DRUG INTERACTIONS

­ • Strong CYP3A Inducers or Moderate CYP2C8 Inducers:                                        Avoid concomitant use.

 • Strong CYP2C8 Inhibitors:                                                                                          Avoid concomitant use; reduce TUKYSA dose if concomitant use cannot be avoided.

• CYP3A Substrates:                                                                                              Avoid concomitant use with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. 

• P-gp Substrates:                                                                                               Consider reducing the dose of P-gp substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. 

U.S. FDA APPROVED  DRUGS DURING 2020

Sr.No-  13

 ADVERSE REACTIONS

­ The most common adverse reactions (=20%) are diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash.

CONTRAINDICATIONS                                                                                              None. 

WARNINGS AND PRECAUTIONS

­ • Diarrhea:                                                                                                              Severe diarrhea, including dehydration, acute kidney injury, and death, has been reported. Administer antidiarrheal treatment as clinically indicated. Interrupt dose, then dose reduce, or permanently discontinue TUKYSA based on severity. 

• Hepatotoxicity:                                                                                                    Severe hepatotoxicity has been reported on TUKYSA. Monitor ALT, AST and bilirubin prior to starting TUKYSA, every 3 weeks during treatment and as clinically indicated. Interrupt dose, then dose reduce, or permanently discontinue TUKYSA based on severity. 

• Embryo-Fetal Toxicity:                                                                                    TUKYSA can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. 

Also, refer to the Full Prescribing Information of trastuzumab and capecitabine for pregnancy and contraception information.

 PATIENT COUNSELING INFORMATION

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

• Inform patients that TUKYSA has been associated with severe diarrhea.         Instruct patients on how to manage diarrhea and to inform their healthcare provider immediately if there is any change in bowel patterns

• Inform patients that TUKYSA has been associated with severe hepatotoxicity and that they should report signs and symptoms of liver dysfunction to their healthcare provider immediately 

Embryo-Fetal Toxicity                                                                                                    • Inform pregnant women and females of reproductive potential of the risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy 

• Advise females of reproductive potential to use effective contraception during treatment with TUKYSA and for at least 1 week after the last dose

• Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TUKYSA and for at least 1 week after the last dose [

• Refer to the Full Prescribing Information of trastuzumab and capecitabine for pregnancy and contraception information.

Lactation                                                                                                                        • Advise women not to breastfeed during treatment with TUKYSA and for at least 1 week after the last dose

Infertility                                                                                                                          • Advise males and females of reproductive potential that TUKYSA may impair fertility 

Manufactured by:                                                                                                 Seattle Genetics, Inc. Bothell, WA 98021 1-855-4SEAGEN TUKYSA is a trademark, and Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc. © 2020 Seattle Genetics, Inc., Bothell, WA 98021.

CLINICAL PHARMACOLOGY

1. Mechanism of Action                                                                                            Tucatinib is a tyrosine kinase inhibitor of HER2. In vitro, tucatinib inhibits phosphorylation of HER2 and HER3, resulting in inhibition of downstream MAPK and AKT signaling and cell proliferation, and showed antitumor activity in HER2 expressing tumor cells.

In vivo, tucatinib inhibited the growth of HER2 expressing tumors. The combination of tucatinib and trastuzumab showed increased anti-tumor activity in vitro and in vivo compared to either drug alone.

2. Pharmacodynamics -                                                                                      Exposure Response Relationship Tucatinib exposure-response relationships and the time course of pharmacodynamics response have not been fully characterized.

Cardiac Electrophysiology                                                                                         No large mean increase in QTc (i.e., > 20 ms) was detected following treatment with TUKYSA at the recommended dose of 300 mg taken orally twice daily.

3. Pharmacokinetics-                                                                                           Tucatinib AUC0-INF and Cmax increases proportionally over a dosage range from 50 mg to 300 mg (0.17 to 1 times the approved recommended dosage).

Tucatinib exhibited 1.7-fold accumulation for AUC and 1.5-fold accumulation for Cmax following administration of TUKYSA 300 mg twice daily for 14 days.

Time to steady state was approximately 4 days.

Absorption-                                                                                                                The median time to peak plasma concentration of tucatinib was approximately 2 hours (range 1 to 4 hours).

Effects of Food                                                                                                     Following administration of a single oral dose of TUKYSA in 11 subjects after a high-fat meal (approximately 58% fat, 26% carbohydrate, and 16% protein), the mean AUC0-INF increased by 1.5-fold, the Tmax shifted from 1.5 hours to 4 hours, and Cmax was unaltered.

The effect of food on the pharmacokinetics of tucatinib was not clinically meaningful.

Distribution-                                                                                                               The geometric mean (CV%) apparent volume of distribution of tucatinib was approximately 1670 L (66%). The plasma protein binding was 97.1% at clinically relevant concentrations.

Elimination-                                                                                                                The geometric mean (CV%) half-life of tucatinib was approximately 8.5 (21%) hours and apparent clearance was 148 L/h (55%).

Metabolism-                                                                                                               Tucatinib is metabolized primarily by CYP2C8 and to a lesser extent via CYP3A.

Excretion-                                                                                                                   Following a single oral dose of 300 mg radiolabeled tucatinib, approximately 86% of the total radiolabeled dose was recovered in feces (16% of the administered dose as unchanged tucatinib) and 4.1% in urine with an overall total recovery of 90% within 13 days post-dose.

In plasma, approximately 76% of the plasma radioactivity was unchanged, 19% was attributed to identified metabolites, and approximately 5% was unassigned.

Specific Populations-                                                                                                 Age (< 65 (n =211); = 65 (n = 27)), albumin (25 to 52 g/L), creatinine clearance (creatinine clearance [CLcr] 60 to 89 mL/min (n = 89); CLcr 30 to 59 mL/min (n = 5)), body weight (41 to 138 kg), and race (White (n=168), Black (n=53), or Asian (n=10)) did not have a clinically meaningful effect on tucatinib exposure.

Renal Impairment-                                                                                                      No clinically significant differences in the pharmacokinetics of tucatinib were observed in patients with mild to moderate renal impairment (creatinine clearance: 30 to 89 mL/min by Cockcroft-Gault).

The effect of severe renal impairment (creatinine clearance: < 30 mL/min) on the pharmacokinetics of tucatinib is unknown.

Hepatic Impairment -                                                                                                        Mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment had no clinically relevant effect on tucatinib exposure.

Tucatinib AUC0-INF was increased by 1.6 fold in subjects with severe (Child-Pugh C) hepatic impairment compared to subjects with normal hepatic function.

Drug Interaction Studies-  

Effect of Other Drugs on TUKYSA-                                                             Concomitant Drug (Dose) TUKYSA Dose Ratio (90% CI) of Tucatinib Exposure With and Without Concomitant Drug Cmax AUC Strong CYP3A Inhibitor Itraconazole (200 mg BID) 1.3 (1.2, 1.4) 1.3 (1.3, 1.4)

Strong CYP3A/Moderate 2C8 Inducer -Rifampin (600 mg once daily) 300 mg single dose 0.6 (0.5, 0.8) 0.5 (0.4, 0.6) Strong CYP2C8 Inhibitor Gemfibrozil (600 mg BID) 1.6 (1.5, 1.8) 3.0 (2.7, 3.5) 

Effect of TUKYSA on Other Drugs- Concomitant Drug Ratio (90% CI) of Exposure Measures of Concomitant Drug with/without Tucatinib (Dose) TUKYSA Dose Cmax AUC CYP2C8 

 USE IN SPECIFIC POPULATIONS-                                                                                 

1. Pregnancy Risk Summary-                                                                                   TUKYSA is used in combination with trastuzumab and capecitabine. Refer to the Full Prescribing Information of trastuzumab and capecitabine for pregnancy information.

Based on findings in animals and its mechanism of action, TUKYSA can cause fetal harm when administered to a pregnant woman 

There are no available human data on TUKYSA use in pregnant women to inform a drug-associated risk.

Advise pregnant women and females of reproductive potential of the potential risk to the fetus. 

The background risk of major birth defects and miscarriage for the indicated population is unknown.

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-                                                                                             TUKYSA is used in combination with trastuzumab and capecitabine. Refer to the Full Prescribing Information of trastuzumab and capecitabine for lactation information.

There are no data on the presence of tucatinib or its metabolites in human or animal milk or its effects on the breastfed child or on milk production.

Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with TUKYSA and for at least 1 week after the last dose.

3. Females and Males of Reproductive Potential-                                                          TUKYSA can cause fetal harm when administered to a pregnant woman [see Use in

Pregnancy Testing-                                                                                                Verify the pregnancy status of females of reproductive potential prior to initiating treatment with TUKYSA.

Contraception Females-                                                                                       Advise females of reproductive potential to use effective contraception during treatment with TUKYSA and for at least 1 week after the last dose.

Males-                                                                                                                    Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TUKYSA and for at least 1 week after the last dose.

Infertility-                                                                                                                Based on findings from animal studies, TUKYSA may impair male and female fertility [see Nonclinical Toxicology (13.1)].

4. Pediatric Use-                                                                                                        The safety and effectiveness of TUKYSA in pediatric patients have not been established.

5. Geriatric Use-                                                                                                            In HER2CLIMB, 82 patients who received TUKYSA were = 65 years, of whom 8 patients were = 75 years. The incidence of serious adverse reactions in those receiving TUKYSA was 34% in patients = 65 years compared to 24% in patients <65 years.

The most frequent serious adverse reactions in patients who received TUKYSA and = 65 years were diarrhea (9%), vomiting (6%), and nausea (5%).

There were no observed overall differences in the effectiveness of TUKYSA in patients = 65 years compared to younger patients. There were too few patients =75 years to assess differences in effectiveness or safety.

6. Renal Impairment-                                                                                                 The use of TUKYSA in combination with capecitabine and trastuzumab is not recommended in patients with severe renal impairment (CLcr < 30 mL/min estimated by Cockcroft-Gault Equation), because capecitabine is contraindicated in patients with severe renal impairment.

No dose adjustment is recommended for patients with mild or moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min).

7. Hepatic Impairment-                                                                                          Tucatinib exposure is increased in patients with severe hepatic impairment (Child-Pugh C). Reduce the dose of TUKYSA for patients with severe (Child-Pugh C) hepatic impairment 

No dose adjustment for TUKYSA is required for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.