DRUG INTERACTIONS- (summary)

­ • Acid-Reducing Agents: Avoid coadministration with proton pump inhibitors (PPIs) and H2 receptor antagonists. If an acid-reducing agent cannot be avoided, administer LUMAKRAS 4 hours before or 10 hours after a local antacid.

 • Strong CYP3A4 Inducers: Avoid coadministration with strong CYP3A4 inducers.

 • CYP3A4 Substrates: Avoid coadministration with CYP3A4 substrates for which minimal concentration changes may lead to therapeutic failures of the substrate. If coadministration cannot be avoided, adjust the substrate dosage in accordance to its Prescribing Information.

 • P-gp substrates: Avoid coadministration with P-gp substrates for which minimal concentration changes may lead to serious toxicities. If coadministration cannot be avoided, decrease the substrate dosage in accordance to its Prescribing Information.

BRIEF SUMMARY

SOTORRSIB- (May 2021)

Indn-  to treat adults with small lung  cancer whose disease meets certain criteria      

Comp-  ­ Tablets: 120 mg. • Recommended dosage: 960 mg orally once daily.

 • Swallow tablets whole with or without food.

ADR-  The most common adverse reactions (= 20%) were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. 

CI-  None.

WARNINGS-

­ • Hepatotoxicity: Monitor liver function tests every 3 weeks for the first 3 months of treatment then once monthly as clinically indicated. Withhold, reduce dose, or permanently discontinue based on the severity.

 • Interstitial Lung Disease (ILD)/Pneumonitis: Monitor for new or worsening pulmonary symptoms. I

Pat Inform-

Hepatotoxicity -                                                                                                                 Advise patients to immediately contact their healthcare provider for signs and symptoms of liver dysfunction .

Interstitial Lung Disease (ILD)/Pneumonitis -                                                                     Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms.

Lactation -                                                                                                                           Advise women not to breastfeed during treatment  and for 1 week after the final dose

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U.S. FDA APPROVED DRUGS SURING 2021                                          

Serial No 23

Name of the Drug-    LUMAKRAS

Active Ingredient -   Sotorasib

Pharmacological Classification-    To treat adults with small lung  cancer whose                                                                 disease meets certain criteria                                                                                                                                                                                                                                                                                                                             Date of Approval-          5/28/2021

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                             LUMAKRAS safely and effectively.                                                                                  See full prescribing information for LUMAKRAS. LUMAKRAS™ (sotorasib) tablets, for oral use

Initial U.S. Approval: 2021

INDICATIONS AND USAGE- 

­ LUMAKRAS is an inhibitor of the RAS GTPase family indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy.

 This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

DOSAGE AND ADMINISTRATION-

­ • Recommended dosage: 960 mg orally once daily.

 • Swallow tablets whole with or without food.

DOSAGE FORMS AND STRENGTHS-

­ Tablets: 120 mg.

CONTRAINDICATIONS

­ None.

WARNINGS AND PRECAUTIONS

­ • Hepatotoxicity: Monitor liver function tests every 3 weeks for the first 3 months of treatment then once monthly as clinically indicated. Withhold, reduce dose, or permanently discontinue LUMAKRAS based on the severity. (2.3, 5.1) • Interstitial Lung Disease (ILD)/Pneumonitis: Monitor for new or worsening pulmonary symptoms. Immediately withhold LUMAKRAS for suspected ILD/pneumonitis and permanently discontinue if no

ADVERSE REACTIONS-

­ The most common adverse reactions (= 20%) were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. The most common laboratory abnormalities = 25% were decreased lymphocytes, decreased hemoglobin, increased aspartate aminotransferase, increased alanine aminotransferase, decreased calcium, increased alkaline phosphatase, increased urine protein, and decreased sodium.

CONTRAINDICATIONS

­ None.

WARNINGS AND PRECAUTIONS

­ • Hepatotoxicity: Monitor liver function tests every 3 weeks for the first 3 months of treatment then once monthly as clinically indicated. Withhold, reduce dose, or permanently discontinue LUMAKRAS based on the severity.

 • Interstitial Lung Disease (ILD)/Pneumonitis: Monitor for new or worsening pulmonary symptoms. Immediately withhold LUMAKRAS for suspected ILD/pneumonitis and permanently discontinue if no  if no other potential causes of ILD/pneumonitis are identified.

 PATIENT COUNSELING INFORMATION -

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

Hepatotoxicity -                                                                                                                 Advise patients to immediately contact their healthcare provider for signs and symptoms of liver dysfunction .

Interstitial Lung Disease (ILD)/Pneumonitis -                                                                     Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms.

Lactation -                                                                                                                           Advise women not to breastfeed during treatment with LUMAKRAS and for 1 week after the final dose

 Drug Interactions-                                                                                                             Advise patients to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, dietary and herbal products. Inform patients to avoid proton pump inhibitors, and H2 receptor antagonists while taking LUMAKRAS

If coadministration with an acid-reducing agent cannot be avoided, inform patients to take LUMAKRAS 4 hours before or 10 hours after a locally acting antacid

Missed Dose-                                                                                                                     If a dose of LUMAKRAS is missed by greater than 6 hours, resume treatment as prescribed the next day

Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 U.S.A. Patent: http://pat.amgen.com/lumakras/ © 2021 Amgen Inc. All rights reserved. 1XXXXXX – V1 Reference ID: 4803215

CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                      Sotorasib is an inhibitor of KRASG12C, a tumor-restricted, mutant-oncogenic form of the RAS GTPase, KRAS. Sotorasib forms an irreversible, covalent bond with the unique cysteine of KRASG12C, locking the protein in an inactive state that prevents downstream signaling without affecting wild-type KRAS. Sotorasib blocked KRAS signaling, inhibited cell growth, and promoted apoptosis only in KRAS G12C tumor cell lines.

2. Pharmacodynamics-                                                                                               Sotorasib exposure-response relationships and the time course of the pharmacodynamic response are unknown.

Cardiac Electrophysiology- At the approved recommended dosage, LUMAKRAS does not cause large mean increases in the QTc interval (> 20 msec).

3. Pharmacokinetics -                                                                                                          The pharmacokinetics of sotorasib have been characterized in healthy subjects and in patients with KRAS G12C-mutated solid tumors, including NSCLC. Sotorasib exhibited non-linear, time-dependent, pharmacokinetics over the dose range of 180 mg to 960 mg (0.19 to 1 time the approved recommended dosage) once daily with similar systemic exposure (i.e., AUC0-24h and Cmax) across doses at steady-state.

Absorption -                                                                                                                    The median time to sotorasib peak plasma concentration is 1 hour.

Effect of Food-                                                                                                                     When 960 mg LUMAKRAS was administered with a high-fat, high-calorie meal (containing approximately 800 to 1000 calories with 150, 250, and 500 to 600 calories from protein, carbohydrate and fat, respectively) in patients, sotorasib AUC0-24h increased by 25% compared to administration under fasted conditions.

Distribution -                                                                                                                  The sotorasib mean volume of distribution (Vd) at steady state is 211 L (CV: 135%). In vitro, sotorasib plasma protein binding is 89%.

Elimination -                                                                                                                     The sotorasib mean terminal elimination half-life is 5 hours (standard deviation (SD): 2). At 960 mg LUMAKRAS once daily, the sotorasib steady state apparent clearance is 26.2 L/hr (CV: 76%).

Metabolism-                                                                                                                     The main metabolic pathways of sotorasib are non-enzymatic conjugation and oxidative metabolism with CYP3As.

Excretion After a single dose of radiolabeled sotorasib, 74% of the dose was recovered in feces (53% unchanged) and 6% (1% unchanged) in urine.

Specific Populations -                                                                                                    No clinically meaningful differences in the pharmacokinetics of sotorasib were observed based on age (28 to 86 years), sex, race (White, Black and Asian), body weight (36.8 to 157.9 kg), line of therapy, ECOG PS (0, 1), mild and moderate renal impairment (eGFR: =30 mL/min/1.73 m2 ), or mild hepatic impairment (AST or ALT < 2.5 × ULN or total bilirubin < 1.5 × ULN).

The effect of severe renal impairment or moderate to severe hepatic impairment on sotorasib pharmacokinetics has not been studied].

Drug Interaction Studies -                                                                                              Clinical Studies Acid-Reducing Agents: Coadministration of repeat doses of omeprazole (PPI) with a single dose of LUMAKRAS decreased sotorasib Cmax by 65% and AUC by 57% under fed conditions, and decreased sotorasib Cmax by 57% and AUC by 42% under fasted conditions.

Coadministration of a single dose of famotidine (H2 receptor antagonist) given 10 hours prior to and 2 hours after a single dose of LUMAKRAS under fed conditions decreased sotorasib Cmax by 35% and AUC by 38% .

Strong CYP3A4 Inducers: Coadministration of repeat doses of rifampin (a strong CYP3A4 inducer) with a single dose of LUMAKRAS decreased sotorasib Cmax by 35% and AUC by 51%. 

Other Drugs: No clinically meaningful effect on the exposure of sotorasib was observed following coadministration of LUMAKRAS with itraconazole (a combined strong CYP3A4 and P-gp inhibitor) and a single dose of rifampin (an OATP1B1/1B3 inhibitor), or metformin (a MATE1/MATE2-K substrate).

CYP3A4 substrates: Coadministration of LUMAKRAS with midazolam (a sensitive CYP3A4 substrate) decreased midazolam Cmax by 48% and AUC by 53%

P-gp substrates: Coadministration of LUMAKRAS with digoxin (a P-gp substrate) increased digoxin Cmax by 91% and AUC by 21%.

MATE1/MATE2-K substrates: No clinically meaningful effect on the exposure of metformin (a MATE1/MATE2-K substrate) was observed following coadministration of LUMAKRAS.

In Vitro Studies Cytochrome P450 (CYP) Enzymes: Sotorasib may induce CYP2C8, CYP2C9 and CYP2B6. Sotorasib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6.

Transporter Systems: Sotorasib may inhibit BCRP.

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-                                                                                          There are no available data on LUMAKRAS use in pregnant women. In rat and rabbit embryo-fetal development studies, oral sotorasib did not cause adverse developmental effects or embryo-lethality at exposures up to 4.6 times the human exposure at the 960 mg clinical dose 

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 sotorasib or its metabolites in human milk, the 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 LUMAKRAS and for 1 week after the final dose.

3. Pediatric Use                                                                                                              The safety and effectiveness of LUMAKRAS have not been established in pediatric patients.

4. Geriatric Use-                                                                                                               Of the 357 patients with any tumor type who received LUMAKRAS 960 mg orally once daily in CodeBreaK 100, 46% were 65 and over, and 10% were 75 and over. No overall differences in safety or effectiveness were observed between older patients and younger patients.