Prescribing Information

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COMPOSITION:

Tagrix   40  Tablet:  Each  film  coated  tablet  contains  Osimertinib  Mesylate  INN  equivalent  to Osimertinib 40 mg.

Tagrix   80  Tablet:  Each  film  coated  tablet  contains  Osimertinib  Mesylate  INN  equivalent  to Osimertinib 80 mg.

CLINICAL PHARMACOLOGY:

Osimertinib is kinase inhibitor of the epidermal growth factor receptor (EGFR), which binds irreversibly to certain mutant forms of EGFR (T790M, L858R, and exon 19  deletion) at approximately 9-fold lower concentrations than wild-type. In cultured cells and animal tumor implantation models, Osimertinib exhibited anti-tumor activity against NSCLC lines harboring  EGFR-mutations (T790M/L858R, L858R, T790M/exon 19 deletion, and exon 19 deletion) and, to a lesser extent, wild-type EGFR amplifications. Two  pharmacologically-active  metabolites  (AZ7550  and  AZ5104  circulating  at  approximately  10% of the parent) with similar inhibitory profiles to Osimertinib have been  identified in the plasma after oral administration  of  Osimertinib.  AZ7550   showed  a  similar  potency  to  Osimertinib,  while  AZ5104 showed greater potency against exon 19 deletion and T790M mutants (approximately 8-fold) and wild- type  (approximately  15-fold)  EGFR.  In  vitro,  Osimertinib  also  inhibited  the  activity  of  HER2,  HER3, HER4, ACK1, and BLK at clinically relevant concentrations.

Pharmacokinetics

The area  under the plasma concentration-time curve (AUC) and maximal plasma concentration (Cmax) of Osimertinib increased  dose  proportionally over 20  to 240  mg dose  range  (i.e., 0.25  to 3  times the recommended dosage) after oral administration and exhibited linear pharmacokinetics (PK). Administration  of  Osimertinib  orally  once  daily  resulted  in  approximately  3-fold  accumulation withsteady state exposures achieved after 15 days of dosing. At steady state, the Cmax to Cmin (minimal concentration) ratio was 1.6-fold.

Absorption

The median time to Cmax  of Osimertinib was 6 hours (range 3-24 hours). Following administration of a

20  mg Osimertinib tablets with a high-fat, high-calorie meal (containing approximately 58  grams of fat and  1000 calories),  the  Cmax   and  AUC of  Osimertinib  increased  by  14%  and  19%  respectively, compared  to fasting conditions.

Distribution

The  mean  volume  of  distribution  at  steady-state  (Vss/F)  of  Osimertinib  was  986   L.  Plasma  protein binding of Osimertinib is likely high based  on its physiochemical properties.

Elimination

Osimertinib  plasma  concentrations  decreased with time and  a  population  estimated  mean  half-life  of

Osimertinib was 48 hours, and oral clearance (CL/F) was 14.2  (L/h).

Metabolism

The main metabolic pathways of Osimertinib were oxidation (predominantly CYP3A) and  dealkylation in vitro. Two pharmacologically active metabolites (AZ7550 and  AZ5104) have been  identified in the plasma after Osimertinib oral administration. The geometric mean exposure (AUC) of each  metabolite (AZ5104 and AZ7550) was approximately 10% of the exposure of Osimertinib at steady-state.

Excretion

Osimertinib  is  primarily  eliminated  in  the  feces  (68%)  and  to  a  lesser  extent  in  the  urine  (14%). Unchanged Osimertinib accounted for approximately 2% of the elimination.

Specific Populations

No  clinically  significant  differences  in the  pharmacokinetics  of  Osimertinib  were  observed  based  on age,  sex, ethnicity, body weight, smoking status, mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment, or mild hepatic impairment (total bilirubin <ULN and AST between 1 to 1.5x ULN or total bilirubin between 1.0 to 1.5 times ULN and any AST ). There are no data on the pharmacokinetics of Osimertinib in patients with severe renal impairment (CLcr less than 30 mL/min) or with moderate  to severe hepatic  impairment  (moderate:  total  bilirubin  between  1.5  to 3.0  times ULN and any AST, and severe: total bilirubin between 3.0-10 times ULN and any AST).

INDICATION:

Osimertinib is a kinase inhibitor indicated for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer  (NSCLC), as detected by an FDA-approved test, who have progressed  on or after EGFR TKI therapy.

DOSAGE AND ADMINISTRATION: Standard Dosage

The  recommended  dose  of  Osimertinib  is  80  mg  tablet  once  a  day  until  disease  progression  or unacceptable toxicity. Osimertinib can be taken with or without food. If a dose of Osimertinib is missed, do not make up the missed dose and take the next dose as scheduled.

Administration to patients who have difficulty in swallowing: Disperse tablet in 4 tablespoons (approximately  50  mL)  of  non-carbonated  water  only.  Stir  until  tablet  is completely  dispersed  and swallow or administer through naso-gastric tube immediately. Do not crush, heat, or ultrasonicate during preparation. Rinse the container with  4  to  8  ounces  of water and  immediately drink or  administer through the naso-gastric tube.

Dose Modification

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‘USE IN SPECIAL POPULATION: Pregnancy

Osimertinib  can  cause  fetal  harm when administered  to a  pregnant  woman.  There  are  no available data on Osimertinib use in pregnant women.

Lactation

There  are  no data  on the  presence  of  Osimertinib  in human milk,  the  effects  of  Osimertinib  on the breastfed infant or on milk production.

Contraception

Females:  Advise females  of  reproductive  potential  to use effective  contraception  during treatment  with

Osimertinib and for 6 weeks after the final dose.

Males:   Advise  male   patients   with  female   partners   of   reproductive   potential   to  use  effective contraception during and for 4 months following the final dose of Osimertinib.

Infertility

Based  on  animal  studies,  Osimertinib  may  impair  fertility  in  females  and  males  of  reproductive potential. It is not known if the effects on fertility are reversible.

Pediatric Use

The safety and effectiveness of Osimertinib in pediatric patients have not been established.

Geriatric Use

No  overall differences in effectiveness were observed  based  on age.  Exploratory analysis suggest a higher  incidence  of Grade  3  and  4  adverse  reactions (32% versus 25%) and  more frequent dose modifications  for  adverse  reactions  (23%  versus 17%)  in patients  65  years  or older  as  compared  to those younger than 65 years.

Renal impairment

There  is no  recommended  dose  of  Osimertinib  for  patients  with  severe  renal  impairment  (CLcr<30 mL/min) or end-stage-renal disease.

Hepatic Impairment

There  is  no  recommended  dose  for  Osimertinib  for  patients  with  moderate  or  severe  hepatic impairment.

CONTRAINDICATION:

None

PRECAUTION:

Interstitial Lung Disease (ILD)/Pneumonitis

Occurred  in  3.3%  of  patients.  Permanently  discontinue  Osimertinib  in  patients  diagnosed   with

ILD/Pneumonitis.

QTc Interval Prolongation

Monitor electrocardiograms and  electrolytes in patients who have a  history or predisposition for QTc prolongation,  or  those  who  are  taking  medications  that  are  known  to  prolong  the  QTc  interval. Withhold then restart at a reduced dose or permanently discontinue Osimertinib.

Cardiomyopathy

Occurred  in 1.4% of patients. Assess left ventricular ejection fraction (LVEF) before treatment and  then every 3 months thereafter.

Embryo–Fetal Toxicity

Osimertinib can  cause  fetal harm.  Advise females of potential risk to the fetus and  to use effective contraception during treatment with Osimertinib and for 6 weeks after final dose.  Advise males to use effective contraception for 4 months, after the last dose of Osimertinib.

ADVERSE REACTION:

Most common adverse reactions (>_ 25%) were diarrhea,  rash, dry skin and nail toxicity.

DRUG INTERACTION: Strong CYP3A Inhibitors

Avoid concomitant administration of Osimertinib with  strong CYP3A inhibitors,  including macrolide antibiotics (e.g., Telithromycin), antifungals (e.g., Itraconazole), antivirals (e.g., Ritonavir), Nefazodone, as concomitant use of strong CYP3A inhibitors may increase  Osimertinib plasma concentrations. If no other alternative exists, monitor patients more closely for adverse reactions of Osimertinib.

Strong CYP3A Inducers

Avoid concomitant administration of Osimertinib with strong CYP3A inducers (e.g., Phenytoin, Rifampicin, Carbamazepine, St. John’s Wort) as  strong CYP3A inducers  may decrease  Osimertinib plasma concentrations.

Effect on  other drugs

Avoid concomitant  administration  of  Osimertinib  with drugs  that  are  sensitive substrates  of  CYP3A, breast cancer resistance protein (BCRP), or CYP1A2 with narrow therapeutic indices, including but not limited to Fentanyl, Cyclosporine, Quinidine, Ergot Alkaloids, Phenytoin, Carbamazepine, as Osimertinib may increase or decrease  plasma concentrations of these drugs.

PHARMACEUTICAL INFORMATION: Storage Conditions

Store in a cool and dry place, away from light. Keep out of the reach of children.

Presentation & Packaging

Tagrix 40 Tablet: Each commercial box contains 30 tablets in Alu-Alu blister pack.

Tagrix 80 Tablet: Each commercial box contains 30 tablets in Alu-Alu blister pack.

Manufactured By
Beacon Pharmaceuticals Limited
Mymensingh, Bangladesh