8/19. Erdafitinib-(BALVERSA)- (Apr-2019- Anti-cancr drug
Drug Name:8/19. Erdafitinib-(BALVERSA)- (Apr-2019- Anti-cancr drug
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
DRUG INTERACTIONS
• Strong CYP2C9 or CYP3A4 inhibitors: Consider alternative agents or monitor closely for adverse reactions.
• Strong CYP2C9 or CYP3A4 inducers: Avoid concomitant use with BALVERSA. (7.1)
• Moderate CYP2C9 or CYP3A4 inducers: Increase BALVERSA dose up to 9 mg.
• Serum phosphate level-altering agents: Avoid concomitant use with agents that can alter serum phosphate levels before the initial dose modification period.
• CYP3A4 substrates: Avoid concomitant use with sensitive CYP3A4 substrates with narrow therapeutic indices.
• OCT2 substrates: Consider alternative agents or consider reducing the dose of OCT2 substrates based on tolerability.
• P-gp substrates: Separate BALVERSA administration by at least 6 hours before or after administration of P-gp substrates with narrow therapeutic indices.
Indication:
BRIEF SUMMARY
ERDAFITINIB -(Apr- 2019)
Indn- To treat adult patients with locally advanced or metastatic cancer
Comp- Tablets: 3 mg, 4 mg, and 5 mg. • Recommended initial dosage: 8 mg orally once daily with a dose increase to 9 mg daily if criteria are met. (2.2) • Swallow whole with or without food.
ADR- - The most common adverse reactions including laboratory abnormalities (=20%) were
phosphate increased, stomatitis, fatigue, creatinine increased, diarrhea, dry mouth, onycholysis, alanine aminotransferase increased, alkaline phosphatase increased, sodium decreased, decreased appetite, albumin decreased, dysgeusia, hemoglobin decreased, dry skin,
CI- None.
Pat Infrm-
FGFR genetic alterations: Advise patients that evidence of a susceptible FGFR3 or FGFR2 mutation or gene fusion within the tumor specimen is necessary to identify patients for whom treatment is indicated
Ocular disorders: Advise patients to contact their healthcare provider if they experience any visual changes
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U.S. FDA APPROVED DRUGS DURING 2019
Sr.No-8
Adverse Reaction:
ADVERSE REACTIONS
- The most common adverse reactions including laboratory abnormalities (=20%) were
phosphate increased, stomatitis, fatigue, creatinine increased, diarrhea, dry mouth, onycholysis, alanine aminotransferase increased, alkaline phosphatase increased, sodium decreased, decreased appetite, albumin decreased, dysgeusia, hemoglobin decreased, dry skin, aspartate aminotransferase increased, magnesium decreased, dry eye, alopecia, palmarplantar erythrodysesthesia syndrome, constipation, phosphate decreased, abdominal pain, calcium increased, nausea, and musculoskeletal pain.
Contra-Indications:
Dosages/ Overdosage Etc:
Patient Information:
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
FGFR genetic alterations: Advise patients that evidence of a susceptible FGFR3 or FGFR2 mutation or gene fusion within the tumor specimen is necessary to identify patients for whom treatment is indicated
Ocular disorders: Advise patients to contact their healthcare provider if they experience any visual changes
In order to prevent or treat dry eyes, advise patients to use artificial tear substitutes, hydrating or lubricating eye gels or ointments frequently, at least every 2 hours during waking hours
Skin, mucous or nail disorders: Advise patients to contact their healthcare provider if they experience progressive or intolerable skin, mucous or nail disorders
Hyperphosphatemia: Advise patients that their healthcare provider will assess their serum phosphate level between 14 and 21 days of initiating treatment and will adjust the dose if needed
During this initial phosphate-assessment period, advise patients to avoid concomitant use with agents that can alter serum phosphate levels.
Advise patients that, after the initial phosphate assessment period, monthly phosphate level monitoring for hyperphosphatemia should be performed during treatment with BALVERSA
Drug Interactions:
Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, and herbal products
Dosing Instructions:
Instruct patients to swallow the tablets whole once daily with or without food. If vomiting occurs any time after taking BALVERSA, advise patients to take the next dose the next day.
Missed dose: If a dose is missed, advise patients to take the missed as soon as possible. Resume the regular daily dose schedule for BALVERSA the next day.
Extra tablets should not be taken to make up for the missed dose
Embryo-Fetal Toxicity:
Advise pregnant women and females of reproductive potential of the potential risk to the fetus.
Advise females to inform their healthcare providers of a known or suspected pregnancy
Advise female patients of reproductive potential to use effective contraception during treatment and for one month after the last dose of BALVERSA.
Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for one month after the last dose of BALVERSA
Lactation:
Advise females not to breastfeed during treatment with BALVERSA and for one month after the last dose
Product of Switzerland Manufactured for: Janssen Products, LP Horsham, PA 19044 Under license from Astex Therapeutics Limited. ©2019 Janssen Pharmaceutical Companies
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1. Mechanism of Action
Erdafitinib is a kinase inhibitor that binds to and inhibits enzymatic activity of FGFR1, FGFR2, FGFR3 and FGFR4 based on in vitro data. Erdafitinib also binds to RET, CSF1R, PDGFRA, PDGFRB, FLT4, KIT, and VEGFR2.
Erdafitinib inhibited FGFR phosphorylation and signaling and decreased cell viability in cell lines expressing FGFR genetic alterations, including point mutations, amplifications, and fusions.
Erdafitinib demonstrated antitumor activity in FGFR-expressing cell lines and xenograft models derived from tumor types, including bladder cancer.
2. Pharmacodynamics Cardiac Electrophysiology
Based on evaluation of QTc interval in an open-label, dose escalation and dose expansion study in 187 patients with cancer, erdafitinib had no large effect (i.e., > 20 ms) on the QTc interval.
Serum Phosphate Erdafitinib increased serum phosphate level as a consequence of FGFR inhibition. BALVERSA should be increased to the maximum recommended dose to achieve target serum phosphate levels of 5.5– 7.0 mg/dL in early cycles with continuous daily dosing
3. Pharmacokinetics
Following administration of 8 mg once daily, the mean (coefficient of variation [CV%]) erdafitinib steady-state maximum observed plasma concentration (Cmax), area under the curve (AUCtau), and minimum observed plasma concentration (Cmin) were 1,399 ng/mL (51%), 29,268 ng·h/mL (60%), and 936 ng/mL (65%), respectively.
Following single and repeat once daily dosing, erdafitinib exposure (maximum observed plasma concentration [Cmax] and area under the plasma concentration time curve [AUC]) increased proportionally across the dose range of 0.5 to 12 mg (0.06 to 1.3 times the maximum approved recommended dose).
Steady state was achieved after 2 weeks with once daily dosing and the mean accumulation ratio was 4-fold.
Absorption
Median time to achieve peak plasma concentration (tmax) was 2.5 hours (range: 2 to 6 hours)
Effect of Food
No clinically meaningful differences with erdafitinib pharmacokinetics were observed following administration of a high-fat and high-calorie meal (800 calories to 1,000 calories with approximately 50% of total caloric content of the meal from fat) in healthy subjects.
Distribution
The mean apparent volume of distribution of erdafitinib was 29 L in patients. Erdafitinib protein binding was 99.8% in patients, primarily to alpha-1-acid glycoprotein.
Elimination
The mean total apparent clearance (CL/F) of erdafitinib was 0.362 L/h in patients. The mean effective half-life of erdafitinib was 59 hours in patients.
Metabolism
Erdafitinib is primarily metabolized by CYP2C9 and CYP3A4. The contribution of CYP2C9 and CYP3A4 in the total clearance of erdafitinib is estimated to be 39% and 20% respectively. Unchanged erdafitinib was the major drug-related moiety in plasma, there were no circulating metabolites.
Excretion
Following a single oral dose of radiolabeled erdafitinib, approximately 69% of the dose was recovered in feces (19% as unchanged) and 19% in urine (13% as unchanged).
Specific Populations
No clinically meaningful trends in the pharmacokinetics of erdafitinib were observed based on age (21 88 years), sex, race, body weight (36-132 kg), mild (eGFR [estimated glomerular filtration rate, using modification of diet in renal disease equation] 60 to 89 mL/min/1.73 m²) or moderate (eGFR 30-59 mL/min/1.73 m²) renal impairment or mild hepatic impairment (total bilirubin = ULN and AST > ULN, or total bilirubin > 1.0–1.5 x ULN and any AST).
The pharmacokinetics of erdafitinib in patients with severe renal impairment, renal impairment requiring dialysis, moderate or severe hepatic impairment is unknown.
Drug Interaction Studies
Clinical Studies and Model-Based Approaches Strong CYP2C9 Inhibitors: Erdafitinib mean ratios (90% CI) for Cmax and AUCinf were 121% (99.9, 147) and 148% (120, 182), respectively, when co-administered with fluconazole, a strong CYP2C9 inhibitor and moderate CYP3A4 inhibitor, relative to erdafitinib alone.
Strong CYP3A4 Inhibitors: Erdafitinib mean ratios (90% CI) for Cmax and AUCinf were 105% (86.7, 127) and 134% (109, 164), respectively, when co-administered with itraconazole (a strong CYP3A4 inhibitor and P-gp inhibitor) relative to erdafitinib alone.
Strong CYP3A4/2C9 Inducers: Simulations suggested that rifampicin (a strong CYP3A4/2C9 inducer) may significantly decrease erdafitinib Cmax and AUC. In Vitro
Studies CYP Substrates: Erdafitinib is a time dependent inhibitor and inducer of CYP3A4. The effect of erdafitinib on a sensitive CYP3A4 substrate is unknown. Erdafitinib is not an inhibitor of other major CYP isozymes at clinically relevant concentrations.
Transporters: Erdafitinib is a substrate and inhibitor of P-gp. P-gp inhibitors are not expected to affect erdafitinib exposure to a clinically relevant extent.
Erdafitinib is an inhibitor of OCT2. Erdafitinib does not inhibit BCRP, OATP1B, OATP1B3, OAT1, OAT3, OCT1, MATE-1, or MATE-2K at clinically relevant concentrations. Acid-Lowering Agents: Erdafitinib has adequate solubility across the pH range of 1 to 7.4.
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. Pregnancy Risk Summary
Based on the mechanism of action and findings in animal reproduction studies, BALVERSA can cause fetal harm when administered to a pregnant woman
Advise pregnant women and females of reproductive potential of the potential risk to the fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
2. Lactation Risk Summary
There are no data on the presence of erdafitinib in human milk, or the effects of erdafitinib on the breastfed child, or on milk production.
Because of the potential for serious adverse reactions from erdafitinib in a breastfed child, advise lactating women not to breastfeed during treatment with BALVERSA and for one month following the last dose.
3. Females and Males of Reproductive Potential
Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with BALVERSA.
Contraception
Females BALVERSA can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose
Males
Advise male patients with female partners of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose [see Use in Specific Populations (8.1)].
Infertility Females
Based on findings from animal studies, BALVERSA may impair fertility in females of reproductive potential
4. Pediatric Use
Safety and effectiveness of BALVERSA in pediatric patients have not been established. In 4 and 13-week repeat-dose toxicology studies in rats and dogs, toxicities in bone and teeth were observed at an exposure less than the human exposure (AUC) at the maximum recommended human dose.
5. Geriatric Use
Of the 416 patients treated with BALVERSA in clinical studies, 45% were 65 years of age or older, and 12% were 75 years of age or older. No overall differences in safety or effectiveness were observed between these patients and younger patients [see Clinical
6. CYP2C9 Poor Metabolizers CYP2C9*3/*3 Genotype:
Erdafitinib plasma concentrations were predicted to be higher in patients with the CYP2C9*3/*3 genotype. Monitor for increased adverse reactions in patients who are known or suspected to have CYP2C9*3/*3 genotype