Brigatinib - Alunbrig-@- (Apr 2017)- Anti-cancer
Drug Name:Brigatinib - Alunbrig-@- (Apr 2017)- Anti-cancer
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
CYP3A Inhibitors:
Avoid concomitant use of ALUNBRIG with strong CYP3A inhibitors.
If concomitant use of a strong CYP3A inhibitor is unavoidable,
reduce the dose of ALUNBRIG.
CYP3A Inducers:
Avoid concomitant use of ALUNBRIG with strong CYP3A inducers.
CYP3A Substrates:
Hormonal contraceptives may be ineffective due to decreased exposure.
Indication:
U.S. FDA APPROVED DRUGS DURING 2017
Sr.No- 16
Name of the Drug- Alunbrig
Active Ingredient- Brigatinib Pharmacological Classification-
To treat patients with anaplastic lymphoma kinase (ALK) -positive
metastaticnon-sm cancer (NSCLC) who have progressed on or are
intolerant to crizotinib
Date of Approval- 04-28-2017
(Ref- FDA approved List 2017) HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
ALUNBRIG safely and effectively.
See full prescribing information for ALUNBRIG.
ALUNBRIGTM (brigatinib) tablets, for oral use
Initial U.S. Approval: 2017
INDICATIONS AND USAGE
ALUNBRIG is a kinase inhibitor indicated for the treatment of patients
with anaplastic lymphoma kinase (ALK)-positive metastatic non-small
cell lung cancer (NSCLC) who have progressed on or are intolerant
to crizotinib.
This indication is approved under accelerated approval based on
tumor response rate and duration of response. Continued approval
for this indication may be contingent upon verification and description
of clinical benefit in a confirmatory trial.
Adverse Reaction:
ADVERSE REACTIONS
The most common adverse reactions (.25%) with ALUNBRIG
were nausea, diarrhea, fatigue, cough, and headache.
Contra-Indications:
CONTRAINDICATIONS
None.
WARNINGS AND PRECAUTIONS
Interstitial Lung Disease (ILD)/Pneumonitis:
Occurred in 9.1% of patients at the recommended dose.
Monitor for new or worsening respiratory symptoms, particularly during
the first week of treatment. Withhold ALUNBRIG for new or worsening
respiratory symptoms and promptly evaluate for ILD/pneumonitis.
Upon recovery, either dose reduce or permanently discontinue ALUNBRIG.
Hypertension:
Monitor blood pressure after 2 weeks and then at least monthly during
treatment.
For severe hypertension, withhold ALUNBRIG, then dose reduce or
permanently discontinue.
Bradycardia:
Monitor heart rate and blood pressure regularly during treatment.
If symptomatic, withhold ALUNBRIG, then dose reduce or permanently
discontinue.
Visual Disturbance:
Advise patients to report visual symptoms. Withhold ALUNBRIG and
obtain ophthalmologic evaluation, then dose reduce or permanently
discontinue ALUNBRIG.
Creatine Phosphokinase (CPK) Elevation:
Monitor CPK levels regularly during treatment. Based on the severity,
withhold ALUNBRIG, then resume or reduce dose.
Pancreatic Enzyme Elevation:
Monitor lipase and amylase levels regularly during treatment.
Based on the severity, withhold ALUNBRIG, then resume or reduce dose.
Hyperglycemia:
Assess fasting serum glucose prior to starting ALUNBRIG and regularly
during treatment. If not adequately controlled with optimal medical
management, withhold ALUNBRIG, then consider dose reduction
or permanently discontinue, based on severity.
Embryo-Fetal Toxicity:
Can cause fetal harm. Advise females of reproductive potential of the
potential risk to a fetus and to use a non- hormonal method of effective
contraception.
-
Dosages/ Overdosage Etc:
INDICATIONS AND USAGE
ALUNBRIG is a kinase inhibitor indicated for the treatment of patients
with anaplastic lymphoma kinase (ALK)-positive metastatic non-small
cell lung cancer (NSCLC) who have progressed on or are intolerant
to crizotinib.
This indication is approved under accelerated approval based on
tumor response rate and duration of response. Continued approval
for this indication may be contingent upon verification and description
of clinical benefit in a confirmatory trial.
DOSAGE AND ADMINISTRATION
90 mg orally once daily for the first 7 days;
if tolerated, increase to 180 mg orally once daily.
May be taken with or without food.
DOSAGE FORMS AND STRENGTHS
Tablets: 30 mg and 90 mg
Patient Information:
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient information).
Inform patients of the following:
Interstitial Lung Disease (ILD)/Pneumonitis
Inform patients of the symptoms and risks of serious pulmonary adverse
reactions such as ILD/pneumonitis.
Advise patients to immediately report any new or worsening respiratory
symptoms.
Hypertension
Advise patients of risks of hypertension and to promptly report signs or
symptoms of hypertension.
Bradycardia
Advise patients to report any symptoms of bradycardia and to inform
their healthcare provider about the use of heart and blood pressure
medications.
Visual Disturbance
Advise patients to inform their healthcare provider of any new or
worsening vision symptoms..
Creatine Phosphokinase (CPK) Elevation
Inform patients of the signs and symptoms of creatinine
phosphokinase (CPK) elevation and the need for monitoring during treatment.
Advise patients to inform their healthcare provider of any new or worsening
symptoms of unexplained muscle pain, tenderness, or weakness.
Pancreatic Enzyme Elevation
Inform patients of the signs and symptoms of pancreatitis and the need
to monitor for amylase and lipase elevations during treatment
Hyperglycemia
Inform patients of the risks of new or worsening hyperglycemia and the need
to periodically monitor glucose levels.
Advise patients with diabetes mellitus or glucose intolerance that
anti-hyperglycemic medications may need to be adjusted during treatment
with ALUNBRIG..
Females and Males of Reproductive Potential
Embryo-Fetal Toxicity
Advise females and males of reproductive potential that ALUNBRIG
can cause fetal harm.
Advise females of reproductive potential to inform their healthcare provider
of a known or suspected pregnancy and to use effective non-hormonal
contraception during treatment with ALUNBRIG and for at least 4 months
after the final dose.
Advise males with female partners of reproductive potential to use
effective contraception during treatment with ALUNBRIG and for at
least 3 months after the final dose.
Lactation-
Advise females not to breastfeed during treatment with ALUNBRIG
and for at least 1 week following the final dose.
Infertility-
Advise males of reproductive potential of the potential for reduced
fertility from ALUNBRIG
Drug Interactions
Advise patients to inform their health care provider of all concomitant
medications, including prescription medicines, over-the-counter drugs,
vitamins, and herbal products.
Inform patients to avoid grapefruit or grapefruit juice while taking
ALUNBRIG.
Dosing and Administration
Instruct patients to start with 90 mg of ALUNBRIG once daily for the first 7 days
and if tolerated, increase the dose to 180 mg once daily.
Advise patients to take ALUNBRIG with or without food.
Missed Dose-
Advise patients that if a dose of ALUNBRIG is missed or if the patient
vomits after taking a dose of ALUNBRIG, not to take an extra dose,
but to take the next dose at the regular time.
Manufactured for:
ARIAD Pharmaceuticals, Inc.,
a wholly owned subsidiary of Takeda Pharmaceutical Company Limited Cambridge, MA
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1. Mechanism of Action
Brigatinib is a tyrosine kinase inhibitor with in vitro activity at clinically
achievable concentrations against multiple kinases including ALK,
ROS1, insulin-like growth factor-1 receptor (IGF-1R), and FLT-3 as well as
EGFR deletion and point mutations.
Brigatinib inhibited autophosphorylation of ALK and ALK-mediated
phosphorylation of the downstream signaling proteins STAT3, AKT,
ERK1/2, and S6 in in vitro and in vivo assays.
Brigatinib also inhibited the in vitro proliferation of cell lines expressing
EML4-ALK and NPM-ALK fusion proteins and demonstrated
dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice.
At clinically achievable concentrations (. 500 nM), brigatinib inhibited the in vitro
viability of cells expressing EML4-ALK and 17 mutant forms associated with
resistance to ALK inhibitors including crizotinib, as well as EGFR-Del
(E746-A750), ROS1-L2026M, FLT3-F691L, and FLT3-D835Y.
Brigatinib exhibited in vivo anti-tumor activity against 4 mutant forms of
EML4-ALK, including G1202R and L1196M mutants identified in NSCLC
tumors in patients who have progressed on crizotinib. Brigatinib also
reduced tumor burden and prolonged survival in mice implanted
intracranially with an ALK-driven tumor cell line.
2. Pharmacodynamics
Brigatinib exposure-response relationships and the time course of the
pharmacodynamic response are unknown.
Cardiac Electrophysiology
The QT interval prolongation potential of ALUNBRIG was assessed in
123 patients following once daily ALUNBRIG doses of
30 mg (1/6th of the approved 180 mg dose)
to 240 mg (1.3 times the approved 180 mg dose).
ALUNBRIG did not prolong the QT interval to a clinically relevant extent.
3, Pharmacokinetics
The geometric mean (CV%) steady-state maximum concentration (Cmax)
of brigatinib at ALUNBRIG doses of 90 mg and 180 mg once daily
was 552 (65%) ng/mL and 1452 (60%) ng/mL, respectively, and the
corresponding area under the concentration-time curve (AUC0-Tau)
was 8165 (57%) ngEh/mL and 20276 (56%) ngEh/mL.
After a single dose and repeat dosing of ALUNBRIG, systemic
exposure of brigatinib was dose proportional over the dose range
of 60 mg (0.3 times the approved 180 mg dose)
to 240 mg (1.3 times the approved 180 mg dose) once daily.
The mean accumulation ratio after repeat dosing was 1.9 to 2.4.
Absorption
Following administration of single oral doses of ALUNBRIG of 30 to 240 mg,
the median time to peak concentration (Tmax) ranged from 1 to 4 hours.
Effect of Food
Brigatinib Cmax was reduced by 13% with no effect on AUC in healthy subjects
administered ALUNBRIG after a high fat meal (approximately 920 calories,
58 grams carbohydrate, 59 grams fat and 40 grams protein) compared to
the Cmax and AUC after overnight fasting.
Distribution
Brigatinib is 66% bound to human plasma proteins and the binding is not
concentration-dependent in vitro. The blood-to-plasma concentration
ratio is 0.69.
Following oral administration of ALUNBRIG 180 mg once daily,
the mean apparent volume of distribution (Vz/F) of brigatinib
at steady-state was 153 L.
Elimination
Following oral administration of ALUNBRIG 180 mg once daily, the mean
apparent oral clearance (CL/F) of brigatinib at steady-state is 12.7 L/h
and the mean plasma elimination half-life is 25 hours.
Metabolism
Brigatinib is primarily metabolized by CYP2C8 and CYP3A4 in vitro.
Following oral administration of a single 180 mg dose of radiolabeled
brigatinib to healthy subjects, N-demethylation and cysteine conjugation
were the two major metabolic pathways.
Unchanged brigatinib (92%) and its primary metabolite, AP26123 (3.5%),
were the major circulating radioactive components.
The steady-state AUC of AP26123 was less than 10% of AUC of brigatinib
exposure in patients. The metabolite, AP26123, inhibited ALK with
approximately 3-fold lower potency than brigatinib in vitro.
Excretion
Following oral administration of a single 180 mg dose of radiolabeled
brigatinib to healthy subjects, 65% of the administered dose was recovered
in feces and 25% of the administered dose was recovered in urine.
Unchanged brigatinib represented 41% and 86% of the total radioactivity
in feces and urine, respectively.
Specific Populations
Age, race, sex, body weight, and albumin concentration have no clinically
meaningful effect on the pharmacokinetics of brigatinib.
Hepatic Impairment
As hepatic elimination is a major route of excretion for brigatinib, hepatic
impairment may result in increased plasma brigatinib concentrations.
Based on a population pharmacokinetic analysis, brigatinib exposures
were similar between 49 subjects with mild hepatic impairment
(total bilirubin within upper limit of normal [ULN] and AST greater than
ULN or total bilirubin greater than 1 and up to 1.5 times ULN and any AST)
and 377 subjects with normal hepatic function (total bilirubin and AST
within ULN).
The pharmacokinetics of brigatinib in patients with moderate
(total bilirubin greater than 1.5 and up to 3.0 times ULN and any AST)
to severe (total bilirubin greater than 3.0 times ULN and any AST)
hepatic impairment has not been studied.
Renal Impairment
Based on a population pharmacokinetic analysis, brigatinib exposures
were similar among 125 subjects with mild renal impairment
(CLcr 60 to less than 90 mL/min), 34 subjects with moderate renal
impairment (CLcr 30 to less than 60 mL/min) and 270 subjects
with normal renal function (CLcr greater than or equal to 90 mL/min),
suggesting that no dose adjustment is necessary in patients with mild
to moderate renal impairment. Patients with severe renal impairment
(CLcr less than 30 mL/min) were not included in clinical trials.
Drug Interactions
Effects of Other Drugs on Brigatinib
Strong CYP3A Inhibitors: Coadministration of 200 mg twice daily doses
of itraconazole (a strong CYP3A inhibitor) with a single 90 mg dose of
ALUNBRIG increased brigatinib Cmax by 21% and AUC0-INF by 101%,
relative to a 90 mg dose of ALUNBRIG administered alone.
Strong CYP2C8 Inhibitors:
Coadministration of 600 mg twice daily doses of gemfibrozil
(a strong CYP2C8 inhibitor) with a single 90 mg dose of ALUNBRIG
decreased brigatinib Cmax by 41% and AUC0-INF by 12%, relative
to a 90 mg dose of ALUNBRIG administered alone.
The effect of gemfibrozil on the pharmacokinetics of brigatinib is not
clinically meaningful and the underlying mechanism for the decreased
exposure of brigatinib is unknown.
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. Pregnancy
Risk Summary
Based on its mechanism of action and findings in animals, ALUNBRIG can
cause fetal harm when administered to a pregnant woman.
There are no clinical data on the use of ALUNBRIG in pregnant women.
Administration of brigatinib to pregnant rats during the period of
organogenesis resulted in dose-related skeletal anomalies at doses as
low as 12.5 mg/kg/day (approximately 0.7 times the human exposure by
AUC at 180 mg once daily) as well as increased post-implantation loss,
malformations, and decreased fetal body weight at doses of 25 mg/kg/day
(approximately 1.26 times the human exposure at 180 mg once daily) or greater.
If this drug is used during pregnancy, or if the patient becomes pregnant while
taking this drug, advise the patient of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth
defects and miscarriage in clinically recognized pregnancies is 2% to 4%
and 15% to 20%, respectively.
2. Lactation
Risk Summary
There are no data regarding the secretion of brigatinib in human milk or its effects
on the breastfed infant or milk production.
Because of the potential for adverse reactions in breastfed infants, advise
lactating women not to breastfeed during treatment with ALUNBRIG and
for 1 week following the final dose.
3. Females and Males of Reproductive Potential
Contraception
ALUNBRIG can cause fetal harm
Females
Advise females of reproductive potential to use effective non-hormonal
contraception during treatment with ALUNBRIG and for at least 4 months
after the final dose.
Counsel patients to use a non-hormonal method of contraception since
ALUNBRIG can render some hormonal contraceptives ineffective.
Males
Because of the potential for genotoxicity, advise males with female partners
of reproductive potential to use effective contraception during treatment with
ALUNBRIG and for at least 3 months after the final dose.
Infertility
Based on findings in male reproductive organs in animals, ALUNBRIG may
cause reduced fertility in males..
4. Pediatric Use
The safety and efficacy of ALUNBRIG in pediatric patients have not been
established.
5. Geriatric Use
Clinical studies of ALUNBRIG did not include sufficient numbers of patients
aged 65 years and older to determine whether they respond differently
from younger patients.
Of the 222 patients in ALTA, 19.4% were 65-74 years and 4.1% were
75 years or older. No clinically relevant differences in safety or efficacy were
observed between patients .65 years and younger patients.
6. Hepatic Impairment
No dose adjustment is recommended for patients with mild hepatic impairment.
(total bilirubin within upper limit of normal [ULN] and AST greater than
ULN or total bilirubin greater than 1 and up to 1.5 times ULN and any AST).
The pharmacokinetics and safety of ALUNBRIG in patients with moderate
or severe hepatic impairment have not been studied..
7. Renal Impairment
No dose adjustment is recommended for patients with mild and moderate
renal impairment [creatinine clearance (CLcr) 30 to 89 mL/min estimated
by Cockcroft-Gault)].
The pharmacokinetics and safety of ALUNBRIG in patients with severe
renal impairment (CLcr 15 to 29 mL/min estimated by Cockcroft-Gault)
have not been studied .
