Balversa (erdafitinib)

If adverse reactions occur during erdafitinib therapy, temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of the drug may be necessary. If dosage modification is required, the dosage of erdafitinib should be reduced as described in Table 1.

Table 1. Dosage Modification for Erdafitinib Toxicity Following Therapy Interruption

Dose Reduction Level Current Dosage of 8 mg Current Dosage of 9 mg Daily Daily First Restart at 6 mg daily Restart at 8 mg daily Second Restart at 5 mg daily Restart at 6 mg daily Third Restart at 4 mg daily Restart at 5 mg daily Fourth Discontinue erdafitinib Restart at 4 mg daily Fifth Discontinue erdafitinib

Erdafitinib is administered orally once daily without regard to meals. The tablets should be swallowed whole.

If a dose of erdafitinib is missed, take the dose as soon as possible on the same day and resume the regular dosing schedule the next day. If vomiting occurs at any time following administration of erdafitinib, a replacement dose should not be administered; take the next dose at the regularly scheduled time.

Store between 20-25degreesC (excursions permitted between 15-30degreesC).

No dosing information is available for this tab.

Erdafitinib is metabolized principally by cytochrome P-450 (CYP) isoenzymes 2C9 and 3A4. In vitro, erdafitinib demonstrates time-dependent inhibition and induction of CYP3A4. In vitro, the drug is not an inhibitor of other major CYP isoenzymes at clinically relevant concentrations.

In vitro studies indicate that erdafitinib is a substrate of P-glycoprotein (P-gp). In vitro, erdafitinib is an inhibitor of P-gp and organic cation transporter (OCT) 2, but does not inhibit breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B or 1B3, organic anion transporter (OAT) 1 or 3, OCT1, and multidrug and toxin extrusion (MATE) 1 or 2K transporters at clinically important concentrations.

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

Erdafitinib/Strong Cyp3a4 Inducers

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: Erdafitinib is a substrate of CYP2C9 and CYP3A4. Strong inducers of CYP2C9 or CYP3A4 may induce the metabolism of erdafitinib.(1)

CLINICAL EFFECTS: The concurrent administration of a strong CYP3A4 inducer may result in decreased levels and effectiveness of erdafitinib.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of erdafitinib states that concurrent use with strong CYP3A4 inducers should be avoided. (1)

DISCUSSION: Simulations suggested that rifampin (a strong CYP3A4 and moderate CYP2C9 inducer) may significantly decrease the Cmax and AUC of erdafitinib.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2-3)

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

Erdafitinib/Moderate Cyp3a4 Inducers

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

MECHANISM OF ACTION: Erdafitinib is a substrate of CYP2C9 and CYP3A4. Moderate inducers of CYP3A4 may induce the metabolism of erdafitinib.(1)

CLINICAL EFFECTS: Concurrent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of erdafitinib.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of erdafitinib states that if a moderate CYP3A4 inducer must be co-administered, increase the erdafitinib dose to 9 mg daily. If a moderate CYP3A4 inducer is discontinued, continue erdafitinib at the same dose in the absence of drug-related toxicity.(1)

DISCUSSION: Carbamazepine (a strong CYP3A4 inducer and weak CYP2C9 inducer) decreased the mean maximum concentration (Cmax) and area-under-curve (AUC) of erdafitinib by 78% and 45%, respectively.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2-3)

Erdafitinib/Serum Phosphate Level-Altering Drugs

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

MECHANISM OF ACTION: Medications that alter serum phosphate may interfere with interpretation of phosphate levels that are needed to determine initial erdafitinib dose.(1)

CLINICAL EFFECTS: Serum phosphate levels that are elevated by concomitant medications may result in an inappropriately low dose and decreased effectiveness of erdafitinib. Serum phosphate levels that are decreased by concomitant medications may result in an inappropriately high dose and increased toxicity from erdafitinib.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of erdafitinib states that agents that alter serum phosphate levels should be avoided before the initial dose increase period for erdafitinib based on serum phosphate levels (days 14 to 21).(1)

DISCUSSION: Concomitant administration of serum phosphate level-altering agents during the initial dose increase period of erdafitinib based on serum phosphate levels (days 14 to 21) may interfere with serum phospate levels and lead to incorrect dosing of erdafitinib.(1) Agents that may alter serum phosphate levels linked to this monograph include: aluminum carbonate, aluminum hydroxide, calcium acetate, calcium carbonate, calcium citrate, cod liver oil, ferric citrate, lanthanum, magnesium carbonate, magnesium hydroxide, potassium phosphate, sevelamer, sodium phosphate, sucroferric oxyhydroxide, tenapanor, and vitamin D.(1)

Erdafitinib/Strong Cyp3a4 Or Strong & Moderate Cyp2c9 Inhib

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

MECHANISM OF ACTION: Erdafitinib is metabolized by CYP3A4 and CYP2C9. Strong inhibitors of CYP3A4 or moderate inhibitors of CYP2C9 may inhibit the metabolism of erdafitinib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 or moderate CYP2C9 inhibitors may increase the levels and effects of erdafitinib, including retinopathy and hyperphosphatemia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US prescribing information states that concurrent use of erdafitinib with strong CYP3A4 inhibitors or moderate CYPC9 inhibitors should be avoided. If concurrent use cannot be avoided, monitor closely for adverse reactions and consider a dose modification based on prescribing information. If the strong CYP3A4 or moderate CYP2C9 inhibitor is discontinued, consider increasing the erdafitinib dose if patient does not have any drug-related toxicity.(1) If concurrent use with nitisinone cannot be avoided, the manufacturer of nitisinone recommends reducing the dosage of a CYP2C9 substrate like erdafitinib by one-half.(2)

DISCUSSION: In PKPB models, concurrent use of fluconazole (a moderate CYP2C9 and CYP3A4 inhibitor) resulted in erdafitinib mean ratios for concentration maximum (Cmax) and area-under-curve (AUC) of 121% and 148% , respectively, compared to erdafitinib alone.(1) In PKPB models, concurrent use of itraconazole (a strong CYP3A4 inhibitor and P-gp inhibitor) resulted in erdafitinib mean ratios for Cmax and AUC of 105% and 134%, respectively, compared to erdafitinib alone.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(3,4) Strong CYP2C9 inhibitors include: camizestrant.(3,4) Moderate inhibitors of CYP2C9 include: adagrasib, amiodarone, apazone, asciminib, benzbromarone, fluconazole, miconazole, mifepristone, milk thistle, nitisinone, oxandrolone, phenylbutazone, and sulfaphenazole.(3,4)

Myelosuppressives; Immunomodulators/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)

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)

PREDISPOSING FACTORS: None determined.

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)

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)

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)

There are no moderate interactions for this drug.

*None.

• Lactation

• Hyperphosphatemia
• Pregnancy
• Retinal pigment epithelial detachment

There are no moderate contraindications for this drug.

Adverse effects and laboratory abnormalities reported in at least 20% of patients receiving erdafitinib include increased phosphate, nail disorders, stomatitis, diarrhea, increased creatinine, increased alkaline phosphatase, increased ALT, decreased hemoglobin, decreased sodium, increased AST, fatigue, dry mouth, dry skin, decreased phosphate, decreased appetite, dysgeusia, constipation, increased calcium, dry eye, palmar-plantar erythrodysesthesia syndrome, increased potassium, alopecia, and central serous retinopathy.

More Frequent

• Abnormal hepatic function tests
• Anemia
• Hypercalcemia
• Hyperphosphatemia
• Hypoalbuminemia
• Hypomagnesemia
• Hyponatremia
• Hypophosphatemia
• Increased alanine transaminase
• Increased aspartate transaminase
• Palmar-plantar erythrodysesthesia

Less Frequent

• Acute kidney injury
• Acute myocardial infarction
• Central serous chorioretinopathy
• Corneal ulcer
• Hyperkalemia
• Leukopenia
• Neutropenic disorder
• Retinal pigment epithelial detachment
• Thrombocytopenic disorder
• Vitreous detachment

Rare or Very Rare

• Calcification of vascular system
• Calcinosis cutis
• Calciphylaxis

More Frequent

• Acute abdominal pain
• Alopecia
• Anorexia
• Constipation
• Diarrhea
• Dry eye
• Dry skin
• Dysgeusia
• Fatigue
• Musculoskeletal pain
• Nausea
• Onycholysis
• Stomatitis
• Xerostomia

Less Frequent

• Arthralgia
• Blurred vision
• Conjunctivitis
• Dyspnea
• Eczema
• Epistaxis
• Exfoliative dermatitis
• Eye tearing
• Hematuria
• Hyperkeratosis
• Nail discoloration
• Pain in extremities
• Pain in oropharynx
• Paronychia
• Peripheral edema
• Retinal edema
• Urinary tract infection
• Weight loss

No enhanced messaging available.

Safety and efficacy of erdafitinib have not been established in pediatric patients.

Chondroid dysplasia or metaplasia in multiple bones and tooth abnormalities (i.e., abnormal or irregular dentin, odontoblast discoloration and degeneration) have been observed in animals receiving erdafitinib for 4 or 13 weeks (at exposure levels less than the AUC in humans at the maximum recommended dosage).

Erdafitinib may cause fetal harm if administered to pregnant females based on its mechanism of action and animal findings.

It is not known whether erdafitinib is distributed into human milk. Because of the potential for serious adverse reactions to erdafitinib in breast-fed infants, females should be advised not to breast-feed while receiving the drug and for 1 month after the last dose. The effects of the drug on breast-fed infants or on the production of milk are unknown.

The manufacturer makes no specific dosage recommendations for geriatric patients.

In clinical trials, 40% of patients receiving erdafitinib were 65 to 74 years of age, while 20% were 75 years of age or older. Patients 65 years of age and older experienced a higher incidence of adverse reactions requiring treatment discontinuation than younger patients. No overall differences in efficacy were observed between geriatric patients and younger adults.