The translational safety intelligence portal

The warnings and precautions section of the FDA approved drug report for Cabenuva indicates that rilpivirine may cause hypersensitivity reactions including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).; serious post-injection reactions (including dyspnea, agitation and flushing). Hepatotoxicity has been reported in patients receiving cabotegravir or rilpivirine. Depressive disorders (including depressed mood, depression, major depression, mood altered, mood swings, dysphoria, negative thoughts, suicidal ideation or attempt) have been reported with Cabenuva or the individual drug products. Other adverse reactions of Cabenuva and its components are listed. [Data from FDA approved drug report for Cabenuva (cabotegravir/rilpivirine)] Regulatory Agency Communication

Study reporting that tamoxifen may be associated with an increased risk of Parkinson's disease (6.2/1,000 patients with tamoxifen use vs 3.6/1,000 patients without tamoxifen use).

Phase I/Ib study evaluating the safety and tolerability of AB680 (25, 50, 75 or 100 mg) in combination with chemotherapy (nab-paclitaxel/gemcitabine) and zimberelimab in patients with treatment-naive metastatic pancreatic adenocarcinoma. The most common treatment-related adverse-events (TRAEs) were fatigue (6 [43%] patients), anemia and neutrophil count decrease (4 [29%] each). The most common grade 3/4 TRAE was anemia (2 [14%]). 1 dose-limiting toxicity of grade 2 autoimmune hepatitis was reported among patients treated with 50 mg AB680. Congress Alert

Phase Ib study of XPro1595 (TNF-alpha inhibitor; 0.3 or 1 mg/kg qwk) in 9 patients with Alzheimer’s disease. Treatment was well tolerated and only caused injection-site reactions. [Data from an Inmune Bio presentation providing expanded phase Ib data of XPro1595] Company Communication

Side effects reported in 5-10% patients receiving Orladeyo include abdominal pain, diarrhea and flatulence. [Data from PMDA package insert for Orladeyo (berotralstat hydrochloride; plasma kallikrein inhibitor)] Regulatory Agency Communication

Analysis of the FDA Vaccine Adverse Event Reporting System (VAERS) evaluating the incidence of allergic reactions to Moderna COVID vaccine. 10 cases of anaphylaxis were identified (2.5 cases per million doses administered; median interval from vaccine receipt to symptom 7.5 minutes), which led to 6 hospitalizations. 43 cases of non-anaphylaxis allergic reactions were identified (median interval from vaccine receipt to symptom 15 minutes; 40% serious). Clinical manifestations of these reactions are listed.

The special warnings and precautions for use section of the EMA EPAR for Roclanda indicates that latanoprost may cause iris pigmentation; macular edema; iritis/uveitis; exacerbation of asthma and/or dyspnea in postmarketing experience; periorbital skin discoloration; and eyelash changes (such as increased length or thickness). Other warnings and precautions of Roclanda are listed, including those observed with the individual component latanoprost. [Data from EMA European public assessment report for Roclanda (latanoprost/netarsudil)] Regulatory Agency Communication

Side effects reported in ≥1% patients receiving Emgality are injection-site pain (10.1% patients) and other injection-site reactions such as erythema, pruritus, internal bleeding and swelling (14.9%). [Data from PMDA package insert for Emgality (galcanezumab; CGRP antagonist)] Regulatory Agency Communication

Adverse reactions reported with unknown frequency during postmarketing experience with Xofluza include hypersensitivity reactions such as anaphylaxis/anaphylactic reactions and angioedema. [Data from EMA European public assessment report for Xofluza (baloxavir marboxil; polymerase acidic protein inhibitor)] Regulatory Agency Communication

First-in-human phase I study of TTI-621 (CD47 inhibitor; 0.05-10 mg/kg q3w) in 164 patients with relapsed or refractory hematologic malignancies. The most common treatment-related adverse events (TRAEs) were infusion-related reactions (70 patients [43%]; 3 [2%] grade ≥3), thrombocytopenia (43 [26%]; 33 [20%]), chills (30 [18%]), fatigue (24 [15%]), anemia (22 [13%]; 15 [9%]), nausea (19 [12%]), pyrexia (17 [10%]) and diarrhea (17 [10%]; 1 [1%]). 37 (23%) patients temporarily interrupted treatment, mainly due to infusion-related reactions (9%) and neutropenia (3%). 6 (4%) patients discontinued treatment due to treatment-related infusion-related reactions (2 patients), sepsis, erythroleukemia, cellulitis and pancytopenia (1 each). Other TRAEs are listed.

The EMA has updated the product information of Tremfya (guselkumab; IL-23 inhibitor) to include new safety and efficacy information following an extension of the indication. Based on pooled phase III studies in psoriatic arthritis, the adverse drug reactions respiratory tract infection, transaminases increase and neutrophil count decrease have been identified and added to the SmPC. Regulatory Agency Communication

Based on data from a Periodic Safety Update Report of Tasigna (nilotinib; BCR/ABL inhibitor), the CHMP has recommended updating the product information to include the risk of rhabdomyolysis caused by a drug-drug interaction with statins. The relationship is considered at least a reasonable possibility. In view of new data from a non-interventional study, the frequencies of the adverse reactions cardiac failure, pneumonia and renal failure will be amended in the product information. Regulatory Agency Communication

Conclusions from a Periodic Safety Update Report of Ocrevus (ocrelizumab; CD20 inhibitor). The CHMP has recommended updating the drug's product information to include the risk of late onset of neutropenia as a plausible class effect of CD20 antibodies. The relationship between ocrelizumab and late onset of neutropenia is considered at least a reasonable possibility. Regulatory Agency Communication

Based on data from a Periodic Safety Update Report of Dupixent (dupilumab; interleukin-4 receptor subunit alpha antagonist), the CHMP has recommended updating the product information to include the risk of keratitis. A causal relationship between dupilumab and keratitis is considered a reasonable possibility at least in atopic dermatitis and asthma conditions. Regulatory Agency Communication

Conclusions from a Periodic Safety Update Report of deoxycholic acid (farnesoid X receptor agonist/GPBA receptor agonist/FPR1 antagonist). The CMDh considers that there is sufficient evidence of a causal association between the occurrence of injection site scarring and the use of deoxycholic acid. Injection site scarring will be added to the product information with frequency "uncommon". Other scarring events reported with the drug are listed. Regulatory Agency Communication

Phase Ib/II clinical trial of xentuzumab (750 or 1,000 mg IV qwk) in combination with exemestane (25 mg PO qd) and everolimus (10 mg PO qd) in patients with breast cancer. The most frequent adverse events (AEs) in the phase Ib study were anemia (16/24 [66.7%] patients; 3 [12.5%] grade ≥3), hyperglycemia (14 [58.3%]; 2 [8.3%]), decreased appetite (14 [58.3%]) and mucosal inflammation (13 [54.2%]). The most common AEs in the phase II study were diarrhea (29/70 [41.4%] with xentuzumab plus exemestane/everolimus vs 20/69 [29%] with exemestane/everolimus), mucosal inflammation (27 [38.6%] vs 21 [30.4%]), stomatitis (24 [34.3%] vs 24 [34.8%]) and nausea (24 [34.3%] vs 16 [23.2%]). 2 treatment-related deaths occurred in patients receiving xentuzumab at 1,000 mg (pneumonitis and liver injury) and 1 in the exemestane/everolimus group (acute kidney injury). Other AEs are listed.

Phase II study of pembrolizumab (200 mg q3w), capecitabine (850 mg/m2 bid) and oxaliplatin (130 mg/m2 q3w) in 36 patients with HER2-negative gastroesophageal adenocarcinoma. Immune-mediated treatment-related adverse events (TRAEs) included thyroid disorders (5 patients [14%]), colitis (4 [11%]), adrenal insufficiency (2 [5%]) and type 1 diabetes (1). Congress Alert

Real-world study comparing the cardiovascular adverse effects of anti-IL-5 therapies (reslizumab and mepolizumab) and IL-5 receptor alpha subunit therapy (benralizumab) to those of omalizumab amongst 2,955 cardiovascular events extracted from VigiBase. Rates of cardiovascular events (ROR: 0.41 [95% CI: 0.36-0.46]), hypertension (0.26 [0.22-0.30]), ventricular arrythmia (0.55 [0.32-0.90]) and venous thromboembolism (0.68 [0.45-0.99]) were significantly lower with anti-IL-5/IL-5 receptor alpha subunit therapy than with omalizumab, although cases of ischemic stroke were significantly higher (1.69 [1.02-2.74]).

EMA assessment of combined cetuximab (400 mg/m2 followed by 250 mg/m2 qwk) and encorafenib (300 mg qd) for the treatment of metastatic colorectal carcinoma. The most common drug-related adverse events (AEs) observed in a phase III trial were diarrhea (38.4% patients in the cetuximab/encorafenib group vs 48.7% in the control group), nausea (38% vs 43.5%), fatigue (33.3% vs 28%), decreased appetite (31% vs 29%), acneiform dermatitis (29.2% vs 39.4%), abdominal pain (27.8% vs 28%) and vomiting (27.3% vs 31.6%). The adjusted rate of AEs resulting in death was 0.74 per 100 patient-months of exposure in the combination group vs 2.06 in the control group. Other AEs are listed.

Case-control study evaluating the risk of pancreatic cancer associated with medications known to induce acute pancreatitis. Metronidazole and ranitidine were significantly associated with an increased risk of pancreatic cancer (adjusted OR = 1.69 [95% CI: 1.18-2.41] and 1.37 [1.10-1.70], respectively). Patients receiving ≥2 erythromycin prescriptions had an increased risk of pancreatic cancer (1.40 [1.00-1.97]). Other drugs not significantly associated with pancreatic cancer are listed.

Retrospective study assessing the magnetic resonance imaging (MRI) abnormalities related to vigabatrin (GABA-T inhibitor) in 200 patients with infantile spasms. 118 patients received vigabatrin. 55 of these patients had an MRI. The MRI showed vigabatrin-related changes in 26 patients, including 6 patients with signal abnormalities in the hippocampi.

Phase I study of the radiolabeled monoclonal antibody 90Y-FF-21101 (cadherin-3 inhibitor) in 31 patients with advanced colorectal and pancreatic-biliary cancer. The most common treatment-related adverse event (TRAE) was myelosuppression including thrombocytopenia (87% patients; 45% grade 3/4), lymphopenia (74%; 61%), anemia (52%; 13%) and leukopenia (32%; 16%). TRAEs were fatigue (68%; grade 3 in 1 patient) and nausea (39%; 1). Grade 3/4 thrombocytopenia led to dose reduction in 3 patients. Anti-drug antibody titers were reported in <5% patients. Congress Alert

Phase Ib study of the bispecific antibody AK104 (CTLA-4/PD-1 inhibitor; 4, 6 and 10 mg/kg q2w) combined with mXELOX (oxaliplatin [85 mg/m2 q2w] and capecitabine [1000 mg/m2 bid]) as first-line therapy in 34 patients with advanced gastric or gastroesophageal junction cancer. The most frequent AK104-related adverse events (AEs) were neutrophil count decrease (26.5%; grade 3 in 8.8%), platelet count decrease (20.6%), white blood cell count decrease, anemia and infusion-related reaction (17.6% each). Grade 3 immune-related AEs were reported in 8.8% patients and consisted of hepatitis, pneumonitis, and hyponatremia. Congress Alert

The NMPA has decided to update the product information of pamidronate disodium preparations. Adverse reactions reported in the postmarketing setting are listed. Regulatory Agency Communication

Phase II study of MEDI-0382 (cotadutide; GLP-1 receptor/glucagon receptor agonist) in 25 patients with type 2 diabetes mellitus. Common non-serious adverse events (AEs; higher than with placebo) included nausea (13 patients), decreased appetite (5), decreased electrocardiogram T wave amplitude, vomiting (4 each), contusion, eructation, lethargy and constipation (3 each). Other non-serious AEs are listed. Clinical Trial Registry

Phase I study of fenretinide (4-HPR; retinoic acid receptor agonist; 600, 905 or 1,414 mg/m2 qd) in 23 patients with malignant solid tumors. The most common treatment-related adverse events (TRAEs) were anemia, hypertriglyceridemia (12 patients [52%] each), fatigue (11 [48%]), AST/ALT increase (10 [43%]), thrombocytopenia, hyperbilirubinemia (7 [30%] each) and dry skin (6 [26%]). Other TRAEs are listed.

Case report of a 39-year-old pregnant woman receiving decitabine (Dnmt1 inhibitor; 10 mg/m2) for acute myeloid leukemia. Teratogenic effects were seen in the fetus, including hypotelorism, mid-facial deformity, absence of nasal bone, cleft lip and palate, polydactyly and rocker-bottom feet.

Meta-analysis of 29 phase II/III trials evaluating hematologic toxicities in cancer patients receiving PARP inhibitors (olaparib, niraparib, talazoparib, rucaparib and veliparib). PARP inhibitors were associated with a significantly increased risk of all-grade and high-grade anemia, neutropenia and thrombocytopenia.

Study reporting that Csf1r-knockout rats show microglial depletion, breathing difficulties, small body size, abnormal teeth development, changes in brain shape and skull morphology, and abnormal cranial case ossification.

Phase II/III study of treprostinil (DP1/EP2/IP receptor agonist; 72 mcg qid) in 163 patients with pulmonary hypertension due to interstitial lung disease. The most common adverse events (AEs) included cough (71 patients [43.6%] with treprostinil vs 54 [33.1%] with placebo), headache (45 [27.6%] vs 32 [19.6%]), dizziness (30 [18.4%] vs 23 [14.1%]), diarrhea (22 [13.5%] vs 19 [11.7%]), throat irritation (20 [12.3%] vs 6 [3.7%]) and oropharyngeal pain (18 [11%] vs 4 [2.5%]). Serious AEs are listed.

Analysis of the FDA Adverse Event Reporting System evaluating the risk of aortic dissection with VEGF-tyrosine kinase inhibitors (VEGF-TKIs). VEGF-TKIs were significantly associated with the risk of aortic dissection (reporting odds ratio 4.31; 95% CI 3.43-5.42). The risk was higher with VEGF-TKIs that strongly increase blood pressure than with those than moderately increase blood pressure.

Phase III trial of ivosidenib (isocitrate dehydrogenase 1 inhibitor; 500 mg qd) in 780 patients with previously treated cholangiocarcinoma. The most frequent treatment-emergent adverse events were nausea (41%), diarrhea (35%), fatigue (31%), cough (25%), abdominal pain, decreased appetite (24% each), ascites, vomiting (23% each), anemia (18%) and constipation (15%). Congress Alert

First-in-human phase I study of MCLA-158 (EGFR inhibitor/LGR5 antagonist; 5-1,500 mg q2w) in 33 patients with colorectal cancer. Adverse events (AEs) suspected to be related to MCLA-158 were nausea, chills, acneiform dermatitis (8 each), vomiting, rash (6 each), diarrhea (5), dyspnea (4), pyrexia, bronchospasm, erythema and flushing (3 each). Grade 3 treatment-related AEs included hypotension, hypoxia, hypertension and hypophosphatemia (1 each). 22 patients experienced infusion-related reactions (including grade 3 cases). Congress Alert

Phase II study of Esbriet (pirfenidone; TGFbeta inhibitor) in patients with unclassifiable interstitial lung disease. The most common treatment-related and treatment-emergent adverse events were gastrointestinal disorders (47% with pirfenidone vs. 26% with placebo), fatigue (13% vs. 10%), rash (10% vs. 7%), dizziness (8% vs. 3%), photosensitivity (8% vs. 2%) and decreased weight (8% vs. 1%). [Data from a Genentech communication announcing that the FDA has granted priority review to pirfenidone for the treatment of unclassifiable interstitial lung disease] Company Communication

Phase II study of bemarituzumab (bema) plus mFOLFOX6 (fluorouracil/leucovorin/oxaliplatin) in 155 patients with advanced gastric/gastroesophageal junction cancer. Adverse events (AEs) more common with bema plus mFOLFOX6 were corneal AEs (51/76 [67.1%] patients with bema plus mFOLFOX6 vs. 8/77 [10.4%] with placebo plus mFOLFOX6), diarrhea (31 [40.8%] vs. 24 [31.2%]), stomatitis (24 [31.6%] vs. 10 [13%]), AST increase (23 [30.3%] vs. 15 [19.5%]) and ALT increase (22 [28.9%] vs. 11 [14.3%]). Corneal AEs led to bema discontinuation in 20 (26.3%) patients, the most common being dry eye, keratitis (4 each), corneal disorder, eye disorder, limbal stem cell deficiency and punctate keratitis (2 each). Other AEs are listed. Congress Alert

Final results from a phase II study of infigratinib (FGFR inhibitor; 125 mg qd) in 108 patients with previously treated advanced cholangiocarcinoma. The most common treatment-emergent adverse events (TEAEs) were hyperphosphatemia (76.9%), eye disorders (67.6%), stomatitis (54.6%), fatigue (39.8%) and central serous retinopathy/retinal pigment epithelium detachment (16.7%; 1 grade 3). Other common grade 3/4 TEAEs were stomatitis (14.8%; all grade 3), hyponatremia (13%; all grade 3) and hypophosphatemia (13%; 13 grade 3 and 1 grade 4). Congress Alert

Case report of a patient receiving roxadustat (HIF-prolyl hydroxylase inhibitor) for anemia who developed rhabdomyolysis.

Phase I study of ulixertinib (ERK1/2 inhibitor; 10-900 mg bid) in 135 patients with advanced malignancies. The most common dermatological adverse events (AEs) included acneiform rash (45/135 patients [33%]), maculopapular rash (36 [27%]), pruritus (34 [25%]) and rash unspecified (31 [23%]). Grade 3 AEs included rash maculopapular (12 [9%]), rash unspecified (5 [4%]), rash acneiform (4 [3%]), pruritus (2 [1%]), photosensitivity and erythema multiforme (1 [1%] each). Other AEs are listed.

Phase III study of henagliflozin (SGLT2 inhibitor; 5-10 mg qd) in 468 patients with type 2 diabetes. The most common adverse events (AEs) more frequent with henagliflozin than with placebo were increased blood parathyroid hormone (16/152 patients [10.5%] with henagliflozin 5 mg; 14/152 [9.2%] with henagliflozin 10 mg; 9/153 [5.9%] with placebo), increased urine albumin/creatinine ratio (11 [7.2%]; 6 [3.9%]; 6 [3.9%]), diabetic ketoacidosis (4 [2.6%]; 7 [4.6%]; 3 [2%]) and increased blood ketone bodies (3 [2%]; 9 [5.9%]; 1 [0.7%]). Other AEs are listed.

Phase II study of neratinib (EGFR/HER2/HER4 inhibitor) in 25 patients with HER2 mutation-positive advanced biliary tract cancers. Treatment-emergent adverse events (AEs) were diarrhea (14 patients [56%] with 6 [24%] grade 3-4), vomiting (12 [48%] with 1 [4%]), fatigue, nausea (10 [40%] each), abdominal pain (9 [36%] with 3 [12%]), decreased appetite (7 [28%]), constipation (6 [24%]), aspartate aminotransferase increased (4 [16%] with 1 [4%]), dehydration (4 [16%] with 2 [8%]), dizziness, dry mouth and pyrexia (4 [16%] each). Grade 5 AEs included general deterioration and sepsis (1 each). Congress Alert

The warnings and precautions section of the FDA approved drug report for Verquvo indicates that it may cause embryo-fetal toxicity and fetal harm based on data from animal reproduction studies. [Data from FDA approved drug report for Verquvo (vericiguat; guanylate cyclase soluble activator)] Regulatory Agency Communication

Development program of setmelanotide (MC4 receptor agonist)) in patients who are obese due to rare genetic diseases. Adverse events (AEs) included injection site reactions, hyperpigmentation, skin lesions, nausea and vomiting. In a phase II study in patients with POMC or LEPR heterozygous variants, AEs leading to discontinuation were hyperpigmentation and muscle cramps (1 patient each). In a phase III study in patients with Bardet-Biedl syndrome or Alström syndrome, serious treatment-emergent AEs were blindness and suicidal ideation (1 each). [Data from a Rhythm Pharmaceuticals presentation on the clinical development of setmelanotide for rare genetic diseases of obesity] Company Communication

Based on data from a Periodic Safety Update Report of Yervoy (ipilimumab; CTLA-4 inhibitor), the CHMP has recommended adding the risk of solid organ transplant rejection and hemophagocytic lymphohistiocytosis to the drug’s product information. A causal relationship between ipilimumab and these events is considered at least a reasonable possibility. Regulatory Agency Communication

The NMPA has decided to update the product information of sulfasalazine preparations. Adverse reactions reported in the postmarketing setting with oral sulfasalazine preparations and suppositories are listed. Sulfasalazine and its metabolites may interfere with laboratory test results. Regulatory Agency Communication

The FDA has updated the product information of Jelmyto (mitomycin; DNA alkylating agent), adding decreased appetite, hypertension and hypernatremia to the list of adverse reactions reported in the phase III OLYMPUS trial. Regulatory Agency Communication

The FDA has updated the product information of Enhertu (fam-trastuzumab deruxtecan-nxki; HER2/DNA topoisomerase 1 inhibitor) to include novel safety data from the DESTINY-Gastric01 trial (listed). Regulatory Agency Communication

First case report of osteonecrosis of the jaw associated with bosutinib (BCR/ABL and Src inhibitor) in a 65-year-old man with chronic myeloid leukemia.

Health Canada has updated the product information of Gilenya (fingolimod; S1P1/5 receptor agonist) to include the risk of liver injury. This follows a report of postmarketing cases of clinically significant liver injury reported in patients with multiple sclerosis, including markedly elevated serum hepatic enzymes, elevated total bilirubin and cases resulting in acute liver failure requiring liver transplant. Regulatory Agency Communication

Swissmedic, together with Roche, have issued a Direct Healthcare Professional Communication reporting that the product information of Tecentriq (atezolizumab; PD-L1 inhibitor) will be updated to include novel recommendations regarding the risk of severe cutaneous adverse reactions (including toxic epidermal necrolysis and Stevens-Johnson syndrome). The decision was taken after reporting a fatal case of toxic epidermal necrolysis in a woman taking Tecentriq. Regulatory Agency Communication

Phase I/II dose-escalation study of birinapant (5.6, 11, 17 or 22 mg/m2) in combination with pembrolizumab (200 mg) in 34 patients with solid tumors. Serious adverse events (AEs) included small intestinal obstruction (3 patients at 22 mg), dyspnea (1 at 5.6 mg; 2 at 17 mg) and abdominal pain (1 each at 5.6 and 22 mg). Other serious and non-serious AEs are listed. Clinical Trial Registry

Phase III study of tafamidis (transthyretin stabilizing agent; 20 mg qd) in 31 patients with transthyretin amyloid cardiomyopathy. Common serious adverse events (AEs) were congestive cardiac failure (9 patients), cardiac failure, fall (6 each), amyloidosis (4), chest pain, cellulitis and dehydration (3 each). Other serious (≥2 patients) and non-serious AEs are listed. Clinical Trial Registry

The special warnings and precautions for use section of the EMA EPAR for Phesgo indicates that it may cause left ventricular dysfunction (including congestive heart failure) in combination with chemotherapy; injection-related reactions and infusion-related reactions; severe hypersensitivity reactions (including anaphylaxis) in combination with chemotherapy; increased risk of febrile neutropenia in combination with a taxane (such as docetaxel); and severe diarrhea in combination with taxane chemotherapy. Trastuzumab has been associated with severe pulmonary events in the postmarketing setting. Other warnings and precautions of Phesgo and its components are listed. [Data from EMA European public assessment report for Phesgo (pertuzumab/trastuzumab)] Regulatory Agency Communication

Systematic review and meta-analysis evaluating the risk of local recurrence of giant-cell tumor of bone in patients receiving denosumab (RANKL inhibitor) followed by curettage. Patients treated with denosumab had a higher risk of recurrence than those treated with curettage only (OR = 3.04; 95% CI [1.48-6.22]; P < 0.01).

Case report of a patient who developed rhombencephalitis after treatment pembrolizumab (PD-1 inhibitor).

The EMA's PRAC has recommended issuing a DHPC warning about the risk of acute adrenal insufficiency in children switching to Alkindi (hydrocortisone; glucocorticoid receptor modulator). The review of the safety signal was triggered by a case report of a baby who developed severe adrenal insufficiency after switching from hydrocortisone soluble tablets to Alkindi granules. Regulatory Agency Communication

The FDA has updated the product information of Xalkori (crizotinib; ALK/Met/Ros inhibitor), adding a warning about the risk of gastrointestinal toxicity (including grade 3 events such as diarrhea, nausea, vomiting and stomatitis) in patients with anaplastic large cell lymphoma. Blurred vision has been included in the “Warnings and Precautions” section for severe visual loss. The “Adverse Reactions” section has also been updated to include novel safety data from the ADVL0912 trial (listed). Regulatory Agency Communication

Phase I/IIa study of the COVID-19 vaccine candidate Ad26.COV2.S (5 x 10e10 or 1 x 10e11 viral particles/ml) in 805 healthy subjects. The most common solicited adverse events (AEs) included systemic symptoms such as fatigue, headache and myalgia, and local symptoms such as injection-site pain. Grade 3 vaccine-related unsolicited AEs were back pain (2 subjects), malaise, hypotensive crisis, insomnia, fever, lightheadedness, vomiting, dizziness, worsening hypertension, and systolic hypertension (1 each). 5 serious AEs were reported, one of which was considered related to vaccination and consisted of pyrexia. Other solicited AEs are listed.

First-in-human phase I study evaluating the safety of the humanized rabbit antibody SSS07 (TNF-alpha inhibitor; 5-100 mg) in healthy volunteers. Treatment-related adverse events (TRAEs) occurring more frequently than with placebo included injection-site itching (6/60 subjects [10%] with SSS07 vs 0/11 with placebo), injection-site erubescence (4 [6.67%] vs 0), increased uric acid, injection-site erythema and fever (3 [5%] vs 0 each). Other TRAEs are listed.

Study in obese mice reporting that long-term administration of risperidone (D2 receptor antagonist; 1 mg/kg) exacerbates glucose intolerance, insulin resistance, non-alcoholic fatty liver disease and renal impairment. Other adverse events of risperidone are listed.

The EMA has updated the product information of Kisplyx (lenvatinib; tyrosine kinase inhibitor) to include data from 3 long-term safety studies. Asian patients had a higher incidence (≥10%) than Caucasians of peripheral edema, hypertension, fatigue, palmar-plantar erythrodysesthesia syndrome, proteinuria, stomatitis, thrombocytopenia and myalgia. Caucasians had a higher incidence of diarrhea, decreased weight, nausea, vomiting, constipation, asthenia, abdominal pain, pain in extremity and dry mouth. Regulatory Agency Communication

Based on data from a Periodic Safety Update Report of zonisamide (carbonic anhydrase inhibitor/sodium channel blocker), the CHMP has recommended updating the product information to include the risk of hyperammonemia. A causal relationship between zonisamide and hyperammonemia is considered at least a reasonable possibility. Regulatory Agency Communication

Based on data from a Periodic Safety Update Report of siponimod (S1P1/S1P5 receptor agonist), the CHMP has recommended updating the product information to include an increased risk of basal cell carcinoma. Regulatory Agency Communication

Phase II study of AK001 (Siglec-8 inhibitor; 25 or 250 mg) in 40 patients with nasal polyposis. Adverse events (AEs; more common than with placebo) included abdominal discomfort, asthma, influenza, nasal congestion, nasopharyngitis and nasal obstruction. Other AEs are listed. Clinical Trial Registry

First-in-human phase I/II study of SAR439859 (estrogen receptor degrader) in 59 patients with breast cancer. The most common treatment-related adverse events were hot flush (16.1%), constipation, arthralgia (9.7% each), decreased appetite, vomiting, diarrhea, nausea (8.1% each) and fatigue (6.5%). Congress Alert

Clinical study of tezepelumab (thymic stromal lymphopoietin inhibitor; 210 mg) in 314 healthy volunteers. Adverse events included nasopharyngitis (24.5%), headache (11.5%), oropharyngeal pain (5.1%), rhinitis, back pain (3.5% each), nausea (3.2%) and injection-site reactions (2.2%). Antidrug antibodies and injection-site pain were also reported.

First-in-human study of ACT-1004-1239 (ACKR3 antagonist) in 36 healthy volunteers. Adverse events included dizziness, abnormal ST segment, headache, rash (2 each), anemia, constipation, increased alanine aminotransferase, increased aspartate aminotransferase, memory impairment, proteinuria, rhinorrhea, sinus congestion and throat irritation (1 each).

Phase III study of AJM300 (carotegrast methyl; integrin, alpha 4 subunit antagonist) in 203 patients with ulcerative colitis. Adverse events included nasopharyngitis, headache and nausea. [Data from a Kissei Pharmaceutical communication announcing that AJM300 has achieved its primary endpoint in a phase III trial with ulcerative colitis patients] Company Communication

Phase Ia study assessing the safety, pharmacokinetics and pharmacodynamics of TQ-A3334 (TLR7 agonist; 0.2-1.8 mg) in healthy volunteers. The most common treatment-emergent adverse events (TEAEs) were decreased lymphocyte count, decreased neutrophil count, decreased white blood cell count, headache, fever and muscle pain. Flu symptoms such as headache and fever were considered related to TLR7 agonism. Other TEAEs are listed.

First-in-human phase I clinical study of MK-4166 (0.0015-900 mg q3w) alone or in combination with pembrolizumab (200 mg q3w) in 113 patients with advanced solid tumors. The most common treatment-related adverse events (AEs) were infusion-related reaction (9/48 patients [18.8%] with MK-4166 vs 22/65 [33.8%] with MK-4166 plus pembrolizumab), pruritus (6 [12.5%] vs 11 [16.9%]), fatigue (4 [8.3%] vs 22 [33.8%]), arthralgia and nausea (3 [6.3%] vs 6 [9.2%]). The most common grade 3/4 treatment-related AE was decreased lymphocyte count (0 vs 2). Other AEs and treatment-related AEs are listed.

First-in-human phase I/Ib trial of PMD-026 (RSK2 inhibitor; 25-200 mg qd or 200-300 mg q12h) in 12 patients with metastatic breast cancer. Adverse events observed in the 200 mg q12h group were gastroesophageal reflux disease and neutropenia (1 patient each). 2 patients receiving PMD-026 at 300 mg q12h experienced dose-limiting toxicities: syncope and acute kidney injury secondary to vomiting and dehydration (1 each). Congress Alert

Phase III clinical trial comparing the antibody-drug conjugate sacituzumab govitecan (tumor-associated calcium signal transducer 2/DNA topoisomerase 1 inhibitor; 10 mg/kg) to chemotherapy in 529 patients with metastatic triple-negative breast cancer. The most common treatment-emergent adverse events were fatigue (63% patients with sacituzumab govitecan vs 52% with chemotherapy), diarrhea (50% vs 13%), neutropenia (43% vs 35%), nausea (43% vs 26%), decreased neutrophil count (33% vs 22%), decreased appetite (30% vs 17%), anemia (23% vs 35%), constipation (23% vs 22%) and alopecia (23% vs 13%). Congress Alert

The MHRA has reviewed the safety of antiepileptic drugs during pregnancy. Valproate is known to cause physical birth abnormalities in children, which may affect brain development and alter learning and thinking abilities. The review concluded that carbamazepine, phenobarbital, phenytoin and topiramate increase the risk of physical birth abnormalities compared with the general population. Lamotrigine and levetiracetam were not associated with physical birth abnormalities. Phenobarbital and phenytoin were also associated with brain developmental disorders and alterations in learning and thinking abilities. Use of phenobarbital, topiramate and zonisamide during pregnancy was associated with reduced baby size at born. Other safety issues are listed. Regulatory Agency Communication

Results from a phase I study of rintodestrant (G1T48; estrogen receptor degrader; 200-1,000 mg qd) in 67 patients with ER+/HER2- locally advanced or metastatic breast cancer. The most common treatment-related adverse events were hot flush (24%), fatigue (21%), nausea (19%), diarrhea (18%) and vomiting (10%). Congress Alert

Conclusions from a Periodic Safety Update Report of flucloxacillin. The CMDh has recommended updating the product information to include the risk of hypokalemia and esophageal pain and related events. A causal relationship between flucloxacillin and these events is considered at least a reasonable possibility. Regulatory Agency Communication

The FDA has updated the product information of Neulasta (pegfilgrastim; granulocyte colony-stimulating factor receptor agonist) to include warnings about thrombocytopenia, and increased risk of myelodysplastic syndrome and acute myeloid leukemia when administered together with chemotherapy and/or radiotherapy. The "Adverse Reactions" section has also been updated to include these terms. Regulatory Agency Communication

Phase I/II study of the probody-drug conjugate praluzatamab ravtansine (CX-2009; CD166/tubulin polymerization inhibitor) in 99 patients with breast cancer. Treatment-related adverse events (AEs) leading to CX-2009 discontinuation included keratitis (6), blurred vision, peripheral neuropathy, nausea, sepsis, back pain, dyspnea and urticaria (1 each). Drug-related ocular toxicity was reported in 43 patients (10 grade ≥3). Dose-limiting toxicities were vomiting, increased liver enzymes and peripheral neuropathy. Other AEs are listed. Congress Alert

Phase I/II study of H3B-6545 (estrogen receptor-alpha antagonist) in 130 patients with advanced breast cancer. Common adverse events (AEs) were sinus bradycardia (35%), anemia (20%), fatigue (16%), nausea (14%), diarrhea and increased aspartate aminotransferase (11% each). 3 patients experienced grade 3 QTcF prolongation. Dose-limiting toxicities included grade 3 fatigue and grade 3 drug eruption. Congress Alert

First-in-human study of MGD019 (CTLA-4/PD-1 inhibitor; 0.03-10 mg/kg q3w) in patients with advanced, previously-treated solid tumors. The most common treatment-related adverse events (AEs) were fatigue (24%), nausea, arthralgia, pruritus and maculopapular rash (18% each). Immune-related AEs (8 patients) included grade 3 myocarditis, enterocolitis and maculopapular rash. Findings in cynomolgus monkeys included a higher incidence of soft/watery feces at ≥40 mg/kg and minor hematological changes at ≥10 mg/kg. Increased spleen weight parameters were observed at ≥40 mg/kg in males and ≥10 mg/kg in females, correlating with generalized lymphoid hyperplasia characterized by increased numbers of lymphocytes. Other AEs are listed.

The warnings section of the FDA Freedom of Information Summary for Laverdia-CA1 indicates that it may cause birth defects and affect male and female fertility based on data from animal studies. Laverdia-CA1 also altered male fertility in humans. [Data from FDA New Animal Drug Application Freedom of Information Summary for Laverdia-CA1 (verdinexor; exportin-1 inhibitor)] Regulatory Agency Communication

Phase II placebo-controlled study of donanemab (beta-amyloid ligand) in patients with early symptomatic Alzheimer's disease. Amyloid-related imaging abnormalities (ARIA) were observed, including ARIA-edema in 27% patients treated with donanemab. [Data from a Lilly communication announcing positive results from a phase II trial of donanemab for the treatment of Alzheimer’s disease] Company Communication

Clinical trial of EDP-305 (farnesoid X receptor agonist) in patients with non-alcoholic steatohepatitis. Pruritus led to treatment discontinuation in 1.8% patients receiving EDP-305 at 1 mg and 20.8% patients on EDP-305 2.5 mg. EDP-305 was also associated with small numeric absolute changes in lipids. [Data from an Enanta corporate presentation] Company Communication

Phase I study of vimseltinib (DCC-3014; CSF-1R inhibitor) in 25 patients with tenosynovial giant cell tumors. Treatment-emergent adverse events (≥25%) included increased blood creatine phosphokinase (52%), increased AST, periorbital edema (44% each), fatigue (40%), increased lipase (32%) and increased ALT (28%). 1 (4%) patient discontinued treatment due to grade 3 AST elevation. [Data from a Deciphera corporate presentation presented at the 39th Annual J.P. Morgan Healthcare Conference] Company Communication

Preliminary report of a phase IV trial comparing tocilizumab (8 mg/kg) and sarilumab (400 mg) in patients with COVID-19. Serious adverse events (SAEs) in the tocilizumab group included bleedings (5 patients), cardiac events (2), visual deterioration and secondary bacterial infection (1 each). There were no SAEs in the sarilumab group.

Population-based cohort study evaluating the risk of dementia and Parkinson’s disease associated with GnRH receptor agonists. Results showed that GnRH receptor agonists increase the risk of dementia (HR = 1.696 [95% CI: 1.425-2.019]). No association between GnRH receptor agonists and Parkinson’s disease was observed.

The warnings and precautions section of the FDA approved drug report for Ebanga indicates that it may cause hypersensitivity reactions (including infusion-associated events such as hypotension, chills and elevation of fever), which may be severe and life-threatening in some patients. [Data from FDA approved drug report for Ebanga (ansuvimab-zykl; Ebola virus glycoprotein inhibitor)] Regulatory Agency Communication

Conclusions from a Periodic Safety Update Report of ethosuximide (Cav3 blocker). The CMDh and the PRAC have recommended updating the drug's product information to include drug reaction with eosinophilia and systemic symptoms (DRESS) and thrombocytopenia as adverse reactions with a frequency “not known”. DRESS has also been included in the warnings section. Regulatory Agency Communication

Very common (≥1/10) adverse reactions reported in clinical trials of the COVID-19 vaccine Moderna were injection-site pain (92% patients), fatigue (70%), headache (65%), myalgia (62%), arthralgia, chills (46% each), nausea/vomiting (23%), lymphadenopathy (including axillary swelling and tenderness; 19.8%), pyrexia (15.5%) and injection-site swelling (14.7%). [Data from MHRA Authorization for Temporary Supply for the COVID-19 vaccine Moderna (COVID-19 mRNA vaccine (nucleoside-modified))] Regulatory Agency Communication

Health Canada has issued a safety review evaluating the potential association between oseltamivir (viral neuraminidase inhibitor) and the risk of hemorrhages. 59 case reports of bleeding after treatment with oseltamivir were identified, including 22 cases of lower gastrointestinal bleeding. There was not enough evidence to support a link between oseltamivir and the risk of hemorrhage. The review concluded that oseltamivir may increase the risk of lower gastrointestinal bleeding. Regulatory Agency Communication

Phase III study of valoctocogene roxaparvovec (coagulation factor VIII gene therapy) in 134 patients with hemophilia A. The most common adverse events (AEs) were increased alanine aminotransferase (115 patients [86%]), headache (51 [38%]), nausea (50 [37%]), increased spartate aminotransferase (47 [35%]), arthralgia (38 [28%]) and fatigue (37 [27%]). Infusion-related reactions and elevations in liver function test enzymes were reported in a phase I/II trial of valoctocogene roxaparvovec. Side effects related to corticosteroid treatment for alanine aminotransferase elevations are listed. [Data from a BioMarin Pharmaceutical communication announcing positive topline results from a phase III study of valoctocogene roxaparvovec for hemophilia A] Company Communication

Phase I study of the antibody-drug conjugate XMT-1536 (sodium phosphate 2/tubulin polymerization inhibitor) for heavily pre-treated patients with ovarian cancer. The most common treatment-related adverse events (TRAEs) were fatigue, nausea, transient AST elevation and transient thrombocytopenia. Serious TRAEs included pyrexia (4 patients), vomiting (3), abdominal pain and pneumonitis (2 each). [Data from a Mersana Therapeutics communication announcing corporate and pipeline updates] Company Communication

Health Canada has issued a safety review evaluating the potential association between SERT/NET inhibitors and the risk of sexual dysfunction. 58 reports of sexual dysfunction after treatment with SERT/NET inhibitors were identified. 43 cases were considered possibly treatment-related. The product information of these medicines will be updated to include the risk of sexual dysfunction, which may persist after treatment discontinuation. Regulatory Agency Communication

The UK MHRA has issued safety advice on the link between aminoglycosides (gentamicin, amikacin, tobramycin and neomycin) and the risk of deafness. Results from a safety review suggested that patients with the mitochondrial DNA mutation m.1555A>G are at increased risk of aminoglycoside-associated ototoxicity. The product information of these medications will be updated to include a warning about this risk. Regulatory Agency Communication

The UK MHRA has issued safety advice on the link between SERT/NET inhibitors and the risk of postpartum hemorrhage. Data from observational studies revealed that use of SERT/NET inhibitors during the month before delivery increases the risk of experiencing postpartum hemorrhages. A warning about postpartum hemorrhage will be included in the product information of these medications (listed). Regulatory Agency Communication

The UK MHRA has issued safety advice on the link between Gilenya (fingolimod; S1P1/5 receptor agonist) and the risks of serious liver injury and herpes meningoencephalitis. A European review has identified 7 cases of fingolimod-associated liver injury, including 3 reports of acute hepatic failure requiring transplantation, 2 cases of hepatic necrosis, and 1 patient with acute hepatitis. Fatal cases of encephalitis and meningitis secondary to herpes simplex or herpes zoster infections were identified. The product information will be updated accordingly. Other safety issues are listed. Regulatory Agency Communication

The UK MHRA has issued safety advice on the link between Tecfidera (dimethyl fumarate; NF-kappaB/kelch-like ECH-associated protein 1 inhibitor) and the risk of progressive multifocal leukoencephalopathy secondary to lymphopenia. A European review identified 11 cases of progressive multifocal leukoencephalopathy with lymphopenia in patients receiving Tecfidera. The drug’s product information has been updated to include the risk of progressive multifocal leukoencephalopathy. Regulatory Agency Communication

Top-line results from a trial of SRP-9001 (dystrophin gene therapy) in 41 patients with Duchenne muscular dystrophy. 85% participants in the treatment group experienced at least 1 treatment-related adverse event, serious in 3 patients (2 cases of rhabdomyolysis and 2 transaminase elevations). [Data from a Sarepta Therapeutics communication announcing top-line results for part 1 of Study 102] Company Communication

Phase III study of vutrisiran (transthyretin tetramer expression inhibitor; 25 mg q3m) in 122 patients with hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy. Treatment-emergent adverse events (AEs; ≥10% patients; similar rates compared with placebo) were diarrhea, pain in extremity, fall and urinary tract infections. Serious treatment-related AEs included dyslipidemia and urinary tract infections. 4.1% patients experienced injection-site reactions. [Data from an Alnylam Pharmaceuticals communication announcing positive topline results from a phase III study of vutrisiran for hATTR amyloidosis] Company Communication

The special warnings and precautions for use section of the EMA EPAR for Vocabria (cabotegravir) indicates that it may cause hepatotoxicity and immune reactivation syndrome. Hypersensitivity reactions characterized by rash, constitutional findings and sometimes organ dysfunction (including liver injury) have been reported in association with other integrase inhibitors. No such reactions have been reported with Vocabria to date. There is risk of developing viral resistance following treatment discontinuation. [Data from EMA European public assessment report for Vocabria (cabotegravir; HIV integrase inhibitor)] Regulatory Agency Communication

Case report of a 32-year-old male with syphilis who had a Jarisch-Herxheimer reaction (JHR) and exfoliative dermatitis secondary to benzathine penicillin (bacterial penicillin-binding protein inhibitor). A search in VigiLyze retrieved 24 reports of JHR suspected to be associated with benzathine penicillin. Other common adverse events reported to the NPRA include rash (4), shortness of breath and injection site reaction (2 each). [Data from the NPRA 03/2020 MADRAC bulletin] Regulatory Agency Communication

Review evaluating the risk of allergic reactions to mRNA vaccines against COVID-19. Hypersensitivity-related adverse events were observed in clinical trials of the Pfizer-BioNTech COVID-19 vaccine (0.63% vs 0.51% with placebo) and the Moderna COVID-19 vaccine (1.5% vs 1.1%). Allergic reactions to mRNA COVID-19 vaccines have been also reported after their approval. Other safety issues are listed.

First-in-human phase I study of LY2775240 (PDE4 inhibitor; 0.1-40 mg) in 34 healthy subjects. The most common treatment-related adverse events (TRAEs) were nausea (14 subjects [41%]), diarrhea (9 [26%]) and headache (8 [24%]). Other TRAEs of LY2775240 or the active comparator apremilast are listed.

Analysis of the FDA Vaccine Adverse Event Reporting System (VAERS) evaluating the incidence of allergic reactions to Pfizer-BioNTech COVID-19 Vaccine. 175 reports of suspected severe allergic reactions were identified, including 21 anaphylactic reactions. Clinical manifestations of these reactions are listed.

The special warnings and precautions for use section of the EMA product information for the COVID-19 vaccine Moderna indicates that it may cause hypersensitivity and anaphylaxis; anxiety-related reactions including vasovagal reactions such as syncope, hyperventilation, stress-related reactions and fainting as a psychogenic response to the needle injection; and bleeding or bruising in patients receiving anticoagulant therapy or those with thrombocytopenia or any coagulation disorder. [Data from EMA European product assessment report for the COVID-19 vaccine Moderna (COVID-19 mRNA vaccine (nucleoside-modified))] Regulatory Agency Communication

Common (≥1/100 to <1/10) adverse reactions (ARs) reported in pivotal studies with Leqvio were ARs at the injection site including injection-site reaction, pain, erythema and rash; and anti-drug antibodies. [Data from EMA European public assessment report for Leqvio (inclisiran; PCSK9 synthesis inhibitor)] Regulatory Agency Communication

First-in-human, two-part study evaluating single and multiple inhalation doses of vardenafil (RT234; PDE5A inhibitor) in 31 healthy subjects (23 subjects received single inhalation doses ranging from 0.2 mg to 2.4 mg; 8 received multiple inhalation doses of 2.4 mg). In addition, 5 subjects who received single 0.6 mg doses of RT234 were compared with 5 subjects who received single oral 20 mg doses of vardenafil in a cross-over period. The most common treatment-related, treatment-emergent adverse events (TRTEAEs) included headache (10/31 [32,3%] patients with RT234 vs 4/5 [80%] with oral vardenafil), dizziness (4 [12.9%] vs 4 [80%]), nausea, cough (3 [9.7%] vs 0 each), abdominal pain, photophobia and nasal congestion (2 [6.4%] vs 0 each). Other TRTEAEs are listed.

Case report of a 32-year-old woman who experienced encephalomyelitis after receiving the Pfizer-BioNTech COVID-19 vaccine. Health Organization

Based on data from a Periodic Safety Update Report of Jakavi (ruxolitinib; JAK1/JAK2 inhibitor), the PRAC considers a causal relationship between ruxolitinib and pancytopenia and HBV reactivation is at least a reasonable possibility. Regulatory Agency Communication

The PRAC has recommended updating the product information of chloroquine and hydroxychloroquine to include psychiatric disorders. Specific psychiatric disorders are listed. Regulatory Agency Communication

Phase I study of ASP-3026 (ALK inhibitor; 25-325 mg) in 29 Japanese patients with solid tumors. The most common drug-related treatment-emergent adverse events (TEAEs) were nausea, decreased appetite, fatigue (7 each), abnormal hepatic function, rash (5 each) and vomiting (4). Dose-limiting toxicities were grade 3 cataract, increased alanine and aspartate aminotransferase and abnormal hepatic function. Other drug-related TEAEs are listed.

EudraVigilance analysis investigating the occurrence of neuropsychiatric events of the PCSK9 inhibitors alirocumab and evolocumab. Adverse drug reactions (listed) belonging to the system organ classes "nervous system disorders" and "psychiatric disorders" did not differ between drugs (ROR = 1.02 [0.91-1.14] and 1.12 [0.94-1.34], respectively). Neuropsychiatric events were significantly more common with these PCSK9 inhibitors than with statins.

Phase II clinical trial of lemborexant (OX1/2 receptor antagonist; 2.5-15 mg qd) in 62 patients with irregular sleep-wake rhythm disorder and Alzheimer’s disease. The most common adverse events (≥2 patients) were constipation, somnolence, arthralgia, headache and nightmare. 1 patient experienced severe arthralgia.

First-in-human phase I study of TU2670 (GnRH receptor antagonist; 20-160 mg) in 16 healthy women. Adverse events included myalgia, acne, diarrhea, contusion and increased blood prolactin (1 subject each).

Real-life study evaluating the risk of lupus nephritis in patients receiving belimumab (BAFF inhibitor) for systemic lupus erythematosus. Belimumab was associated with a higher risk of de novo lupus nephritis than controls (HR = 10.7 [95% CI: 1.7-67.9]).

Phase II study assessing the efficacy and safety of the COVID-19 vaccine BBV152 (3 or 6 mcg) in 380 healthy subjects. The most common adverse events (AEs) were injection-site pain, fever and malaise. Other AEs are listed.

Phase I study of AV-101 (720 or 1,440 mg) in 10 healthy subjects. Adverse events included diarrhea and elated feeling (1 subject each). Compared with placebo, AV-101 significantly reduced diastolic blood pressure and pulse rate.

Phase III trial of LY-CoV555 (SARS-CoV-2 spike protein inhibitor; 7,000 mg) in 314 patients with COVID-19. Signs and symptoms reported during infusion and 2 hours post-infusion (more common than with placebo) included bronchospasm, chills, fever, headache, pruritus, myalgia, nausea, rash, tachycardia and vomiting. Serum creatinine levels were slightly lower with LY-CoV555 than with placebo. Serious adverse events are listed.

Phase III trial of the mRNA-1273 COVID-19 vaccine (100 mcg) in 30,450 volunteers. Solicited adverse reactions were more common with mRNA-1273 than with placebo, consisting of local reactions (pain, erythema, swelling, axillary swelling and axillary tenderness) and systemic reactions (fever, headache, fatigue, myalgia, arthralgia, nausea, vomiting and chills). Other adverse events are listed.

Very common (≥1/10 patients) adverse reactions to AstraZeneca’s COVID-19 vaccine are headache, nausea, myalgia, arthralgia, fatigue, malaise, pyrexia, chills, and injection-site tenderness, pain, warmth, erythema, pruritus, swelling and bruising. [Data from MHRA Authorization for Temporary Supply for AstraZeneca COVID-19 vaccine (ChAdOx1-S [recombinant]; SARS-CoV-2 proteins-directed immunity inducer)] Regulatory Agency Communication

Health Canada has issued a safety review evaluating the potential association between tramadol (opioid mu receptor agonist) and hallucinations. 2 serious events of hallucinations related to tramadol use were identified in Canada. A review of published data revealed 101 additional cases of hallucinations after tramadol use, which were mainly visual and auditory. The product information of tramadol-containing products will be updated to include the risk of visual and auditory hallucinations. Regulatory Agency Communication

The FDA has updated the product information of Invanz (ertapenem sodium; bacterial penicillin-binding protein inhibitor) to include hypersensitivity vasculitis as an adverse reaction reported postmarketing. Regulatory Agency Communication

The FDA has updated the product information of Imbruvica (ibrutinib; BTK inhibitor), adding the risk of cardiac failure (including grade ≥3 events) to the “Warnings and Precautions” section. Regulatory Agency Communication

Phase III clinical trial of pegunigalsidase alfa (alpha-galactosidase A analog; 1 mg/kg biw) in 22 patients with Fabry disease. 2 patients discontinued treatment after experiencing hypersensitivity reactions. [Data from a Protalix and Chiesi communication announcing final results from the BRIDGE trial] Company Communication

Phase III clinical trial of AXS-07 (meloxicam 20 mg/rizatriptan 10 mg) in 706 patients with migraine. The most common adverse events (≥3% patients) were nausea, dizziness and vomiting. [Data from an Axsome communication announcing positive results from the MOVEMENT trial] Company Communication

The FDA has updated the product information of Gonal-F (follitropin alfa; FSH receptor agonist), adding hypersensitivity reactions, anaphylaxis, asthma exacerbation and thromboembolism as adverse reactions reported postmarketing. Regulatory Agency Communication

Phase I clinical trial of afatinib (20 or 30 mg qd) in combination with selumetinib (25 or 50 mg bid) in 26 patients with colorectal, non-small cell lung or pancreatic cancers. Dose-limiting toxicities were diarrhea (3 patients; including a grade 3 event), dehydration (2; including a grade 3 event), decreased appetite, nausea, vomiting and grade 3 mucositis (1 each).

Results from a phase I/II study and an open-label extension study of pegzilarginase (ARG1 analog) in pediatric and adult patients with arginase 1 deficiency. The most common treatment-related adverse events (TRAEs; ≥15% of patients) were vomiting (5/16 [31.1%] patients), hypersensitivity (4 [25%]), abdominal pain, hyperammonemia and pruritus (3 [18.8%] each). 5 (31.3%) patients experienced serious TRAEs: 3 had hypersensitivity reactions and 2 had hyperammonemia. Anti-pegzilarginase antibodies occurred in 8/16 (50%) patients.

Analysis of the JADER database comparing the safety profile of lenvatinib (tyrosine kinase inhibitor) in thyroid and hepatocellular carcinomas. Adverse events (AEs) significantly more common in patients with thyroid carcinomas were bleeding, hypertension, cardiac disorders, myelosuppression, acute cholecystitis, delayed wound healing, infection, gastrointestinal perforation and fistula formation, and pneumothorax. AEs significantly more common in patients with hepatocellular carcinomas included liver damage and hepatic encephalopathy. Other AEs without significant difference in rates between groups are listed.

Case report of a 49-year-old man with pachydermoperiostosis associated a homozygous mutation in SLCO2A1 (c.1807C>T). He was also diagnosed with SLCO2A1-associated chronic enteropathy.

Case series of 3 patients with COVID-19 who developed severe neutropenia associated with metamizole (COX-1/2 inhibitor). 1 patient also developed hypoxemic respiratory failure, agranulocytosis and erythrophagocytosis. Another patient developed leukopenia, severe mixed hypercapnic-hypoxemic respiratory failure, septic shock associated with acute kidney injury, electrolytes imbalance and finally died.

Case report of a 42-year-old man who suffered from an acute uveitis after being treated with miltefosine (100 mg) for a post-kala-azar dermal leishmaniasis.

Review on novel therapies for the treatment of diffuse large B-cell lymphoma. Safety issues are listed.

Phase II study of MIN-117 (5-HT1A/5-HT2A receptor antagonist and DAT/SERT inhibitor; 2.5 or 5.0 mg qd) in 360 adult patients with major depressive disorder. Serious adverse events (AEs) were suicidal ideation and feeling guilty (1/92 patients in the 2.5 mg group each). Non-serious headache was reported in 11/92 patients in the 2.5 mg group (11.96%), 11/91 in the 5.0 mg group (12.09%) and 13/177 in the placebo group (7.34%). Clinical Trial Registry

Case report of a 62-year-old woman with brain metastasis who developed bone marrow suppression (grade 3 thrombocytopenia and grade 2 neutropenia) after receiving niraparib (PARP-1/2 inhibitor; 200 mg qd).

Study of relebactam/imipenem/cilastatin in 12 healthy Chinese participants. The most common adverse event (AE) was nausea. Drug-related AEs were retching, dizziness, dysgeusia, headache and oropharyngeal pain. Patients on multiple-dose relebactam/imipenem/cilastatin reported tongue discoloration, loss of taste and loss of appetite. Other AEs are listed.

Case report of a mother and her child carrying a pathogenic CDC42 variant (c.511G>A; p.Glu171Lys). Both affected individuals presented short stature, distinctive craniofacial features, pectus deformity and heart and eye anomalies associated with Noonan syndrome. 1 patient also exhibited aplasia cutis congenita of the scalp.

Subgroup analysis from a phase III study including 51 Japanese patients who received apalutamide (APA; androgen receptor antagonist) or placebo for metastatic castration-sensitive prostate cancer. Treatment-emergent adverse events (TEAEs) of special interest were consistent with those seen in the overall population, with the exception of a higher incidence of skin rash (14/28 [50%] patients in the Japanese population vs 142/524 [27.1%] in the overall population). The most frequent TEAEs (≥10% of patients) in the Japanese subgroup included viral upper respiratory tract infection (11/28 [39.3%] patients with APA; 6/23 [26.6%] with placebo), hot flush (9 [32.1%]; 6 [26.1%]), pruritus (7 [25.0%]; 2 [8.7%]) and rash (7 [25.0%]; 0). Grade 3-4 TEAEs with APA were hypertension (3 [10.7%]), generalized rash (2 [7.1%]), maculopapular rash and rash (1 [3.6%] each). Other TEAEs are listed.

Phase I study evaluating the safety and pharmacokinetics of MSI-195 (PDE4B inhibitor; 400-1,600 mg) in healthy volunteers. Common treatment-related adverse events (TRAEs) reported in stage 1 included upper abdominal pain, dizziness (3/24 subjects each), abdominal pain and flatulence (2 each). TRAEs observed in stage 2 included somnolence (6/24 fed subjects; 2/26 fasted subjects), headache (4; 1) and abdominal pain (2; 2). Other TRAEs of MSI-195 or the commercial reference compound (SAM-e Complete) are listed.

Retrospective study of blinatumomab (CD19/CD3 interacting agent; 5 mcg/m2 qd) in 38 pediatric patients with relapsed/refractory acute lymphoblastic leukemia. The most common adverse event (AE) was hematological toxicity, including grade 3/4 AEs of neutropenia (31 [83%] patients during the first cycle), anemia, thrombocytopenia (24 [63%] each) and febrile neutropenia (20 [52%]). 20/38 (52%) patients experienced cytokine release syndrome during the first cycle, and 40/78 (51%) over all cycles. 8 (15%) cases of neurotoxicity were reported including tremor, seizure, slurred speech and loss of sense of vibration. Grade 4/5 sepsis occurred in 7 patients during the first cycle, including 2 patients who died from systemic mycotic infection with rhizomucor pusillus (1 patient), and acute respiratory distress syndrome with evidence of pseudomonas aeruginosa in the sputum (1). Other AEs are listed.

Results from 2 first-in-human phase I studies of FP-025 (MMP12 inhibitor; 50-800 mg) in 96 healthy subjects. 1 subject receiving FP-025 at 800 mg in the single-ascending dose study experienced drug-related diarrhea. Drug-related adverse events reported in the multiple-ascending dose study were headache (2 subjects), fatigue, cough, eye irritation, erythema, dizziness and rash (1 each).

First case report of a 75-year-old man with cecum cancer who suffered rectourethral fistula during treatment with bevacizumab (VEGF inhibitor).

Phase II study of M2951 (evobrutinib; BTK inhibitor; 25 mg qd, 75 mg qd or 50 mg bid) in 469 patients with systemic lupus erythematosus. Serious adverse events (AEs; ≥2 patients in any treatment group) were non-cardiac chest pain (2 patients each in the 25 mg qd and 50 mg bid vs 0 with placebo) and otitis media (2 in the 75 mg qd group vs 0). Non-serious AEs (>placebo in any treatment group) included urinary tract infection (21/118 [17.8%] with 25 mg qd; 26/117 [22.2%] with 75 mg qd; 21/117 [18.0%] with 50 mg bid; 16/117 [13.7%] with placebo), diarrhea (12 [10.2%]; 17 [14.5%]; 10 [8.6%]; 11 [9.4%]), nasopharyngitis (13 [11.0%]; 15 [12.8%]; 7 [6.0%]; 8 [6.8%]) and upper respiratory tract infection (15 [12.7%]; 6 [5.1%]; 8 [6.8%]; 12 [10.3%]). Other non-serious AEs are listed. Clinical Trial Registry

Phase I study comparing durvalumab plus dabrafenib and trametinib (cohort A) to combined durvalumab and trametinib given concomitantly (cohort B) or sequentially (cohort C) in patients with advanced melanoma. The most common treatment-related adverse events (TRAEs) were pyrexia (20/26 [76.9%]), chills (17 [65.4%]) and fatigue (16 [61.5%]) in cohort A; diarrhea (11/20 [55%]), rash (7 [35%]) and acneiform dermatitis (6 [30%]) in cohort B; and rash (11/22 [50%]), diarrhea (9 [40.9%]) and vomiting (8 [36.4%]) in cohort C. Other TRAEs are listed.

Systematic review and meta-analysis of 10 randomized trials assessing the effectiveness of atropine (muscarinic receptor antagonist; 0.05-1%) for controlling the progression of myopia. The most common adverse events (AEs) were photophobia, reading problems, headache, allergic or hypersensitivity reactions and discomfort. Other AEs are listed.

Preclinical studies evaluating the safety of intravitreal FHTR2163 (serine protease HTRA1 inhibitor) in cynomolgus monkeys. Transient retinal detachment was observed in monkeys receiving 100 mcL of FHTR2163. Other ocular effects included inflammation and perivascular infiltration, consistent with immune responses. Anti-FHTR2163 antibodies were detected in 90% animals. Other safety issues are listed.

Systematic review and meta-analysis of clinical trials evaluating the efficacy of dexmedetomidine (alpha2-adrenoceptor agonist) in critically ill patients with delirium. The risk of bradycardia was significantly higher in patients treated with dexmedetomidine than in those receiving other drugs (OR = 3.48 [95% CI: 1.47-8.23]).

Case report of a premature male neonate who presented severe intrauterine growth retardation, microcytic anemia, and fulminant liver failure associated with a compound heterozygote for 2 novel deleterious mutations in LARS1. He was diagnosed with infantile liver failure syndrome type 1 and suffered lethal hepatocellular injury and skeletal muscular dysgenesis.

Study in mice investigating the mechanisms of thalidomide-induced peripheral neuropathy. Thalidomide (1-100 mg/kg) caused mechanical allodynia by activating TRPA1 and TRPV4 channels, and caused cold allodynia via TRPA1 activation. In vitro assays in rat neurons suggested that oxidative stress may be involved in thalidomide-induced allodynia. Similar results were observed in mice receiving pomalidomide (1 mg/kg) or lenalidomide (5 mg/kg). Other safety issues are listed.

Study in mice suggesting that angiotensin II causes depressive-like behaviors and hippocampal inflammation via microglial activation. Other adverse events observed in the study included ventricular hypertrophy and perivascular infiltration/fibrosis, indicative of a hypertensive state.

Study in mice and human HEK293 cells investigating the role of MRGPRX2 in clozapine-induced pseudo-allergic reactions. Clozapine induced paw swelling, mast cell degranulation and vasodilation when administered to mice. In vitro observations suggested that MRGPRX2 may be involved in these pseudo-allergic reactions.

Pharmacovigilance analysis evaluating the risk of drug-induced stuttering using data from VigiBase. 724 reports of stuttering were identified. The main drugs involved were methylphenidate (ROR = 19.58 [95% CI: 13.3-28.8]), topiramate (12.5 [7.1-22.1]), olanzapine (12 [8-17.9]) and golimumab (10.2 [5.5-19.1]).

Phase I/II study of BMS-986277 in 10 patients with cancer. Serious adverse events (AEs) included ascites, cytokine release syndrome and dehydration (1 patient each). Non-serious AEs are listed. The study was terminated due to business decisions. Clinical Trial Registry