Sulfasalazine (sulfasalazine)

No dosing information is available for this tab.

Sulfasalazine conventional and delayed-release tablets are administered orally. The total daily dosage should be divided into equally divided doses, and, if possible, doses should be administered after meals.

Delayed-release sulfasalazine tablets should be swallowed whole.

Sulfasalazine shares the potential drug interactions of the sulfonamides. In addition, sulfasalazine may interact with other agents.

It has been postulated that concomitant use of anti-infectives may alter the action of sulfasalazine by altering intestinal flora and consequently sulfasalazine metabolism.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Antimicrobials/Live Typhoid Vaccine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The antimicrobial may be active against the organism in the live-vaccine. Antimicrobial therapy may prevent the vaccine organism from replicating enough to trigger an immune response.(1)

CLINICAL EFFECTS: Vaccination may be ineffective.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Do not give oral typhoid vaccine until 72 hours after the last dose of antimicrobial. If possible, to optimize vaccine effectiveness, do not start antibacterial drugs for 72 hours after the last dose of oral typhoid vaccine. A longer interval should be considered for long-acting antimicrobials, such as azithromycin.(3)

DISCUSSION: Because antimicrobial therapy may prevent sufficient vaccine-organism replication to generate an immune response, the manufacturer of live-attenuated typhoid vaccine and the Centers for Disease Control (CDC) state that the vaccine should not be administered to patients receiving antimicrobial therapy.(1-3)

Bcrp, Oatp1b1, And Oatp1b3 Substrates/Leniolisib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Leniolisib is an inhibitor of the BCRP, OATP1B1, and OATP1B3 transporters and may increase the absorption and/or decrease the elimination of drugs that are substrates of these transporters.(1)

CLINICAL EFFECTS: Concurrent use of leniolisib with drugs that are substrates of the BCRP, OATP1B1, and OATP1B3 transporters may result in increased toxicity of the substrate.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid coadministration of leniolisib with substrates of BCRP, OATP1B1, and OATP1B3.(1)

DISCUSSION: When co-administered, leniolisib increased rosuvastatin (a substrate of BCRP, OATP1B1, and OATP1B3) systemic exposure by 2-fold.(1) Substrates of BCRP, OATP1B1, and OATP1B3 that are linked to this monograph include: diclofenac, fluvastatin, glecaprevir, glyburide, imatinib, irinotecan, letermovir, lovastatin, methotrexate, mitoxantrone, momelotinib, paritaprevir, pitavastatin, pravastatin, repaglinide, simvastatin, and sulfasalazine.(1,2)

Selected Photosensitizers/Tretinoin-Mequinol

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Tretinoin, anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides are all known photosensitizers.(1)

CLINICAL EFFECTS: Concurrent use of tretinoin in patients taking anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides may increase the risk of phototoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer states that tretinoin-mequinol should not be administered to patients receiving photosensitizers including anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides.(1)

DISCUSSION: Because of the risk of increased photosensitivity, the US manufacturer states that tretinoin-mequinol should not be administered to patients receiving photosensitizers including anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), methotrexate, phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides.(1)

Sulfonamides/Methenamine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Methenamine is hydrolyzed to formaldehyde in acidic urine. Sulfonamides may form an insoluble precipitate with formaldehyde in the urine.(1,2)

CLINICAL EFFECTS: The concurrent administration of methenamine and sulfamethizole or sulfathiazole is likely to form a precipitate in the urine.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Methenamine should not be administered to patients receiving sulfonamides.(1-3)

DISCUSSION: Methenamine is hydrolyzed to formaldehyde in acidic urine. An in vitro study showed that addition of methenamine and mandelic acid to saturated solutions of sulfamethizole at pH 5.0 and 6.0 produced a precipitate in one hour.(4)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Agents That Affect Iodide/Radioactive Iodide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds can affect iodide protein binding and alter iodide pharmacokinetics and pharmacodynamics.(1)

CLINICAL EFFECTS: Compounds that affect iodide pharmacokinetics and pharmacodynamics may impact the effectiveness of radioactive iodide.(1)

PREDISPOSING FACTORS: Compounds that affect iodide pharmacokinetics and pharmacodynamics are expected to have the most impact during therapy using radioactive iodide. Diagnostic procedures would be expected to be impacted less.

PATIENT MANAGEMENT: Discuss the use of agents that affect iodide pharmacokinetics and pharmacodynamics with the patient's oncologist.(1) Because indocyanine green contains sodium iodide, the iodine-binding capacity of thyroid tissue may be reduced for at least one week following administration. Do not perform radioactive iodine uptake studies for at least one week following administration of indocyanine green.(2) The manufacturer of iopamidol states administration may interfere with thyroid uptake of radioactive iodine and decrease therapeutic and diagnostic efficacy. Avoid thyroid therapy or testing for up to 6 weeks post administration of iopamidol.(3)

DISCUSSION: Many agents interact with radioactive iodine. The average duration of effect is: anticoagulants - 1 week antihistamines - 1 week anti-thyroid drugs, e.g: carbimazole, methimazole, propylthiouracil - 3-5 days corticosteroids - 1 week iodide-containing medications, e.g: amiodarone - 1-6 months expectorants - 2 weeks Lugol solution - 3 weeks saturated solution of potassium iodine - 3 weeks vitamins - 10-14 days iodide-containing X-ray contrast agents - up to 1 year lithium - 4 weeks phenylbutazone - 1-2 weeks sulfonamides - 1 week thyroid hormones (natural or synthetic), e.g.: thyroxine - 4 weeks tri-iodothyronine - 2 weeks tolbutamide - 1 week topical iodide - 1-9 months (1)

Myelosuppressives That Affect Iodide/Sodium Iodide I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1) Many compounds can affect iodide protein binding and alter iodide pharmacokinetics and pharmacodynamics.

CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1) Compounds that affect iodide pharmacokinetics and pharmacodynamics may impact the effectiveness of radioactive iodide.(1,2)

PREDISPOSING FACTORS: Compounds that affect iodide pharmacokinetics and pharmacodynamics are expected to have the most impact during therapy using radioactive iodide. Diagnostic procedures would be expected to be impacted less.

PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1) Discuss the use of agents that affect iodide pharmacokinetics and pharmacodynamics with the patient's oncologist.(1,2)

DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1) Many agents interact with radioactive iodine. The average duration of effect is: anticoagulants - 1 week antihistamines - 1 week anti-thyroid drugs, e.g: carbimazole, methimazole, propylthiouracil - 3-5 days corticosteroids - 1 week iodide-containing medications, e.g: amiodarone - 1-6 months expectorants - 2 weeks Lugol solution - 3 weeks saturated solution of potassium iodine - 3 weeks vitamins - 10-14 days iodide-containing X-ray contrast agents - up to 1 year lithium - 4 weeks phenylbutazone - 1-2 weeks sulfonamides - 1 week thyroid hormones (natural or synthetic), e.g.: thyroxine - 4 weeks tri-iodothyronine - 2 weeks tolbutamide - 1 week topical iodide - 1-9 months (1,2)

Selected Bcrp Substrates/Darolutamide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Darolutamide inhibits BCRP, which may result in increased absorption of BCRP substrates.(1)

CLINICAL EFFECTS: Administration of darolutamide with BCRP substrates may result in elevated levels of and toxicity from these agents.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer recommends avoiding concurrent use of darolutamide with BCRP substrates when possible.

DISCUSSION: Concurrent administration of darolutamide with rosuvastatin increased the mean area-under-the-curve (AUC) and maximum concentration (Cmax) of rosuvastatin approximately 5-fold.(1) BCRP substrates linked to this monograph include: diclofenac, glyburide, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, sulfasalazine, and topotecan.(1-3)

Selected Bcrp Substrates/Oteseconazole

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Oteseconazole is an inhibitor of the BCRP transporter, which may result in increased absorption of BCRP substrates.(1)

CLINICAL EFFECTS: Administration of oteseconazole with BCRP substrates may result in elevated levels of and toxicity of the BCRP substrates.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of oteseconazole states that the lowest possible starting dose of the BCRP substrate should be used and to consider reducing the dose of the substrate drug according to the product labeling and monitor for adverse reactions.(1)

DISCUSSION: Oteseconazole increased the area-under-curve (AUC) and maximum concentration (Cmax) of rosuvastatin, a BCRP substrate, by 118% and 114%, respectively.(1) BCRP substrates linked to this monograph include: diclofenac, glyburide, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, and sulfasalazine.(1-2)

Selected Myelosuppressive Agents/Clozapine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clozapine and other myelosuppressive agents may be associated with neutropenia or agranulocytosis.(2)

CLINICAL EFFECTS: Moderate neutropenia, even if due to combination therapy, may require abrupt discontinuation of clozapine resulting in decompensation of the patient's psychiatric disorder (e.g. schizophrenia). The disease treated by the myelosuppressive agent may be compromised if myelosuppression requires dose reduction, delay, or discontinuation of the myelosuppressive agent. Undetected severe neutropenia or agranulocytosis may be fatal.

PREDISPOSING FACTORS: Low white blood counts prior to initiation of the myelosuppressive agent may increase risk for clinically significant neutropenia.

PATIENT MANAGEMENT: If a patient stabilized on clozapine therapy requires treatment with a myelosuppressive agent, the clozapine prescriber should consult with prescriber of the myelosuppressive agent (e.g. oncologist) to discuss treatment and monitoring options.(2) More frequent absolute neutrophil count (ANC) monitoring or treatment alternatives secondary to neutropenic episodes may need to be considered. The U.S. Food and Drug Administration (FDA) recommends that prescribers monitor patients' ANC according to the monitoring frequencies described in the prescribing information. Severe neutropenia remains a serious, potentially fatal risk that is greatest in the first several months of clozapine treatment. ANC monitoring can help identify neutropenia early to allow for timely intervention.(1-2) Australia, Canada, and U.K.: Clozapine is only available through a restricted distribution system which requires documentation of the ANC prior to dispensing. For most clozapine patients, clozapine treatment must be interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter. For patients with benign ethnic neutropenia (BEN), treatment must be interrupted for suspected clozapine-induced neutropenia < 500 cells/microliter.(2)

DISCUSSION: Concurrent use of clozapine and selected myelosuppressive agents may require more frequent ANC monitoring or consideration of treatment alternatives secondary to neutropenic episodes. Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(3-26)

Selected Myelosuppressive Agents/Deferiprone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1)

CLINICAL EFFECTS: Concurrent use of deferiprone and myelosuppressive agents may result in severe neutropenia or agranulocytosis, which may be fatal.

PREDISPOSING FACTORS: Agranulocytosis may be less common in patients receiving deferiprone for thalassemia, and more common in patients treated for other systemic iron overload conditions (e.g. myelodysplastic syndromes, sickle cell disease).(2,3) Inadequate monitoring appears to increase the risk for severe outcomes. Manufacturer post market surveillance found that in all fatal cases of agranulocytosis reported between 1999 and 2005, data on weekly white blood count (WBC) monitoring was missing. In three fatal cases, deferiprone was continued for two to seven days after the detection of neutropenia or agranulocytosis.(2)

PATIENT MANAGEMENT: If possible, discontinue one of the drugs associated with risk for neutropenia or agranulocytosis. If alternative therapy is not available, documentation and adherence to the deferiprone monitoring protocol is essential. Baseline absolute neutrophil count (ANC) must be at least 1,500/uL prior to starting deferiprone. Monitor ANC weekly during therapy. If infection develops, interrupt deferiprone therapy and monitor ANC more frequently. If ANC is less than 1,500/uL but greater than 500/uL, discontinue deferiprone and any other drugs possibly associated with neutropenia. Initiate ANC and platelet counts daily until recovery (i.e. ANC at least 1,500/uL). If ANC is less than 500/uL, discontinue deferiprone, evaluate patient and hospitalize if appropriate. Do not resume deferiprone unless potential benefits outweigh potential risks.(1)

DISCUSSION: Drugs linked to this monograph have an FDA Boxed Warning for risk of neutropenia, agranulocytosis, or pancytopenia, or have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(1-25) In pooled clinical studies submitted to the FDA, 6.1% of deferiprone patients met criteria for neutropenia and 1.7% of patients developed agranulocytosis.(1) The time to onset of agranulocytosis was highly variable with a range of 65 days to 9.2 years (median, 161 days).(3)

Selected Myelosuppressive Agents/Dipyrone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of dipyrone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1-29)

CLINICAL EFFECTS: Concurrent use of dipyrone with agents that cause bone marrow depression, including myelosuppressives, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding. Undetected severe neutropenia or agranulocytosis may be fatal.(1-29)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of dipyrone and myelosuppressive agents should be avoided. The European Medicines Agency states dipyrone is contraindicated in patients with a prior medical history of dipyrone-induced agranulocytosis (or from other pyrazolones/pyrazolidines), impaired bone marrow function or diseases of the hematopoietic system.(3) International labeling for dipyrone and methotrexate state that co-administration may increase the hematotoxicity of methotrexate, especially in elderly patients, and therefore should be avoided.(1-2) The European Medicines Agency advises if agranulocytosis is suspected with dipyrone, a complete blood count (including differential blood count) should be performed immediately, and treatment must be stopped while waiting for the results. If confirmed, treatment must not be reintroduced.(1-3)

DISCUSSION: A retrospective cohort study analyzed new users of dipyrone (n=444,972), non-steroidal anti-inflammatory drugs (n=3,814,367) which served as a reference cohort, and opioids-paracetamol (n=3,129,221) which was the negative control. During continuous treatment over a median of 37-40 days, 26 cases of hospitalized agranulocytosis occurred. With the assumption that agranulocytosis onset was 7 days prior to admission, the hazard ratio of agranulocytosis associated with dipyrone was 4.40 [0.90-21.57] compared to NSAIDs and 2.45 [0.68-8.83] compared to opioid-paracetamol. HR of neutropenia from dipyrone was 2.98 [1.57-5.65] compared to NSAIDs and not statistically significant compared to opioids-paracetamol. In a sensitivity analysis assuming that the onset of agranulocytosis was the date of hospitalization, the HR of dipyrone-induced agranulocytosis was 7.20 [95% confidence interval: 1.92-26.99] compared to NSAIDs and 3.31 [1.17-9.34] compared to opioids-paracetamol. Agranulocytosis was very rare but more than 4 times more common with dipyrone than other analgesics.(4) In a review of 1,448 reports of agranulocytosis attributed to dipyrone, patients with fatal outcomes were older and more often had also received methotrexate compared to those with non-fatal outcomes (odds ratio: 5.18; 95% confidence interval: 3.06-8.78).(5) Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(2,6-26)

Selected Oral Bcrp Substrates/Oral Tedizolid

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Oral tedizolid may may inhibit Breast Cancer Resistance Protein (BCRP) in the intestine, which may result in increased absorption of orally administered BCRP substrates.(1-3)

CLINICAL EFFECTS: Concurrent use of oral tedizolid may result in elevated levels of and toxicity from orally administered BCRP substrates.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, consider interrupting therapy with orally administered BCRP substrates during therapy with oral tedizolid. If concurrent therapy is warranted, monitor patients for toxicity.(1-3)

DISCUSSION: Orally administered tedizolid (200 mg) increased the area-under-curve (AUC) and maximum concentration (Cmax) of rosuvastatin (10 mg) by 70% and 55%, respectively.(1-3) BCRP substrates include: imatinib, lapatinib, methotrexate, rosuvastatin, sulfasalazine, and topotecan.(1-3)

Selected Photosensitizers/Aminolevulinic Acid

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Aminolevulinic acid, anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides are all known photosensitizers.(1)

CLINICAL EFFECTS: Concurrent use of aminolevulinic acid in patients taking anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides may increase the risk of phototoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer states that aminolevulinic acid should be avoided in patients receiving photosensitizers including anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides for 24 hours before and after administration of aminolevulinic acid.(1)

DISCUSSION: Because of the risk of increased photosensitivity, the US manufacturer states that aminolevulinic acid should be avoided in patients receiving photosensitizers including anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides for 24 hours before and after administration of aminolevulinic acid.(1)

Selected Photosensitizers/Methoxsalen

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Methoxsalen causes photosensitivity due to residual drug which is present in all parts of the skin from photopheresis. Anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides are other known photosensitizers.(1)

CLINICAL EFFECTS: Concurrent use of methoxsalen in patients taking anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides may increase the risk of phototoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of methoxsalen states that concurrent use of methoxsalen with anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides should be avoided.(1)

DISCUSSION: All patients who have received methoxsalen become photosensitive. It is unknown what the risk of photosensitivity reactions is when methoxsalen is used concurrently with other photosensitizing agents.(1)

Selected Photosensitizers/Porfimer

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Porfimer causes photosensitivity due to residual drug which is present in all parts of the skin. Anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides are other known photosensitizers.(1)

CLINICAL EFFECTS: Concurrent use of porfimer in patients taking anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides may increase the risk of phototoxicity.(1)

PREDISPOSING FACTORS: Patients with any hepatic impairment and patients with severe renal impairment have reduced drug elimination and may remain photosensitive for 90 days or longer.(1)

PATIENT MANAGEMENT: The US manufacturer of porfimer states that concurrent use of porfimer with photosensitizers including anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides should be avoided.(1) Since the photosensitive effect of porfimer may persist for at least 30 days (and for 90 days in some patients), it would be prudent to avoid other photosensitizing agents for at least 30 days after administration of porfimer.

DISCUSSION: All patients who have received porfimer become photosensitive. It is unknown what the risk of photosensitivity reactions is when porfimer is used concurrently with other photosensitizing agents. When porfimer was used in clinical trials, photosensitivity reactions occurred in about 20% of cancer patients and in 69% of high-grade dysplasia in Barretts esophagus patients. Most of the reactions were mild to moderate erythema, but they also included swelling, pruritus, burning sensation, feeling hot, or blisters. The majority of reactions occurred within 90 days of porfimer administration.(1)

Sulfasalazine/Methotrexate (Oncology-Injection)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sulfasalazine may decrease the renal clearance of methotrexate or produce a synergistically-induced folate deficiency. Sulfasalazine may decrease protein binding of methotrexate.

CLINICAL EFFECTS: Concurrent use of sulfasalazine may increase systemic levels of and toxicity from methotrexate, leading to increased risk of severe neurotoxicity, stomatitis, and myelosuppression, including neutropenia.

PREDISPOSING FACTORS: Risk factors for methotrexate toxicity include: - High-dose oncology regimens - Impaired renal function, ascites, or pleural effusions

PATIENT MANAGEMENT: Monitor patients who are receiving concurrent therapy or patients who have recently finished methotrexate therapy and who are beginning sulfasalazine therapy for signs of toxicity, including bone marrow suppression, pancytopenia, thrombocytopenia, and stomatitis.

DISCUSSION: In one study in pediatric leukemia patients, concurrent administration of methotrexate and trimethoprim-sulfamethoxazole resulted in an increase in free methotrexate and a decrease in free methotrexate clearance. These changes resulted in a 66% increase in systemic exposure to methotrexate, although there were no significant changes in total methotrexate clearance or methotrexate half-life. In another study in pediatric leukemia patients, concurrent therapy with methotrexate and trimethoprim-sulfamethoxazole did not alter the intestinal absorption, degree of plasma protein binding, or average concentration of methotrexate. Case reports have documented methotrexate toxicities such as bone marrow hypoplasia, pancytopenia, thrombocytopenia, and stomatitis during concurrent therapy and during therapy with trimethoprim-sulfamethoxazole following the conclusion of methotrexate therapy. While some of these reports involved patients receiving low-dose methotrexate for rheumatoid arthritis, a randomized clinical trial of concurrent methotrexate and sulfasalazine therapy in rheumatoid arthritis patients showed superior efficacy and similar toxicity compared to methotrexate alone. Methotrexate plasma protein binding and renal clearance have been shown to be decrease by the concurrent administration of sulfisoxazole. Although in one study concurrent administration of sulfasalazine had no effect on methotrexate pharmacokinetics, both drugs are substrates for folate transporters as well as BCRP (breast cancer resistance protein) and so caution is still warranted during concurrent therapy.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Aminosalicylate Derivatives/Azathioprine; Mercaptopurine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is not known. Aminosalicylic acid and its derivatives (balsalazide, mesalamine, olsalazine, sulfasalazine) may inhibit azathioprine or mercaptopurine inactivation via the thiopurine methyltransferase (TPMT) pathway. Aminosalicylates, azathioprine and mercaptopurine are all associated risk for neutropenia, thrombocytopenia, and anemia and so these risks could be additive.

CLINICAL EFFECTS: Concurrent use of azathioprine or mercaptopurine with aminosalicylates may increase the risk for anemia, neutropenia, or thrombocytopenia.

PREDISPOSING FACTORS: Patients with reduced or absent thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) activity are at higher risk of accumulating thiopurine metabolites and severe myelosuppression. Approximately 0.3 % of patients of European, Latino, or African descent have mutations of the TPMT gene resulting in little to no TPMT activity (homozygous deficiency), and approximately 10 % have intermediate TPMT activity (heterozygous deficiency). NUDT15 deficiency is not seen in patients of African descent and is seen in less than 1 % of patients of European descent. Approximately 1 % of patients of East Asian descent, 0.5 % of patients of central/south Asian descent, and 2 % of patients of Latino descent have homozygous NUDT15 deficiency. About 17 % of patients of East Asian descent, 13 % of patients of central/south Asian descent, and 8 % of patients of Latino descent have heterozygous NUDT15 deficiency. Added risk for myelosuppression would be expected in patients who also receive allopurinol or other agents which block xanthine oxidase (XO), the other major inactivation pathway for azathioprine and mercaptopurine.

PATIENT MANAGEMENT: Use the lowest possible dose of each drug and monitor closely for myelosuppression.

DISCUSSION: Manufacturer prescribing information states that concurrent use of aminosalicylates with azathioprine or mercaptopurine has been reported to cause bone marrow suppression. In a prospective study, 22 inflammatory bowel disease (IBD) patients on concurrent 5-aminosalicylate with (2 g daily and later increased to 4 g daily) with azathioprine had increased levels of 6-thioguanine (6-TGN) metabolites. One patient had signs of myelosuppression.(3) A prospective study in 183 IBD patients on concurrent 5-aminosalicylic acid and thiopurines found no significant interaction between thiopurines and 5-aminosalicylic acid.(4) A retrospective study in 199 IBD patients reported an increased rate of adverse events in the dual 5-aminosalicylates and azathioprine dual therapy group compared (48%) to the monotherapy azathioprine group (30%)(chi = 6.4, p = 0.05). Discontinuation of azathioprine because of adverse events was higher in the dual therapy group (52% vs. 24%).(5) In a prospective study, 16 Crohn's disease patients on a stable dose of azathioprine with sulfasalazine or mesalamine discontinued the aminosalicylate after 3 months, which resulted in an average decrease 0f 10% in 6-TGN levels. Myelosuppression may be related to increased levels of 6-TGN.(6) In a 8 week non-randomized parallel group drug interaction study, 34 patients with Crohn's disease receiving azathioprine or 6-mercaptopurine with mesalamine (4 g/day), or sulfasalazine (4 g/day), or balsalazide (6.75 g/day) had a high frequency of leukopenia (20-55%) and significant increases in whole blood 6-TGN levels.(7) A 16 year-old Crohn's disease patient on concurrent 6-mercaptopurine (75 mg) and olsalazine (1000 mg) developed leukopenia (WBC count 1.7 x 10*9/L, ANC 1.309 x 10*9/L, hemoglobulin 113 gm/L, platelet count 550 x 10*9/L) and required a dose reduction for 6-mercaptopurine. Another episode occurred later on after increasing her dose of olsalazine and 6-mercaptopurine which resulted in discontinuation of olsalazine.(8) An in vitro study showed that sulfasalazine and other aminosalicylate derivatives were able to inhibit recombinant human TPMT.(9) In a prospective study, 17 IBD patients on stable mercaptopurine and mesalamine therapy had a 23% reduction in 6-TGN levels after discontinuing mercaptopurine.(10)

Selected Bcrp Substrates/Momelotinib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Momelotinib is an inhibitor of the BCRP transporter, which may result in increased absorption and decreased hepatic uptake of BCRP substrates.(1)

CLINICAL EFFECTS: Administration of momelotinib with BCRP substrates may result in elevated levels of and toxicity of the BCRP substrates.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of momelotinib states concurrent use with BCRP substrates should be approached with caution. If concurrent use is warranted, consider reducing the dose of the substrate drug according to the product labeling and monitor for adverse reactions.(1)

DISCUSSION: Momelotinib increased the area-under-curve (AUC) and maximum concentration (Cmax) of rosuvastatin, a BCRP substrate, by 220% and 170%, respectively.(1) BCRP substrates linked to this monograph include: glyburide, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, and sulfasalazine.(1-2)

Selected Bcrp Substrates/Safinamide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Safinamide transiently inhibits BCRP in the small intestine, which may result in increased absorption of BCRP substrates.(1)

CLINICAL EFFECTS: Administration of safinamide with BCRP substrates may result in elevated levels of and toxicity from these agents.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The EMA and UK manufacturer of safinamide recommend monitoring patients who are on concomitant drugs that are substrates of BCRP, including diclofenac, methotrexate, rosuvastatin, and topotecan. Dose adjustment of the BCRP substrate should be performed according to the prescribing information for the BCRP substrate.(1) On the other hand, the US manufacturer of safinamide states that rosuvastatin did not have a clinically significant effect on the pharmacokinetics of safinamide.(2)

DISCUSSION: Safinamide transiently inhibits BCRP in the small intestine, which may result in increased absorption of BCRP substrates.(1) In a clinical study, safinamide increased the AUC of rosuvastatin by 1.25- to 2-fold.(1,3) BCRP substrates linked to this monograph include: diclofenac, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, sulfasalazine, and topotecan.(1,3)

Sulfonamide Antibacterials/Paba

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Sulfonamide antibacterials are structurally similar to PABA (p-aminobenzoic acid). PABA is an essential precursor for synthesis of tetrahydrofolate. Sulfonamides competitively inhibit utilization of PABA and therefore disrupt tetrahydrofolate biosynthesis. Supplementation with PABA antagonizes sulfonamide antibacterials.

CLINICAL EFFECTS: Reduced antibacterial effectiveness of sulfonamides with concomitant use.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concomitant administration of these drugs.

DISCUSSION: This interaction is well documented.

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• Gastrointestinal obstruction
• Glucose-6-phosphate dehydrogenase (g6Pd) deficiency
• Hemoglobin H disease
• Hemolytic anemia from pyruvate kinase and g6PD deficiencies
• Porphyria
• Urinary tract obstructive uropathy

• Aplastic anemia
• Disease of liver
• Neutropenic disorder
• Severe infection

• Asthma
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Slow acetylator due to n-acetyltransferase enzyme variant

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More Frequent

• Allergic dermatitis
• Drug fever
• Pruritus of skin
• Skin photosensitivity
• Skin rash

Less Frequent

• Agranulocytosis
• Blood dyscrasias
• Cyanosis
• Hemolytic anemia
• Hepatitis
• Thrombocytopenic disorder
• Ulcerative colitis

Rare or Very Rare

• Abnormal hepatic function tests
• Acute generalized exanthematous pustulosis
• Alveolitis
• Anaphylaxis
• Angioedema
• Anuria
• Aplastic anemia
• Cholestasis
• DRESS syndrome
• Enterocolitis
• Eosinophilia
• Eosinophilic pneumonia
• Erythema multiforme
• Exfoliative dermatitis
• Glucose-6-phosphate dehydrogenase (g6Pd) deficiency anemia
• Guillain-barre syndrome
• Hallucinations
• Hearing loss
• Hemolytic uremic syndrome
• Hepatic failure
• Hepatic necrosis
• Hepatocellular damage
• Hyperbilirubinemia
• Hypoprothrombinemia
• Increased alanine transaminase
• Increased aspartate transaminase
• Interstitial pneumonitis
• Intracranial hypertension
• Jaundice
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Kidney stone
• Methemoglobinemia
• Myelitis
• Myelodysplastic syndrome
• Myocarditis
• Nephritis
• Nephrotic syndrome
• Neutropenic colitis
• Obstructive hyperbilirubinemia
• Pancreatitis
• Pneumonia
• Rhabdomyolysis
• Sepsis
• Serum sickness
• Stevens-johnson syndrome
• Stomatitis
• Toxic epidermal necrolysis
• Urticaria

More Frequent

• Acute abdominal pain
• Anorexia
• Diarrhea
• Dizziness
• Dyschromia
• Dyspepsia
• Headache disorder
• Nausea
• Oligospermia
• Urine discoloration
• Vomiting

Less Frequent

• Leukopenia

Rare or Very Rare

• Alopecia
• Ataxia
• Crystalluria
• Drowsy
• Folate deficiency
• Hematuria
• Insomnia
• Oliguria
• Pain in oropharynx
• Pallor
• Periorbital edema
• Peripheral neuropathy
• Proteinuria
• Purpura
• Tinnitus
• Urinary tract infection
• Vertigo

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