Description

Product Name: Tucaxen

Generic Name: Tucatinib

Formulation: Tablets

Available Pack Size: 30’s in a bottle

Available Strengths: 150 mg

Manufacturer: Everest Pharmaceuticals Ltd.

Tucaxen 150 Mg (Tucatinib), generic Tukysa, is used with trastuzumab (Herceptin) and capecitabine (Xeloda) to treat a certain type of hormone receptor-positive breast cancer that has spread to other parts of the body and cannot be treated with surgery in adults who have already been treated with at least one other chemotherapy medication. Tucatinib is in a class of drugs called kinase inhibitors. It works by blocking the action of the abnormal protein that signals cancer cells to multiply. This helps stop or slow the spread of cancer cells.

Composition

Tucaxen 50 Tablet: Each film-coated tablet contains Tucatinib INN 50 mg. 

Tucaxen 150 Tablet: Each film-coated tablet contains Tucatinib INN 150 mg. 

Pharmacology 

 Mechanism of Action 

Tucatinib is a tyrosine kinase inhibitor of HER2. In vitro, it inhibits phosphorylation of HER2 and HER3, resulting in inhibition of downstream MAPK and AKT signaling and cell proliferation, and showed anti-tumor activity in HER2 expressing tumor cells. In vivo, it 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. 

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 at the recommended dose of 300 mg taken orally twice daily.

Pharmacokinetics: Tucatinib AUCO-INF and Cmax increase 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 after administering Tucatinib 300 mg twice daily for 14 days. The 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:

• After administering a single oral dose of Tucatinib to 11 subjects after a high-fat meal (approximately 58% fat, 26% carbohydrate, and 16% protein), the mean AUCO-INF increased by 1.5-fold.
• The Tmax shifted from 1.5 hours to 4 hours.
• 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 somewhat 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. Approximately 76% of the plasma radioactivity was unchanged, 19% was attributed to identified metabolites, and approximately 5% was unassigned. 

INDICATION

Tucatinib is combined with trastuzumab and capecitabine to treat adult patients with advanced unrespectable or metastatic HER2-positive breast cancer, including patients with brain metastases who have received one or more prior anti-HER2-based regimens in the metastatic setting.

DOSAGE AND ADMINISTRATION 

Recommended Dosage: The recommended dosage is 300 mg, taken orally twice daily in combination with trastuzumab and capecitabine until disease progression or unacceptable toxicity.

The tablets should be swallowed whole, not chewed, crushed, or split. It would be best if you never consumed a tablet that is broken, cracked, or otherwise non-intact. Each dose should be taken approximately 12 hours apart and simultaneously with or without a meal daily.

If the patient vomits or misses a dose, the patient is advised to take the following amount at its usual scheduled time.

When given in combination with Tucatinib, the recommended dosage of capecitabine is 1000 mg/m2 orally twice daily, taken within 30 minutes after a meal. Tucatinib and capecitabine can be taken at the same time.

Dosage Modifications for Adverse Reactions

 Recommended Dose Reductions for Adverse Reactions. Permanently discontinue Tucatinib in patients unable to tolerate 150 mg orally twice daily.

Dosage Modifications for Severe Hepatic Impairment 

for patients with severe hepatic impairment (Child-Pugh C) reduce the recommended dosage to 200 mg orally twice daily. 

 Dosage Modifications for Concomitant Use with Strong CYP2C8 Inhibitors 

Avoid concomitant use of strong CYP2C8 inhibitors with Tucatinib. If concomitant use with a strong CYP2C8 inhibitor cannot be avoided, reduce the recommended dosage to 100 mg orally twice daily. After discontinuing the strong CYP2C8 inhibitor for 3 elimination half-lives, resume the dose taken before initiating the inhibitor.

CONTRAINDICATION

None.

WARNING AND PRECAUTION 

Diarrhea: Tucatinib can cause severe diarrhea, dehydration, hypotension, acute kidney injury, and death. In HER2CLIMB, 81% of patients who received this experienced diarrhea, including 12% with Grade 3 diarrhea and 0.5% with Grade 4 diarrhea. Both patients who developed Grade 4 diarrhea subsequently died, with diarrhea contributing to death. The median time to onset of the first episode of diarrhea was 12 days and the median time to resolution was 8 days. Diarrhea led to dose reductions in 6% of patients and discontinuation in 1% of patients. Prophylactic use of antidiarrheal treatment was not required on HER2CLIMB. 

If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea. Based on the severity of diarrhea, interrupt the dose, then reduce the dose or permanently discontinue the dose. 

Hepatotoxicity: Tucatinib can cause severe hepatotoxicity. In HER2CLIMB, 8% of patients who received had an ALT increase > 5 x ULN, 6% had an AST increase > 5 x ULN, and 1.5% had a bilirubin increase > 3 x ULN (Grade 23). Hepatotoxicity led to dose reduction in 8% of patients and discontinuation in 1.5% of patients. 

Monitor ALT, AST, and bilirubin before starting Tucatinib, every 3 weeks during treatment, and as clinically indicated. Based on the severity of hepatotoxicity, interrupt the dose, then reduce the dose or permanently discontinue the dose. 

Embryo-Fetal Toxicity:

Based on animal studies and its mechanism of action, it can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration to pregnant rats and rabbits during organogenesis caused embryo-fetal mortality, reduced fetal weight and fetal abnormalities at maternal exposures > 1.3 times the human exposure (AUC) at the recommended dose. 

Pregnant women and females with reproductive potential should be informed of the potential risk to their fetuses. Use effective contraception during treatment with Tucatinib and for at least one week after the last dose if you are a female with reproductive potential. Men with female partners of reproductive potential should use effective contraception during and after treatment with Tucatinib.

It is used in combination with trastuzumab and capecitabine.

SIDE EFFECTS 

The following clinically significant side effects are observed: 

• Diarrhea 
• Hepatotoxicity 

The most common side effects in patients (20%) were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash. 

USE IN SPECIFIC POPULATIONS

 Pregnancy 

Risk Summary: Tucatinib is used in combination with trastuzumab and capecitabine. 

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. 

Based on animal findings and its mechanism of action, Tucatinib can cause fetal harm when administered to a pregnant woman. There are no available human data on Tucatinib 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 congenital disabilities and miscarriage for the indicated population is unknown. 

Lactation 

Risk Summary: Tucatinib is used in the capecitabine combination.

There is no data on the presence of Tucatinib, its metabolites in human or animal milk, or its effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with Tucatinib and for at least 1 week after the last dose. 

Females and Males of Reproductive Potential: Tucatinib can cause fetal harm when administered to a pregnant woman Tucatinib is used in combination with trastuzumab and capecitabine.

Pregnancy Testing: Verifies the pregnancy status of females of reproductive potential before initiating treatment with Tucatinib. 

Contraception

 Females: During and after treatment with Tucatinib, females of reproductive potential should use effective contraception.

Males: Male patients with female partners of reproductive potential are advised to use effective contraception during treatment with Tucatinib and for at least 1 week after the last dose. 

Infertility: Based on findings from animal studies, Tucatinib may impair male and female fertility. 

Pediatric Use: The safety and effectiveness of Tucatinib in pediatric patients have not been established. 

Geriatric Use: In HER2CLIMB, 82 patients who received Tucatinib were > 65 years, of whom 8 were > 75 years old. The incidence of serious adverse reactions in those receiving Tucatinib was 34% in patients 2 65 years compared to 24% in patients <65 years. The most frequent serious adverse reactions in patients who received Tucatinib and 2 65 years were diarrhea (9%), vomiting (6%), and nausea (5%). There were no observed overall differences in the effectiveness of Tucatinib in patients > 65 years compared to younger patients. There were too few patients at 275 years to assess differences in effectiveness or safety. 

Renal Impairment: Tucatinib, 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). 

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

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

OVERDOSE 

There is no specific antidote, and hemodialysis’s benefit in treating Tucatinib overdose is unknown. The treatment should be withheld in case of an overdose and should take general supportive measures.

PHARMACEUTICAL INFORMATION 

Storage 

Store below 25°C, in a cool and dry place. Keep away from light. Keep out of the reach of children. 

How Supplied 

Tucaxen 50 tablet: Each HDPE container contains 30 film-coated tablets (each tablet contains 50 mg Tucatinib), a silica gel desiccant and a polyester coil with a child-resistant closure. 

Males Male patients with female partners of reproductive potential are advised to use effective contraception during treatment with Tucatinib and for at least 1 week after the last dose. 

Tucaxen 150 tablet: Each HDPE container contains 30 film-coated tablets (each tablet contains 150 mg Tucatinib), a silica gel desiccant and a polyester coil with a child-resistant closure. 

 

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