Ixazomib Capsules

Product Name: LuciXaz

Chinese Name: Ixazomib

English Name: Ixazomib

Specification: 4 mg/capsule; 3 capsules/box.

[Summary]

Ixazomib is a reversible inhibitor of the proteasome—an enzyme complex that regulates intracellular protein homeostasis. Specifically, it reversibly inhibits the chymotrypsin-like activity of the 20S proteasome β5 subunit, leading to the activation of signaling cascades, cell cycle arrest, and apoptosis.

[Indications]

Multiple Myeloma: For patients with multiple myeloma who have received at least one prior therapy (in combination with lenalidomide and dexamethasone).

[Specification]

4 mg/capsule; 3 capsules/box.

[Storage]

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

[Dosage and Administration]

Usual Adult Dosage for Multiple Myeloma:

1. The recommended starting dose is 4 mg orally, administered on Days 1, 8, and 15 of a 28-day treatment cycle.

2. It should be taken at least one hour before food or at least two hours after food.

Ixazomib in Combination with Lenalidomide and Dexamethasone:

The recommended starting dose of Ixazomib is 4 mg orally once weekly, administered on Days 1, 8, and 15 of a 28-day treatment cycle.

The recommended starting dose of Lenalidomide is 25 mg orally once daily, administered on Days 1 through 21 of a 28-day treatment cycle.

The recommended starting dose of Dexamethasone is 40 mg orally, administered on Days 1, 8, 15, and 22 of a 28-day treatment cycle.

Missed Dose

- If a dose is delayed or missed, the missed dose should be taken only if the next scheduled dose is 72 hours or more away. A missed dose should not be taken within 72 hours of the next scheduled dose. Do not take a double dose to make up for a missed dose. If vomiting occurs after administration, the patient should not repeat the dose. The patient should resume dosing at the next scheduled dose time.

【Adverse Reactions】

>10%

Cardiovascular: Peripheral edema (25%)

Central Nervous System: Peripheral neuropathy (28%; Grade 3: 2%), Peripheral sensory neuropathy (19%)

Dermatologic: Rash (19%)

Gastrointestinal: Diarrhea (42%), Constipation (34%), Nausea (26%), Vomiting (22%)

Hematologic/Oncologic: Thrombocytopenia (78%; Grade 3/4: 26%), Neutropenia (67%; Grade 3/4: 26%)

Neuromuscular/Skeletal: Back pain (21%)

Ophthalmic: Eye disorders (26%)

Respiratory: Upper respiratory tract infection (19%)

1% - >10%

Hepatic: Hepatic impairment (6%)

Infection: Herpes zoster (4%; <1% with antiviral prophylaxis)

Ophthalmic: Blurred vision (6%), Conjunctivitis (6%), Dry eye (5%)

Cholestatic hepatitis, Hepatocellular hepatitis, Hepatotoxicity, Hepatic steatosis, Peripheral motor neuropathy, Reversible posterior leukoencephalopathy syndrome (RPLS), Stevens-Johnson syndrome (SJS), Sweet's syndrome, Thrombotic thrombocytopenic purpura (TTP), Transverse myelitis, Tumor lysis syndrome (TLS)

【Contraindications】

Hypersensitivity to ixazomib or to any of the components of the formulation.

【Precautions】

Myelosuppression: Neutropenia and thrombocytopenia were commonly reported in clinical trials; Grade 3 and 4 toxicities were also observed. Platelet nadirs typically occur between Days 14 and 21 of each cycle and recover to baseline levels by the start of the subsequent cycle. Monitor platelet counts at least monthly during treatment, and consider more frequent monitoring during the first 3 cycles. Treatment interruption, dose reduction, and/or platelet transfusion may be required. Monitor complete blood counts (with differential) for neutropenia; treatment interruption or dose adjustment may be necessary.

**Dermatologic Toxicity:** Rash has been observed following ixazomib administration; most cases were Grade 1 or 2 (with Grade 3 rash occurring in a small number of patients). Maculopapular rash and macular rash were the most common dermatologic reactions. Monitor for dermatologic toxicity and provide supportive care or adjust the doses of ixazomib and lenalidomide (for Grade 2 or higher toxicity).

**Gastrointestinal Toxicity:** Diarrhea, constipation, nausea, and vomiting have been reported. Antidiarrheals, antiemetics, and supportive care may be required to manage toxicity. Dose adjustments are recommended for Grade 3 or 4 symptoms.

**Hepatotoxicity:** Drug-induced liver injury, hepatocellular injury, hepatic steatosis, cholestatic hepatitis, and hepatotoxicity were rarely reported in clinical trials. Monitor liver enzymes periodically; dose adjustment may be required for Grade 3 or 4 toxicity.

**Herpes Zoster Infection:** Herpes zoster infection has been reported; the incidence was lower in patients receiving antiviral prophylaxis. Consider antiviral prophylaxis during ixazomib treatment to reduce the risk of herpes zoster reactivation.

**Peripheral Edema:** Peripheral edema occurred in one-quarter of patients treated with ixazomib (generally Grade 1 or 2 reactions). If peripheral edema occurs, assess for potential underlying causes and provide supportive care. If necessary, dose adjustments for dexamethasone and ixazomib may be required for Grade 3 or 4 symptoms.

**Peripheral Neuropathy:** Peripheral neuropathy has been observed (primarily Grade 1 or 2). Peripheral sensory neuropathy was the most common symptom, while peripheral motor neuropathy was rarely seen. Monitor closely for symptoms of neuropathy; dose adjustment (of ixazomib and lenalidomide) or treatment discontinuation may be required.

Males and females of reproductive potential should use effective contraception during treatment and for 90 days following the last dose. [Safety and Efficacy]

Ixazomib is an investigational oral proteasome inhibitor currently being studied for use in multiple myeloma spectrum disorders and systemic light-chain (AL) amyloidosis. It is the first oral proteasome inhibitor to enter Phase 3 clinical trials and receive regulatory approval. The U.S. Food and Drug Administration (FDA) granted Ixazomib Priority Review status and approved it in November 2015. The European Union approved it in November 2016. In the United States and Europe, Ixazomib is indicated for use in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy.

As the first oral proteasome inhibitor, Ixazomib demonstrates confirmed efficacy, rapid onset of action, and the ability to overcome high-risk cytogenetic factors. Its side effects are safe and manageable, the incidence of peripheral neuropathy (PN) is low, and its oral administration offers convenience; these attributes ensure that patients can maintain long-term adherence to the treatment, thereby achieving durable control over their multiple myeloma (MM). For patients with high-risk cytogenetics, the median progression-free survival (PFS) in the Ixazomib group was similar across both the overall study population and the specific high-risk cytogenetic subgroup. Furthermore, it extended PFS by nearly 10 months compared to the control group. Ixazomib also demonstrates a very rapid onset of action, with a median time to response of 1.1 months. Regarding safety, Ixazomib did not result in a significant increase in adverse events when compared to the control group. With respect to the incidence of peripheral neuropathy (PN)—a side effect specific to proteasome inhibitors—the Ixazomib group showed no significant increase in the overall incidence of PN; specifically, there was no difference in the incidence of Grade 3 PN, and no cases of Grade 4 PN were observed. The C16010 China extension study enrolled 115 patients. The median progression-free survival (PFS) was 6.7 months in the Ixazomib group and 4.0 months in the placebo group (placebo + lenalidomide + dexamethasone); the median overall survival (OS) was 25.8 months and 15.8 months, respectively (with a median follow-up of 19.8 months). The objective response rates (ORR) were 56.1% and 31%, respectively. The rate of complete response (CR) or very good partial response (VGPR) was 24.6% in the Ixazomib group, compared to 12.1% in the placebo group. The time to progression was longer in the Ixazomib group than in the placebo group (median: 7.3 months vs. 4.1 months).