Instructions for completing the VITRAKVI (larotrectinib) prescription and patient support program enrollment form Please complete the following short steps to enroll your patients in support services available through TRAK Assist for VITRAKVI. STEP 1 STEP 2 STEP 3 VITRAKVI Prescription Prescriber completes the Patient Contact Information, Prescriber Contact Information, Diagnostics Information, and Prescription Information sections, and signs and dates where indicated Patient Support Opt-In Patient checks the services he/she wishes to receive, initials where indicated, and signs and dates the Written Permission to Share Protected Health Information Submission Fax the form, along with copies of the patient s pharmacy insurance card(s) (front and back), to 1-888-506-TRAK (1-888-506-8725) For more information and assistance completing the form, please call 1-844-634-TRAK (1-844-634-8725). Additional copies of the form are available at VITRAKVI.com. Please see Indication and full Important Safety Information on page 5 and accompanying full Prescribing Information.
VITRAKVI (larotrectinib) prescription and patient support program enrollment form 1-888-506-TRAK 1-844-634-TRAK PATIENT CONTACT INFORMATION Patient name* DOB* Male Female MM/DD/YYYY Address* City* State* Zip* Preferred phone* Email Alternate phone Preferred language Please fax a copy of the patient s insurance card(s) (front and back) along with this form. Please complete section below or include a copy of the patient s pharmacy benefits. Primary caregiver Preferred contact method PRIMARY PRESCRIPTION INSURER Prescription insurer Phone Policy ID Group number Prescription BIN Prescription PCN Subscriber name SECONDARY PRESCRIPTION INSURER PRESCRIBER Prescription insurer Phone Policy ID Group number Prescription BIN Prescription PCN Subscriber name PRESCRIBER CONTACT INFORMATION Prescriber name* NPI* Name of supervising/collaborating physician (if applicable) Address* City State ZIP Office contact Fax Phone Email DIAGNOSTICS INFORMATION Has the patient tested positive for NTRK gene fusion? Yes. If yes, please include copy of results or provide lab name and lab test date. Lab name Lab test date No. If no, is assistance needed to find an appropriate lab? Yes No Test type Next-Generation Sequencing (NGS) Fluorescence in situ hybridization (FISH) Immunohistochemistry (IHC) Polymerase chain reaction (PCR) Select if patient needs appeal or financial assistance with diagnostic support for NTRK gene fusion testing. *Required field. Following a positive TRK IHC test, confirmation of NTRK gene fusion is needed prior to initiation of VITRAKVI treatment. To report any adverse events, product technical complaints, or medication errors associated with the use of VITRAKVI, contact Bayer at 1-888-842-2937, or send the information to DrugSafety.GPV.US@bayer.com. FAX THIS FORM AND THE PATIENT INSURANCE INFORMATION TO 1-888-506-TRAK (1-888-506-8725). Please see Indication and full Important Safety Information on page 5 and accompanying full Prescribing Information. 2
Name of patient* PRESCRIPTION INFORMATION VITRAKVI (larotrectinib) prescription and patient support program enrollment form 1-888-506-TRAK DOB* 1-844-634-TRAK MM/DD/YYYY ICD-10 Diagnosis Code(s) Dosage Form* VITRAKVI in: 25-mg capsule 100-mg capsule 20-mg/mL oral solution PRESCRIBER SIG* Quantity/Supply* Refills Home Healthcare Visits (physician please select an option): Home healthcare nurse visit (During the home visit, the home healthcare nurse will educate patient/caregiver on insertion of adapter and use of syringes for medication withdrawal) Patient/caregiver will be seen in this physician s office for education on insertion of adapter and use of syringes for medication withdrawal Preferred Pharmacy (not guaranteed): Accredo Phone: 1-855-540-1797 Fax: 1-877-327-7120 CVS Specialty Phone: 1-800-790-1698 Fax: 1-855-296-0210 US Bioservices Phone: 1-833-230-1407 Fax: 1-833-878-5917 Allergies Other medications taken I certify that the above therapy is medically necessary and that the information provided is accurate to the best of my knowledge. I appoint TRAK Assist TM, on my behalf, to convey this prescription to the dispensing pharmacy. I understand that I may not delegate signature authority. Prescriber Signature and Date* (sign and indicate the date on only one of the lines below; no stamps allowed) Dispense as written Substitutions permitted *Required field. Date Date I grant permission for TRAK Assist to leave a message at the phone number(s) listed on the previous page, including the name of the drug, if I am not available. PATIENT PATIENT SUPPORT PROGRAM ENROLLMENT Bayer provides patient support services for VITRAKVI patients that include (A) financial assistance for eligible patients and temporary assistance for eligible patients; (B) temporary assistance through the Bridge Program for eligible patients with delays or lapses in coverage. You may enroll in one or both of these programs. Enrollment allows TRAK Assist counselors to contact you and discuss support options available to you through Bayer or external resources. Any assistance provided through TRAK Assist is at no cost to you, and any free drug or resources received should not be billed to you or any third party. If you experience an adverse event, it will be forwarded to Bayer Drug Safety, which may contact you or your treating physician. Enrollment will be for five years. You may opt out of this program at any time by calling 1-844-634-8725 or writing to: TRAK Assist, PO Box 220765, Charlotte, NC 28222-0765. You do not have to provide HIPAA Authorization to enroll in Option A (financial assistance). Enroll me in (check all that apply): (A) Financial Assistance (B) Bridge Program Please initial here to confirm your elections To report any adverse events, product technical complaints, or medication errors associated with the use of VITRAKVI, contact Bayer at 1-888-842-2937, or send the information to DrugSafety.GPV.US@bayer.com. FAX THIS FORM AND THE PATIENT INSURANCE INFORMATION TO 1-888-506-TRAK (1-888-506-8725). Please see Indication and full Important Safety Information on page 5 and accompanying full Prescribing Information. 3
VITRAKVI (larotrectinib) prescription and patient support program enrollment form 1-888-506-TRAK 1-844-634-TRAK PATIENT Name of patient* WRITTEN PERMISSION TO SHARE PROTECTED HEALTH INFORMATION I authorize the use and disclosure of my Protected Health Information ( PHI ) as defined by the Health Insurance Portability and Accountability Act of 1996, which was amended by the Health Information Technology for Economic and Clinical Health Act (as amended, HIPAA ). I understand that Protected Health Information is health information that identifies me or that could reasonably be used to identify me and that this authorization to release my information is voluntary. I authorize my healthcare provider, including my physician, pharmacies and my health plan, to disclose my name, address, and telephone number along with certain medical information including my treatment, my eligibility for assistance, the coordination of my treatment, the receipt of my medication and my participation in the Patient Support Program, TRAK Assist, to Bayer and its agents. I allow the use and disclosure of my PHI for the following purposes: (1) To verify my insurance information; (2) to ensure the accuracy and completeness of the TRAK Assist enrollment form; (3) to help with my reimbursement questions; (4) to determine if I qualify for patient assistance; (5) to determine my eligibility for other sources of funding; (6) to provide education, training, and ongoing support on the use of my medication; (7) to send me information on related products and services related to my treatment; (8) to send me refill reminders for my prescription and to encourage appropriate use; (9) to communicate with me, my healthcare providers and health plan insurers about my medical care and treatment; (10) to contact me for market research feedback; (11) for sales support purposes and (12) to comply with applicable law. This authorization shall be in effect for 10 years from the date of my signature, or the date of last enrollment, whichever comes first, unless a shorter period is required by law. If I (or my representative) revoke this authorization, healthcare providers will stop using my PHI for the purposes outlined in this authorization, but the revocation will not affect prior use or disclosure of my PHI in reliance on this authorization. I (or DOB* MM/DD/YYYY my representative) may revoke this authorization at any time by calling 1-844-634-8725 or writing to: TRAK Assist, PO Box 220765, Charlotte, NC 28222-0765. I also understand that, under this authorization, entities that receive my PHI may not be required by law to keep the information private and it will no longer be protected by the privacy law. It may become available in the public domain. I understand that I do not need to sign this form to receive medical treatment or medication. I (or my representative) have read and understand the terms of this authorization form, and have had an opportunity to ask questions about the uses and disclosures of PHI described above. All of my questions have been answered to my satisfaction. I authorize the use and disclosure of my information as described in this form. I (or my representative) have the right to receive a copy of this authorization upon request. I understand that my healthcare providers, insurers, and health plans may receive remuneration (payment) from Bayer in exchange for disclosing my PHI to Bayer. Patient or Patient Representative Signature Date Name of Patient Representative Relation to Patient If signed by the Patient s Representative, a description of the representative s relationship to the Patient and such person s authority to act for the Patient must be provided in the space above. To report any adverse events, product technical complaints, or medication errors associated with the use of VITRAKVI, contact Bayer at 1-888-842-2937, or send the information to DrugSafety.GPV.US@bayer.com. FAX THIS FORM AND THE PATIENT INSURANCE INFORMATION TO 1-888-506-TRAK (1-888-506-8725). Please see Indication and full Important Safety Information on page 5 and accompanying full Prescribing Information. 4
Indication VITRAKVI is indicated for the treatment of adult and pediatric patients with solid tumors that: have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Important Safety Information Neurotoxicity: Among the 176 patients who received VITRAKVI, neurologic adverse reactions of any grade occurred in 53% of patients, including Grade 3 and Grade 4 neurologic adverse reactions in 6% and 0.6% of patients, respectively. The majority (65%) of neurological adverse reactions occurred within the first three months of treatment (range: 1 day to 2.2 years). Grade 3 neurologic adverse reactions included delirium (2%), dysarthria (1%), dizziness (1%), gait disturbance (1%), and paresthesia (1%). Grade 4 encephalopathy (0.6%) occurred in a single patient. Neurologic adverse reactions leading to dose modification included dizziness (3%), gait disturbance (1%), delirium (1%), memory impairment (1%), and tremor (1%). Advise patients and caretakers of these risks with VITRAKVI. Advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dose when resumed. Hepatotoxicity: Among the 176 patients who received VITRAKVI, increased transaminases of any grade occurred in 45%, including Grade 3 increased AST or ALT in 6% of patients. One patient (0.6%) experienced Grade 4 increased ALT. The median time to onset of increased AST was 2 months (range: 1 month to 2.6 years). The median time to onset of increased ALT was 2 months (range: 1 month to 1.1 years). Increased AST and ALT leading to dose modifications occurred in 4% and 6% of patients, respectively. Increased AST or ALT led to permanent discontinuation in 2% of patients. Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed. Embryo-Fetal Toxicity: VITRAKVI can cause fetal harm when administered to a pregnant woman. Larotrectinib resulted in malformations in rats and rabbits at maternal exposures that were approximately 11- and 0.7-times, respectively, those observed at the clinical dose of 100 mg twice daily. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment and for 1 week after the final dose of VITRAKVI. Most Common Adverse Reactions ( 20%): The most common adverse reactions ( 20%) were: increased ALT (45%), increased AST (45%), anemia (42%), fatigue (37%), nausea (29%), dizziness (28%), cough (26%), vomiting (26%), constipation (23%), and diarrhea (22%). Drug Interactions: Avoid coadministration of VITRAKVI with strong CYP3A4 inhibitors (including grapefruit or grapefruit juice), strong CYP3A4 inducers (including St. John s wort), or sensitive CYP3A4 substrates. If coadministration of strong CYP3A4 inhibitors or inducers cannot be avoided, modify the VITRAKVI dose as recommended. If coadministration of sensitive CYP3A4 substrates cannot be avoided, monitor patients for increased adverse reactions of these drugs. Lactation: Advise women not to breastfeed during treatment with VITRAKVI and for 1 week after the final dose. Please see accompanying full Prescribing Information. 2018 Bayer and Loxo Oncology, Inc. All rights reserved. Bayer, the Bayer Cross, and VITRAKVI are registered trademarks of Bayer, and TRAK Assist is a trademark of Bayer. PP-912-US-0155 11/18 5
HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use VITRAKVI safely and effectively. See full prescribing information for VITRAKVI. VITRAKVI (larotrectinib) capsules, for oral use VITRAKVI (larotrectinib) oral solution Initial U.S. Approval: 2018 ----------------------------INDICATIONS AND USAGE--------------------------- VITRAKVI is a kinase inhibitor indicated for the treatment of adult and pediatric patients with solid tumors that: have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a Instructions for completing the VITRAKVI (larotrectinib) prescription and patient support program enrollment form known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials (1,14). Please complete the following short steps to enroll your patients in support services available through TRAK Assist for VITRAKVI. ----------------------DOSAGE AND ADMINISTRATION------------------------ Select patients for treatment with VITRAKVI based on the presence of a NTRK gene fusion (2.1, 14). Recommended Dosage in Adult and Pediatric Patients with Body Surface Area of at Least 1.0 Meter-Squared: 100 mg orally twice daily (2.2) Recommended Dosage in Pediatric Patients with Body Surface Area of Less Than 1.0 Meter-Squared: 100 mg/m 2 orally twice daily (2.2) ---------------------DOSAGE FORMS AND STRENGTHS---------------------- Capsules: 25 mg, 100 mg (3) Oral Solution: 20 mg/ml (3) 1 2 -------------------------------CONTRAINDICATIONS------------------------------ None. (4) STEP VITRAKVI Prescription Prescriber completes the Patient Contact Information, 2.1 Patient Selection Prescriber Contact Information, 2.2 Recommended Dosage Diagnostics Information, and Prescription Information Inhibitors sections, and signs and dates Inducers where indicated STEP -----------------------WARNINGS AND PRECAUTIONS------------------------ Neurotoxicity: Advise patients and caretakers of the risk of neurologic adverse reactions. Advise patients not to drive or operate hazardous Patient Support Opt-In Patient checks the services he/she wishes to 8.1 receive, Pregnancy 8.2 Lactation initials where indicated, and signs and dates the Written Permission to Share Protected Health Information Please see Indication and full Important Safety Information on page 5 and accompanying full Prescribing Information. machinery if experiencing neurotoxicity. Withhold and modify dosage, or permanently discontinue VITRAKVI based on severity. (2.3, 5.1) Hepatotoxicity: Monitor liver tests including ALT and AST every 2 weeks during the first month of treatment, then monthly thereafter and as clinically indicated. Withhold and modify dosage, or permanently discontinue VITRAKVI based on severity. (2.6, 5.2) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females with reproductive potential of potential risk to the fetus and to use effective contraception. (5.3, 8.3) -----------------------------ADVERSE REACTIONS------------------------------- The most common adverse reactions ( 20%) with VITRAKVI were fatigue, nausea, dizziness, vomiting, increased AST, cough, increased ALT, constipation, and diarrhea. (6). To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------- Strong CYP3A4 Inhibitors: Avoid coadministration of strong CYP3A4 inhibitors with VITRAKVI. If coadministration cannot be avoided, reduce the VITRAKVI dose. (2.4, 7.1) Strong CYP3A4 Inducers: Avoid coadministration of strong CYP3A4 inducers with VITRAKVI. If coadministration cannot be avoided, increase the VITRAKVI dose. (2.5, 7.1) Sensitive CYP3A4 Substrates: Avoid coadministration of sensitive CYP3A4 substrates with VITRAKVI. (7.2) -----------------------USE IN SPECIFIC POPULATIONS------------------------ Lactation: Advise not to breastfeed. (8.2) Hepatic Impairment: Reduce the starting dose of VITRAKVI in patients with moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment. (2.6, 8.7) STEP 3Revised: 11/2018 See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.3 Dosage Modifications for Adverse Reactions 2.4 Dosage Modifications for Coadministration with Strong CYP3A4 2.5 Dosage Modifications for Coadministration with Strong CYP3A4 8 USE IN SPECIFIC POPULATIONS Submission Fax the form, along with copies of the patient s pharmacy insurance card(s) (front and back), to 1-888-506-TRAK (1-888-506-8725) 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 11 DESCRIPTION 2.6 Dosage Modifications for Patients with Hepatic Impairment 12 CLINICAL PHARMACOLOGY 2.7 Administration 12.1 Mechanism of Action 3 DOSAGE FORMS AND STRENGTHS 12.2 Pharmacodynamics 4 CONTRAINDICATIONS 12.3 Pharmacokinetics 5 WARNINGS AND PRECAUTIONS 13 NONCLINICAL TOXICOLOGY 5.1 Neurotoxicity 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.2 Hepatotoxicity 13.2 Animal Toxicology and/or Pharmacology 5.3 Embryo-Fetal Toxicity 14 CLINICAL STUDIES 6 ADVERSE REACTIONS 16 HOW SUPPLIED/STORAGE AND HANDLING 6.1 Clinical Trial Experience 17 PATIENT COUNSELING INFORMATION 7 DRUG INTERACTIONS For 7.1 more Effects information of Other Drugs and on VITRAKVI assistance completing the form, please *Sections call or subsections omitted from the full prescribing information are not 7.2 Effects of VITRAKVI on Other Drugs listed. 1-844-634-TRAK (1-844-634-8725). Additional copies of the form are available at VITRAKVI.com.
PRESCRIBER PATIENT 1 CONTACT INDICATIONS INFORMATION AND USAGE Patient name* DOB* Male Female MM/DD/YYYY Address* City* State* Zip* Preferred phone* Alternate phone have no satisfactory alternative treatments or Preferred that have language progressed following treatment. Please fax a copy of the patient s insurance card(s) (front and back) along with this form. Please complete section below or include a copy of the patient s pharmacy benefits. This indication is approved under accelerated approval based on overall response rate and Primary caregiver duration of response [see Clinical Studies (14)]. Continued Preferred contact approval method for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. PRIMARY PRESCRIPTION INSURER Prescription 2 insurer DOSAGE AND ADMINISTRATION Phone Policy ID Group number 2.1 Patient Selection Prescription BIN Prescription PCN Subscriber name Select patients for treatment with VITRAKVI based on the presence of a NTRK gene fusion in SECONDARY PRESCRIPTION INSURER tumor specimens [see Clinical Studies (14)]. An FDA-approved test for the detection of NTRK Prescription insurer Phone Policy ID gene fusion is not currently available. Group number 2.2 Recommended Prescription Dosage BIN Prescription PCN Subscriber name PRESCRIBER Recommended CONTACT INFORMATION Dosage in Adult and Pediatric Patients with Body Surface Area of at Least 1.0 Meter-Squared Prescriber The name* recommended dosage of VITRAKVI is 100 mg orally twice daily, NPI* with or without food, until disease progression or until unacceptable toxicity. Name of supervising/collaborating physician (if applicable) Recommended Dosage in Pediatric Patients with Body Surface Area Less Than 1.0 Meter- Address* City State ZIP Squared Office contact The recommended dosage of VITRAKVI is 100 mg/m Phone 2 orally twice daily, with or without food, until disease progression or until unacceptable toxicity. Fax Email 2.3 Dosage Modifications for Adverse Reactions DIAGNOSTICS INFORMATION For Grade 3 or 4 adverse reactions: Has the patient tested positive for NTRK gene fusion? Withhold VITRAKVI until adverse reaction resolves or improves to baseline or Grade 1. Yes. If yes, please include copy of results or provide lab name and lab test date. Resume at the next dosage modification if resolution occurs within 4 weeks. Lab name Lab test date Permanently discontinue VITRAKVI if an adverse reaction does not resolve within 4 weeks. No. If no, is assistance needed to find an appropriate lab? Yes No Test type VITRAKVI (larotrectinib) prescription and patient support program enrollment form FULL PRESCRIBING INFORMATION Email Next-Generation Sequencing (NGS) Fluorescence in situ hybridization (FISH) Immunohistochemistry (IHC) Polymerase chain reaction (PCR) Select if patient needs appeal or financial assistance with diagnostic support for NTRK gene fusion testing. *Required field. Following a positive TRK IHC test, confirmation of NTRK gene fusion is needed prior to initiation of VITRAKVI treatment. 1-888-506-TRAK VITRAKVI is indicated for the treatment of adult and pediatric patients with solid tumors that: have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and 1-844-634-TRAK To report any adverse events, product technical complaints, or medication errors associated with the use of VITRAKVI, contact Bayer at 1-888-842-2937, or send the information to DrugSafety.GPV.US@bayer.com. FAX THIS FORM AND THE PATIENT INSURANCE INFORMATION TO 1-888-506-TRAK (1-888-506-8725). Please see Indication and full Important Safety Information on page 5 and accompanying full Prescribing Information. 2
PRESCRIBER PATIENT The recommended dosage modifications for VITRAKVI for adverse reactions are provided in Name of Table patient* 1. DOB* To report any adverse events, product technical complaints, or medication errors associated with the use of VITRAKVI, contact Bayer at 1-888-842-2937, or send the information to DrugSafety.GPV.US@bayer.com. MM/DD/YYYY PRESCRIPTION INFORMATION Table 1 Recommended Dosage Modifications for VITRAKVI for Adverse Reactions ICD-10 Diagnosis Code(s) Adult and Dosage Form* VITRAKVI in: 25-mg capsule 100-mg capsule 20-mg/mL oral solution Pediatric Patients with Body Pediatric Patients with Body Dosage Modification SIG* Surface Area of at Least 1.0 m 2 Surface Area Less Than 1.0 m Quantity/Supply* Refills 2 Home Healthcare First Visits (physician please select 75 an mg option): orally twice daily 75 mg/m 2 orally twice daily Home healthcare nurse visit (During the home visit, the home healthcare nurse will educate patient/caregiver on insertion of adapter and use of syringes Second for medication withdrawal) 50 mg orally twice daily 50 mg/m 2 orally twice daily Patient/caregiver will be seen in this physician s office for education on insertion of adapter and use of syringes for medication withdrawal Preferred Third Pharmacy (not guaranteed): Accredo 100 mg Phone: orally 1-855-540-1797 once daily Fax: 1-877-327-7120 25 mg/m 2 orally twice daily CVS Specialty Phone: 1-800-790-1698 Fax: 1-855-296-0210 Permanently discontinue VITRAKVI in patients who are unable to tolerate VITRAKVI after US Bioservices Phone: 1-833-230-1407 Fax: 1-833-878-5917 three dose modifications. Allergies 2.4 Dosage Modifications for Coadministration Other with medications Strong taken CYP3A4 Inhibitors I certify that the above therapy is medically necessary and that the information provided is accurate to the best of my knowledge. Avoid coadministration of strong CYP3A4 inhibitors with VITRAKVI. If coadministration of a I appoint TRAK Assist TM, on my behalf, to convey this prescription to the dispensing pharmacy. I understand that I may not delegate signature authority. strong CYP3A4 inhibitor cannot be avoided, reduce the VITRAKVI dose by 50%. After the Prescriber inhibitor Signature has and been Date* discontinued (sign and indicate for the 3 to date 5 elimination only one of the half-lives, lines below; resume no stamps the allowed) VITRAKVI dose taken prior to initiating the CYP3A4 inhibitor [see Drug Interactions (7.1), Clinical Dispense as written Date Pharmacology (12.3)]. Substitutions 2.5 permitted Dosage Modifications for Coadministration with Strong CYP3A4 Inducers Date *Required field. Avoid coadministration of strong CYP3A4 inducers with VITRAKVI. If coadministration of a I grant strong permission CYP3A4 for inducer TRAK cannot Assist be avoided, to leave a double message the VITRAKVI at the phone dose. number(s) After the listed inducer has on been the previous discontinued page, for including 3 to 5 elimination the name of half-lives, the drug, resume if I am the not VITRAKVI available. dose taken prior to initiating the CYP3A4 inducer [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]. PATIENT 2.6SUPPORT Dosage PROGRAM Modifications ENROLLMENT for Patients with Hepatic Impairment Bayer provides patient support services for VITRAKVI patients that include (A) financial assistance for eligible patients Reduce the starting dose of VITRAKVI by 50% in patients with moderate (Child-Pugh B) to and temporary assistance for eligible patients; (B) temporary assistance through the Bridge Program for eligible severe (Child-Pugh C) hepatic impairment [see Use in Specific Populations (8.6), Clinical patients with delays or lapses in coverage. You may enroll in one or both of these programs. Enrollment allows TRAK Assist Pharmacology counselors (12.3)]. to contact you and discuss support options available to you through Bayer or external resources. 2.7 Any Administration assistance provided through TRAK Assist is at no cost to you, and any free drug or resources received should not be billed to you or any third party. If you experience an adverse event, it will be forwarded to Bayer Drug Safety, VITRAKVI capsule or oral solution may be used interchangeably. which may contact you or your treating physician. Enrollment will be for five years. You may opt out of this program at any Do time not by make calling up 1-844-634-8725 a missed dose within or writing 6 hours to: TRAK of the Assist, next PO scheduled Box 220765, dose. Charlotte, NC 28222-0765. You do If not vomiting have to occurs provide after HIPAA taking Authorization a dose to of enroll VITRAKVI, in Option take A (financial the next assistance). dose at the scheduled time. Enroll me in (check all that apply): (A) Financial Assistance (B) Bridge Program Please initial here to confirm your elections VITRAKVI (larotrectinib) prescription and patient support program enrollment form 1-888-506-TRAK 1-844-634-TRAK FAX THIS FORM AND THE PATIENT INSURANCE INFORMATION TO 1-888-506-TRAK (1-888-506-8725). Please see Indication and full Important Safety Information on page 5 and accompanying full Prescribing Information. 3
PATIENT VITRAKVI (larotrectinib) prescription and patient support program enrollment form Capsules Name of Swallow patient* capsules whole with water. Do not chew or crush the capsules. 1-888-506-TRAK MM/DD/YYYY WRITTEN Oral PERMISSION Solution TO SHARE PROTECTED HEALTH INFORMATION Store the glass bottle of VITRAKVI oral solution in the refrigerator. Discard any unused I authorize VITRAKVI the use and disclosure oral solution of my Protected remaining Health after 90 days my of representative) first opening may the revoke bottle. this authorization at any time Information ( PHI ) as defined by the Health Insurance by calling 1-844-634-8725 or writing to: TRAK Assist, Prior to preparing an oral dose for administration, refer to the Instructions for Use. Portability and Accountability Act of 1996, which was PO Box 220765, Charlotte, NC 28222-0765. amended 3 by the DOSAGE Health Information FORMS Technology AND STRENGTHS for Economic I also understand that, under this authorization, entities and Clinical Health Act (as amended, HIPAA ). I understand that receive my PHI may not be required by law to keep the that Protected Capsules Health Information is health information that information private and it will no longer be protected by the identifies me or that could reasonably be used to identify me and that 25 this mg: authorization white opaque to release hard my gelatin information capsule, is size 2, privacy with law. blue It may printing become of available LOXO in the and public LARO domain. voluntary. 25 mg on body of capsules. 25 mg larotrectinib I understand is equivalent that to I do 30.7 not need mg larotrectinib to sign this form to receive sulfate. medical treatment or medication. I (or my representative) have I authorize my healthcare provider, including my physician, read and understand the terms of this authorization form, and pharmacies 100 and mg: my health white plan, opaque to disclose hard gelatin my name, capsule, size have 0, with had an blue opportunity printing to of ask LOXO questions and about the uses and address, and LARO telephone 100 number mg along body with of certain capsule. medical 100 mg larotrectinib disclosures of is PHI equivalent described above. to 123 All mg of my questions have information larotrectinib including my treatment, sulfate. my eligibility for been answered to my satisfaction. I authorize the use and assistance, the coordination of my treatment, the receipt of Oral Solution disclosure of my information as described in this form. my medication and my participation in the Patient Support Program, TRAK Assist, to Bayer and its agents. I (or my representative) have the right to receive a copy 20 mg/ml: clear yellow to orange solution. 20 mg/ml of this authorization larotrectinib upon is request. equivalent I understand to that my I allow the use 24.6and mg/ml disclosure larotrectinib of my PHI for sulfate. the following healthcare providers, insurers, and health plans may receive purposes: (1) To verify my insurance information; (2) to ensure remuneration (payment) from Bayer in exchange for disclosing the accuracy 4 and CONTRAINDICATIONS completeness of the TRAK Assist enrollment my PHI to Bayer. form; (3) None. to help with my reimbursement questions; (4) to determine if I qualify for patient assistance; (5) to determine Patient or Patient Representative Signature my eligibility 5 for WARNINGS other sources of AND funding; PRECAUTIONS (6) to provide education, training, and ongoing support on the use of my medication; 5.1 (7) Neurotoxicity send me information on related products Date and services Among related the 176 to my patients treatment; who (8) received to send me VITRAKVI, refill neurologic adverse reactions of any grade reminders occurred for my in prescription 53% of patients, and to encourage including appropriate Grade 3 and Name Grade of 4 neurologic Patient Representative adverse reactions in 6% use; (9) and to communicate 0.6% of patients, with me, respectively my healthcare [see providers Adverse Reactions (6.1)]. The majority (65%) of and health neurologic plan insurers adverse about reactions my medical occurred care and within the first three months of treatment (range: 1 day to treatment; 2.2 years). (10) to contact Grade me 3 neurologic for market research adverse feedback; reactions included delirium (2%), dysarthria (1%), (11) for dizziness sales support (1%), purposes gait disturbance and (12) to comply (1%), with and paresthesia Relation (1%). to Grade Patient 4 encephalopathy (0.6%) applicable occurred law. in a single patient. Neurologic adverse reactions leading to dose modification included This authorization dizziness (3%), shall be gait in effect disturbance for 10 years (1%), from delirium the date (1%), memory impairment (1%), and tremor of my signature, (1%). or the date of last enrollment, whichever comes first, unless a shorter period is required by law. If I If signed by the Patient s Representative, a description Advise patients and caretakers of these risks with VITRAKVI. (or my representative) revoke this authorization, healthcare of the representative s Advise patients relationship not to to drive the Patient or and providers operate will stop hazardous using my machinery PHI for the purposes if they are outlined experiencing in such neurologic person s authority adverse reactions. to for the Withhold Patient must or be this authorization, permanently but discontinue the revocation VITRAKVI will not affect based prior use on the provided severity. in If the withheld, space above. modify the VITRAKVI or disclosure dosageof when my PHI resumed in reliance [see on this Dosage authorization. and Administration I (or (2.3)]. 5.2 Hepatotoxicity Among the 176 patients who received VITRAKVI, increased transaminases of any grade To report any adverse events, product technical complaints, or medication errors associated with the use of VITRAKVI, occurred in 45%, including Grade 3 increased AST or ALT in 6% of patients [see Adverse contact Bayer at 1-888-842-2937, or send the information to DrugSafety.GPV.US@bayer.com. Reactions (6.1)]. One patient (0.6%) experienced Grade 4 increased ALT. The median time to FAX THIS FORM AND THE PATIENT INSURANCE INFORMATION TO 1-888-506-TRAK (1-888-506-8725). Please see Indication and full Important Safety Information on page 5 and accompanying full Prescribing Information. 4 DOB* 1-844-634-TRAK
Indication VITRAKVI onset is of indicated increased for AST the treatment was 2 months of adult (range: and pediatric 1 month patients to 2.6 with years). solid The tumors median that: time to onset of have increased a neurotrophic ALT was receptor 2 months tyrosine (range: kinase 1(NTRK) month gene to 1.1 fusion years). without Increased a known AST acquired and resistance ALT leading mutation, to are dose metastatic modifications or where occurred surgical resection in 4% and is likely 6% of to patients, result in severe respectively. morbidity, Increased and AST or ALT led have to permanent no satisfactory discontinuation alternative treatments in 2% ofor patients. that have progressed following treatment. This Monitor indication liver is approved tests, including under accelerated ALT and approval AST, every based 2 weeks on overall during response the first rate month and duration of treatment, of response. then monthly Continued thereafter, approval and for this as clinically indication indicated. may be contingent Withhold upon or permanently verification and discontinue description of clinical VITRAKVI benefit in confirmatory based the trials. severity. If withheld, modify the VITRAKVI dosage when resumed [see Dosage and Administration (2.3)]. Important Safety Information Neurotoxicity: 5.3 Embryo-Fetal Among the 176 Toxicity patients who received VITRAKVI, neurologic adverse reactions of any grade occurred Based in on 53% literature of patients, reports including human Grade subjects 3 and Grade with 4 congenital neurologic mutations adverse reactions leading in to 6% changes and 0.6% in of patients, respectively. The majority (65%) of neurological adverse reactions occurred within the first three TRK signaling, findings from animal studies, and its mechanism of action, VITRAKVI can months of treatment (range: 1 day to 2.2 years). Grade 3 neurologic adverse reactions included delirium (2%), cause fetal harm when administered to a pregnant woman. Larotrectinib resulted in dysarthria (1%), dizziness (1%), gait disturbance (1%), and paresthesia (1%). Grade 4 encephalopathy (0.6%) malformations in rats and rabbits at maternal exposures that were approximately 11- and 0.7- occurred in a single patient. Neurologic adverse reactions leading to dose modification included dizziness times, respectively, those observed at the clinical dose of 100 mg twice daily. Advise women of (3%), gait disturbance (1%), delirium (1%), memory impairment (1%), and tremor (1%). the potential risk to a fetus. Advise females of reproductive potential to use an effective method Advise patients and caretakers of these risks with VITRAKVI. Advise patients not to drive or operate hazardous of contraception during treatment and for 1 week after the final dose of VITRAKVI [see Use in machinery if they are experiencing neurologic adverse reactions. Withhold or permanently discontinue Specific Populations (8.1, 8.3)]. VITRAKVI based on the severity. If withheld, modify the VITRAKVI dose when resumed. Hepatotoxicity: 6 ADVERSE Among the REACTIONS 176 patients who received VITRAKVI, increased transaminases of any grade occurred in 45%, including Grade 3 increased AST or ALT in 6% of patients. One patient (0.6%) experienced Grade The 4 increased following ALT. clinically The median significant time to adverse onset of reactions increased are AST described was 2 months elsewhere (range: in1 the month labeling: to 2.6 years). Neurotoxicity The median time [see to Warnings onset of and increased Precautions ALT was (5.1)] 2 months (range: 1 month to 1.1 years). Increased AST and ALT leading dose modifications occurred in 4% and 6% of patients, respectively. Increased AST or Hepatotoxicity [see Warnings and Precautions (5.2)] ALT led to permanent discontinuation in 2% of patients. Monitor 6.1 liver Clinical tests, including Trial Experience ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, Because and clinical as clinically trials indicated. are conducted Withhold under or permanently widely varying discontinue conditions, VITRAKVI adverse based reaction the rates severity. If withheld, observed modify in the the clinical VITRAKVI trials dosage of a drug when cannot resumed. be directly compared to rates in the clinical trials Embryo-Fetal of another Toxicity: drug and VITRAKVI may not can reflect cause the fetal rates harm observed when administered practice. to a pregnant woman. Larotrectinib resulted in malformations in rats and rabbits at maternal exposures that were approximately 11- and Data 0.7-times, in WARNINGS respectively, AND those PRECAUTIONS observed at the clinical and below dose reflects of 100 mg exposure twice daily. to VITRAKVI in 176 patients, including 70 (40%) patients exposed for greater than 6 months and 35 (20%) patients Advise women of the potential risk to a fetus. Advise females of reproductive potential to use an effective exposed for greater than 1 year. VITRAKVI was studied in one adult dose-finding trial method of contraception during treatment and for 1 week after the final dose of VITRAKVI. [LOXO-TRK-14001 (n = 70)], one pediatric dose-finding trial [SCOUT (n = 43)], and one single Most arm Common trial [NAVIGATE Adverse Reactions (n = 63)]. ( 20%): All patients The most had common an unresectable adverse reactions or metastatic ( 20%) solid were: tumor increased and no ALT satisfactory (45%), increased alternative AST (45%), treatment anemia options (42%), fatigue or disease (37%), progression nausea (29%), following dizziness treatment. (28%), cough (26%), vomiting (26%), constipation (23%), and diarrhea (22%). Across these 176 patients, the median age was 51 years (range: 28 days to 82 years); 25% were Drug Interactions: Avoid coadministration of VITRAKVI with strong CYP3A4 inhibitors (including grapefruit 18 years or younger; 52% were male; and 72% were White, 11% were Hispanic/Latino, 8% were or grapefruit juice), strong CYP3A4 inducers (including St. John s wort), or sensitive CYP3A4 substrates. If coadministration Black, and 3% of strong were Asian. CYP3A4 The inhibitors most common or inducers tumors cannot in be order avoided, of decreasing modify the frequency VITRAKVI were dose soft as recommended. tissue sarcoma If coadministration (16%), salivary of gland sensitive (11%), CYP3A4 lung substrates (10%), thyroid cannot (9%), be avoided, colon monitor (8%), infantile patients for increased fibrosarcoma adverse reactions (8%), primary of these central drugs. nervous system (CNS) (7%), or melanoma (5%). NTRK gene Lactation: fusions Advise were women present not in 60% to breastfeed of VITRAKVI-treated during treatment patients. with VITRAKVI Most and adults for 1 (80%) week after received the final dose. VITRAKVI 100 mg orally twice daily and 68% of pediatrics (18 years or younger) received Please VITRAKVI see accompanying 100 mg/mfull 2 twice Prescribing daily up Information. to a maximum dose of 100 mg twice daily. The dose ranged from 50 mg daily to 200 mg twice daily in adults and 9.6 mg/m 2 twice daily to 120 mg/m 2 twice daily in pediatrics [see Pediatric Use (8.4)]. 2018 Bayer and Loxo Oncology, Inc. All rights reserved. Bayer, the Bayer Cross, and VITRAKVI are registered trademarks of Bayer, and TRAK Assist is a trademark of Bayer. PP-912-US-0155 11/18 5
The most common adverse reactions ( 20%) in order of decreasing frequency were fatigue, nausea, dizziness, vomiting, anemia, increased AST, cough, increased ALT, constipation, and diarrhea. The most common serious adverse reactions ( 2%) were pyrexia, diarrhea, sepsis, abdominal pain, dehydration, cellulitis, and vomiting. Grade 3 or 4 adverse reactions occurred in 51% of patients; adverse reactions leading to dose interruption or reduction occurred in 37% of patients and 13% permanently discontinued VITRAKVI for adverse reactions. The most common adverse reactions (1-2% each) that resulted in discontinuation of VITRAKVI were brain edema, intestinal perforation, pericardial effusion, pleural effusion, small intestinal obstruction, dehydration, fatigue, increased ALT, increased AST, enterocutaneous fistula, increased amylase, increased lipase, muscular weakness, abdominal pain, asthenia, decreased appetite, dyspnea, hyponatremia, jaundice, syncope, vomiting, acute myeloid leukemia, and nausea. The most common adverse reactions ( 3%) resulting in dose modification (interruption or reduction) were increased ALT (6%), increased AST (6%), and dizziness (3%). Most (82%) adverse reactions leading to dose modification occurred during the first three months of exposure. Adverse reactions of VITRAKVI occurring in 10% of patients and laboratory abnormalities worsening from baseline in 5% of patients are summarized in Table 2 and Table 3, respectively. Table 2 Adverse Reaction Adverse Reactions Occurring in 10% of Patients Treated with VITRAKVI VITRAKVI All Grades* (%) N = 176 Grade 3-4** (%) General Fatigue 37 3 Pyrexia 18 1 Edema peripheral 15 0 Gastrointestinal Nausea 29 1 Vomiting 26 1 Constipation 23 1 Diarrhea 22 2 Abdominal pain 13 2 Nervous System Dizziness 28 1 Headache 14 0 Respiratory, Thoracic and Mediastinal Cough 26 0 Dyspnea 18 2 Nasal congestion 10 0
Adverse Reaction All Grades* (%) VITRAKVI N = 176 Grade 3-4** (%) Investigations Increased weight 15 4 Musculoskeletal and Connective Tissue Arthralgia 14 1 Myalgia 14 1 Muscular weakness 13 0 Back pain 12 1 Pain in extremity 12 1 Metabolism and Nutrition Decreased appetite 13 2 Vascular Hypertension 11 2 Injury, Poisoning and Procedural Complications Fall 10 1 * National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v 4.03. ** One Grade 4 adverse reaction of pyrexia. Table 3 Laboratory Abnormalities Occurring in 5% Patients Treated with VITRAKVI Laboratory Abnormality VITRAKVI* All Grades** (%) Grade 3-4 (%) Chemistry Increased ALT 45 3 Increased AST 45 3 Hypoalbuminemia 35 2 Increased alkaline phosphatase 30 3 Hematology Anemia 42 10 Neutropenia 23 7 *Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available which ranged from 170 to 174 patients. ** NCI-CTCAE v 4.03.
7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on VITRAKVI Strong CYP3A4 Inhibitors Coadministration of VITRAKVI with a strong CYP3A4 inhibitor may increase larotrectinib plasma concentrations, which may result in a higher incidence of adverse reactions [see Clinical Pharmacology (12.3)]. Avoid coadministration of VITRAKVI with strong CYP3A4 inhibitors, including grapefruit or grapefruit juice. If coadministration of strong CYP3A4 inhibitors cannot be avoided, modify VITRAKVI dose as recommended [see Dosage and Administration (2.4)]. Strong CYP3A4 Inducers Coadministration of VITRAKVI with a strong CYP3A4 inducer may decrease larotrectinib plasma concentrations, which may decrease the efficacy of VITRAKVI [see Clinical Pharmacology (12.3)]. Avoid coadministration of VITRAKVI with strong CYP3A4 inducers, including St. John s wort. If coadministration of strong CYP3A4 inducers cannot be avoided, modify VITRAKVI dose as recommended [see Dosage and Administration (2.5)]. 7.2 Effects of VITRAKVI on Other Drugs Sensitive CYP3A4 Substrates Coadministration of VITRAKVI with sensitive CYP3A4 substrates may increase their plasma concentrations, which may increase the incidence or severity of adverse reactions [see Clinical Pharmacology (12.3)]. Avoid coadministration of VITRAKVI with sensitive CYP3A4 substrates. If coadministration of these sensitive CYP3A4 substrates cannot be avoided, monitor patients for increased adverse reactions of these drugs. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on literature reports in human subjects with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action [see Clinical Pharmacology (12.1)], VITRAKVI can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on VITRAKVI use in pregnant women. Administration of larotrectinib to pregnant rats and rabbits during the period of organogenesis resulted in malformations at maternal exposures that were approximately 11- and 0.7-times, respectively, those observed at the clinical dose of 100 mg twice daily (see Data). 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. Data Human Data Published reports of individuals with congenital mutations in TRK pathway proteins suggest that decreases in TRK-mediated signaling are correlated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis.
Animal Data Larotrectinib crosses the placenta in animals. Larotrectinib did not result in embryolethality at maternally toxic doses [up to 40 times the human exposure based on area under the curve (AUC) at the clinical dose of 100 mg twice daily] in embryo-fetal development studies in pregnant rats dosed during the period of organogenesis; however, larotrectinib was associated with fetal anasarca in rats from dams treated at twice-daily doses of 40 mg/kg [11 times the human exposure (AUC) at the clinical dose of 100 mg twice daily]. In pregnant rabbits, larotrectinib administration was associated with omphalocele at twice-daily doses of 15 mg/kg (0.7 times the human exposure at the clinical dose of 100 mg twice daily). 8.2 Lactation Risk Summary There are no data on the presence of larotrectinib or its metabolites in human milk and no data on its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with larotrectinib and for 1 week after the final dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating VITRAKVI [see Use in Specific Populations (8.1)]. Contraception VITRAKVI can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Females Advise female patients of reproductive potential to use effective contraception during treatment with VITRAKVI and for at least 1 week after the final dose. Males Advise males with female partners of reproductive potential to use effective contraception during treatment with VITRAKVI and for 1 week after the final dose. Infertility Females Based on histopathological findings in the reproductive tracts of female rats in a 1-month repeated-dose study, VITRAKVI may reduce fertility [See Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of VITRAKVI in pediatric patients was established based upon data from three multicenter, open-label, single-arm clinical trials in adult or pediatric patients 28 days and older [see Adverse Reactions (6.1), Clinical Studies (14)]. The efficacy of VITRAKVI was evaluated in 12 pediatric patients and is described in the Clinical Studies section [see Clinical Studies (14)]. The safety of VITRAKVI was evaluated in