Selinexor

Risk Summary

Based on findings in animal studies and its mechanism of action, selinexor can cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of selinexor to pregnant rats during organogenesis resulted in structural abnormalities and alterations to growth at exposures that were below those occurring clinically at the recommended dose (see Data). Advise pregnant women of the risks 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.

Data

Animal data

In an embryo-fetal development study in pregnant rats, daily oral administration of selinexor at 0, 0.25, 0.75, or 2 mg/kg throughout organogenesis caused incomplete or delayed ossification, skeletal variations, and reduced fetal weight compared with controls at a dose of 0.75 mg/kg (approximately 0.08-fold of human area under the curve [AUC] at the recommended dose). Malformations were observed at 2 mg/kg, including microphthalmia, fetal edema, malpositioned kidney, and persistent truncus arteriosus.

Risk Summary

There is no information regarding the presence of selinexor or its metabolites in human milk, or their effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with selinexor and for 1 week after the last dose.

Carcinogenicity studies have not been conducted with selinexor.

Selinexor was not mutagenic in vitro in a bacterial reverse mutation (Ames) assay and was not clastogenic in either the in vitro cytogenetic assay in human lymphocytes or in the in vivo rat micronucleus assay.

Fertility studies in animals have not been conducted with selinexor. In repeat-dose oral toxicity studies, selinexor was administered for up to 13 weeks in rats and monkeys. Reduced sperm, spermatids, and germ cells in epididymides and testes were observed in rats at ≥1 mg/kg, decreased ovarian follicles were observed in rats at ≥2 mg/kg, and single cell necrosis of testes was observed in monkeys at ≥1.5 mg/kg. These dose levels resulted in systemic exposures approximately 0.11, 0.28, and 0.53 times, respectively, the exposure (AUC_last) in humans at the recommended human dose of 80 mg.

Advise patients that they may experience confusion and dizziness. Advise patients to report symptoms of neurological toxicity right away. Advise patients not to drive or operate hazardous machinery until the neurological toxicity fully resolves. Advise patients to use fall prevention measures as warranted.

The following clinically significant adverse reactions are described in detail in other labeling sections:

• Thrombocytopenia
• Neutropenia
• Gastrointestinal Toxicity
• Hyponatremia
• Serious Infection
• Neurological Toxicity

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Multiple Myeloma

The safety of selinexor in combination with dexamethasone was evaluated in STORM. Patients received selinexor 80 mg orally with dexamethasone 20 mg on Days 1 and 3 of every week (n=202). The median duration of selinexor treatment was 8 weeks (range: 1 to 60 weeks). The median dose was 115 mg (range: 36 to 200 mg) per week.

Fatal adverse reactions occurred in 9% of selinexor treated patients. Serious adverse reactions occurred in 58% of patients.

The treatment discontinuation rate due to adverse reactions was 27%; 53% of patients had a reduction in the selinexor dose, and 65% had the dose of selinexor interrupted. Thrombocytopenia was the leading cause of dose modification, resulting in dose reduction and/or interruption in >25% of patients. The most frequent adverse reactions requiring permanent discontinuation in 4% or greater of patients who received selinexor included fatigue, nausea, and thrombocytopenia.

Table 5 summarizes the adverse reactions in STORM.

Table 5. Adverse Reactions (≥10%) in Patients Who Received selinexor in STORM:

^a Thrombocytopenia includes thrombocytopenia and platelet count decreased.
^b Fatigue includes fatigue and asthenia.
^c Anemia includes anemia and hematocrit decreased.
^d Neutropenia includes neutropenia and neutrophil count decreased.
^e Dyspnea includes dyspnea, dyspnea exertional, and dyspnea at rest.
^f Upper respiratory tract infection includes upper respiratory tract infection, respiratory tract infection, pharyngitis, nasopharyngitis, bronchitis, bronchiolitis, respiratory syncytial virus infection, parainfluenza virus infection, rhinitis, rhinovirus infection, and adenovirus infection.
^g Cough includes cough, productive cough, and upper-airway cough syndrome.
^h Mental status changes includes mental status changes, confusional state, and delirium.
ⁱ. Hypercreatininemia includes hypercreatininemia and hypercreatinemia.
^j Pneumonia includes pneumonia, atypical pneumonia, lung infection, lower respiratory tract infection, pneumocystis jirovecii pneumonia, pneumonia aspiration, pneumonia influenzal, and pneumonia viral.
^k Includes fatal event.

Diffuse Large B-Cell Lymphoma

The safety of selinexor was evaluated in SADAL. Patients received selinexor 60 mg orally on Days 1 and 3 of every week (n=134). The study required an absolute neutrophil count ≥1000/μL, platelet count ≥75,000/μL, hepatic transaminases ≤2.5 times upper limit of normal (ULN) unless abnormal from lymphoma, and bilirubin ≤2 times ULN. The study permitted a maximum of 5 prior systemic regimens for DLBCL. Antiemetic prophylaxis with a 5HT-3 receptor antagonist was required. The median duration of selinexor treatment was 2.1 months (range: 1 week to 3.7 years) with 38% receiving at least 3 months and 22% receiving at least 6 months of treatment. The median exposure was 100 mg per week.

Fatal adverse reactions occurred in 3.7% of patients within 30 days and 5% of patients within 60 days of last treatment; the most frequent fatal adverse reaction was infection (4.5% of patients). Serious adverse reactions occurred in 46% of patients who received selinexor; the most frequent serious adverse reaction was infection (21% of patients).

Discontinuation due to adverse reactions occurred in 17% of patients who received selinexor. Adverse reactions which results in discontinuation in ≥2% of patients included: infection, fatigue, thrombocytopenia, and nausea.

Adverse reactions led to selinexor dose interruption in 61% of patients and dose reduction in 49%, with 17% of all patients having 2 or more dose reductions. The median time to first dose modification (reduction or interruption) was 4 weeks, with the leading causes being thrombocytopenia (40% of all patients), neutropenia (16%), fatigue (16%), nausea (10%), and anemia (10%). The median time to first dose reduction was 6 weeks, with 83% of first dose reductions occurring within the first 3 months.

The most common adverse reactions, excluding laboratory abnormalities, in ≥20% of patients were fatigue, nausea, diarrhea, appetite decrease, weight decrease, constipation, vomiting, and pyrexia. Table 6 summarizes selected adverse reactions in SADAL.

Table 6. Adverse Reactions (≥10%), Excluding Laboratory Terms, in Patients with DLBCL Who Received selinexor in SADAL:

^a Fatigue includes fatigue and asthenia.
^b Edema includes edema, swelling, swelling face, edema peripheral, peripheral swelling, acute pulmonary edema.
^c Diarrhea includes diarrhea, post-procedural diarrhea, gastroenteritis. |
^d Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, epigastric discomfort.
^e Appetite decrease includes decreased appetite and hypophagia.
^f Cough includes cough and productive cough.
^g Dyspnea includes dyspnea and dyspnea exertional.
^h Upper respiratory tract infection includes upper respiratory tract infection, sinusitis, nasopharyngitis, pharyngitis, rhinitis, viral upper respiratory infection.
ⁱ Urinary tract infection includes urinary tract infection and specific types of urinary tract infection.
^j Dizziness includes dizziness and vertigo.
^k Taste disorder includes taste disorder, dysgeusia, ageusia.
^l Mental status changes include confusional state, amnesia, cognitive disorder, hallucination, delirium, somnolence, depressed level of consciousness, memory impairment.
^m Peripheral neuropathy includes peripheral neuropathy, peripheral sensory neuropathy, sensory disturbance, paresthesia, neuralgia.
ⁿ Musculoskeletal pain includes musculoskeletal pain, back pain, musculoskeletal chest pain, neck pain, pain in extremity, bone pain.
^o Hemorrhage includes hemorrhage, hematoma, hematuria, epistaxis, rectal hemorrhage, injection site hematoma, subdural hematoma, upper gastrointestinal hemorrhage, corneal bleeding.
^p Vision blurred includes vision blurred, visual acuity reduced, visual impairment.

Clinically relevant adverse reactions in <10% of patients who received selinexor included:

• Injury: fall (8%)
• Metabolic and nutrition disorders: dehydration (7%)
• Neurologic disorders: headache (4.5%), syncope (2.2%)
• Infection: sepsis (6%), herpesvirus infection (3%)
• Eye disorders: cataract (3.7%)
• Blood and lymphatic disorders: febrile neutropenia (3%)
• Cardiac disorders: cardiac failure (3%)

Table 7 summarizes selected new or worsening laboratory abnormalities in SADAL. Grade 3-4 laboratory abnormalities in ≥15% included thrombocytopenia, lymphopenia, neutropenia, anemia, and hyponatremia. Grade 4 laboratory abnormalities in ≥5% were thrombocytopenia (18%), lymphopenia (5%), and neutropenia (9%).

Table 7. Select Laboratory Abnormalities (≥15%) Worsening from Baseline in Patients with DLBCL Who Received selinexor in SADAL:

The denominator used to calculate the rate varied from 107 to 128 based on the number of patients with at least one post-treatment value.
^a Not fasting.
^b CK increase was not associated with reports of myopathy or myalgia.