Drug Information

Drug Interaction:

DRUG INTERACTIONS-

Strong CYP3A Inhibitors: Avoid concurrent administration with TAGRISSO if possible. If no alternative exists, the patient should be closely monitored for signs of toxicity.

Strong CYP3A Inducers: Avoid if possible because concomitant use may decrease osimertinib plasma concentrations.

.

Indication:

36/15 PRODUCT DETAILS

Name of the druaag- TAGRISSO

Active ingriendents- Osimertinib

FDA approved use- To treat certain patients with non-small cell lung cancer

Date of Approval 11/13/2015

HIGHLIGHTS OF PRESCRIBING INFORMATION-

These highlights do not include all the information needed to use TAGRISSO safely and effectively.

See full prescribing information for TAGRISSO. TAGRISSO™ (osimertinib) tablet, for oral use

Initial U.S. Approval: 2015

INDICATIONS AND USAGE -

TAGRISSO 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.

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 confirmatory trials.

Adverse Reaction:

ADVERSE REACTIONS-

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

Contra-Indications:

CONTRAINDICATIONS -

None.

WARNINGS AND PRECAUTIONS -

Interstitial Lung Disease (ILD)/Pneumonitis: Occurred in 3.3% of patients.

Permanently discontinue TAGRISSO in patients diagnosed with ILD/Pneumonitis.

QTc Interval Prolongation: Monitor electrocardiograms and electrolytes in patients who have a history of those who are taking medications that are known to prolong the QTc interval. Withhold then restart at a reduced dose or permanently discontinue TAGRISSO.

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

Embryo-Fetal Toxicity: TAGRISSO can cause fetal harm. Advise females of potential risk to the fetus and to use effective contraception during treatment with TAGRISSO and for 6 weeks after final dose.

Advise males to use effective contraception for 4 months, after the last dose of TAGRISSO.

(

Dosages/ Overdosage Etc:

DOSAGE AND ADMINISTRATION-

Confirm the presence of T790M mutation in tumor specimens prior to initiation of treatment with TAGRISSO. 80 mg orally once daily, with or without food.

DOSAGE FORMS AND STRENGTHS-

Tablets: 80 mg and 40 mg

Patient Information:

PATIENT COUNSELING INFORMATION -

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Interstitial Lung Disease/Pneumonitis- Inform patients of the risks of severe or fatal ILD, including pneumonitis.

Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms

QTc Interval Prolongation- Inform patients of symptoms that may be indicative of significant QTc prolongation including dizziness, lightheadedness, and syncope.

Advise patients to report these symptoms and to inform their physician about the use of any heart or blood pressure medications].

Cardiomyopathy- TAGRISSO can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider

Embryo-Fetal Toxicity - TAGRISSO can cause fetal harm if taken during pregnancy. Advise pregnant women of the potential risk to a fetus.

Advise females to inform their healthcare provider if they become pregnant or if pregnancy is suspected, while taking TAGRISSO

Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the final dose

Advise males to use effective contraception during treatment and for 4 months after the final dose of TAGRISSO

Lactation- Advise women not to breastfeed during treatment with TAGRISSO and for 2 weeks after the final dose

Distributed by: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850 TAGRISSO is a trademark of the AstraZeneca group of companies ©AstraZeneca 2015

Pharmacology/ Pharmacokinetics:

CLINICAL PHARMACOLOGY

1. Mechanism of Action

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.

2. Pharmacodynamics

Cardiac Electrophysiology

The QTc interval prolongation potential of osimertinib was assessed in 210 patients who received TAGRISSO 80 mg daily

3 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).

Absorption

The median time to Cmax of osimertinib was 6 hours (range 3-24 hours).

Following administration of a 20 mg TAGRISSO 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

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 or total bilirubin between 1.0 to 1.5 times ULN and any AST ).

Drug Interactions

Effect of Other Drugs on TAGRISSO:

Strong CYP3A Inhibitors: Clinical studies evaluating TAGRISSO in the presence of strong CYP3A inhibitors have not been conducted .

Strong CYP3A Inducers: Clinical studies evaluating TAGRISSO in the presence of strong CYP3A inducers have not been conducted.

Gastric Acid Reducing Agents: The exposure of osimertinib was not affected by concurrent administration of a single 80 mg TAGRISSO tablet following 40 mg omeprazole administration for 5 days.

Pregnancy and lactation:

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary

Based on data from animal studies and its mechanism of action, TAGRISSO can cause fetal harm when administered to a pregnant woman. There are no available data on TAGRISSO use in pregnant women.

. Advise pregnant women 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 on the presence of osimertinib in human milk, the effects of osimertinib on the breastfed infant or on milk production.

. Because of the potential for serious adverse reactions in breastfed infants from osimertinib, advise a lactating woman not to breastfeed during treatment with TAGRISSO and for 2 weeks after the final dose.

3. Females and Males of Reproductive Potential

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO 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 TAGRISSO [see

Infertility

Based on animal studies, TAGRISSO may impair fertility in females and males of reproductive potential.

It is not known if the effects on fertility are reversible

4. Pediatric Use

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

5.Geriatric use-

One hundred eighty-seven (45%) of the 411 patients in clinical trials of TAGRISSO were 65 years of age and older, and 54 patients (13%) were 75 years of age and older. No overall differences in effectiveness were observed based on age.

6. Renal Impairment

No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of osimertinib.

Based on population pharmacokinetic analysis, no dose adjustment is recommended in patients with mild [creatinine clearance (CLcr) 60-89 mL/min] or moderate (CLcr 30-59 mL/min) renal impairment.

There is no recommended dose of TAGRISSO for patients with severe renal

impairment (CLcr <30 mL/min) or end-stage-renal disease

8.7 Hepatic Impairment

No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of osimertinib.

36/15. Osimertinib- (TAGRISSO)- (Nov 2015)- to be used in combination with vemurafenib to treat advanced melonoma that has spread to other parts of the body or cant be removed by surgergy and that has a certain type of abnormal gene BRAF V600E or V600k mutation

Drug Interaction

Indication

Adverse Reaction

Contra-Indications

Dosages/ Overdosage Etc

Patient Information

Pharmacology/ Pharmacokinetics

Pregnancy and lactation