The translational safety intelligence portal

First case reports of bilateral acute angle closure secondary to the use of oral benzodiazepines (clonazepam [0.25 mg] and alprazolam [0.5 mg]).

First-in-human phase I/Ib study of ABTL0812 (PPARalpha/gamma agonist) in 29 patients with advanced solid malignancies. The most common grade 1-2 treatment-related adverse events (TRAEs) reported in cycle 1 were nausea (7 patients [24%]), asthenia (6 [21%]), oropharyngeal discomfort, vomiting (5 each [17%]) and diarrhea (4 [14%]). Grade 3-4 TRAEs included diarrhea, pharyngeal inflammation, maculopapular rash, bronchitis, peripheral edema and hepatotoxicity (1 each [3%]). Other AEs observed in cycle 1 or the expansion cohort are listed.

First case report of a 56-year-old woman positive for SARS-CoV-2 who developed anaphylaxis due to remdesivir (RNA polymerase [viral] inhibitor; 200 mg).

Pooled analysis of 4 clinical trials of ChAdOx1 nCoV-19 (SARS-CoV-2 proteins-directed immunity inducer). The most common serious adverse events (AEs) were infections and infestations (23/12,282 [0.2%] patients in the treatment group vs. 41/11,962 [0.3%] in the control group) including appendicitis (6 [<0.1%] vs. 7 [0.1%]) and diverticulitis (3 [<0.1%] vs. 0). Grade 3/4 AEs included myalgia (27 [0.2%] grade 3 cases in the treatment group; 4 [<0.1%] grade 4 cases vs. 12 [0.1%] grade 3 cases in the control group; 1 [<0.1%] grade 4 case), pyrexia (37 [0.3%]; 2 [<0.1%] vs. 7 [0.1%]) fatigue (18 [0.1%] vs. 4 [<0.1%]; 2 [<0.1%]), vaccination-site pain (15 [0.1%]; 6 [<0.1%] vs. 12 [0.1%]; 2 [<0.1%]) and chills (12 [0.1%]; 1 [<0.1%] vs. 1 [<0.1%]; 1 [<0.1%]). Other AEs are listed.

In a phase II trial of TD-0903, an investigational nebulized lung-selective pan-JAK inhibitor for COVID-19, 1 patient in the 10 mg dose cohort discontinued therapy due to an isolated increase in liver alanine aminotransferase. [Data from a Theravance Biopharma communication reporting fourth quarter and full year 2020 financial results and providing business update] Company Communication

The FDA has updated the product information of Risperdal (risperidone; D2 receptor antagonist), adding catatonia as an adverse reaction reported postmarketing. Extrapyramidal symptoms such as dystonia and dyskinesia have been reported in patients taking Risperdal concomitantly with methylphenidate. Regulatory Agency Communication

The FDA has updated the product information of Libtayo (cemiplimab-rwlc; PD-1 inhibitor), adding the risk of nausea, pyrexia, rash and dyspnea to the “Warnings and Precautions” section for infusion-related reactions. The “Adverse Reactions” section has also been updated to include novel safety data from a phase III study comparing Libtayo to chemotherapy in patients with non-small cell lung cancer. Regulatory Agency Communication

The FDA has updated the product information of Invega (paliperidone; 5-HT2A/D2 receptor antagonist), adding the risk of sedation and dizziness to the “Warnings and Precautions” section. Catatonia and thrombotic thrombocytopenic purpura have also been included as adverse reactions reported postmarketing. Regulatory Agency Communication

First-in-human studies of LTI-291 (glucosylceramidase activator; 3-90 mg) in 80 healthy volunteers. The most common adverse events (AEs) considered possibly related to LTI-291 were headache (28.6% at 3 mg; 25% at 10 mg; 62.4% at 30 mg; 27.5% at 60 mg), myalgia (14.3% at 3 mg; 12.5% at 30 mg; 37.5% at 60 mg; 12.5% with placebo) and somnolence (14.3% at 3 mg; 50% at 60 mg; 12.5% with placebo). Other AEs are listed.

Swissmedic has issued a safety communication about the risk of delayed local reactions to COVID-19 vaccines. Swissmedic has received several reports of injection-site reactions (including redness, swelling, pain and itching) appearing around one week after vaccination. These local reactions were also observed during clinical studies. Most of the reports involved the Moderna COVID-19 vaccine. Regulatory Agency Communication

Phase Ib study of MET409 (farnesoid X receptor agonist; 50 or 80 mg qd) in 145 patients with nonalcoholic steatohepatitis. Treatment-related adverse events were generalized pruritus (3 patients [16%] with 50 mg; 8 [40%] with 80 mg; 0 with placebo), decreased appetite (4 [21%]; 2 [10%]; 1 [5%]), headache (3 [16%]; 1 [5%]; 0) and diarrhea (2 [11%]; 2 [10%]; 1 [5%]).

Study of the monoclonal antibody c4G12 (PD-L1 inhibitor; 5 mg/kg q2w) in 29 dogs with pulmonary metastatic oral malignant melanoma. The most common treatment-related adverse events (TRAEs) were ALT increase (8 [27.6%] dogs; 1 [3.4%] grade 3), vomiting (4 [13.8%]), AST and lipase increase (each 3 [10.8%]; 1 [3.4%]) and diarrhea (3 [10.8%]). 1 dog discontinued due to grade 3 pneumonitis. Other TRAEs are listed.

Phase III study comparing andecaliximab (ADX; 800 mg) plus FOLFOX6 (leucovorin calcium, fluorouracil and oxaliplatin) to FOLFOX6 alone in patients with gastric or gastroesophageal junction adenocarcinoma. The most common treatment-emergent adverse events (TEAEs) were decreased absolute neutrophil count (151/216 [70%] patients in ADX+FOLFOX6 group vs. 142/210 [68%] in FOLFOX6 group), decreased white blood cells (147 [68%] vs. 138 [66%]) and decreased platelet count (132 [61%] vs. 117 [56%]). Common grade ≥3 TEAEs included decreased absolute neutrophil count (65 [30%] vs. 61 [29%]), neutropenia (48[22%] vs. 56 [27%]), decreased white blood cells (28 [13%] vs. 25 [12%]), decreased lymphocyte count (23 [11%] vs. 26 [12%]) and anemia (18 [8%] vs. 23 [11%]). Other TEAEs are listed.

The special warnings and precautions for use section of the EMA EPAR for Tukysa indicates that it may cause elevations in ALT/AST, bilirubin and creatinine levels; and diarrhea (including severe events such as dehydration, hypotension, acute kidney injury and death). Tukysa may interact with CYP3A and P-gp substrates, with strong CYP3A or moderate CYP2C8 inducers, and with strong/moderate CYP2C8 inhibitors. Based on findings from animal studies (fetal abnormalities in pregnant rats) and its mechanism of action, tucatinib may cause embryo-fetal toxicity (including harmful effects to the fetus). [Data from EMA European public assessment report for Tukysa (tucatinib; HER2 inhibitor)] Regulatory Agency Communication

Preclinical study evaluating the toxicity and toxicokinetics of LPM4870108 (TRK inhibitor; 5-20 mg/kg/day) in healthy monkeys. All monkeys exhibited dose-dependent adverse events of gait disturbance, impaired balance, poor coordination and decreased grip strength, all of which resolved after the 4-week recovery period. These events were attributed to excessive on-target toxicity. No alterations in body weight, ophthalmoscopy or urinalysis were observed.

Retrospective pharmacovigilance study evaluating the risk of cardiac adverse events associated with COVID-19 therapies using data from the FAERS database. Antiviral agents significantly associated with an increased risk of cardiac disorders were moxifloxacin (ROR = 2.23 [95% CI: 2.08-2.39]), combined piperacetazine/tazobactam (2.06 [1.72-2.47]), ceftriaxone (1.92 [1.80-2.05]), chloroquine/hydroxychloroquine (1.68 [1.66-1.70]), chloroquine/hydroxychloroquine plus azithromycin (1.60 [1.46-1.77]), combined lopinavir/ritonavir (1.52 [1.39-1.66]) and azithromycin (1.37 [1.30-1.44]). Other safety issues are listed.

The warnings and precautions section of the AEMPS Summary of Product Characteristics for ARI-0001 indicates that it may cause graft-versus-host disease; infusion-related reactions; tumor lysis syndrome in patients with hematologic malignancies; grade ≥3 cytokine release syndrome; neurologic effects (including 1 case of immune effector cell-associated neurotoxicity syndrome possibly related to ARI-0001); B-cell lymphocyte aplasia; secondary malignancies; hepatitis B reactivation; infections and febrile neutropenia; serious cytopenias (including neutropenia, lymphopenia, anemia and thrombocytopenia); and laboratory test interferences (including false positive HIV test). Other warnings and precautions of ARI-0001 are listed. [Data from AEMPS Summary of Product Characteristics for ARI-0001 (CD19-targeted CAR T-cell therapy)] Regulatory Agency Communication

Phase IIb study of telazorlimab (OX40 antagonist; 75 mg q4w, 300 mg q2w/q4w or 600 mg q2w) in patients with moderate-to-severe atopic dermatitis. Common adverse events (>5% patients) included nasopharyngitis, upper respiratory tract infection and headache. [Data from an Ichnos corporate update, February 2021] Company Communication

Phase I clinical trial evaluating the safety and pharmacokinetics of treprostinil palmitil (DP1/EP2/IP receptor agonist; 112.5-675 mcg) in healthy volunteers. Prostanoid-related adverse events (AEs) observed in the single-ascending dose part included dizziness (7/26 subjects [26.9%]), nausea, hypotension (4 each [15.4%]), headache (2 [7.7%]) and vomiting (1 [3.8%]). In the multiple-ascending dose part, prostanoid-related AEs were headache (6/15 [37.5%]), nausea (4 [25%]), dizziness (3 [18.8%]), syncope, diarrhea and abdominal pain (1 each [6.3%]). Other AEs are listed. [Data from an Insmed presentation summarizing results from a phase I study of treprostinil palmitil] Company Communication

Phase I/IIa study of lenadogene nolparvovec (rAAV2/2-ND4; NADH-ubiquinone oxidoreductase chain 4 gene therapy) in 15 patients with Leber hereditary optic neuropathy. The most common ocular treatment-emergent adverse events (AEs) considered related to lenadogene nolparvovec were intraocular inflammation, increased intraocular pressure and ocular hypertension. Severe AEs were septic shock, non-cardiac chest pain, pneumonia, radius fracture, fall, anterior chamber inflammation, vitritis, uveitis flare and vitreous haze. Neutralizing anti-drug antibodies were also observed.

Phase I first-in-human study of TAS4464 (NEDD8-activating enzyme E1 inhibitor; 10-56 mg/m2 qwk) in 17 patients with advanced solid tumors. The most common treatment-related adverse events (TRAEs) were ALT increase (11 [68.8%] patients; 5 [31.3%] grade ≥3), AST increase (10 [62.5%]; 5 [31.3%]), ALP increase (7 [43.8%]; 1 [6.3%]), nausea (7 [43.8%]) and decreased appetite (5 [31.3%]). Dose-limiting toxicities were grade 4 ALT increase and grade 3 ALT and AST increase (1 patient at 56 mg/m2 each). Other TRAEs are listed.

Results from 3 phase I studies of BI 1265162 (ENaC blocker) in healthy volunteers. In the single-rising-dose trial, drug-related adverse events (DRAEs) included cough and dry eye (1/57 patient [16.7%] each). In the multiple-rising-dose trial, DRAEs included oropharyngeal pain (3/40 [7.5%]) and diarrhea, dyspepsia, dizziness and cough (2 [5%] each).

Article on repurposed plitidepsin (elongation factor 1-alpha 2 inhibitor) for the treatment of COVID-19. Mice administered plitidepsin (0.3 mg/kg qd for 2 days, or 1 mg/kg once) exhibited body weight loss.

The NMPA has decided to update the product information of oral and cream preparations of methimazole (thyroid peroxidase inhibitor). Events listed in the "adverse reaction" and "precautions" sections are listed. Regulatory Agency Communication

First-in-human phase I/IIa study of dalcinonacog alfa (coagulation factor IX analog; 75 and/or 150 IU/kg) in 11 male patients with hemophilia B. Systemic adverse events (AEs) related to dalcinonacog alfa were fatigue/malaise, headache and dizziness (1/16 [6.3%] patient each). Injection-site reactions included pain (12 [75%]), erythema (8 [50%]), papules (4 [25%]), pruritus (2 [12.5%]) and discomfort (1 [6.3%]). 6 patients were positive for anti-dalcinonacog alfa antibodies, 2 of whom developed neutralizing antibodies. Other AEs are listed.

Phase I study of combined avelumab (PD-L1 inhibitor; 10 mg/kg q2w) and cabozantinib (AXL/MET/VEGFR-2 inhibitor; 20-60 mg qd) in 12 patients with newly diagnosed metastatic clear cell renal cell carcinoma. 6 (50%) patients developed immune-related adverse events (irAE) including hypothyroidism, colitis, nephritis, allergic rhinitis and rash. 6 patients required cabozantinib dose reductions, mainly due to oral mucositis and hand-foot syndrome. 1 serious AE of thromboembolism was reported, deemed related to study treatment. 1 patient discontinued avelumab due to immune-related nephritis. Congress Alert

The FDA has updated the product information of Clozaril (clozapine; 5-HT2A/D2 receptor antagonist) to include restless leg syndrome, myocarditis and polyserositis as adverse reactions reported postmarketing. Regulatory Agency Communication

The UK MHRA has issued safety advice on the link between Alkindi (hydrocortisone granules; glucocorticoid receptor modulator) and the risk of acute adrenal insufficiency. A case of severe adrenal insufficiency has been reported in a child switching from hydrocortisone tablets to granules. Regulatory Agency Communication

The UK MHRA has issued safety advice on the link between Lyrica (pregabalin; voltage-dependent calcium channel subunit alpha-2/delta-1 ligand) and the risk of severe respiratory depression. A European review identified several cases of respiratory depression in patients receiving pregabalin, with or without concomitant opioids. A warning for respiratory depression will be included in the product information of Lyrica. Regulatory Agency Communication

Kyowa Kirin communication announcing positive results from a phase II study of KHK4083 (OX40 antagonist) in 274 patients with moderate to severe atopic dermatitis. Common treatment-emergent adverse events reported in KHK4083 cohorts included pyrexia, nasopharyngitis and chills. Company Communication

Case report of a 64-year-old woman with rheumatoid arthritis who developed immunodeficiency-associated lymphoproliferative disorders associated with methotrexate (DHFR inhibitor). She switched to tocilizumab (interleukin-6 receptor, alpha subunit antagonist) but suffered multiple organ failure as a result of streptococcus pyogenes infection-induced fatal toxic shock syndrome complicated with necrotizing fasciitis.

In 2 phase I studies of HPP737 (PDE4 inhibitor), few or no gastrointestinal adverse events (such as nausea, vomiting or diarrhea) were reported. [Data from a vTv Therapeutics communication announcing the initiation of a phase I multiple ascending dose study of HPP737 in healthy adult volunteers] Company Communication

Lilly communication announcing that two of its clinical trials, SURPASS-3 and SURPASS-5, have met their primary and all key secondary endpoints. In SURPASS-3, a 52-week phase III study comparing tirzepatide (GIP/GLP-1 receptor agonist; 5, 10 and 15 mg) to insulin degludec in adults with inadequately-controlled type 2 diabetes, the most common adverse events (AEs) in the tirzepatide arms were gastrointestinal-related. AEs more frequent with tirzepatide than with insulin degludec were nausea (11.5% with 5 mg; 22.5% with 10 mg; 23.7% with 15 mg vs 1.7% with insulin degludec), diarrhea (15.4%; 16.7%; 15.6% vs 3.9%) and vomiting (5.9%; 9.4%; 10% vs 1.1%). Company Communication

Swissmedic has issued a Direct Healthcare Professional Communication on the risk of cardiac valve regurgitation and insufficiency associated with systemic and inhaled fluoroquinolones (DNA gyrase/topoisomerase 4 inhibitors; including ciprofloxacin, delafloxacin, levofloxacin, moxifloxacin, norfloxacin and ofloxacin). A recent study revealed that the risk of mitral/aortic valve regurgitation was 2-fold higher in patients receiving fluoroquinolones than in those taking other antibiotics (amoxicillin or azithromycin). In some cases, a causal association between fluoroquinolones and cardiac valve regurgitation/insufficiency has been suggested. An in vitro study with ciprofloxacin suggested that collagen degradation may be involved in the risk of valvular regurgitation/insufficiency. The product information of fluoroquinolones will be updated accordingly. Regulatory Agency Communication

The "precautions regarding persons with a specific background" section of the PMDA package insert for Comirnaty indicates that it may cause bleeding and bruising in subjects receiving anticoagulant therapy, or in those with thrombocytopenia or coagulopathy at baseline; and reduced immune response to vaccination in patients diagnosed with immunodeficiency. [Data from PMDA package insert for Comirnaty (COVID-19 mRNA vaccine; SARS-CoV-2 proteins-directed immunity inducer)] Regulatory Agency Communication

Bluebird bio has temporarily suspended marketing of Zynteglo (hemoglobin subunit beta gene therapy) after reporting a case of cancer (acute myeloid leukemia) in a clinical trial of bb1111, a product using the same lentiviral vector. Acute myeloid leukemia was considered possibly related to treatment. Another patient in the same clinical trial developed myelodysplastic syndrome. No cases of cancer have yet been reported with Zynteglo. Regulatory Agency Communication

Phase III study comparing osimertinib and gefitinib (EGFR inhibitors; 80 and 250 mg qd, respectively) in 136 Chinese patients with EGFR-mutated advanced non-small cell lung cancer. The most common adverse events (AEs) considered possibly treatment-related were white blood cell count decrease (24 [33.8%] patients with osimertinib; grade ≥3 in 3 [4.2%] vs. 4 [6.2%] with gefitinib), platelet count decrease (18 [25.4%]; 2 [2.8%] vs. 1 [1.5%]) and anemia (12 [16.9%] vs. 5 [7.7%]). QT prolongation occurred in 6 patients in the osimertinib group (4 [5.6%] grade 1/2; 2 [2.8%] grade 3), and 3 in the gefitinib group (3 [4.6%]). Fatal AEs considered treatment-related were cardiac tamponade and upper gastrointestinal hemorrhage (1 each) in the osimertinib group and interstitial lung disease (1) in the gefitinib group. Other AEs are listed.

Swissmedic has issued a Direct Healthcare Professional Communication on the risk of drug-induced liver injury associated with metamizole (COX-1/2 inhibitor). Some cases led to acute liver failure requiring transplantation. Metamizole-induced liver injury mainly showed a hepatocellular pattern and may be accompanied by other hypersensitivity reactions such as rash blood dyscrasias, fever or eosinophilia. Some patients receiving metamizole exhibited signs of autoimmune hepatitis. The product information of metamizole will be updated to include warnings on the risk of drug-induced liver injury. Regulatory Agency Communication

Disproportionality analysis using the FAERS database assessing the association between diabetic retinopathy and GLP-1 receptor agonists. Dulaglutide, exenatide, liraglutide and semaglutide showed signals for diabetic retinopathy events.

Phase I/IIa study of RGX-314 (VEGF inhibitor; 3E9-2.5E11 GC/eye) in 42 patients with severe wet age-related macular degeneration. The most common ocular adverse reactions were post-operative conjunctival hemorrhage (69% patients), retinal pigmentary changes mainly in the peripheral inferior retina (67%), post-operative inflammation (36%), eye irritation, eye pain and post-operative visual acuity reduction (17% each). 1 patient suffered serious decrease in vision considered possibly related to RGX-314. [Data from a Regenxbio communication announcing additional positive interim data of RGX-314] Company Communication

The NPRA has reviewed safety post-authorization data of the COVID-19 vaccine Cominarty. Severe allergic reactions to Cominarty (such as anaphylaxis and anaphylactoid reactions) have been reported in UK (130 cases) and USA (50). 23 elderly Norwegian individuals have died after receiving Cominarty, but a causal association with vaccination could not be confirmed. An initial report by the Norwegian Medicines Agency suggested that adverse reactions to Cominarty (such as fever or nausea) may have contributed to a more serious course in those elderly people. Other common reactions are listed. Regulatory Agency Communication

Bluebird bio communication announcing the temporary suspension of its phase I/II and phase III trials of bb1111 (LentiGlobin gene therapy for sickle cell disease) due to a suspected unexpected serious adverse reaction (SUSAR) of acute myeloid leukemia reported in a patient participating in the phase I/II trial. A second SUSAR of myelodysplastic syndrome was reported last week in another patient participating in the same trial. Company Communication

The FDA has put a partial clinical hold on atuzaginstat (gingipain inhibitor) after reporting reversible hepatic adverse events in a phase II/III trial. [Data from a Cortexyme communication providing regulatory updates on the clinical development of atuzaginstat] Company Communication

Phase III clinical study of lenvatinib (L; 18 or 20 mg qd) in combination with pembrolizumab (P; 200 mg q3w) or everolimus (E; 5 mg qd) compared to sunitinib (50 mg qd) in 1,069 patients with advanced renal cell carcinoma. The most common treatment-related adverse events (TRAEs) were diarrhea (192/352 patients [54.5%]; 29 [8.2%] grade ≥3 with L+P vs 212/355 [59.7%]; 34 [9.6%] with L+E vs 151/340 [44.4%]; 15 [4.4%] with sunitinib), hypertension (184 [52.3%]; 89 [25.3%] vs 153 [43.1%]; 74 [20.8%] vs 133 [39.1%]; 61 [17.9%]), hypothyroidism (150 [42.6%]; 4 [1.1%] vs 87 [24.5%]; 1 [0.3%] vs 79 [23.2%]) and decreased appetite (123 [34.9%]; 12 [3.4%] vs 124 [34.9%]; 18 [5.1%] vs 84 [24.7%]; 5 [1.5%]). Grade 5 TRAEs were acute renal failure, uncontrolled hypertension, myasthenic syndrome and autoimmune hepatitis (1 each) with L+P; pneumonia, urosepsis and colon perforation (1 each) with L+E; and unspecified death (1 patient) with sunitinib. Other TRAEs and AEs are listed.

The special warnings and precautions for use section of the EMA EPAR for Rukobia indicates that it may cause serious immune reconstitution inflammatory syndrome (including inflammatory reactions to asymptomatic or residual opportunistic infections and autoimmune disorders); QTc prolongation at supratherapeutic doses; serious hepatic adverse reactions in patients with chronic hepatitis B or C receiving combination antiretroviral therapy; and osteonecrosis. Coadministration of fostemsavir and elbasvir/grazoprevir may increase grazoprevir concentration resulting in ALT elevations. Other drug interactions and adverse reactions are listed, including those of other therapies. [Data from EMA European public assessment report for Rukobia (fostemsavir; envelope glycoprotein gp160 inhibitor)] Regulatory Agency Communication

Analysis of 2 phase III trials of tirbanibulin (Src inhibitor/tubulin polymerization inhibitor; 1% ointment) in 702 patients with actinic keratoses. The most common local reactions to tirbanibulin were erythema (91% patients) and flaking (82%). Other local skin reactions included crusting, swelling, vesiculation, pustulation, erosions and ulceration. Other adverse events are listed.

The warnings and precautions section of the FDA approved drug report for Cosela indicates that it may cause injection-site reactions (including phlebitis and thrombophlebitis); acute drug hypersensitivity reactions (including facial edema and urticaria); severe interstitial lung disease/pneumonitis; and embryo-fetal toxicity (including fetal harm) when administered to pregnant women, based on its mechanism of action. Other warnings and precautions of Cosela are listed. [Data from FDA approved drug report for Cosela (trilaciclib; CDK4/6 inhibitor)] Regulatory Agency Communication

The most common adverse reactions to Evkeeza (≥5%) are nasopharyngitis, influenza-like illness, dizziness, rhinorrhea and nausea. [Data from FDA approved drug report for Evkeeza (evinacumab-dgnb; angiopoietin like 3 inhibitor)] Regulatory Agency Communication

The EMA has started a review on amfepramone (DAT/NET inhibitor) following recent PRAC findings involving heart problems and high blood pressure in the lungs. Regulatory Agency Communication

Phase I clinical trial of NNZ-2591 in healthy volunteers. The most common adverse event was drowsiness. 1 subject discontinued treatment due to drowsiness and incoordination. [Data from a Neuren communication announcing positive results from a phase I study of NNZ-2591] Company Communication