DRUG INTERACTIONS- summary

 Strong or moderate CYP3A inhibitors: Avoid coadministration. 

 Strong or moderate CYP3A inducers: Avoid coadministration. 

 DRUG INTERACTIONS- details

1. Effect of Other Drugs on ZEPZELCA Strong and Moderate CYP3A Inhibitors- Coadministration with a strong or a moderate CYP3A inhibitor increases lurbinectedin systemic exposure which may increase the incidence and severity of adverse reactions to ZEPZELCA.

Avoid coadministration of ZEPZELCA with strong or moderate CYP3A inhibitors.

If the coadministration of ZEPZELCA with a moderate CYP3A inhibitor cannot be avoided, consider dose reduction of ZEPZELCA, if clinically indicated.

Strong and Moderate CYP3A Inducers-                                                   Coadministration with a strong CYP3A inducer decreases lurbinectedin systemic exposure  which may reduce ZEPZELCA efficacy.

Avoid coadministration of ZEPZELCA with strong or moderate CYP3A inducers.

U.S. FDA APPROVED  DRUGS DURING 2020

Sr.No-  24

 Hepatotoxicity: Monitor liver function tests prior to initiating ZEPZELCA, periodically during treatment and as clinically indicated.

Withhold, reduce the dose, or permanently discontinue ZEPZELCA based on severity. 

Embryo-Fetal Toxicity: Can cause fetal harm. Advise females and males of reproductive potential of the potential risk to a fetus and to use an effective method of contraception. 

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

Myelosuppression -                                                                                              Advise patients to immediately contact their healthcare provider for fever, other signs of infection, unusual bruising, bleeding, tiredness or pallor

Hepatotoxicity-                                                                                                      Advise patients to contact their healthcare provider immediately for signs and symptoms suggestive of hepatotoxicity 

Embryo-Fetal Toxicity -                                                                                         Advise pregnant women and females of reproductive potential of the potential 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 ZEPZELCA and for 6 months after the final dose.   

 Advise males with female partners of reproductive potential to use effective contraception during treatment with ZEPZELCA and for 4 months after the final dose 

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

Drug Interactions-                                                                                                 Advise patients to inform their healthcare providers of all concomitant medications, herbal and dietary supplements.

Advise patients to avoid grapefruit products during treatment with ZEPZELCA

Distributed by: Jazz Pharmaceuticals, Inc. Palo Alto, CA 94304 Under license from Pharma Mar, S.A. Protected by U.S. Patent No. 7,763,615

 CLINICAL PHARMACOLOGY

.1 Mechanism of Action-                                                                                        Lurbinectedin is an alkylating drug that binds guanine residues in the minor groove of DNA, forming adducts and resulting in a bending of the DNA helix towards the major groove.

2 Pharmacodynamics-                                               

Lurbinectedin exposure-response relationships and the pharmacodynamic time-course for efficacy have not been fully characterized. Increased incidence of Grade 4 neutropenia and Grade = 3 thrombocytopenia were observed with increased lurbinectedin exposure.

Cardiac Electrophysiology-     

No large mean increase in QTc (i.e. > 20 ms) was detected following treatment with ZEPZELCA at the recommended dose of 3.2 mg/m2 . 

3. Pharmacokinetics -                                                                                           Following the approved recommended dosage, geometric means (%CV) of plasma Cmax and AUC0-inf, were 107 µg/L (79%) and 551 µg•h/L (94%), respectively. No accumulation of lurbinectedin in plasma is observed upon repeated administrations every 3 weeks.

Distribution-                                                                                                                 The volume of distribution of lurbinectedin at steady state is 504 L (39%). Plasma protein binding is approximately 99%, to both albumin and a-1-acid glycoprotein.

Elimination-                                                                                                                The terminal half-life of lurbinectedin is 51 hours. Total plasma clearance of lurbinectedin is 11 L/h (50%).

Metabolism-                                                                                                   Lurbinectedin is metabolized by CYP3A4, in vitro.

Excretion-                                                                                                                 After a single dose of radiolabeled lurbinectedin administration, 89% of the radioactivity was recovered in feces (< 0.2% unchanged) and 6% in urine (1% unchanged).

Specific Populations-                                                                                           No clinically significant differences in the pharmacokinetics of lurbinectedin were identified based on age (18-85 years), sex, body weight (39-154 kg), mild to moderate renal impairment (CLcr 30 to 89 mL/min) or mild hepatic impairment (total bilirubin = ULN and AST > ULN, or total bilirubin between 1.0 – 1.5 × ULN and any AST).

The effects of severe renal impairment (CLcr < 30 mL/min) and moderate or severe hepatic impairment (total bilirubin > 1.5 × ULN and any AST) on the pharmacokinetics of lurbinectedin have not been studied.

Drug Interactions Studies-                                                                               Dedicated clinical drug-drug interaction studies with CYP3A modulators have not been conducted with lurbinectedin.

In vitro Studies Cytochrome P450 (CYP) Enzymes: Lurbinectedin is metabolized by CYP3A4.                                                                                                               Lurbinectedin is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4.                                                                        Lurbinectedin is not an inducer of CYP1A2 or CYP3A4.

Transporter Systems:                                                                                         Lurbinectedin is a substrate of MDR1, but is not a substrate of OATB1P1, OATP1B3, OCT1, or MATE1.                                                                                                   Lurbinectedin inhibits MDR1, OATP1B1, OATP1B3, and OCT1 but not BCRP, BSEP, MATE1, OAT1, OAT3, or OCT2.

 USE IN SPECIFIC POPULATIONS                                                                               

  1. Pregnancy Risk Summary-                                                                              Based on animal data and its mechanism of action .,ZEPZELCA can cause fetal harm when administered to a pregnant woman.

Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

2. Lactation Risk Summary-                                                                                           There are no data on the presence of lurbinectedin in human milk or its effects on the breastfed child or on milk production.

Because of the potential for serious adverse reactions from  ZEPZELCA in breastfed children, advise women not to breastfeed during treatment with ZEPZELCA and for 2 weeks after the final dose.

3. Females and Males of Reproductive Potential-                                                ZEPZELCA can cause embryolethality at doses lower than the human dose of 3.2 mg/m2 . Verify the pregnancy status of females of reproductive potential prior to initiating ZEPZELCA.

Contraception -                                                                                                      Females -                                                                                                                 Advise female patients of reproductive potential to use effective contraception during treatment with ZEPZELCA and for 6 months after the final dose.

Males-                                                                                                                     Advise males with a female sexual partner of reproductive potential to use effective contraception during treatment with ZEPZELCA and for 4 months after the final dose.

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

5. Geriatric Use-                                                                                                       Of the 105 patients with SCLC administered ZEPZELCA in clinical studies, 37 (35%) patients were 65 years of age and older, while 9 (9%) patients were 75 years of age and older.

No overall difference in effectiveness was observed between patients aged 65 and older and younger patients.

There was a higher incidence of serious adverse reactions in patients = 65 years of age than in patients < 65 years of age (49% vs. 26%, respectively).

The serious adverse reactions most frequently reported in patients = 65 years of age were related to myelosuppression and consisted of febrile neutropenia (11%), neutropenia (11%), thrombocytopenia (8%), and anemia (8%) . 

6. Hepatic Impairment-                                                                                               The effect of moderate or severe hepatic impairment (total bilirubin > 1.5 × ULN and any AST) on the pharmacokinetics of lurbinectedin has not been studied.                             

No dose adjustment of ZEPZELCA is recommended for patients with mild hepatic impairment (total bilirubin = ULN and AST > ULN, or total bilirubin 1.0-1.5 × ULN and any AST).