DRUG INTERACTIONS (summary)

­ Strong CYP3A4 Inhibitors: Closely monitor for TIVDAK adverse reactions.

DRUG INTERACTIONS- (details)

1 Effects of Other Drugs on [TIVDAK] Strong CYP3A4 Inhibitors-                         MMAE is a CYP3A4 substrate. Concomitant use of [TIVDAK] with strong CYP3A4 inhibitors may increase unconjugated MMAE exposure  which may increase the risk of [TIVDAK] adverse reactions. 

 Closely monitor patients for adverse reactions of [TIVDAK] when used concomitantly with strong CYP3A4 inhibitors.

BRIEF SUMMARY

TISOTUMAB- (Sep 2021)

Indn-   To treat  recurrent or metastic cervical cancer  with  disease progression on of after  chemotherapy  

Comp- For Injection: 40 mg as a lyophilized cake or powder in a single-dose vial for reconstitution.  The recommended dose  is 2 mg/kg (up to a maximum of 200 mg) given as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.

ADR-   The most common adverse reactions, including laboratory abnormalities, were hemoglobin decreased, fatigue, lymphocytes decreased, nausea, peripheral neuropathy, alopecia, epistaxis, conjunctival adverse reactions, hemorrhage, leukocytes decreased,

CI-  None. 

 WARNINGS- 

­ • Peripheral neuropathy: Monitor patients for new or worsening peripheral neuropathy. Withhold, reduce the dose, or permanently discontinue..

• Hemorrhage: Monitor patients for signs and symptoms of hemorrhage. Withhold, reduce the dose, or permanently discontinue .

Pat Inform-

Ocular Adverse Reactions                                                                                                   • Inform patients about the eye exam they will receive before treatment and prior to each dose.

• Inform patients that ocular adverse reactions may occur during treatment and to contact their healthcare provider if they experience new or worsening ocular signs and symptoms

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U.S. FDA APPROVED DRUGS SURING 2021                                          

Serial No 39

Name of the Drug-    TIVDAK

Active Ingredient -   Tisotumab Vedotin -tftv

Pharmacological Classification- To treat  recurrent or metastic cervical cancer                                                                with  disease progression on of after                                                                                 chemothrrapy                                                                                                                                                                                                               Date of Approval-          9/20/2021                                                                                                                                                                                                                                                                                 

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                             TIVDAK safely and effectively.                                                                                        See full prescribing information for TIVDAK. TIVDAK TM (tisotumab vedotin-tftv) for injection, for intravenous use

Initial U.S. Approval: 2021

WARNING: OCULAR TOXICITY See full prescribing information for complete boxed warning.

• TIVDAK caused changes in the corneal epithelium and conjunctiva resulting in changes in vision, including severe vision loss, and corneal ulceration.                                            • Conduct an ophthalmic exam at baseline, prior to each dose, and as clinically indicated. • Adhere to premedication and required eye care before, during, and after infusion.          • Withhold TIVDAK until improvement and resume, reduce the dose, or permanently discontinue, based on severity. 

 INDICATIONS AND USAGE

­ TIVDAK is a tissue factor-directed antibody and microtubule inhibitor conjugate indicated for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

 This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. 

 ADVERSE REACTIONS-

­ The most common (=25%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased, fatigue, lymphocytes decreased, nausea, peripheral neuropathy, alopecia, epistaxis, conjunctival adverse reactions, hemorrhage, leukocytes decreased, creatinine increased, dry eye, prothrombin international normalized ratio increased, activated partial thromboplastin time prolonged, diarrhea, and rash.

 CONTRAINDICATIONS-                                                                                                    None. 

 WARNINGS AND PRECAUTIONS- 

­ • Peripheral neuropathy: Monitor patients for new or worsening peripheral neuropathy. Withhold, reduce the dose, or permanently discontinue TIVDAK based on severity.

• Hemorrhage: Monitor patients for signs and symptoms of hemorrhage. Withhold, reduce the dose, or permanently discontinue TIVDAK based on severity.

 • Pneumonitis: Severe, life-threatening or fatal pneumonitis may occur. Withhold TIVDAK for persistent or recurrent Grade 2 pneumonitis and consider dose reduction. Permanently discontinue TIVDAK for Grade 3 or 4 pneumonitis.

 • Embryo-fetal toxicity: TIVDAK can cause fetal harm. Advise of the potential risk to a fetus and to use effective contraception.

 DOSAGE AND ADMINISTRATION

­ • For intravenous infusion only. Do not administer TIVDAK as an intravenous push or bolus. Do not mix with, or administer as an infusion with, other medicinal products.               

 • The recommended dose of TIVDAK is 2 mg/kg (up to a maximum of 200 mg) given as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity. 

 DOSAGE FORMS AND STRENGTHS-                                                                                For Injection: 40 mg as a lyophilized cake or powder in a single-dose vial for reconstitution. 

PATIENT COUNSELING INFORMATION -                                                           

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Ocular Adverse Reactions                                                                                                   • Inform patients about the eye exam they will receive before treatment and prior to each dose.

• Inform patients that ocular adverse reactions may occur during treatment with TIVDAK and to contact their healthcare provider if they experience new or worsening ocular signs and symptoms

 • Instruct patients to bring their eye drops to each infusion and advise on how to administer the eye drops throughout treatment

 • Inform patients to avoid wearing contact lenses during treatment unless directed by an eye care provider

 Peripheral Neuropathy                                                                                                      • Advise patients to report to their healthcare provider any numbness and tingling of the hands or feet or muscle weakness

Hemorrhage                                                                                                                         • Instruct patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual severe bleeding or hemorrhage

 Pneumonitis                                                                                                                       • Advise patients to immediately report new or worsening respiratory symptoms

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

 • Advise females of reproductive potential to use effective contraception during treatment and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose

Lactation                                                                                                                             • Advise women not to breastfeed during treatment with TIVDAK and for 3 weeks after the last dose

Manufactured by: Seagen Inc. Bothell, WA 98021 1-855-4SEAGEN Marketed by: Seagen Inc. Bothell, WA 98021 and Genmab US, Inc. Plainsboro, NJ 08536 U.S. License XXXX TIVDAKTM is a trademark owned by Seagen Inc. ©2021 Seagen Inc. and Genmab US, Inc.

CLINICAL PHARMACOLOGY-                                                                               

1. Mechanism of Action-                                                                                      Tisotumab vedotin-tftv is a tissue factor (TF)-directed antibody drug conjugate (ADC). The antibody is a human IgG1 directed against cell surface TF. TF is the primary initiator of the extrinsic blood coagulation cascade.

2. Pharmacodynamics-                                                                                               Tisotumab vedotin-tftv exposure-response relationships and the time course of pharmacodynamics response have not been fully characterized. Cardiac Electrophysiology At the recommended dose, tisotumab vedotin-tftv had no large mean effect on QTc prolongation (>20 msec).

3. Pharmacokinetics -                                                                                                    Table  summarizes the exposure parameters of tisotumab vedotin-tftv and unconjugated MMAE (the cytotoxic component of tisotumab vedotin-tftv) following administration of one 3-week cycle of tisotumab vedotin-tftv 2 mg/kg to patients.

Tisotumab vedotin-tftv concentrations peaked near the end of the infusion, while unconjugated MMAE concentrations peaked approximately 2 to 3 days after tisotumab vedotin-tftv dosing.

Tisotumab vedotin-tftv Cmax increased proportionally, while AUC0-last increased in a more than doseproportional manner, after a single dose ranging from 0.3–2.2 mg/kg (0.15 to 1.1 times the approved recommended dose). There was no accumulation of tisotumab vedotin-tftv and unconjugated MMAE.

Steadystate concentrations of tisotumab vedotin-tftv and unconjugated MMAE were reached after 1 treatment cycle.

 Exposure Parameters of Tisotumab Vedotin-tftv and Unconjugated MMAE Tisotumab Vedotin-tftv Unconjugated MMAE Mean (± SD) Mean (± SD) Cmax 40.8 (8.12) µg/mL 5.91 (4.2) ng/mL AUC 57.5 (13.4) day*µg/mL 50 (35.8) day*ng/mL Cmax=maximum concentration, AUC = area under the concentration-time curve from time 0 to 21 days (3 weeks)

Distribution-                                                                                                                   The tisotumab vedotin-tftv steady state volume of distribution is 7.83 (%CV: 19.1) L. Plasma protein binding of MMAE ranged from 68% to 82%, in vitro.

Elimination-                                                                                                                    The median terminal half-life of tisotumab vedotin-tftv and unconjugated MMAE is 4.04 (range: 2.26-7.25) days and 2.56 (range: 1.81-4.10) days, respectively. The linear clearance of tisotumab vedotin-tftv and unconjugated MMAE was 1.54 (%CV: 28.8) L/day and 45.9 (%CV: 61.1) L/day, respectively.

Elimination of MMAE appeared to be limited by its rate of release from tisotumab vedotin-tftv.

Metabolism-                                                                                                            Tisotumab vedotin-tftv is expected to undergo catabolism to small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites. Tisotumab vedotin-tftv releases unconjugated MMAE via proteolytic cleavage, and unconjugated MMAE is primarily metabolized by CYP3A4 in vitro.

Excretion-                                                                                                                       The excretion of tisotumab vedotin-tftv is not fully characterized. Following a single-dose of another ADC that contains MMAE, 17% of the total MMAE administered was recovered in feces and 6% in urine over a 1-week period, primarily as unchanged drug. A similar excretion profile of MMAE is expected after tisotumab vedotintftv administration.

Specific Populations-                                                                                                         No clinically significant differences in the pharmacokinetics of tisotumab vedotin-tftv were observed based on age (21 to 81 years), sex, race (white vs non-white) or ethnicity (Hispanic or Latino vs non-Hispanic or nonLatino).

No clinically significant differences in exposures of tisotumab vedotin-tftv and unconjugated MMAE were observed in patients with mild to moderate renal impairment (CLcr 30 to < 90 mL/min using the Cockcroft-Gault equation) compared to patients with normal renal function.

The effect of severe renal impairment (CLcr 15 to < 30 mL/min) or end-stage renal disease with or without dialysis on pharmacokinetics of tisotumab vedotin-tftv and unconjugated MMAE is unknown.

Patients with Hepatic Impairment Unconjugated MMAE exposures were 37% higher, but there were no clinically significant differences in exposures of tisotumab vedotin-tftv in patients with mild hepatic impairment (bilirubin of 1 to 1.5 X ULN and AST < ULN, or bilirubin = ULN and AST > ULN) compared to patients with normal hepatic function.

The effect of moderate or severe hepatic impairment (AST > 3 x ULN or total bilirubin > 1.5 x ULN) or liver transplantation on the pharmacokinetics of tisotumab vedotin-tftv or unconjugated MMAE is unknown.

Drug Interaction Studies-                                                                                              Clinical Studies- No clinical studies evaluating the drug-drug interaction potential of tisotumab vedotin-tftv have been conducted. To characterize the drug-drug interaction potential of unconjugated MMAE, clinical studies with another ADC that contains MMAE are described below, and similar effects on tisotumab vedotin-tftv and unconjugated MMAE exposures are expected with concomitant use of TIVDAK.

There were no clinically significant differences in midazolam (sensitive CYP3A4 substrate) pharmacokinetics when used concomitantly with another ADC that contains MMAE.

Strong CYP3A4 Inhibitors: Ketoconazole (strong CYP3A4 inhibitor) used concomitantly with another ADC that contains MMAE increased unconjugated MMAE Cmax by 25% and AUC by 34%, with no change in ADC exposure.

Strong CYP3A4 Inducers: Rifampin (strong CYP3A4 inducer) used concomitantly with another ADC that contains MMAE decreased unconjugated MMAE Cmax by 44% and AUC by 46%, with no change in ADC exposure.

In Vitro Studies-                                                                                                       Cytochrome P450 (CYP) Enzymes: MMAE does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. MMAE did not induce any major CYP450 enzymes in human hepatocytes.

Transporter Systems: MMAE is a substrate of P-glycoprotein (P-gp), but not an inhibitor of P-gp.

8 USE IN SPECIFIC POPULATIONS-

1. Pregnancy Risk Summary-                                                                                      Based on the mechanism of action and findings in animals, TIVDAK can cause fetal harm when administered to a pregnant woman .

There are no available human data on TIVDAK use in pregnant women to inform a drug-associated risk. In an animal reproduction study, administration of the small molecule component of TIVDAK, MMAE, to pregnant rats during organogenesis caused embryo-fetal mortality and structural abnormalities at exposures below the clinical exposure at the recommended dose

 Advise patients of the potential risk to a 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-                                                                                               There are no data on the presence of tisotumab vedotin-tftv in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise lactating women not to breastfeed during treatment with TIVDAK and for 3 weeks after the last dose.

3. Females and Males of Reproductive Potential-                                                   TIVDAK can cause fetal harm when administered to a pregnant woman

 Pregnancy testing-                                                                                                       Verify pregnancy status in females of reproductive potential prior to initiating TIVDAK treatment.

Contraception-                                                                                                            Females- Advise females of reproductive potential to use effective contraception during treatment with TIVDAK and for 2 months after the last dose.

Males -Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TIVDAK and for 4 months after the last dose.

Infertility-                                                                                                                    Males -Based on findings from animal studies, TIVDAK may impair male fertility

4. Pediatric Use-                                                                                                         Safety and effectiveness of TIVDAK in pediatric patients have not been established.

5. Geriatric Use-                                                                                                               Of the 101 patients treated with TIVDAK in innovaTV 204, 13% were =65 years of age. Grade =3 adverse reactions occurred in 69% patients =65 years and in 59% patients <65 years. Serious adverse reactions occurred in 54% patients =65 years and in 41% patients <65 years.

No patients aged =65 years treated with TIVDAK in innovaTV 204 experienced a tumor response.

6. Hepatic Impairment-                                                                                                       Avoid use of TIVDAK in patients with moderate or severe hepatic impairment (total bilirubin > 1.5 × ULN) [see Clinical Pharmacology (12.3)]. In patients with mild hepatic impairment (total bilirubin = ULN and AST >ULN or total bilirubin > 1 to 1.5 × ULN and any AST), closely monitor patients for adverse reactions of TIVDAK, but no dosage adjustment in the starting dose of TIVDAK is recommended.