Ixazomib for multiple myeloma

Ixazomib instruction manual

Product Name: LuciXaz

Manufacturer: Lucius Pharmaceuticals

Chinese name: Ishazomib

English Name: Ixazomib
Drug approval number: 10 L 1026/23

 

【Summary】

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

 

【Indications】

Multiple myeloma: Patients with multiple myeloma who have received at least one previous treatment (combination of lenalidomide and dexamethasone)

 

【Specification】  

4 mg/ pill, 3 pills / box.

 

【Storage】

 Store at 20 ° C to 25 ° C (68 ° C to 77 ° F) ; short-distance transportation is permitted within the temperature range of 15 to 30 ° C (59 – 86 ° F) .

 

【Usage and Dosage】

Common doses for multiple myeloma in adults:

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

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

Ixazomib combined with lenalidomide and dexamethasone:

The recommended starting dose of ixazomib is 4 mg orally once a week on days 1, 8, and 15 of a 28-day treatment cycle.

The recommended starting dose of lenalidomide is 25 mg/day, on days 1 to 21 of a 28-day treatment cycle.

The recommended starting dose of dexamethasone is 40 mg/time on days 1, 8, 15, and 22 of a 28-day treatment cycle.

Missed dose

-If a dose is delayed or missed, that 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. A double dose cannot be used to make up for a missed dose. If vomiting occurs after taking a dose, the patient should not repeat the dose. The patient should resume dosing at the next scheduled dose.

 

【Adverse Reactions】

>10%

Cardiovascular: peripheral edema (25%)

Central nervous system: peripheral neuropathy (28%; grade 3: 2%), peripheral sensory neuropathy (19%)

Dermatology: Rash (19%)

Gastrointestinal: diarrhea (42%), constipation (34%), nausea (26%), vomiting (22%)

Hematology and Oncology: Thrombocytopenia (78%; Grade 3/4: 26%), Neutropenia (67%; Grade 3/4: 26%)

Neuromuscular and skeletal: back pain (21%)

Ophthalmology: Eye diseases (26%)

Respiratory tract: Upper respiratory tract infection (19%)

 

1% - >10%

Liver: Hepatic insufficiency (6%)

Infections: Herpes zoster (4%; <1%, antiviral prophylaxis)

Ophthalmology: blurred vision (6%), conjunctivitis (6%), dry eyes (5%)

Cholestatic hepatitis, hepatocellular hepatitis, hepatotoxicity, hepatic steatosis, peripheral motor neuropathy, reversible posterior leukoencephalopathy syndrome, Stevens-Johnson syndrome, Sweet syndrome, thrombotic thrombocytopenic purpura, transverse myelitis, tumor lysis syndrome

 

【Taboo】

Hypersensitivity to ixazomib or any component of the formulation

 

【Notes】

Myelosuppression: Neutropenia and thrombocytopenia were commonly reported in clinical trials; Grade 3 and 4 toxicities were also observed. Platelet nadirs typically occurred on Days 14 to 21 of each cycle and returned 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 for neutropenia (variable); treatment interruption or dose adjustment may be required.

Skin Toxicity: Rash has occurred following administration of ixazomib; most cases were Grade 1 or 2 (a few patients had Grade 3 rash). Maculopapular and macular rash were the most common skin reactions. Monitor for skin toxicity and administer supportive care or dose adjustments of ixazomib and lenalidomide (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 modifications are recommended for Grade 3 or 4 symptoms.

Hepatotoxicity: Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestasis, and hepatotoxicity have been reported rarely in clinical trials. Monitor liver enzymes regularly and dose adjustments may be required for grade 3 or 4 toxicities.

Herpes zoster infections: Herpes zoster infections have been reported; the infection rate 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, evaluate for potential underlying causes and provide supportive care. Grade 3 or 4 symptoms may require dose adjustment of dexamethasone and ixazomib, if necessary.

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

Males and females of reproductive potential should use effective contraception during treatment and for 90 days after the last dose.

 

Safety and efficacy

Ixazomib is an investigational oral proteasome inhibitor currently being studied across the multiple myeloma spectrum and systemic light-chain (AL) amyloidosis. It is the first oral proteasome inhibitor to enter Phase 3 clinical trials and be approved. The U.S. Food and Drug Administration (FDA) granted priority review to ixazomib and approved it in November 2015. The European Union approved it in November 2016. In the United States and Europe, ixazomib is indicated 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 has a definite efficacy, rapid onset, can overcome high-risk cytogenetic factors, has safe and controllable side effects, a low incidence of PN, and is convenient for oral administration, ensuring that patients can take it for a long time to achieve lasting control of MM (multiple myeloma). For patients with high-risk cytogenetics, the median PFS (progression-free survival) of the ixazomib group is similar to that of the high-risk cytogenetic population. And it is nearly 10 months longer than that of the control group. Ixazomib also takes effect very quickly, with an onset time of 1.1 months. In terms of safety, ixazomib did not significantly increase adverse events compared with the control group. In terms of the incidence of proteasome inhibitor-specific peripheral neuropathy (PN), the ixazomib group did not significantly increase the incidence of PN, the incidence of grade 3 PN was no different, and no grade 4 PN occurred.

The C16010 China Continuation Study enrolled 115 patients. The median PFS (progression-free survival) of the ixazomib group and the placebo group (placebo + lenalidomide + dexamethasone) were 6.7 and 4 months, respectively, the median OS (overall survival) were 25.8 and 15.8 months (median follow-up 19.8 months), and the ORR (objective response rate) were 56.1% and 31%, respectively. The complete response (CR) and very good partial response (VGPR) rates were 24.6% in the ixazomib group and 12.1% in the placebo group. The time to progression in the ixazomib group was longer than that in the placebo group (median 7.3 and 4.1 months, respectively).