Sotoxen Tablet

Sotoxen is 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.

Sotorasib is a potent and highly selective KRASG12C (Kirsten rat sarcoma viral oncogene homolog) inhibitor, which covalently and irreversibly binds to the unique cysteine of KRASG12C. Inactivation of KRASG12C by Sotorasib blocks tumour cell signalling and survival, inhibits cell growth, and promotes apoptosis selectively in tumours harbouring KRASG12C, an oncogenic driver of tumourigenesis across multiple cancer types. The potency and selectivity of Sotorasib is enhanced through the unique binding to both the P2 pocket and the His95 surface groove, locking the protein in an inactive state that prevents downstream signalling, without affecting wild-type KRAS.

Sotorasib demonstrated in vitro and in vivo inhibition of KRASG12C with minimal detectable off-target activity against other cellular proteins and processes. Sotorasib impaired oncogenic signalling and tumour cell survival at clinically relevant exposures in numerous pre-clinical models expressing KRASG12C. Sotorasib also enhanced antigen presentation and inflammatory cytokine production only in tumour cells with KRASG12C. Sotorasib induced anti-tumour inflammatory responses and immunity, driving permanent and complete tumour regressions in immunocompetent mice implanted with KRASG12C expressing tumours.

The recommended dosage of Sotorasib is 960 mg (eight 120 mg tablets) orally once daily until disease progression or unacceptable toxicity. Take Sotorasib at the same time each day with or without food. Swallow tablets whole. Do not chew, crush or split tablets. If a dose of Sotorasib is missed by more than 6 hours, take the next dose as prescribed the next day. Do not take 2 doses at the same time to make up for the missed dose. If vomiting occurs after taking Sotorasib, do not take an additional dose. Take the next dose as prescribed the next day.

Effects of other medicinal products on Sotoxen-

Acid-reducing agents: Coadministration of Sotoxen with gastric acidreducing agents decreased Sotoxen concentrations, which may reduce the efficacy of Sotoxen. Avoid coadministration of Sotoxen with proton pump inhibitors (PPIs), H2 receptor antagonists, and locally acting antacids. If coadministration with an acidreducing agent cannot be avoided, administer Sotoxen 4 hours before or 10 hours after administration of a locally acting antacid.

Strong CYP3A4 inducers: Coadministration of Sotoxen with a strong CYP3A4 inducer decreased Sotoxen concentrations, which may reduce the efficacy of Sotoxen. Avoid coadministration of Sotoxen with strong CYP3A4 inducers.

Effect of Sotoxen on other medicinal products-

CYP3A4 substrates: Coadministration of Sotoxen with a CYP3A4 substrate decreased its plasma concentrations, which may reduce the efficacy of the substrate. Avoid coadministration of Sotoxen with CYP3A4 sensitive substrates, for which minimal concentration changes may lead to therapeutic failures of the substrate. If coadministration cannot be avoided, increase the sensitive CYP3A4 substrate dosage in accordance with its Prescribing Information.

P-glycoprotein (P-gp) Substrates: Coadministration of Sotoxen with a P-gp substrate (digoxin) increased digoxin plasma concentrations, which may increase the adverse reactions of digoxin. Avoid coadministration of Sotoxen with P-gp substrates, for which minimal concentration changes may lead to serious toxicities. If coadministration cannot be avoided, decrease the P-gp substrate dosage in accordance with its Prescribing Information.

Two serious adverse effects were reported with the use of Sotoxen: hepatotoxicity and interstitial lung disease (ILD).

Hepatotoxicity: Twenty-five percent of trial participants experienced liver dysfunction, resulting in elevated hepatic transaminases, elevated bilirubin, and drug-induced hepatitis. Liver function tests should be performed before starting Sotoxen and every 3 weeks for the first 3 months, then once a month. Liver function tests should include AST, ALT, and bilirubin levels.2 Patients should be instructed to report signs or symptoms of liver dysfunction such as abdominal pain, jaundice, dark urine, or itching to their oncology team. Sotoxen should be held if a patient develops grade 2, 3, or 4 hepatotoxicity until the symptoms resolve to a grade 1 or better, and then resumed at a lower dose.

Interstitial Lung Disease: Although ILD was rare, several trial participants developed the condition. Patients should be evaluated regularly for respiratory symptoms such as shortness of breath, cough, and fever, and should be encouraged to quickly report these symptoms to their healthcare team. If ILD is suspected, Sotoxen should be held while the patient undergoes work-up for their symptoms.

Pregnancy: There are no data from the use of Sotorasib in pregnant women. Studies in animals have shown reproductive toxicity. Patients must be informed of the potential hazards to the foetus if Sotorasib is used during pregnancy, or if the patient becomes pregnant while taking Sotorasib.

Breast-feeding: It is unknown if Sotorasib or its metabolites are excreted in human milk. A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Sotorasib therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Hepatotoxicity: Sotoxen can cause hepatotoxicity, which may lead to drug-induced liver injury and hepatitis. Among 357 patients who received Sotoxen in Code BreaK 100, hepatotoxicity occurred in 1.7% (all grades) and 1.4%. (Grade 3). A total of 18% of patients who received Sotoxen had increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST); 6% were Grade 3 and 0.6% were Grade 4. The median time to first onset of increased ALT/AST was 9 weeks (range: 0.3 to 42). Increased ALT/AST leading to dose interruption or reduction occurred in 7% of patients. Sotoxen was discontinued due to increased ALT/AST in 2.0% of patients. In addition to dose interruption or reduction, 5% of patients received corticosteroids for the treatment of hepatotoxicity.

Monitor liver function tests (ALT, AST, and total bilirubin) prior to the start of Sotoxen, every 3 weeks for the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop transaminase and/or bilirubin elevations. Withhold, dose reduce or permanently discontinue Sotoxen based on severity of adverse reaction.

Interstitial Lung Disease (ILD)/Pneumonitis: Sotoxen can cause ILD/pneumonitis that can be fatal. Among 357 patients who received Sotoxen in CodeBreaK 100, ILD/pneumonitis occurred in 0.8% of patients, all cases were Grade 3 or 4 at onset, and 1 case was fatal. The median time to first onset for ILD/pneumonitis was 2 weeks (range: 2 to 18 weeks). Sotoxen was discontinued due to ILD/pneumonitis in 0.6% of patients. Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold Sotoxen in patients with suspected ILD/pneumonitis and permanently discontinue Sotoxen if no other potential causes of ILD/pneumonitis are identified.

There is no clinical experience with overdose with Sotoxen. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required.

Cytotoxic Chemotherapy

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