The translational safety intelligence portal

First-in-human study of BR101801 (PI3Kdelta/DNA-PK inhibitor; 50-325 mg PO qd) in 11 patients with advanced hematologic malignancies. Adverse events included G3 hepatotoxicity (3 patients) and G3 skin reactions (2). Congress Alert

Phase Ia study of MRG001 (CD20/tubulin polymerization inhibitor; 0.15-2.5 mg/kg IV q3w) in 21 patients with relapsed/refractory advanced non-Hodgkin lymphoma. The most common treatment-related adverse events (TRAEs) were white blood cell count decrease, neutrophil count decrease, lymphocyte count decrease, ALT/AST elevation, pyrexia, hypertension, increased LDH, QT prolongation and thrombocytopenia. The most common grade ≥3 TRAEs were leukopenia, neutropenia, lymphopenia, hypertension and ALT elevation. Dose-limiting toxicities were grade 3 hyperlipidemia and grade 4 neutropenia (1 patient each). Congress Alert

Case report of a 61-year-old female with pneumonia who experienced loss of consciousness during treatment with ceftriaxone (bacterial penicillin-binding protein inhibitor). Previous to ceftriaxone therapy, the woman had experienced diarrhea due to amoxicillin/clavulanate treatment. The NPRA had already warn of the risk of disturbed consciousness, convulsions and encephalopathy with the use of ceftriaxone. To date, 8 reports of convulsions and 7 of loss of consciousness have been reported to the NPRA, but there were no reports of encephalopathy. However, the WHO ADR database has recorded 116 cases of encephalopathy associated with ceftriaxone use. Other adverse events of risperidone reported to the NPRA are listed. [Data from the NPRA 03/2021 MADRAC bulletin] Regulatory Agency Communication

The EMA has started a review of medications containing terlipressin (V1A/V1B/V2 receptor agonist) due to safety concerns observed in a clinical trial involving patients with hepatorenal syndrome. The results of this trial suggested that patients treated with terlipressin were more likely to experience and die from respiratory disorders such as respiratory failure (including severe breathing difficulties). Regulatory Agency Communication

Conclusions from a Periodic Safety Update Report on Tecfidera (dimethyl fumarate; NF-kappaB/kelch-like ECH-associated protein 1 inhibitor). The PRAC considers that a causal relationship between dimethyl fumarate and alopecia is at least a reasonable possibility. The product information of products containing dimethyl fumarate will be amended accordingly. Regulatory Agency Communication

The warnings section of the FDA Freedom of Information Summary for Solensia indicates that it may cause hypersensitivity reactions (including anaphylaxis) in case of accidental self-injection. Safety issues observed in cats, rodents and nonhuman primates are listed. [Data from FDA New Animal Drug Application Freedom of Information Summary for Solensia (frunevetmab; nerve growth factor inhibitor)] Regulatory Agency Communication

The FDA has updated the product information of Toprol-XL (metoprolol succinate; beta1-adrenoceptor antagonist), removing the Box Warning about ischemic heart disease and adding a warning on bradycardia (including sinus pause, heart block and cardiac arrest). Regulatory Agency Communication

Conclusions from a Periodic Safety Update Report on Selincro (nalmefene; opioid receptor antagonist). Based on data from clinical trials and spontaneous reports, a causal relationship between nalmefene and visual impairment is considered at least a reasonable possibility. The product information of products containing nalmefene will be amended accordingly. Regulatory Agency Communication

Conclusions from a Periodic Safety Update Report of dobutamine (beta1/2-adrenoceptor agonist). Based on data from clinical trials, the literature and spontaneous reports, a causal relationship between dobutamine and stress cardiomyopathy (Takotsubo syndrome) is considered at least a reasonable possibility. The “Special warnings and precautions for use” and the “Undesirable effects” sections will be updated to include stress cardiomyopathy (Takotsubo syndrome) with frequency “unknown”. Regulatory Agency Communication

The FDA has issued a drug safety communication warning about the risk of dental problems associated with buprenorphine-containing medicines dissolved in the mouth to treat opioid use disorder and pain (including single-ingredient products and in combination with naloxone). Dental problems include tooth decay, cavities, dental abscesses/infection, tooth erosion and total tooth loss. The FDA requires updating the prescribing information of all buprenorphine-containing medicines that are dissolved in the mouth to include a warning about the risk of dental problems. Regulatory Agency Communication

Conclusions from a Periodic Safety Update Report on Zoely (nomegestrol/estradiol). The CHMP has recommended updating the drug’s product information to include a warning on exacerbation of symptoms of hereditary and acquired angioedema. Regulatory Agency Communication

Conclusions from a Periodic Safety Update Report on Saxenda (liraglutide; GLP-1 receptor agonist). Based on data from clinical trials, the literature and spontaneous reports, a causal relationship between liraglutide and headache is considered at least a reasonable possibility. The “Undesirable effects” section will be updated to include headache with frequency “very common”. Regulatory Agency Communication

Conclusions from a Periodic Safety Update Report on Imnovid (pomalidomide; cereblon/VEGF inhibitor). Based on data from the literature and spontaneous reports, a causal relationship between pomalidomide and solid organ transplant rejection is established. The product information of products containing pomalidomide will be amended accordingly. Regulatory Agency Communication

Phase I study of datopotamab deruxtecan (DNA topoisomerase 1/tumor-associated calcium signal transducer 2 inhibitor; 6 mg/kg IV q3w) in 43 patients with triple-negative breast cancer. The most common treatment-emergent adverse events included nausea (58% patients any grade; 0% grade ≥3), stomatitis (53%; 9%), alopecia (35%; N/A), vomiting (35%; 2%) and fatigue (33%; 7%). 1 patient exhibited grade 3 decreased neutrophil count. 9 patients required dose reductions due to stomatitis, fatigue, mucosal inflammation, dry eye, retinal exudates and blurred vision. 3 patients had their dose interrupted due to stomatitis, mucosal inflammation, bronchitis and musculoskeletal chest pain. Congress Alert

The warnings and precautions section of the FDA approved drug report for Quviviq indicates that it may cause central nervous system depressant effects and daytime wakefulness impairment (somnolence, falls, drowsiness, impaired alertness, driving ability and motor coordination); worsening of depression and suicidal ideation/actions (including completed suicides) in patients with psychiatric disorders, including insomnia; sleep paralysis, hypnagogic/hypnopompic hallucinations, cataplexy-like symptoms (such as leg weakness); complex sleep behaviors (sleepwalking, sleep-driving, and engaging in other activities while not fully awake); and effects on respiratory function in patients with compromised respiratory function. Co-administration with other CNS depressants increases the risk of CNS depression, which can cause daytime impairment. [Data from FDA approved drug report for Quviviq (daridorexant; OX1/2 receptor antagonist)] Regulatory Agency Communication

In preclinical studies, BDTX-1535 (EGFR inhibitor) caused no effects on body weight. [Data from a Black Diamond communication announcing that the FDA has cleared an investigational new drug application for BDTX-1535 for the treatment of glioblastoma and non-small cell lung cancer] Company Communication

Clinical study of SRP-9001 (dystrophin gene therapy) in 41 patients with Duchenne muscular dystrophy. In part 2, the most common treatment-related adverse event was vomiting. [Data from a Sarepta Therapeutics communication announcing topline results from part 2 of the SRP-9001-102 study] Company Communication

In toxicology studies of MGTA-117 (KIT inhibitor), no drug-related effects on hepatic, reproductive, neurologic, cardiovascular or respiratory organs were observed. [Magenta Therapeutics communication announcing recent pipeline progress and milestone expectations for 2022] Company Communication

Phase I study of Anavex 3-71 (M1/sigma1 receptor agonist; 5-200 mg PO qd) in healthy volunteers. No clinically significant changes in ECG parameters were reported, including QTcF interval. [Data from an Anavex Life Sciences communication announcing positive top-line results from a phase I study of Anavex 3-71] Company Communication

The PRAC has recommended updating the product information of olmesartan-containing medicinal products (including fixed-dose combinations) to include autoimmune hepatitis as an adverse reaction with frequency “unknown”. Regulatory Agency Communication

Conclusions from a Periodic Safety Update Report on Pradaxa (dabigatran etexilate; thrombin inhibitor). The PRAC considers that a causal relationship between dabigatran etexilate and anticoagulant-related nephropathy is at least a reasonable possibility. The product information of products containing dabigatran etexilate will be amended accordingly. Regulatory Agency Communication

The Australian Therapeutic Goods Administration (TGA) has updated the product information of medications containing tenofovir alafenamide (reverse transcriptase inhibitor) to include warnings about renal adverse effects such as acute renal failure, proximal renal tubulopathy and Fanconi syndrome. Regulatory Agency Communication

Phase I study of the CORAL samRNA vaccine (GRT-R910; 10 mcg) as a boost after ChAdOx1 COVID-19 vaccination in 10 healthy volunteers. The most common adverse events included injection site tenderness (100%), injection site pain (80%), fatigue (60%), headache, pyrexia (50% each), myalgia and malaise (40% each). Other AEs are listed. [Data from a Gritstone communication presenting data from the CORAL-BOOST Study] Company Communication