globulins, alkylating agents, antimetabolites, radiation, some antirheumatic agents, high dosages of corticosteroids or adrenocorticotropic agents (greater than 10 mg/day or 1 mg/kg/day, whichever is less, of prednisone or equivalent for more than 2 weeks), or long-term topical or inhaled corticosteroids.

MANAGEMENT: In general, the U.S. Department of Public Health Advisory Committee on Immunization Practices (ACIP) recommends that inactivated or killed vaccines be administered to non-HIV immunosuppressed patients according to the same guidelines as for healthy patients. However, higher dosages or more frequent boosters may be required in some cases. For Haemophilus influenzae b vaccine, some experts recommend that it be administered at least 2 weeks before starting or 3 months after discontinuing chemotherapy when used in patients with Hodgkin's disease. Vaccines may generally be administered to patients receiving corticosteroids as replacement therapy (e.g., for Addison's disease).

Oxaliplatin

MONITOR: Theoretically, coadministration with drugs that are nephrotoxic may delay and/or decrease the clearance of oxaliplatin, which is primarily eliminated unchanged by the kidney. However, formal studies have not been conducted.

MANAGEMENT: Caution is advised if oxaliplatin is used in patients who have recently received or are receiving treatment with potentially nephrotoxic drugs (e.g., aminoglycosides, polypeptide and polymyxin antibiotics, vancomycin, amphotericin B, adefovir, cidofovir, tenofovir, foscarnet, cisplatin, gallium nitrate, lithium, mesalamine, certain immunosuppressants, intravenous bisphosphonates, intravenous pentamidine, high intravenous dosages of methotrexate, high dosages of nonsteroidal anti-inflammatory agents). The potential for increased toxicity of oxaliplatin such as peripheral sensory neuropathies and neutropenia should be considered. Renal function should be closely monitored during therapy.

Aminolevulinic acid

MONITOR: Theoretically, photosensitivity reactions of actinic keratoses may be additively or synergistically increased in patients taking photosensitizing drugs during aminolevulinic acid therapy.

MANAGEMENT: The patient's response to photodynamic therapy should be monitored. Patients should be advised to avoid exposure to sunlight or bright indoor light during the period between application of aminolevulinic acid and photoactivation.

Alemtuzumab

MONITOR: The use of alemtuzumab with other immunosuppressive or myelosuppressive agents may increase the risk of infections. Alemtuzumab alone may cause severe and prolonged myelosuppression, lymphopenia, and rarely, fatal bone marrow aplasia/hypoplasia, autoimmune idiopathic thrombocytopenia, and autoimmune hemolytic anemia. Serious, sometimes fatal opportunistic infections have been reported, and the risk may theoretically increase when coadministered with other immunosuppressive therapy. Agents that may be significantly myelo- or immunosuppressive include antineoplastic agents, radiation, zidovudine, linezolid, some antirheumatic agents, high dosages of corticosteroids or adrenocorticotropic agents (greater than 10 mg/day to 1 mg/kg/day, whichever is less, of prednisone or equivalent for more than 2 weeks), and long-term topical or inhaled corticosteroids.

MANAGEMENT: Caution is advised if alemtuzumab must be used in patients who have recently received or are receiving treatment with other immunosuppressive or myelosuppressive drugs, and vice versa. The manufacturer recommends that single doses of alemtuzumab not exceed 30 mg and cumulative weekly doses not exceed 90 mg, since higher dosages are associated with an increased incidence of pancytopenia. Close clinical and laboratory monitoring for the development of severe hematologic adverse effects is recommended both during and after discontinuation of therapy.

Topotecan

MONITOR: The use of topotecan with other cytotoxic agents is likely to result in greater myelosuppression due to additive or synergistic pharmacologic effects. Severe neutropenia and neutropenic sepsis resulting in death were reported with topotecan and cisplatin.

MANAGEMENT: Caution is advised if topotecan is used with other cytotoxic agents. Dosage reductions may be required, and bone marrow function should be closely monitored. Patients should be advised to contact their doctor if they develop signs and symptoms of myelosuppression such as pallor, dizziness, fatigue, lethargy, easy bruising or bleeding, or signs of infection such as fever, chills, or sore throat.

Nitazoxanide

Nitazoxanide may increase the potential for toxicity of other highly plasma protein bound drugs. The mechanism of action is competition for plasma protein binding sites. Tizoxanide, its active metabolite, is over 99.9% plasma protein bound. The clinical significance is unknown. Caution is recommended when highly protein bound drugs with narrow therapeutic indices are administered concurrently. Additionally, total plasma concentrations should be interpreted cautiously, because a greater amount of free drug may be present.

Pegaspargase

Pegaspargase, a drug which inhibits protein synthesis and cell replication may interfere with the action of methotrexate, a drug that requires cell replication for its beneficial effect. However, these drugs are often used together in oncology drug treatment protocols. It is recommended that clinicians using these agents in a treatment protocol be completely familiar with the benefits and risks associated with their coadministration.

Vincristine

The concurrent administration of methotrexate and vincristine increases the cellular uptake of methotrexate. In one case study, administration of vincristine consistently increased the concentration of methotrexate in the cerebrospinal fluid to two and one-half times the baseline values. An animal study has concluded that the interaction may diminish the toxicity of methotrexate to nonmalignant cells.

Echinacea

Use of echinacea beyond 8 weeks may have hepatotoxic effects. The magnitude of echinacea's potential hepatotoxicity is unclear. However, caution is recommended if echinacea is to be taken for long periods of time concomitantly with other potentially hepatotoxic medications.

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