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Conclusions from a Periodic Safety Update Report of Tegsedi (inotersen; transthyretin inhibitor). The PRAC considers that a causal relationship between Tegsedi and hypersensitivity is at least a reasonable possibility. The “Undesirable effects” section will be updated to include hypersensitivity with frequency “uncommon”. Regulatory Agency Communication

The FDA has updated the product information of Lemtrada (alemtuzumab; CD52 inhibitor) to include the risk of thrombotic thrombocytopenic purpura in the “Warnings and Precautions” and “Adverse Reactions” sections. Regulatory Agency Communication

A phase II trial of miricorilant (glucocorticoid/mineralocorticoid receptor antagonist; 600 or 900 mg qd) for the treatment of non-alcoholic steatohepatitis was suspended after 4 of the first 5 patients experienced elevations in ALT and AST levels. These changes in liver enzymes resolved after drug discontinuation. [Data from a Corcept Therapeutics communication providing an update from a phase II study of miricorilant] Company Communication

Phase II study of pamiparib (PARP-1/2 inhibitor) in 113 patients with advanced ovarian, fallopian tube or primary peritoneal cancer. The most common adverse events (AEs; ≥10%) were anemia, leukopenia, nausea, neutropenia, vomiting, thrombocytopenia, decreased appetite, fatigue, abdominal pain, increased ALT/AST/GGT, diarrhea, lymphopenia, upper respiratory tract infection, increased blood bilirubin, malaise, decreased weight and dizziness. Grade ≥3 AEs included anemia, neutropenia, leukopenia, thrombocytopenia, lymphopenia, vomiting, diarrhea, increased GGT, hypokalemia, abdominal pain, fatigue, upper respiratory tract infections, pancytopenia and hypertension. Some of these AEs were also observed in a pooled analysis of 3 clinical trials. [Data from a BeiGene communication announcing the NMPA approval of pamiparib for the treatment of advanced ovarian cancer] Company Communication

Phase I and II trials of the SARS-CoV-2 vaccine KCONVAC (5 or 10 mcg) in 560 healthy Chinese patients. The most common injection-site adverse event (AE) and systemic AE were injection-site pain and fatigue, respectively. Abnormal changes in blood chemistry, hematology or urinalysis included urine erythrocyte positive (2 [8%] patients at 5 mcg; 1 [1%] at 10 mcg), ALT increase, lymphocyte count decrease, blood glucose increase (1 [4%] at 5 mcg each) and urine glucose positive (1 [4%] at 10 mcg). Other AEs are listed.

Phase IIa/b study of the NVX-CoV2373 COVID-19 vaccine in 4,387 HIV-negative and HIV-positive adults (38/41 sequenced SARS‑CoV‑2 positives had the B.1.351 variant). The most common local adverse event (AE) after the first dose was injection-site pain (37% HIV-negative participants and 15% HIV-positive participants in the vaccination group vs. 15% and 16% participants in the placebo group). The most common systemic AEs were headache (20-25%), muscle pain (17-20%) and fatigue (12-16%). Unsolicited, medically-attended, treatment-emergent AEs included limb abscess (2 [1.3%]), tonsillitis, contusion, pityriasis rosea and abdominal pain (1 [0.3%] each). Other AEs are listed.

First-in-human phase I study of BAY-1862864 (thorium-227-labeled anti-CD22 antibody) in 21 patients with CD22-positive non-Hodgkin lymphoma. The most common treatment-related adverse events (AEs) were thrombocytopenia (10 patients [48%]; 2 [10%] grade ≥3), neutropenia (5 [24%]; 2 [10%]), fatigue (5 [24%]; 0), leukopenia (3 [14%]; 2 [10%]) and anemia (3 [14%]; 1 [5%]). Other AEs are listed.

Phase III study evaluating the safety and efficacy of avacopan (C5a1 receptor antagonist; 30 mg bid) as an add-on to prednisone and standard-of-care (rituximab or cyclophosphamide followed by azathioprine maintenance) in 331 patients with ANCA-associated vasculitis. 6 serious hepatobiliary disorders were considered related to avacopan, including 1 event of abnormal hepatic function. Serious hypersensitivity reactions to avacopan included angioedema and rash/fever (1 each). Other adverse events are listed. [Data from FDA Briefing Information (avacopan) for the May 6, 2021 Meeting of the Arthritis Advisory Committee] Regulatory Agency Communication

Pooled analysis of 2 phase II studies of avacopan (C5a1 receptor antagonist) added to prednisone and cyclophosphamide or rituximab in patients with ANCA-associated vasculitis. 1 patient in the avacopan group developed life-threatening neutropenia, which was considered related to rituximab. [Data from ChemoCentryx Briefing Information (avacopan) for the May 6, 2021 Meeting of the Arthritis Advisory Committee] Company Communication

Genetic study reporting that some mutations and polymorphisms of the VEGF gene are associated with higher renal allograft rejection. VEGF serum levels were increased in patients harboring these variants. Congress Alert

Conclusions from a Periodic Safety Update Report of quetiapine (D2 receptor antagonist). The CMDh has recommended to include cardiomyopathy, myocarditis and cutaneous vasculitis to the “Undesirable effect” section with a frequency "unknown" based on data from postmarketing spontaneous reports. The PRAC considers that a causal relationship between quetiapine and cardiomyopathy, myocarditis and cutaneous vasculitis is at least a reasonable possibility. The product information will be updated accordingly. Regulatory Agency Communication

First-in-human study of the antibody-drug conjugate MORAb-202 (folate receptor alpha antagonist/tubulin polymerization inhibitor; 0.3-1.2 mg/kg IV q3w) in 22 patients with FR-alpha-positive advanced solid tumors. The most common treatment-related adverse events (TRAEs) were leukopenia, neutropenia (10 patients [45%] each), alanine aminotransferase increase (7 [32%]), anemia and aspartate aminotransferase increase (6 [27%] each). Other TEAEs are listed.

Phase I dose-escalation study of selinexor (exportin-1 inhibitor; 60, 80 and 100 mg qwk) in combination with FLAG-Ida (fludarabine, cytarabine, granulocyte colony-stimulating factor and idarubicin) in 14 adult patients with refractory/relapsed acute myeloid leukemia. The most common non-hematologic adverse events (AEs; ≥50% patients) were febrile neutropenia, nausea/vomiting (8 [57.1%] patients each), diarrhea, mucositis and pulmonary infection (7 [50%] each). The most frequent selinexor-related AEs were diarrhea (5 [35.7%]), nausea/vomiting and mucositis (4 [28.6%] each). Grade 4 neutropenia and thrombocytopenia were also reported. Other AEs are listed.

The special warnings and precautions for use section of the EMA EPAR for Pemazyre indicates that it may cause hyperphosphatemia leading to hypocalcemia, soft tissue mineralization, cutaneous calcification and calcinosis, anemia, secondary hyperparathyroidism, muscle cramps, seizure activity, QT interval prolongation and arrhythmias; grade ≥3 hypophosphatemia and serum phosphate level decrease; serous retinal detachment causing blurred vision; dry eye; embryofetal toxicity and fetal harm; and increased blood creatinine and decreased renal tubular secretion of creatinine due to inhibition of renal transporters OCT2 and MATE1. Concomitant use of Pemazyre and strong CYP3A4 inhibitors requires dose adjustment, and concomitant use with proton pump inhibitors or CYP3A4 inducers is not recommended. [Data from EMA European public assessment report for Pemazyre (pemigatinib; FGFR1-3 inhibitor)] Regulatory Agency Communication

The enrolment in a phase II study of elranatamab (PF-06863135; anti-BCMA/CD3 bispecific antibody) in patients with relapsed/refractory multiple myeloma has been paused after the report of 3 cases of peripheral neuropathy in an ongoing phase I study. Meanwhile, Pfizer will provide additional information to the FDA regarding this safety issue. [Data from a Pfizer communication announcing first quarter 2021 results] Company Communication

Case report of a 30-year-old Caucasian woman who had an allergic reaction to polyethylene glycol after receiving the first dose of the Pfizer COVID-19 vaccine. She exhibited erythematous spots on the face and neck, “slurred mouth” and hoarseness. A basophil activation test with polyethylene glycol showed significant activation of the patient’s basophils.

First-in-human phase I study assessing the drug-drug interaction potential and pharmacokinetics of enerisant (H3 receptor antagonist/inverse agonist; 1-150 mg) in healthy male subjects. Adverse events included increased white blood cell count, insomnia, feeling hot, salivary hypersecretion, night sweats and headache.

The PRAC has recommended updating the product information of Vaxzevria (ChAdOx1-S [recombinant]) to include a warning of splanchnic vein thrombosis (including fatal events). Thrombocytopenia and thrombosis in combination with thrombocytopenia have been included as adverse events with frequency “common” and “very rare”, respectively. Severe venous thrombosis (such as cerebral venous sinus thrombosis, splanchnic vein thrombosis and arterial thrombosis) has also been included. Regulatory Agency Communication

The PRAC has recommended updating the product information of COVID-19 vaccine Janssen (Ad26.COV2-S [recombinant]) to include a warning of thrombocytopenia and coagulation disorders (sometimes accompanied by bleeding) including severe and fatal cases of venous thrombosis at unusual sites such as cerebral venous sinus thrombosis, splanchnic vein thrombosis and arterial thrombosis concomitant with thrombocytopenia. Thrombosis in combination with thrombocytopenia has been included as an adverse event with frequency “very rare”. Regulatory Agency Communication

Preclinical studies assessing the transduction efficiency and safety of intravitreal ADVM-062 (OPN1LW gene therapy; 5E9-5E11 vg) in monkeys. High dose ADVM-062 caused transient ocular inflammation. No retinal abnormalities were observed in a histopathology evaluation. ADVM-062 caused no neurological adverse events. Congress Alert

Results from preclinical studies evaluating the safety of the new antifungal agent amphotericin A21. Rats receiving amphotericin A21 orally at 2 mg/kg exhibited testicular damage accompanied by changes in testosterone levels. These adverse events disappeared 8 weeks after treatment discontinuation. Adverse effects observed in rabbits receiving topical amphotericin A21 at 200 or 1,000 mg/kg included skin thickening and reddening, and changes in liver enzymes, renal parameters and platelet counts.

Phase II study of SRP-5051 (dystrophin interacting agent; 30 mg/kg qm) in patients with Duchenne muscular dystrophy. 2 patients experienced serious treatment-related adverse events including grade 4 hypomagnesemia (2 patients) and grade 3 hypokalemia (1). [Data from a Sarepta Therapeutics communication reporting updated results from the 30 mg/kg cohort of the MOMENTUM study] Company Communication

The FDA has updated the product information of Ferriprox (deferiprone; iron sequestrant), adding novel safety data from a study comparing Ferriprox and deferoxamine for the treatment of sickle cell disease or other anemias. Adverse events are listed. Regulatory Agency Communication

Health Canada has issued a safety review evaluating the potential association between Janssen COVID-19 vaccine and the risk of thrombosis with thrombocytopenia. 8 cases of thrombosis with thrombocytopenia have been reported in the US, including a fatal outcome. The agency concluded that a causal association between Janssen COVID-19 vaccine and the risk of thrombosis with thrombocytopenia is possible. The product information will be updated accordingly. Regulatory Agency Communication

New Zealand’s Medsafe has issued a safety review on adverse events (AEs) following immunization with Pfizer-BioNTech COVID-19 vaccine. The most common AEs reported to the Centre for Adverse Reactions Monitoring (CARM) were headache (175 reports), dizziness (169), nausea (128), injection-site pain (91), fever (52), flu-like illness, muscle pain (39 each), syncope (37), musculoskeletal pain (34) and lethargy (29). 7 serious AEs have been recently reported to the CARM, which included allergic reactions (6) and chest discomfort with increased heart rate (1). Other AEs are listed. Regulatory Agency Communication

Acella Pharmaceuticals is voluntarily recalling various lots of NP Thyroid (levothyroxine/liothyronine) due to sub potency. This may be related to 43 reports of serious adverse events received by the company. Patients treated with sub potent NP Thyroid for hypothyroidism may experience signs and symptoms of hypothyroidism such as fatigue, increased sensitivity to cold, constipation, dry skin, puffy face, hair loss, slow heart rate, depression, swelling of the thyroid gland and weight gain or difficulty losing weight. Newborn infants and pregnant women with hypothyroidism have a reasonable risk of serious injury, including early miscarriage, fetal hyperthyroidism and impairments to fetal neural and skeletal development. Elderly patients and patients with underlying cardiac disease may develop cardiac manifestations such as cardiac pain, palpitations and cardiac arrhythmia. Regulatory Agency Communication

The special warnings and precautions for use section of the EMA EPAR for Jemperli indicates that it may cause immune-related adverse reactions (which may be severe or fatal) including endocrinopathies such as hypothyroidism, hyperthyroidism, thyroiditis, hypophysitis, type 1 diabetes mellitus and adrenal insufficiency; pneumonitis; colitis; hepatitis; nephritis; rash including pemphigoid; arthralgia; and severe or life-threatening infusion-related reactions. Serious or fatal transplant-related complications have been reported with PD-1/PD-L1 inhibitors including hyperacute graft-versus-host disease (GvHD), acute GvHD, chronic GvHD, hepatic veno-occlusive disease and febrile syndrome. Other immune-related adverse events associated with PD-1 and/or PD-L1 inhibitors are listed. [Data from EMA European public assessment report for Jemperli (dostarlimab; PD-1 inhibitor)] Regulatory Agency Communication

Pooled analysis of 2 phase III studies of tirbanibulin (Src/tubulin polymerization inhibitor; 1% ointment) in 705 patients with actinic keratosis. The most common treatment-related adverse events were application-site pain (35/353 patients [10%] with tirbanibulin vs 11/349 [3%] with vehicle) and pruritus (32 [9%] vs 21 [6%]). Local skin reactions included erythema and flaking/scaling. Congress Alert

Phase III trial of dasiglucagon (glucagon receptor agonist; 0.6 mg) for the treatment of severe hypoglycemia in 170 patients with diabetes. The most common adverse events (≥2% patients) were nausea, vomiting, headache, diarrhea and injection site pain. [Data from a Zealand Pharma communication summarizing published results from a phase III study of dasiglucagon] Company Communication

Phase II study of SRP-5051 (dystrophin interacting agent; 30 mg/kg qm) in patients with Duchenne muscular dystrophy. 2 serious events of hypomagnesemia were reported. [Data from a Sarepta Therapeutics communication reporting positive results from a phase II study of SRP-5051] Company Communication

Secondary analysis of a phase IV study comparing the incidence of neuropsychiatric adverse events (NPSAEs) of varenicline (nicotinic receptor alpha4beta2 agonist; 1 mg bid), bupropion (DAT/NET inhibitor; 150 mg bid) and nicotine patch (nicotinic receptor agonist; 21 mg qd) to matched placebos in smokers with or without psychiatric disorders. Bayes factors provided moderate-to-very-strong evidence that the use of varenicline, bupropion or nicotine patch for smoking cessation does not increase the risk of NPSAEs compared to placebo. The most common AE in each treatment group was nausea (varenicline [25%]), insomnia (bupropion [12%]) and abnormal dreams (nicotine patch [12%]).

Phase III trial of bardoxolone methyl (Nrf2 activator and NF-kappaB/STAT3 inhibitor) in 157 patients with chronic kidney disease due to Alport syndrome. Adverse events occurring more frequently than with placebo included muscle spasms and increased aminotransferase levels. [Data from a Reata Pharmaceuticals communication announcing that the FDA has accepted the NDA filing for bardoxolone methyl] Company Communication

Conclusions from a Periodic Safety Update Report of mifepristone (glucocorticoid receptor/progesterone receptor antagonist). The PRAC considers that a causal relationship between mifepristone and acute generalized exanthematous pustulosis is at least a reasonable possibility. The “Special warnings and precautions for use” and the “Undesirable effects” sections will be updated to include acute generalized exanthematous pustulosis with frequency “unknown”. Regulatory Agency Communication

Conclusions from a Periodic Safety Update Report of fosphenytoin (sodium channel blocker). The PRAC considers that a warning should be added about the increased risk of severe cutaneous adverse reactions in carriers of the CYP2C9*3 allele and about the increased risk of toxicities in intermediate or poor metabolizers of CYP2C9 substrates. The Lead Member State considers that a causal relationship between fosphenytoin and urticaria is at least a reasonable possibility, and has recommended it be included in the “Undesirable effects” section with frequency “not known”. Regulatory Agency Communication

Conclusions from a Periodic Safety Update Report of Dacogen (decitabine; Dnmt1 inhibitor). The PRAC considers that a causal relationship between Dacogen and differentiation syndrome is at least a reasonable possibility. The product information will be amended accordingly. Regulatory Agency Communication

Conclusions from a Periodic Safety Update Report of cisatracurium (muscle-type nicotinic receptor antagonist). The PRAC considers that a causal relationship between cisatracurium and anaphylactic shock has been established. The “Undesirable effects” section will be updated to include anaphylactic shock with frequency “very rare”. Regulatory Agency Communication

Phase II clinical trial of Korsuva (difelikefalin; opioid kappa receptor agonist; 0.25-1 mg bid) in 401 patients with atopic dermatitis and pruritus. The most common treatment-emergent adverse events (>5% and higher than with placebo) were abdominal pain, nausea, dry mouth, headache, dizziness and hypertension. [Data from a Cara Therapeutics communication announcing that the KARE trial did not meet its primary efficacy endpoint] Company Communication

The FDA has updated the product information of Naprosyn (naproxen; COX-1/2 inhibitor) to include warnings about drug reaction with eosinophilia and systemic symptoms, premature closure of fetal ductus arteriosus, oligohydramnios (which may lead to limb contractures and delayed lung maturation), fetal renal dysfunction and neonatal renal impairment, which are class effects of NSAIDs. Regulatory Agency Communication

UniQure communication announcing that the FDA have removed the clinical hold on their hemophilia B gene therapy program (etranacogene dezaparvovec; coagulation factor IX gene therapy) after determining that the drug is very unlikely to have contributed to the development of hepatocellular carcinoma in the patient enrolled in the HOPE-B pivotal trial. Company Communication

The EMA has updated the product information of Thalidomide Celgene (thalidomide; VEGF/cereblon inhibitor) to include a warning about progressive multifocal leukoencephalopathy (including fatal cases). Regulatory Agency Communication

Conclusions from a Periodic Safety Update Report of Ozempic (semaglutide; GLP-1 receptor agonist). The PRAC considers that a causal relationship between SC semaglutide and angioedema is at least a reasonable possibility. The “Undesirable effects” section will be updated to include angioedema with frequency “not known”. Regulatory Agency Communication

Conclusions from a Periodic Safety Update Report of Repatha (evolocumab; PCSK9 inhibitor). The PRAC considers that a causal relationship between evolocumab and headache is at least a reasonable possibility. The “Undesirable effects” section will be updated to include headache with frequency “common”. Regulatory Agency Communication

Conclusions from a Periodic Safety Update Report of Blincyto (blinatumomab; CD19/CD3 interacting agent). The PRAC considers that a causal relationship between blinatumomab and CD19 negativity of Ph negative acute lymphatic leukemia in relapsed patients has been established, and that a causal relationship for the switch from acute lymphatic leukemia to acute myeloid leukemia in relapsed patients is at least a reasonable possibility. The product information will be updated. Regulatory Agency Communication

The Australian Therapeutic Goods Administration (TGA) has issued a safety communication about the adverse effects that may occur after accidental overdose with clonidine (alpha2-adrenoceptor agonist). To date, the TGA Database of Adverse Event Notifications has received 43 adverse drug reaction reports related to overdose, incorrect dose or off-label clozapine use in children. Common adverse events observed in these patients included slow heart rate, low blood pressure and decreased level of consciousness. Other symptoms that may appear after clonidine poisoning are listed. Regulatory Agency Communication

Single-dose escalation study of IL12FHAB (albumin ligand/interleukin-12 receptor agonist; 250, 125 and 62.5 mcg/kg) in cynomolgus macaques. Transient leukocytopenia and neutropenia were reported. At day 7, elevated AST was also observed. Congress Alert

First-in-human clinical study assessing the long-term safety and efficacy of GC027 (CD7-targeted CAR T-cell therapy; 6x10e6, 1x10e7 or 1.5x10e7 cells/kg) in 6 patients with relapsed/refractory T-cell acute lymphoblastic leukemia. Hematological treatment-emergent adverse events (TEAEs) were grade 3 febrile neutropenia (6 patients), grade 4 neutropenia, grade 4 thrombocytopenia (4 each) and grade 3 anemia (3). Non-hematological TEAEs were hypoalbuminemia (6), AST increase (4), ALT increase and grade 3 pulmonary infection (3 each). All patients developed grade ≥3 cytokine release syndrome. Congress Alert

Preclinical characterization of LNS8801 (GPER agonist). Dogs receiving high doses of LNS8801 died from bone marrow hypocellularity and subsequent lymphoid depletion. Congress Alert

Study investigating the role of cardiac endothelium in the development of cancer treatment-induced cardiotoxicity using an orthotopic mouse model of breast cancer treated with doxorubicin/trastuzumab (5/4 mg/kg qwk). After 4 months of treatment, findings included decreased heart mass, decreased thickness of the interventricular septum, modest cardiac deformation, worsening of diastolic function, increased biomarkers of fibrosis and increased serum levels of cardiac troponin I and brain natriuretic peptide. Other findings included increased vascular permeability and impaired cardiac endothelial cell viability and function.

Prospective observational study evaluating the safety and efficacy of the Pfizer-BioNTech and Oxford-AstraZeneca COVID-19 vaccines in the UK. Common side effects of the Pfizer-BioNTech vaccine included injection-site tenderness (57.2% subjects after the first dose; 50.9% after the second dose), injection-site pain (29.2%; 34.3%), fatigue (8.4%; 14.4%) and headache (7.8%; 13.2%). Side effects observed with the Oxford-AstraZeneca vaccine included injection-site tenderness (49.3%), headache (22.8%), fatigue (21.1%), injection-site pain (19.1%) and chills (14.7%). Other safety issues are listed.