Hyaluronidase

July 10, 2026 2:10 pm EDT First and only PD-1 inhibitor plus antibody-drug conjugate regimens approved for patients with MIBC regardless of cisplatin eligibility Approvals based on Phase 3 KEYNOTE-B15 trial, combined with previous approvals based on Phase 3 KEYNOTE-905 trial, bring forward new options for these patients RAHWAY, N.J.--(BUSINESS WIRE)-- Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced the U.S. Food and Drug Administration (FDA) approved KEYTRUDA® (pembrolizumab) and KEYTRUDA QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph), Merck’s anti-PD-1 therapies, each in combination with Padcev® (enfortumab vedotin-ejfv), as neoadjuvant treatment and then continued after cystectomy as adjuvant treatment for the treatment of adult patients with muscle-invasive bladder cancer (MIBC). These approvals represent the first and only PD-1 inhibitor plus antibody-drug conjugate (ADC) regimens approved for adults with MIBC regardless of cisplatin eligibility. These approvals are based on data from the Phase 3 KEYNOTE-B15 trial (also known as EV-304), which was conducted in collaboration with Pfizer and Astellas and enrolled 808 patients. They also expand the previously approved indication based on the Phase 3 KEYNOTE-905 trial (also known as EV-303) for KEYTRUDA and KEYTRUDA QLEX, each in combination with Padcev, in the U.S. as treatment before and after surgery for adult patients with MIBC who are ineligible for cisplatin-based chemotherapy. In KEYNOTE-B15, KEYTRUDA plus Padcev, given before and after surgery, demonstrated a statistically significant improvement in event-free survival (EFS), reducing the risk of EFS events (defined as disease progression, recurrence or death) by 47% (HR=0.53 [95% CI, 0.41-0.70]; p<0.0001; 87/405 [21%] versus 146/403 [36%]) in patients with MIBC who are eligible for cisplatin-based chemotherapy compared to neoadjuvant chemotherapy (gemcitabine and cisplatin) and surgery. Median EFS was not reached (NR) (95% CI, NR-NR) for perioperative KEYTRUDA plus Padcev versus 48.5 months (95% CI, 43.3-NR) for neoadjuvant chemotherapy and surgery. KEYTRUDA plus Padcev also demonstrated a statistically significant improvement in overall survival (OS), reducing the risk of death by 35% (HR=0.65 [95% CI, 0.48-0.89]; p=0.0029; 69/405 [17%] versus 99/403 [25%]) in these patients when compared to neoadjuvant chemotherapy and surgery. Median OS was NR (95% CI, NR-NR) for either regimen. The trial showed KEYTRUDA plus Padcev demonstrated a statistically significant improvement in pathologic complete response (pCR) rate compared to neoadjuvant chemotherapy (55.8% [95% CI: 50.8, 60.7] versus 32.5% [95% CI: 28.0, 37.3]; p<0.0001). The effectiveness of KEYTRUDA QLEX for its approved indications has been established based upon evidence from the adequate and well-controlled studies conducted with KEYTRUDA and additional data from MK-3475A-D77 comparing the pharmacokinetic, efficacy and safety profiles of KEYTRUDA QLEX and KEYTRUDA. KEYTRUDA QLEX is contraindicated in patients with known hypersensitivity to berahyaluronidase alfa, hyaluronidase or to any of its excipients. KEYTRUDA and KEYTRUDA QLEX are associated with the following Warnings and Precautions: severe and fatal immune-mediated adverse reactions in any or multiple organs, which can occur during or after treatment, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, other transplant (including corneal graft) rejection; severe and life-threatening infusion or injection-related reactions; fatal and other serious complications in patients who receive allogeneic hematopoietic stem cell transplantation before or after beginning treatment; embryo-fetal toxicity; and increased mortality in patients with multiple myeloma when KEYTRUDA or KEYTRUDA QLEX is added to a thalidomide analogue plus dexamethasone, which is not recommended outside of controlled trials. Immune-mediated adverse reactions listed here may not include all such possible severe or fatal reactions. For more information, see “Selected Safety Information” below. “Today’s FDA approvals represent a meaningful development for patients who have muscle-invasive bladder cancer, as nearly half of these patients experience disease recurrence following bladder removal surgery,” said Dr. Matthew Galsky, Lillian and Howard Stratton professor of medicine, Icahn School of Medicine at Mount Sinai, director of genitourinary medical oncology, Mount Sinai Tisch Cancer Center. “This shift away from traditional cisplatin-based chemotherapy, which has been recommended for eligible patients for more than 20 years, provides important new treatment options for individuals with muscle-invasive bladder cancer regardless of cisplatin eligibility.” “We’re expanding the use of KEYTRUDA and KEYTRUDA QLEX, each in combination with Padcev, for patients with muscle-invasive bladder cancer who are eligible for cisplatin-based chemotherapy with these approvals,” said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. “The results from KEYNOTE-B15, together with KEYNOTE-905, highlight the potential of these new treatment options for patients regardless of cisplatin eligibility in the perioperative setting and mark a promising step forward in the treatment of muscle-invasive bladder cancer." Study design and additional data from KEYNOTE-B15 supporting this approval KEYNOTE-B15, also known as EV-304, is an open-label, randomized, multicenter, active-control Phase 3 trial (ClinicalTrials.gov, NCT04700124) evaluating perioperative KEYTRUDA in combination with Padcev and surgery (radical cystectomy [RC] and pelvic lymph node dissection [PLND]) versus neoadjuvant chemotherapy (gemcitabine plus cisplatin) and surgery in patients with previously untreated MIBC who are eligible for cisplatin-based chemotherapy. The trial enrolled 808 patients who were randomized 1:1 to receive either: Neoadjuvant KEYTRUDA 200 mg intravenously on Day 1 and Padcev 1.25 mg/kg intravenously on Days 1 and 8 of each 21-day cycle for four cycles prior to surgery, followed by adjuvant KEYTRUDA 200 mg on Day 1 of each 21-day cycle for 13 cycles and adjuvant Padcev 1.25 mg/kg on Days 1 and 8 of each 21-day cycle for five cycles (n=405), or; Neoadjuvant gemcitabine 1000 mg/m 2 on Days 1 and 8 and cisplatin 70 mg/m 2 on Day 1 of each 21-day cycle for four cycles prior to surgery, followed by observation (n=403). The major efficacy outcome measure was EFS as assessed by blinded independent central review (BICR), defined as the time from randomization to the first occurrence of the following events: disease progression preventing curative surgery, failure to undergo surgery for participants with muscle invasive residual disease, incomplete surgical resection, local or distant recurrence after surgery or death. Additional efficacy outcome measures were OS and pCR rate as assessed by blinded independent pathology review. Treatment continued until completion of study medications, disease progression, not undergoing or refusal of RC and PLND, disease recurrence in the adjuvant phase or unacceptable toxicity. Assessment of tumor status, including CT/MRI, was performed at baseline, within five weeks prior to RC and PLND, and at six weeks post-RC. Following RC and PLND, assessment of tumor status, including cystoscopy and urine cytology for patients who did not undergo surgery, was performed every 12 weeks up to two years and every 24 weeks thereafter. A total of 351 (87%) patients receiving KEYTRUDA in combination with Padcev and 361 (90%) patients receiving gemcitabine with cisplatin underwent RC and PLND. A total of 25 (6%) of patients in the gemcitabine with cisplatin arm received adjuvant nivolumab. The trial was not designed to isolate the effect of KEYTRUDA in each phase (neoadjuvant or adjuvant) of treatment. For the 403 patients who received KEYTRUDA in the neoadjuvant phase, the median duration of exposure to KEYTRUDA 200 mg every three weeks was 2.1 months (range: 1 day to 3.9 months) and the median number of cycles of KEYTRUDA was four (range: 1 to 4) out of the planned four cycles in the neoadjuvant phase. For the 262 patients randomized to receive KEYTRUDA in combination with Padcev and who received any adjuvant treatment, 249 patients received KEYTRUDA in the adjuvant phase. The median duration of exposure to KEYTRUDA 200 mg every three weeks was 8.3 months (range: 1 day to 18.9 months) and the median number of cycles of KEYTRUDA was 13 (range: 1 to 13) out of the planned 13 cycles for patients who received KEYTRUDA in the adjuvant phase. Across the combined neoadjuvant and adjuvant phases (n=403), the median number of cycles of KEYTRUDA was 10 (range: 1 to 17) out of the planned 17 cycles. In the neoadjuvant phase of KEYNOTE-B15, serious adverse reactions occurred in 27% of patients who received KEYTRUDA in combination with Padcev. The most frequent (≥1.5%) serious adverse reactions were rash (3.2%), pneumonitis/interstitial lung disease (ILD) (2.2%) and diarrhea (1.7%). Fatal adverse reactions occurred in 1.7% of patients, including multiple organ dysfunction syndrome (0.5%) and COVID-19 pneumonia, cardiac arrest, pneumonia, septic shock and urosepsis (0.2% each). Additional fatal adverse reactions were reported in two patients in the post-surgery phase before adjuvant treatment started, including pneumonia and sepsis (one patient each). Permanent discontinuation of KEYTRUDA in the neoadjuvant phase due to an adverse reaction occurred in 17% of patients. The most frequent (>1%) adverse reactions resulting in permanent discontinuation of KEYTRUDA were rash (2.2%), increased alanine aminotransferase (ALT) and pneumonitis/ILD (1.7% each) and hepatitis (1.2%). Adverse reactions leading to dose interruption of KEYTRUDA in the neoadjuvant phase occurred in 29% of patients. The most common adverse reactions (≥2%) leading to dose interruption of KEYTRUDA were rash (8%), increased ALT (3.7%), neutropenia (3.2%) and hyperglycemia (2.5%). Of the 403 patients who received neoadjuvant treatment with KEYTRUDA in combination with Padcev, 13 patients (3.2%) did not receive surgery due to adverse reactions. The adverse reactions that led to cancellation of surgery were multiple organ dysfunction syndrome (0.5%) and adenocarcinoma of colon, COVID-19 pneumonia, cardiac arrest, chronic obstructive pulmonary disease, coronary artery disease, glomerulonephritis, immune-mediated lung disease, myocarditis, pneumonia, pneumonitis and urosepsis (0.2% each). Of the 351 patients who received neoadjuvant treatment with KEYTRUDA in combination with Padcev and underwent RC, 26 (7%) patients experienced delay of surgery (defined as time from last neoadjuvant treatment to surgery exceeding eight weeks) due to adverse reactions. In the adjuvant phase of KEYNOTE-B15, serious adverse reactions occurred in 35% of patients who received KEYTRUDA in the adjuvant phase; the most frequent (≥1.5%) serious adverse reactions were urinary tract infection (8%), sepsis (2.8%), diarrhea, hyperglycemia and pneumonitis/ILD (1.6% each). Fatal adverse reactions occurred in 3.2% of patients who received KEYTRUDA in the adjuvant phase, including death (0.8%) and cardiac arrest, duodenal ulcer perforation, acute pancreatitis, renal failure, small cell lung cancer and toxic shock syndrome (0.4% each). Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 23% of patients who received KEYTRUDA in the adjuvant phase. The most frequent (>1%) adverse reactions resulting in permanent discontinuation of KEYTRUDA were diarrhea and pneumonitis/ILD (2.4% each), rash (2%), and hyperglycemia and sepsis (1.2% each). Adverse reactions leading to dose interruption of KEYTRUDA in the adjuvant phase occurred in 39% of patients who received KEYTRUDA in the adjuvant phase. The most common adverse reactions (≥2%) leading to dose interruption of KEYTRUDA were diarrhea (6%), urinary tract infection (5%), COVID-19 (3.6%), rash (2.8%) and nausea (2%). Study design and additional data from KEYNOTE-905 supporting the previous approval KEYNOTE-905, also known as EV-303, is an open-label, randomized, multi-arm, controlled Phase 3 trial (ClinicalTrials.gov, NCT03924895) evaluating perioperative KEYTRUDA, with or without Padcev, versus surgery alone in patients with MIBC who are either not eligible for or declined cisplatin-based chemotherapy. The trial was conducted in collaboration with Pfizer and Astellas and enrolled 344 patients who were randomized 1:1 to receive either: Neoadjuvant KEYTRUDA 200 mg intravenously on Day 1 and Padcev 1.25 mg/kg intravenously on Days 1 and 8 of each 21-day cycle for three cycles prior to surgery, followed by adjuvant KEYTRUDA 200 mg on Day 1 of each 21-day cycle for 14 cycles and adjuvant Padcev 1.25 mg/kg on Days 1 and 8 of each 21-day cycle for six cycles (n=170). Immediate RC and PLND alone (n=174). The major efficacy outcome measure was EFS as assessed by BICR, defined as the time from randomization to the first occurrence of the following events: disease progression preventing curative surgery, failure to undergo surgery for participants with muscle invasive residual disease, incomplete surgical resection, local or distant recurrence after surgery or death. Overall survival and pCR rate as assessed by blinded independent pathology review were additional efficacy outcome measures. In KEYNOTE-905, KEYTRUDA plus Padcev, given before and after surgery, demonstrated a statistically significant improvement in EFS, reducing the risk of EFS events by 60% (HR=0.40 [95% CI, 0.28-0.57]; p<0.0001; 48/170 [28%] versus 95/174 [55%]) compared to surgery alone in patients with MIBC who are not eligible for or declined cisplatin-based chemotherapy. Median EFS was not reached (NR) (95% CI, 37.3-NR) for perioperative KEYTRUDA plus Padcev versus 15.7 months (95% CI, 10.3-20.5) for surgery alone. KEYTRUDA plus Padcev also demonstrated a statistically significant improvement in OS, reducing the risk of death by 50% (HR=0.50 [95% CI, 0.33-0.74]; p=0.0002; 38/170 [22%] versus 68/174 [39%]) in these patients when compared to surgery alone. Median OS was NR (95% CI, NR-NR) for the regimen containing KEYTRUDA plus Padcev compared to 41.7 months (95% CI, 31.8-NR) for surgery alone. The trial showed KEYTRUDA plus Padcev demonstrated a statistically significant improvement in pCR rate compared to surgery alone (57.1% [95% CI: 49.3, 64.6] versus 8.6% [95% CI: 4.9, 13.8]; p<0.0001). The effectiveness of KEYTRUDA QLEX for its approved indications has been established based upon evidence from the adequate and well-controlled studies conducted with KEYTRUDA and additional data from MK-3475A-D77 comparing the pharmacokinetic, efficacy, and safety profiles of KEYTRUDA QLEX and KEYTRUDA. A total of 149 (88%) patients in the arm receiving KEYTRUDA in combination with Padcev and 156 (90%) patients in the RC and PLND alone arm underwent RC and PLND. A total of 29 (17%) of patients in the RC and PLND alone arm received adjuvant nivolumab. The trial was not designed to isolate the effect of KEYTRUDA in each phase (neoadjuvant or adjuvant) of treatment. Treatment continued until completion of study medications, disease progression, not undergoing or refusal of RC and PLND, disease recurrence in the adjuvant phase, or unacceptable toxicity. Assessment of tumor status, including CT/MRI, was performed at baseline, within five weeks prior to RC and PLND and at six weeks post-radical cystectomy. Following RC and PLND, assessment of tumor status, including cystoscopy and urine cytology for patients who did not undergo surgery, was performed every 12 weeks up to two years and every 24 weeks thereafter. For the 167 patients who received KEYTRUDA in the neoadjuvant phase, the median duration of exposure to KEYTRUDA 200 mg every three weeks was 1.4 months (range: 1 day to 2.7 months) and the median number of cycles of KEYTRUDA was three (range: 1 to 3) out of the planned three cycles in the neoadjuvant phase. For the 100 patients randomized to receive KEYTRUDA in combination with Padcev and who received any adjuvant treatment, 96 patients received KEYTRUDA in the adjuvant phase. The median duration of exposure to KEYTRUDA 200 mg every three weeks was 8.5 months (range: 1 day to 12.9 months) and the median number of cycles of KEYTRUDA was 12 (range: 1 to 14) out of the planned 14 cycles for patients who received KEYTRUDA in the adjuvant phase. Across the combined neoadjuvant and adjuvant phases (n=167), the median number of cycles of KEYTRUDA was five (range: 1 to 17) out of the planned 17 cycles. In the neoadjuvant phase, serious adverse reactions occurred in 27% of patients receiving KEYTRUDA in combination with Padcev. The most frequent (≥2%) serious adverse reactions were urinary tract infection (3.6%) and hematuria (2.4%). Fatal adverse reactions occurred in 1.2% of patients, including myasthenia gravis and toxic epidermal necrolysis (0.6% each). Additional fatal adverse reactions were reported in 2.7% of patients in the post-surgery phase before adjuvant treatment started, including sepsis and intestinal obstruction (1.4% each). Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 15% of patients. The most frequent (>1%) adverse reactions resulting in permanent discontinuation of KEYTRUDA were rash (2.4%, including generalized exfoliative dermatitis), increased ALT, increased aspartate aminotransferase (AST), diarrhea, dysgeusia and toxic epidermal necrolysis (1.2% each). Adverse reactions leading to dose interruption of KEYTRUDA in the neoadjuvant phase occurred in 20% of patients. The most common adverse reactions (≥2%) leading to dose interruption of KEYTRUDA were rash (4.8%) and neutropenia (2.4%). Of the 167 patients in the KEYTRUDA in combination with Padcev arm who received neoadjuvant treatment, seven (4.2%) patients did not receive surgery due to adverse reactions. The adverse reactions that led to cancellation of surgery were acute myocardial infarction, bile duct cancer, colon cancer, respiratory distress, urinary tract infection, and the two deaths due to myasthenia gravis and toxic epidermal necrolysis (0.6% each). Of the 146 patients who received neoadjuvant treatment with KEYTRUDA in combination with Padcev and underwent radical cystectomy, six (4.1%) patients experienced delay of surgery (defined as time from last neoadjuvant treatment to surgery exceeding eight weeks) due to adverse reactions. In the adjuvant phase, serious adverse reactions occurred in 45% of patients who received KEYTRUDA in the adjuvant phase; the most frequent (≥2%) serious adverse reactions were urinary tract infection (8%), acute kidney injury and pyelonephritis (5% each), urosepsis (4.2%), and hypokalemia, intestinal obstruction and sepsis (2.1% each). Fatal adverse reactions occurred in 7% of patients who received KEYTRUDA in the adjuvant phase, including urosepsis, intracranial hemorrhage, death, myocardial infarction, multiple organ dysfunction syndrome and pseudomonal pneumonia (1% each). Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 29% of patients who received KEYTRUDA in the adjuvant phase. The most frequent (>2%) adverse reactions resulting in permanent discontinuation of KEYTRUDA were diarrhea (5%) and peripheral neuropathy, acute kidney injury and pneumonitis (2% each). Adverse reactions leading to dose interruption of KEYTRUDA in the adjuvant phase occurred in 40% of patients who received KEYTRUDA in the adjuvant phase. The most common adverse reactions (≥2%) leading to dose interruption of KEYTRUDA were rash (7%), urinary tract infection (6%), diarrhea (4%) and abdominal pain, COVID-19, fatigue, pruritus and pyelonephritis (2% each). About bladder cancer Bladder cancer is the eighth most common cancer worldwide, diagnosed in more than 635,000 patients each year globally. In the U.S., it is estimated there will be more than 84,000 new cases of bladder cancer diagnosed and more than 17,000 deaths from the disease in 2026. According to some clinical practice guidelines, about 25% of newly diagnosed bladder cancer cases are MIBC. The standard of care for patients with MIBC is neoadjuvant cisplatin-based chemotherapy followed by surgery, which is shown to prolong survival. However, nearly half of patients who undergo this standard treatment experience recurrence. Additionally, up to half of patients with MIBC are not eligible to receive cisplatin and face limited treatment options, typically undergoing surgery alone. About Merck’s research in genitourinary cancers Merck is advancing research aimed at helping transform the treatment landscape and broaden options for people with genitourinary (GU) cancers, including bladder, kidney and prostate cancers. Globally, GU cancers account for an estimated 2.6 million new cancer diagnoses each year, equaling over 1 in 8 of all cancer incidences. Through a robust clinical development program with more than 50 ongoing clinical trials evaluating more than 22,000 patients around the world, Merck is investigating the potential of several portfolio medicines and pipeline assets, leveraging multiple novel combination strategies, across various stages of disease, to help address unmet needs in GU cancers. About Merck’s early-stage cancer clinical program Finding cancer at an earlier stage may give patients a greater chance of long-term survival. Many cancers are considered most treatable and potentially curable in their earliest stage of disease. Building on the strong understanding of the role of KEYTRUDA in later-stage cancers, Merck is evaluating our portfolio of medicines and pipeline candidates in earlier disease states, with more than 30 ongoing registrational studies across multiple types of cancer. About KEYTRUDA® (pembrolizumab) injection for intravenous use, 100 mg KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells. Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 2,800 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers. About KEYTRUDA QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph) injection for subcutaneous use, 165 mg + 2,000 units/mL KEYTRUDA QLEX is a fixed-combination drug product of pembrolizumab and berahyaluronidase alfa. Pembrolizumab is a programmed death receptor-1 (PD-1) blocking antibody and berahyaluronidase alfa enhances dispersion and permeability to enable subcutaneous administration of pembrolizumab. KEYTRUDA QLEX is administered as a subcutaneous injection into the thigh or abdomen, avoiding the 5 cm area around the navel, over one minute every three weeks (2.4 mL) or over two minutes every six weeks (4.8 mL). Selected Indications in the U.S. for KEYTRUDA® (pembrolizumab) and KEYTRUDA QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph). Urothelial Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with enfortumab vedotin-ejfv, for the treatment of adult patients with locally advanced or metastatic urothelial cancer. KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma: who are not eligible for any platinum-containing chemotherapy, or who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with enfortumab vedotin-ejfv, as neoadjuvant treatment and then continued after cystectomy as adjuvant treatment for the treatment of adult patients with muscle invasive bladder cancer (MIBC). KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated for the treatment of adult patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. See additional selected indications in the U.S. for KEYTRUDA and KEYTRUDA QLEX after the Selected Safety Information. Selected Safety Information for KEYTRUDA and KEYTRUDA QLEX Contraindications KEYTRUDA QLEX is contraindicated in patients with known hypersensitivity to berahyaluronidase alfa, hyaluronidase or to any of its excipients. Severe and Fatal Immune-Mediated Adverse Reactions KEYTRUDA and KEYTRUDA QLEX are monoclonal antibodies that belong to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA or KEYTRUDA QLEX in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue KEYTRUDA and KEYTRUDA QLEX depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA and KEYTRUDA QLEX require interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy. Immune-Mediated Pneumonitis KEYTRUDA and KEYTRUDA QLEX can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients. Immune-mediated pneumonitis occurred in 5% (13/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including fatal (0.4%), Grade 3 (2%), and Grade 2 (1.2%) adverse reactions. Pneumonitis occurred in 7% (41/580) of adult patients with resected NSCLC who received KEYTRUDA as a single agent for adjuvant treatment of NSCLC, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. Patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% had resolution. Immune-Mediated Colitis KEYTRUDA and KEYTRUDA QLEX can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients. Immune-mediated colitis occurred in 1.2% (3/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 3 (0.8%) and Grade 2 (0.4%) adverse reactions. Hepatotoxicity and Immune-Mediated Hepatitis KEYTRUDA and KEYTRUDA QLEX can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients. Immune-mediated hepatitis occurred in 0.4% (1/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (0.4%) adverse reactions. KEYTRUDA With Axitinib or KEYTRUDA QLEX With Axitinib KEYTRUDA and KEYTRUDA QLEX, when either is used in combination with axitinib, can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib or KEYTRUDA QLEX and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT ≥3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event. Immune-Mediated Endocrinopathies Adrenal Insufficiency KEYTRUDA and KEYTRUDA QLEX can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA and KEYTRUDA QLEX depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Adrenal insufficiency occurred in 2% (5/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 3 (0.4%) and Grade 2 (0.8%) adverse reactions. Hypophysitis KEYTRUDA and KEYTRUDA QLEX can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA and KEYTRUDA QLEX depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Thyroid Disorders KEYTRUDA and KEYTRUDA QLEX can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA and KEYTRUDA QLEX depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients. Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hyperthyroidism was higher in 580 patients with resected NSCLC, occurring in 11% of patients receiving KEYTRUDA as a single agent as adjuvant treatment, including Grade 3 (0.2%) hyperthyroidism. The incidence of new or worsening hypothyroidism was higher in 580 patients with resected NSCLC, occurring in 22% of patients receiving KEYTRUDA as a single agent as adjuvant treatment (KEYNOTE-091), including Grade 3 (0.3%) hypothyroidism. Thyroiditis occurred in 0.4% (1/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (0.4%). Hyperthyroidism occurred in 8% (20/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (3.2%). Hypothyroidism occurred in 14% (35/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (11%). Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA and KEYTRUDA QLEX depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Type 1 DM occurred in 0.4% (1/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy. Immune-Mediated Nephritis With Renal Dysfunction KEYTRUDA and KEYTRUDA QLEX can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients. Immune-Mediated Dermatologic Adverse Reactions KEYTRUDA and KEYTRUDA QLEX can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with anti–PD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA and KEYTRUDA QLEX depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients. Immune-mediated dermatologic adverse reactions occurred in 1.6% (4/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 4 (0.8%) and Grade 3 (0.8%) adverse reactions. Other Immune-Mediated Adverse Reactions The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA, KEYTRUDA QLEX, or were reported with the use of other anti–PD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis (2.8%), duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associatedsequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia,aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatoryresponse syndrome, histiocytic necrotizing lymphadenitis (Kikuchilymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organtransplant rejection, other transplant (including corneal graft) rejection; Other: Myocarditis-Myositis-Myasthenia Gravis (or Myasthenia-Like) Overlap syndrome, reported as the co-occurrence of either two or all three adverse reactions. Hypersensitivity and Infusion- or Administration-Related Reactions KEYTRUDA and KEYTRUDA QLEX can cause severe or life-threatening administration-related reactions, including hypersensitivity and anaphylaxis. With KEYTRUDA and KEYTRUDA QLEX, monitor for signs and symptoms of infusion- and administration-related systemic reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. Infusion-related reactions have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA. Hypersensitivity and administration related systemic reactions occurred in 3.2% (8/251) of patients receiving KEYTRUDA QLEX in combination with platinum doublet chemotherapy, including Grade 2 (2.8%). Interrupt injection (if not already fully administered) and resume if symptoms resolve for mild or moderate systemic reactions. For severe or life-threatening systemic reactions, stop injection and permanently discontinue KEYTRUDA QLEX. Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after anti–PD-1/PD-L1 treatments. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between anti–PD-1/PD-L1 treatments and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using anti–PD-1/PD-L1 treatments prior to or after an allogeneic HSCT. Increased Mortality in Patients With Multiple Myeloma In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an anti–PD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials. Embryofetal Toxicity Based on their mechanism of action, KEYTRUDA and KEYTRUDA QLEX can each cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA or KEYTRUDA QLEX and advise them to use effective contraception during treatment and for 4 months after the last dose. Adverse Reactions In study MK-3475A-D77, when KEYTRUDA QLEX was administered with chemotherapy in metastatic non–small cell lung cancer (NSCLC), serious adverse reactions occurred in 39% of patients. Serious adverse reactions in ≥1% of patients who received KEYTRUDA QLEX were pneumonia (10%), thrombocytopenia (4%), febrile neutropenia (4%), neutropenia (2.8%), musculoskeletal pain (2%), pneumonitis (2%), diarrhea (1.6%), rash (1.2%), respiratory failure (1.2%), and anemia (1.2%). Fatal adverse reactions occurred in 10% of patients including pneumonia (3.2%), neutropenic sepsis (2%), death not otherwise specified (1.6%), respiratory failure (1.2%), parotitis (0.4%), pneumonitis (0.4%), pneumothorax (0.4%), pulmonary embolism (0.4%), neutropenic colitis (0.4%), and seizure (0.4%). KEYTRUDA QLEX was permanently discontinued due to an adverse reaction in 16% of 251 patients. Adverse reactions which resulted in permanent discontinuation of KEYTRUDA QLEX in ≥2% of patients included pneumonia and pneumonitis. Dosage interruptions of KEYTRUDA QLEX due to an adverse reaction occurred in 45% of patients. Adverse reactions which required dosage interruption in ≥2% of patients included neutropenia, anemia, thrombocytopenia, pneumonia, rash, and increased aspartate aminotransferase. The most common adverse reactions (≥20%) were nausea (25%), fatigue (25%), and musculoskeletal pain (21%). In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (≥20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%). In KEYNOTE-054, when KEYTRUDA was administered as a single agent to patients with stage III melanoma, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (≥20%) with KEYTRUDA was diarrhea (28%). In KEYNOTE-716, when KEYTRUDA was administered as a single agent to patients with stage IIB or IIC melanoma, adverse reactions occurring in patients with stage IIB or IIC melanoma were similar to those occurring in 1011 patients with stage III melanoma from KEYNOTE-054. In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%). In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407. In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (≥20%) was fatigue (25%). In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (≥20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%). In KEYNOTE-671, adverse reactions occurring in patients with resectable NSCLC receiving KEYTRUDA in combination with platinum-containing chemotherapy, given as neoadjuvant treatment and continued as single-agent adjuvant treatment, were generally similar to those occurring in patients in other clinical trials across tumor types receiving KEYTRUDA in combination with chemotherapy. The most common adverse reactions (reported in ≥20%) in patients receiving KEYTRUDA in combination with chemotherapy or chemoradiotherapy were fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, insomnia, palmar-plantar erythrodysesthesia, urinary tract infection, hypothyroidism, radiation skin injury, dysphagia, dry mouth, and musculoskeletal pain. In the neoadjuvant phase of KEYNOTE-671, when KEYTRUDA was administered in combination with platinum-containing chemotherapy as neoadjuvant treatment, serious adverse reactions occurred in 34% of 396 patients. The most frequent (≥2%) serious adverse reactions were pneumonia (4.8%), venous thromboembolism (3.3%), and anemia (2%). Fatal adverse reactions occurred in 1.3% of patients, including death due to unknown cause (0.8%), sepsis (0.3%), and immune-mediated lung disease (0.3%). Permanent discontinuation of any study drug due to an adverse reaction occurred in 18% of patients who received KEYTRUDA in combination with platinum-containing chemotherapy; the most frequent adverse reactions (≥1%) that led to permanent discontinuation of any study drug were acute kidney injury (1.8%), interstitial lung disease (1.8%), anemia (1.5%), neutropenia (1.5%), and pneumonia (1.3%). Of the KEYTRUDA-treated patients who received neoadjuvant treatment, 6% of 396 patients did not receive surgery due to adverse reactions. The most frequent (≥1%) adverse reaction that led to cancellation of surgery in the KEYTRUDA arm was interstitial lung disease (1%). In the adjuvant phase of KEYNOTE-671, when KEYTRUDA was administered as a single agent as adjuvant treatment, serious adverse reactions occurred in 14% of 290 patients. The most frequent serious adverse reaction was pneumonia (3.4%). One fatal adverse reaction of pulmonary hemorrhage occurred. Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 12% of patients who received KEYTRUDA as a single agent, given as adjuvant treatment; the most frequent adverse reactions (≥1%) that led to permanent discontinuation of KEYTRUDA were diarrhea (1.7%), interstitial lung disease (1.4%), increased aspartate aminotransferase (1%), and musculoskeletal pain (1%). Adverse reactions observed in KEYNOTE-091 were generally similar to those occurring in other patients with NSCLC receiving KEYTRUDA as a single agent, with the exception of hypothyroidism (22%), hyperthyroidism (11%), and pneumonitis (7%). Two fatal adverse reactions of myocarditis occurred. Adverse reactions observed in KEYNOTE-483 were generally similar to those occurring in other patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. In KEYNOTE-689, the most common adverse reactions (≥20%) in patients receiving KEYTRUDA were stomatitis (48%), radiation skin injury (40%), weight loss (36%), fatigue (33%), dysphagia (29%), constipation (27%), hypothyroidism (26%), nausea (24%), rash (22%), dry mouth (22%), diarrhea (22%), and musculoskeletal pain (22%). In the neoadjuvant phase of KEYNOTE-689, of the 361 patients who received at least one dose of single agent KEYTRUDA, 11% experienced serious adverse reactions. Serious adverse reactions that occurred in more than one patient were pneumonia (1.4%), tumor hemorrhage (0.8%), dysphagia (0.6%), immune-mediated hepatitis (0.6%), cellulitis (0.6%), and dyspnea (0.6%). Fatal adverse reactions occurred in 1.1% of patients, including respiratory failure, clostridium infection, septic shock, and myocardial infarction (one patient each). Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 2.8% of patients who received KEYTRUDA as neoadjuvant treatment. The most frequent adverse reaction which resulted in permanent discontinuation of neoadjuvant KEYTRUDA in more than one patient was arthralgia (0.6%). Of the 361 patients who received KEYTRUDA as neoadjuvant treatment, 11% did not receive surgery. Surgical cancellation on the KEYTRUDA arm was due to disease progression in 4%, patient decision in 3%, adverse reactions in 1.4%, physician’s decision in 1.1%, unresectable tumor in 0.6%, loss of follow-up in 0.3%, and use of non-study anti-cancer therapy in 0.3%. Of the 323 KEYTRUDA-treated patients who received surgery following the neoadjuvant phase, 1.2% experienced delay of surgery (defined as on-study surgery occurring ≥9 weeks after initiation of neoadjuvant KEYTRUDA) due to adverse reactions, and 2.8% did not receive adjuvant treatment due to adverse reactions. In the adjuvant phase of KEYNOTE-689, of the 255 patients who received at least one dose of KEYTRUDA, 38% experienced serious adverse reactions. The most frequent serious adverse reactions reported in ≥1% of KEYTRUDA-treated patients were pneumonia (2.7%), pyrexia (2.4%), stomatitis (2.4%), acute kidney injury (2.0%), pneumonitis (1.6%), COVID-19 (1.2%), death not otherwise specified (1.2%), diarrhea (1.2%), dysphagia (1.2%), gastrostomy tube site complication (1.2%), and immune-mediated hepatitis (1.2%). Fatal adverse reactions occurred in 5% of patients, including death not otherwise specified (1.2%), acute renal failure (0.4%), hypercalcemia (0.4%), pulmonary hemorrhage (0.4%), dysphagia/malnutrition (0.4%), mesenteric thrombosis (0.4%), sepsis (0.4%), pneumonia (0.4%), COVID-19 (0.4%), respiratory failure (0.4%), cardiovascular disorder (0.4%), and gastrointestinal hemorrhage (0.4%). Permanent discontinuation of adjuvant KEYTRUDA due to an adverse reaction occurred in 17% of patients. The most frequent (≥1%) adverse reactions that led to permanent discontinuation of adjuvant KEYTRUDA were pneumonitis, colitis, immune-mediated hepatitis, and death not otherwise specified. In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (≥20%) were fatigue (33%), constipation (20%), and rash (20%). In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (≥20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%). In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (≥20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism. In KEYNOTE-A39, when KEYTRUDA was administered in combination with enfortumab vedotin-ejfv to patients with locally advanced or metastatic urothelial cancer (n=440), fatal adverse reactions occurred in 3.9% of patients, including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%). Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with enfortumab vedotin-ejfv; the serious adverse reactions in ≥2% of patients were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%). Permanent discontinuation of KEYTRUDA occurred in 27% of patients. The most common adverse reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA were pneumonitis/ILD (4.8%) and rash (3.4%). The most common adverse reactions (≥20%) occurring in patients treated with KEYTRUDA in combination with enfortumab vedotin-ejfv were rash (68%), peripheral neuropathy (67%), fatigue (51%), pruritus (41%), diarrhea (38%), alopecia (35%), weight loss (33%), decreased appetite (33%), nausea (26%), constipation (26%), dry eye (24%), dysgeusia (21%), and urinary tract infection (21%). In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those ≥2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (≥20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%). In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those ≥2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (≥20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%). In KEYNOTE-B15, the most common adverse reactions (≥20%) occurring in cisplatin-eligible patients with MIBC treated with KEYTRUDA in combination with enfortumab vedotin-ejfv (n=403) were rash (63%), fatigue (48%), pruritus (46%), peripheral neuropathy (43%), diarrhea (36%), alopecia (32%), decreased appetite (29%), nausea and dysgeusia (28% each), constipation (27%), urinary tract infection and dry eye (25% each), weight loss (22%), and hyperglycemia (20%). In the neoadjuvant phase of KEYNOTE-B15, serious adverse reactions occurred in 27% (n=403) of patients; the most frequent (≥ 1.5%) were rash (3.2%), pneumonitis/ILD (2.2%), and diarrhea (1.7%). Fatal adverse reactions occurred in 1.7% of patients, including multiple organ dysfunction syndrome (0.5%), and COVID-19 pneumonia, cardiac arrest, pneumonia, septic shock, and urosepsis (0.2% each). Additional fatal adverse reactions were reported in 2 patients in the post-surgery phase before adjuvant treatment started, including pneumonia and sepsis (1 patient each). Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 17% of patients. The most frequent (>1%) adverse reactions resulting in permanent discontinuation of KEYTRUDA were rash (2.2%), increased alanine aminotransferase (ALT) and pneumonitis/ILD (1.7% each) and hepatitis (1.2%). Of the 403 patients in the KEYTRUDA in combination with enfortumab vedotin-ejfv arm who received neoadjuvant treatment, 13 patients (3.2%) did not receive surgery due to adverse reactions. The adverse reactions that led to cancellation of surgery were multiple organ dysfunction syndrome (0.5%) and adenocarcinoma of colon, COVID-19 pneumonia, cardiac arrest, chronic obstructive pulmonary disease, coronary artery disease, glomerulonephritis, immune-mediated lung disease, myocarditis, pneumonia, pneumonitis, and urosepsis (0.2% each). Of the 351 patients who received neoadjuvant treatment with KEYTRUDA in combination with enfortumab vedotin-ejfv and underwent radical cystectomy, 26 patients (7%) experienced delay of surgery (defined as time from last neoadjuvant treatment to surgery exceeding 8 weeks) due to adverse reactions. In the adjuvant phase of KEYNOTE-B15, serious adverse reactions occurred in 35% (n=249) of patients who received KEYTRUDA in the adjuvant phase. The most frequent (≥1.5%) were urinary tract infection (8%), sepsis (2.8%), diarrhea, hyperglycemia, and pneumonitis/ILD (1.6% each). Fatal adverse reactions occurred in 3.2% of patients, including death (0.8%) and cardiac arrest, duodenal ulcer perforation, acute pancreatitis, renal failure, small cell lung cancer and toxic shock syndrome (0.4% each). Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 23% of patients; the most frequent (>1%) were diarrhea and pneumonitis/ILD (2.4% each), rash (2%), and hyperglycemia and sepsis (1.2% each). In KEYNOTE-905, the most common adverse reactions (≥20%) occurring in cisplatin-ineligible patients with MIBC treated with KEYTRUDA in combination with enfortumab vedotin-ejfv (n=167) were rash (54%), pruritus (47%), fatigue (47%), peripheral neuropathy (39%), alopecia (35%), dysgeusia (35%), diarrhea (34%), constipation (28%), decreased appetite (28%), nausea (26%), urinary tract infection (24%), dry eye (21%), and weight loss (20%). In the neoadjuvant phase of KEYNOTE-905, serious adverse reactions occurred in 27% (n=167) of patients; the most frequent (≥2%) were urinary tract infection (3.6%) and hematuria (2.4%). Fatal adverse reactions occurred in 1.2% of patients, including myasthenia gravis and toxic epidermal necrolysis (0.6% each). Additional fatal adverse reactions were reported in 2.7% of patients in the post-surgery phase before adjuvant treatment started, including sepsis and intestinal obstruction (1.4% each). Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 15% of patients; the most frequent (>1%) were rash (2.4%, including generalized exfoliative dermatitis), increased alanine aminotransferase, increased aspartate aminotransferase, diarrhea, dysgeusia, and toxic epidermal necrolysis (1.2% each). Of the 167 patients in the KEYTRUDA in combination with enfortumab vedotin-ejfv arm who received neoadjuvant treatment, 7 (4.2%) patients did not receive surgery due to adverse reactions. The adverse reactions that led to cancellation of surgery were acute myocardial infarction, bile duct cancer, colon cancer, respiratory distress, urinary tract infection, and two deaths due to myasthenia gravis and toxic epidermal necrolysis (0.6% each). Of the 146 patients who received neoadjuvant treatment with KEYTRUDA in combination with enfortumab vedotin-ejfv and underwent radical cystectomy, 6 (4.1%) patients experienced delay of surgery (defined as time from last neoadjuvant treatment to surgery exceeding 8 weeks) due to adverse reactions. In the adjuvant phase of KEYNOTE-905, serious adverse reactions occurred in 45% (n=96) of patients; the most frequent (≥2%) were urinary tract infection (8%); acute kidney injury and pyelonephritis (5% each); urosepsis (4.2%); and hypokalemia, intestinal obstruction, and sepsis (2.1% each). Fatal adverse reactions occurred in 7% of patients, including urosepsis, intracranial hemorrhage, death, myocardial infarction, multiple organ dysfunction syndrome, and pseudomonal pneumonia (1% each). Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 29% of patients; the most frequent (>2%) were diarrhea (5%), peripheral neuropathy, acute kidney injury, and pneumonitis (2% each). In KEYNOTE-057, KEYTRUDA was discontinued due to adverse reactions in 11% of 148 patients with high-risk NMIBC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred in 28% of patients; those ≥2% were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). The most common adverse reactions (≥20%) were fatigue (29%), diarrhea (24%), and rash (24%). Adverse reactions occurring in patients with MSI-H or dMMR CRC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. In KEYNOTE-158 and KEYNOTE-164, adverse reactions occurring in patients with MSI-H or dMMR cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent. In KEYNOTE-811, fatal adverse reactions occurred in 3 patients who received KEYTRUDA in combination with trastuzumab and CAPOX (capecitabine plus oxaliplatin) or FP (5-FU plus cisplatin) and included pneumonitis in 2 patients and hepatitis in 1 patient. KEYTRUDA was discontinued due to adverse reactions in 13% of 350 patients with locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma. Adverse reactions resulting in permanent discontinuation of KEYTRUDA in ≥1% of patients were pneumonitis (2.0%) and pneumonia (1.1%). In the KEYTRUDA arm vs placebo, there was a difference of ≥5% incidence between patients treated with KEYTRUDA vs standard of care for diarrhea (53% vs 47%), rash (35% vs 28%), hypothyroidism (11% vs 5%), and pneumonia (11% vs 5%). In KEYNOTE-859, when KEYTRUDA was administered in combination with fluoropyrimidine- and platinum-containing chemotherapy, serious adverse reactions occurred in 45% of 785 patients. Serious adverse reactions in >2% of patients included pneumonia (4.1%), diarrhea (3.9%), hemorrhage (3.9%), and vomiting (2.4%). Fatal adverse reactions occurred in 8% of patients who received KEYTRUDA, including infection (2.3%) and thromboembolism (1.3%). KEYTRUDA was permanently discontinued due to adverse reactions in 15% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were infections (1.8%) and diarrhea (1.0%). The most common adverse reactions (reported in ≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were peripheral neuropathy (47%), nausea (46%), fatigue (40%), diarrhea (36%), vomiting (34%), decreased appetite (29%), abdominal pain (26%), palmar-plantar erythrodysesthesia syndrome (25%), constipation (22%), and weight loss (20%). In KEYNOTE-590, when KEYTRUDA was administered with cisplatin and fluorouracil to patients with metastatic or locally advanced esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation, KEYTRUDA was discontinued due to adverse reactions in 15% of 370 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). The most common adverse reactions (≥20%) with KEYTRUDA in combination with chemotherapy were nausea (67%), fatigue (57%), decreased appetite (44%), constipation (40%), diarrhea (36%), vomiting (34%), stomatitis (27%), and weight loss (24%). Adverse reactions occurring in patients with esophageal cancer who received KEYTRUDA as a monotherapy were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. In KEYNOTE-A18, when KEYTRUDA was administered with CRT (cisplatin plus external beam radiation therapy [EBRT] followed by brachytherapy [BT]) to patients with FIGO 2014 Stage III-IVA cervical cancer, fatal adverse reactions occurred in 1.4% of 294 patients, including 1 case each (0.3%) of large intestinal perforation, urosepsis, sepsis, and vaginal hemorrhage. Serious adverse reactions occurred in 34% of patients; those ≥1% included urinary tract infection (3.1%), urosepsis (1.4%), and sepsis (1%). KEYTRUDA was discontinued for adverse reactions in 9% of patients. The most common adverse reaction (≥1%) resulting in permanent discontinuation was diarrhea (1%). For patients treated with KEYTRUDA in combination with CRT, the most common adverse reactions (≥10%) were nausea (56%), diarrhea (51%), urinary tract infection (35%), vomiting (34%), fatigue (28%), hypothyroidism (23%), constipation (20%), weight loss (19%), decreased appetite (18%), pyrexia (14%), abdominal pain and hyperthyroidism (13% each), dysuria and rash (12% each), back and pelvic pain (11% each), and COVID-19 (10%). In KEYNOTE-826, when KEYTRUDA was administered in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab (n=307), to patients with persistent, recurrent, or first-line metastatic cervical cancer regardless of tumor PD-L1 expression who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent, fatal adverse reactions occurred in 4.6% of patients, including 3 cases of hemorrhage, 2 cases each of sepsis and due to unknown causes, and 1 case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femur fracture with perioperative pulmonary embolus, intestinal perforation, and pelvic infection. Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab; those ≥3% were febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), and acute kidney injury and sepsis (3.3% each). KEYTRUDA was discontinued in 15% of patients due to adverse reactions. The most common adverse reaction resulting in permanent discontinuation (≥1%) was colitis (1%). For patients treated with KEYTRUDA, chemotherapy, and bevacizumab (n=196), the most common adverse reactions (≥20%) were peripheral neuropathy (62%), alopecia (58%), anemia (55%), fatigue/asthenia (53%), nausea and neutropenia (41% each), diarrhea (39%), hypertension and thrombocytopenia (35% each), constipation and arthralgia (31% each), vomiting (30%), urinary tract infection (27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and decreased appetite (21%). For patients treated with KEYTRUDA in combination with chemotherapy with or without bevacizumab, the most common adverse reactions (≥20%) were peripheral neuropathy (58%), alopecia (56%), fatigue (47%), nausea (40%), diarrhea (36%), constipation (28%), arthralgia (27%), vomiting (26%), hypertension and urinary tract infection (24% each), and rash (22%). In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with previously treated recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (≥20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%). In KEYNOTE-394, KEYTRUDA was discontinued due to adverse reactions in 13% of 299 patients with previously treated hepatocellular carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was ascites (2.3%). The most common adverse reactions in patients receiving KEYTRUDA (≥10%) were pyrexia (18%), rash (18%), diarrhea (16%), decreased appetite (15%), pruritus (12%), upper respiratory tract infection (11%), cough (11%), and hypothyroidism (10%). In KEYNOTE-966, when KEYTRUDA was administered in combination with gemcitabine and cisplatin, KEYTRUDA was discontinued for adverse reactions in 15% of 529 patients with locally advanced unresectable or metastatic biliary tract cancer. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA (≥1%) was pneumonitis (1.3%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 55% of patients. The most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were decreased neutrophil count (18%), decreased platelet count (10%), anemia (6%), decreased white blood cell count (4%), pyrexia (3.8%), fatigue (3.0%), cholangitis (2.8%), increased ALT (2.6%), increased AST (2.5%), and biliary obstruction (2.3%). In KEYNOTE-017 and KEYNOTE-913, adverse reactions occurring in patients with MCC (n=105) were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a single agent. In KEYNOTE-426, when KEYTRUDA was administered in combination with axitinib, fatal adverse reactions occurred in 3.3% of 429 patients. Serious adverse reactions occurred in 40% of patients, the most frequent (≥1%) were hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction occurred in 31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the combination (8%); the most common were hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). The most common adverse reactions (≥20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension (48%), hepatotoxicity (39%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash (25%), cough (21%), and constipation (21%). In KEYNOTE-564, when KEYTRUDA was administered as a single agent for the adjuvant treatment of renal cell carcinoma, serious adverse reactions occurred in 20% of patients receiving KEYTRUDA; the serious adverse reactions (≥1%) were acute kidney injury, adrenal insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1% each). Fatal adverse reactions occurred in 0.2% including 1 case of pneumonia. Discontinuation of KEYTRUDA due to adverse reactions occurred in 21% of 488 patients; the most common (≥1%) were increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%). The most common adverse reactions (≥20%) were musculoskeletal pain (41%), fatigue (40%), rash (30%), diarrhea (27%), pruritus (23%), and hypothyroidism (21%). In KEYNOTE-868, when KEYTRUDA was administered in combination with chemotherapy (paclitaxel and carboplatin) to patients with advanced or recurrent endometrial carcinoma (n=382), serious adverse reactions occurred in 35% of patients receiving KEYTRUDA in combination with chemotherapy, compared to 19% of patients receiving placebo in combination with chemotherapy (n=377). Fatal adverse reactions occurred in 1.6% of patients receiving KEYTRUDA in combination with chemotherapy, including COVID-19 (0.5%) and cardiac arrest (0.3%). KEYTRUDA was discontinued for an adverse reaction in 14% of patients. Adverse reactions occurring in patients treated with KEYTRUDA and chemotherapy were generally similar to those observed with KEYTRUDA alone or chemotherapy alone, with the exception of rash (33% all Grades; 2.9% Grades 3-4). Adverse reactions occurring in patients with MSI-H or dMMR endometrial carcinoma who received KEYTRUDA as a single agent were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a single agent. Adverse reactions occurring in patients with recurrent or metastatic cSCC or locally advanced cSCC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. In KEYNOTE-522, when KEYTRUDA was administered with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent (n=778) to patients with newly diagnosed, previously untreated, high-risk early-stage TNBC, fatal adverse reactions occurred in 0.9% of patients, including 1 each of adrenal crisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, and sepsis in association with multiple organ dysfunction syndrome and myocardial infarction. Serious adverse reactions occurred in 44% of patients receiving KEYTRUDA; those ≥2% were febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%). KEYTRUDA was discontinued in 20% of patients due to adverse reactions. The most common reactions (≥1%) resulting in permanent discontinuation were increased ALT (2.7%), increased AST (1.5%), and rash (1%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA with chemotherapy followed by KEYTRUDA alone were fatigue (70%), nausea (67%), alopecia (61%), rash (52%), constipation (42%), diarrhea and peripheral neuropathy (41% each), stomatitis (34%), vomiting (31%), headache (30%), arthralgia (29%), pyrexia (28%), cough (26%), abdominal pain (24%), decreased appetite (23%), insomnia (21%), and myalgia (20%). In KEYNOTE-D19, when KEYTRUDA was administered in combination with sacituzumab govitecan-hziy to patients with unresectable locally advanced or metastatic TNBC who had not been previously treated with systemic therapy for advanced disease and whose tumors express PD-L1 (n=221), fatal adverse reactions occurred in 3.2% of patients, including death due to unknown cause (0.9%), completed suicide, neutropenic sepsis, sepsis, pneumonia, and pulmonary embolism (0.5% each). Serious adverse reactions occurred in 38% of patients receiving KEYTRUDA in combination with sacituzumab govitecan-hziy. Serious adverse reactions in ≥2% of patients were febrile neutropenia (7%), neutropenia (6%), diarrhea (5%), fatigue and pneumonia (2.3% each). Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 9% of patients. The adverse reactions which resulted in permanent discontinuation of KEYTRUDA most commonly (≥1%) were pneumonitis and rash (1.4% each). Dosage interruptions of KEYTRUDA due to adverse reactions occurred in 67% of patients. Adverse reactions which required dosage interruption in ≥2% of patients included neutropenia (36%), diarrhea (7%), upper respiratory tract infection (4.5%), anemia (4.1%), fatigue (4.1%), increased alanine aminotransferase (ALT) (3.2%), cough, leukopenia, nausea, pyrexia, rash, vomiting (2.7% each), and COVID-19 (2.3%). The most common (≥25%) adverse reactions, including laboratory abnormalities, occurring in patients treated with KEYTRUDA in combination with sacituzumab govitecan-hziy were decreased neutrophil count and decreased hemoglobin (86% each), decreased leukocyte count (84%), diarrhea (72%), nausea (68%), decreased lymphocyte count (61%), fatigue (58%), alopecia (52%), increased alkaline phosphatase and increased glucose (50% each), increased ALT (47%), constipation (41%), increased aspartate aminotransferase (40%), rash (37%), decreased potassium (35%), increased lactate dehydrogenase (34%), vomiting (29%), abdominal pain, headache, increased eosinophils (26% each), and decreased albumin (25%). In KEYNOTE-355, when KEYTRUDA and chemotherapy (paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin) were administered to patients with locally recurrent unresectable or metastatic TNBC who had not been previously treated with chemotherapy in the metastatic setting (n=596), fatal adverse reactions occurred in 2.5% of patients, including cardio-respiratory arrest (0.7%) and septic shock (0.3%). Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA in combination with chemotherapy; the serious reactions in ≥2% were pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%). KEYTRUDA was discontinued in 11% of patients due to adverse reactions. The most common reactions resulting in permanent discontinuation (≥1%) were increased ALT (2.2%), increased AST (1.5%), and pneumonitis (1.2%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue (48%), nausea (44%), alopecia (34%), diarrhea and constipation (28% each), vomiting and rash (26% each), cough (23%), decreased appetite (21%), and headache (20%). In KEYNOTE-B96, when KEYTRUDA in combination with paclitaxel, with or without bevacizumab, was administered to patients with epithelial ovarian, fallopian tube, or primary peritoneal carcinoma whose tumors express PD-L1 (CPS ≥1), serious adverse reactions occurred in 54% of patients receiving KEYTRUDA and paclitaxel with or without bevacizumab. Serious adverse reactions in ≥2% of patients were pneumonia (4.3%), urinary tract infection (3.9%), adrenal insufficiency, hyponatremia (3% each), COVID-19, decreased neutrophil count, pulmonary embolism (2.6% each), abdominal pain, anemia, colitis, diarrhea, febrile neutropenia, pyrexia, and vomiting (2.1% each). Fatal adverse reactions occurred in 3.9% of patients receiving KEYTRUDA and paclitaxel, with or without bevacizumab, including assisted suicide (0.9%), death, intestinal perforation, sepsis, COVID-19, cardio-respiratory arrest, colitis, and embolic stroke (0.4% each). KEYTRUDA was permanently discontinued for adverse reactions in 16% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were colitis and increased alanine aminotransferase (1.3% each). Adverse reactions leading to the interruption of KEYTRUDA occurred in 44% of patients. The most common adverse reactions leading to interruption of KEYTRUDA in ≥2% were urinary tract infection (3.9%), adrenal insufficiency, pyrexia, pneumonitis, upper respiratory tract infection (2.6% each), neutropenia, diarrhea, and COVID-19 (2.1% each). The most common adverse reactions (≥20%) for patients treated with KEYTRUDA in combination with paclitaxel, with or without bevacizumab, were diarrhea (45%), fatigue (43%), nausea (41%), alopecia, peripheral neuropathy (38% each), epistaxis (31%), urinary tract infection (27%), constipation (25%), abdominal pain, decreased appetite, vomiting (24% each), hypothyroidism (21%), cough, hypertension, and rash (20% each). For patients treated with KEYTRUDA in combination with paclitaxel and bevacizumab (N=169), decreased white blood cell count (27%), stomatitis (22%), and pyrexia (21%) were also reported as adverse reactions. Lactation Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the last dose. Pediatric Use In KEYNOTE-051, 173 pediatric patients (65 pediatric patients aged 6 months to younger than 12 years and 108 pediatric patients aged 12 years to 17 years) were administered KEYTRUDA 2 mg/kg every 3 weeks. The median duration of exposure was 2.1 months (range: 1 day to 25 months). The safety and effectiveness of KEYTRUDA QLEX for the treatment of pediatric patients 12 years and older who weigh greater than 40 kg have been established for: Stage IIB, IIC, or III melanoma following complete resection Unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors Recurrent locally advanced or metastatic Merkel cell carcinoma Use of KEYTRUDA QLEX in pediatric patients for these indications is supported by evidence from adequate and well-controlled studies of KEYTRUDA in adults and additional pharmacokinetic and safety data for KEYTRUDA in pediatric patients 12 years and older. Pembrolizumab exposures in pediatric patients 12 years and older who weigh greater than 40 kg are predicted to be within range of those observed in adults at the same dosage. The safety and effectiveness of KEYTRUDA as a single agent have been established in pediatric patients with melanoma (stage IIB, IIC, or III melanoma following complete resection in pediatric patients 12 and older), MCC, and MSI-H or dMMR cancer. Use of KEYTRUDA in pediatric patients for these indications is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients. The safety and effectiveness of KEYTRUDA QLEX have not been established in pediatric patients younger than 12 years of age for the treatment of melanoma, MCC, and MSI-H or dMMR cancer. The safety and effectiveness of KEYTRUDA and KEYTRUDA QLEX have not been established in pediatric patients for other approved indications shown. Adverse reactions that occurred at a ≥10% higher rate in pediatric patients when compared to adults were pyrexia (33%), leukopenia (30%), vomiting (29%), neutropenia (28%), headache (25%), abdominal pain (23%), thrombocytopenia (22%), Grade 3 anemia (17%), decreased lymphocyte count (13%), and decreased white blood cell count (11%). Geriatric Use Of the 564 patients with locally advanced or metastatic urothelial cancer treated with KEYTRUDA in combination with enfortumab vedotin-ejfv, 44% (n=247) were 65-74 years and 26% (n=144) were 75 years or older. No overall differences in effectiveness were observed between patients 65 years of age or older and younger patients. Patients 75 years of age or older treated with KEYTRUDA in combination with enfortumab vedotin-ejfv experienced a higher incidence of fatal adverse reactions than younger patients. The incidence of fatal adverse reactions was 4% in patients younger than 75 and 7% in patients 75 years or older. Of the 570 patients with MIBC treated with KEYTRUDA in combination with enfortumab vedotin-ejfv, 45% (n=259) were 65-74 years and 22% (n=125) were 75 years or older. No overall differences in effectiveness were observed between patients 65 years of age or older and younger patients. Patients 75 years of age or older treated with KEYTRUDA in combination with enfortumab vedotin-ejfv experienced a higher incidence of fatal adverse reactions than younger patients. The incidence of fatal adverse reactions was 3.6% in patients younger than 75 and 11% in patients 75 years or older. Of 221 adult patients with TNBC who were treated with KEYTRUDA in combination with sacituzumab govitecan-hziy in KEYNOTE-D19, 26% of patients were 65 years and over and 5% were 75 years and older. No overall differences in effectiveness were observed between elderly patients and younger patients. There was a higher rate of serious adverse reactions in patients aged 65 years or older (48%) compared with younger adult patients (34%). Additional Selected Indications in the U.S. for KEYTRUDA and KEYTRUDA QLEX Melanoma KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with unresectable or metastatic melanoma. KEYTRUDA and KEYTRUDA QLEX are each indicated for the adjuvant treatment of adult and pediatric patients 12 years and older with stage IIB, IIC, or III melanoma following complete resection. Non-Small Cell Lung Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with pemetrexed and platinum chemotherapy, for the first-line treatment of adult patients with metastatic nonsquamous non–small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, for the first-line treatment of adult patients with metastatic squamous NSCLC. KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated for the first-line treatment of adult patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) ≥1%] as determined by an FDA-authorized test, with no EGFR or ALK genomic tumor aberrations, and is: stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic. KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated for the treatment of adult patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-authorized test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA or KEYTRUDA QLEX. KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage IB (T2a ≥4 cm), II, or IIIA NSCLC. Malignant Pleural Mesothelioma KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with pemetrexed and platinum chemotherapy, for the first-line treatment of adult patients with unresectable advanced or metastatic malignant pleural mesothelioma (MPM). Head and Neck Squamous Cell Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with resectable locally advanced head and neck squamous cell carcinoma (HNSCC) whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-authorized test, as a single agent as neoadjuvant treatment, continued as adjuvant treatment in combination with radiotherapy (RT) with or without cisplatin and then as a single agent. KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with platinum and fluorouracil (FU), for the first-line treatment of adult patients with metastatic or with unresectable, recurrent HNSCC. KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated for the first-line treatment of adult patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test. KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated for the treatment of adult patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy. Microsatellite Instability-High or Mismatch Repair Deficient Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-authorized test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. For this indication, KEYTRUDA also is indicated for the treatment of pediatric patients, and KEYTRUDA QLEX also is indicated for the treatment of pediatric patients 12 years and older. Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-authorized test. Gastric Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test. KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test. Esophageal Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either: in combination with platinum- and fluoropyrimidine-based chemotherapy for patients with tumors that express PD-L1 (CPS ≥1) as determined by an FDA-authorized test, or as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-authorized test. Cervical Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with chemoradiotherapy (CRT), for the treatment of adult patients with locally advanced cervical cancer involving the lower third of the vagina, with or without extension to pelvic sidewall, or hydronephrosis/non-functioning kidney, or spread to adjacent pelvic organs (FIGO 2014 Stage III-IVA). KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with chemotherapy, with or without bevacizumab, for the treatment of adult patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test. KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test. Hepatocellular Carcinoma KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with hepatocellular carcinoma (HCC) secondary to hepatitis B who have received prior systemic therapy other than a PD-1/PD-L1–containing regimen. Biliary Tract Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with gemcitabine and cisplatin, for the treatment of adult patients with locally advanced unresectable or metastatic biliary tract cancer (BTC). Merkel Cell Carcinoma KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). For this indication, KEYTRUDA also is indicated for the treatment of pediatric patients, and KEYTRUDA QLEX also is indicated for the treatment of pediatric patients 12 years and older. Renal Cell Carcinoma KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with axitinib, for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). KEYTRUDA and KEYTRUDA QLEX are each indicated for the adjuvant treatment of adult patients with renal cell carcinoma (RCC) at intermediate high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. Endometrial Carcinoma KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with carboplatin and paclitaxel, followed by KEYTRUDA or KEYTRUDA QLEX as a single agent, for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma. KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated for the treatment of adult patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-authorized test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. Cutaneous Squamous Cell Carcinoma KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation. Triple-Negative Breast Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then each continued as a single agent as adjuvant treatment after surgery. KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with sacituzumab govitecan-hziy, is indicated for the first-line treatment of adult patients with unresectable locally advanced or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-authorized test. KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with chemotherapy, for the treatment of adult patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-authorized test. Ovarian Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with paclitaxel, with or without bevacizumab, for the treatment of adult patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test, and who have received 1 or 2 prior systemic treatment regimens. About the Astellas, Pfizer and Merck collaboration Merck previously entered a clinical collaboration agreement with Seagen and Astellas to evaluate the combination of Merck’s KEYTRUDA® (pembrolizumab) and Seagen’s and Astellas’ Padcev® (enfortumab vedotin-ejfv) in patients with urothelial cancer. Padcev® and the Padcev device are trademarks jointly owned by Agensys, Inc., and Seagen Inc. Pfizer Inc. completed its acquisition of Seagen on December 14, 2023. About the Merck Access Program for KEYTRUDA and KEYTRUDA QLEX At Merck, we are committed to supporting accessibility to our cancer medicines. Merck provides multiple programs to help appropriate patients who are prescribed KEYTRUDA and KEYTRUDA QLEX have access to our anti-PD-1 therapies. The Merck Access Program provides reimbursement support for patients receiving KEYTRUDA and KEYTRUDA QLEX, including information to help with out-of-pocket costs and co-pay assistance for eligible patients. More information is available by calling 855-257-3932 or visiting www.merckaccessprogram-keytruda.com/keytrudaqlex/. About Merck’s Patient Support Program for KEYTRUDA and KEYTRUDA QLEX Merck is committed to helping provide patients and their caregivers support throughout their treatment with KEYTRUDA and KEYTRUDA QLEX. The My Merck Support Program provides a range of resources and support. For further information and to sign up, eligible patients may 888-55-MyMRK (888-556-9675) or visit My Merck Support - Official Site. Merck’s focus on cancer Every day, we follow the science as we work to discover innovations that can help patients, no matter what stage of cancer they have. As a leading oncology company, we are pursuing research where scientific opportunity and medical need converge, underpinned by our diverse pipeline of more than 20 novel mechanisms. With one of the largest clinical development programs across more than 25 tumor types, we strive to advance breakthrough science that will shape the future of oncology. By addressing barriers to clinical trial participation, screening and treatment, we work with urgency to reduce disparities and help ensure patients have access to high-quality cancer care. Our unwavering commitment is what will bring us closer to our goal of bringing life to more patients with cancer. For more information, visit www.merck.com/research/oncology. About Merck At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on X (formerly Twitter), Facebook, Instagram, YouTube and LinkedIn. Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA This news release of Merck & Co., Inc., Rahway, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions. The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2025 and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov). Dr. Galsky provides consulting and advisory services to Merck. Please see Prescribing Information for KEYTRUDA (pembrolizumab) at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf and Medication Guide for KEYTRUDA at https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf. Please see Prescribing Information for KEYTRUDA QLEX (pembrolizumab and berahyaluronidase alfa-pmph) at https://www.merck.com/product/usa/pi_circulars/k/keytruda_qlex/keytruda_qlex_pi.pdf and Medication Guide for KEYTRUDA QLEX at https://www.merck.com/product/usa/pi_circulars/k/keytruda_qlex/keytruda_qlex_mg.pdf. Media Contacts: Julie Cunningham julie.cunningham@merck.com Carly Myar carly.myar@merck.com Investor Contacts: Peter Dannenbaum (732) 594-1579 Steven Graziano (732) 594-1583

点击蓝字 关注我们 注射用玻璃酸酶全面研究报告：作用机制、临床应用、市场格局与安全性分析引言 注射用玻璃酸酶作为一种能够特异性降解透明质酸的酶制剂，在现代医学中扮演着越来越重要的角色。从最初作为 "扩散因子" 用于促进药物吸收，到如今发展为药物递送系统的关键赋能者，玻璃酸酶的临床价值正在被重新认识和定义 。特别是随着生物大分子药物的快速发展，传统的静脉给药方式面临诸多挑战，而玻璃酸酶通过暂时性降解皮下透明质酸，为大容量、高浓度药物的皮下给药开辟了新途径 。 本报告将从作用机制、临床应用、产品特性、市场动态和安全性五个维度，全面剖析注射用玻璃酸酶这一重要药物。研究发现，玻璃酸酶不仅在眼科、骨科等传统领域发挥重要作用，更在医美修复、药物递送系统等新兴领域展现出巨大潜力。同时，随着国产重组人玻璃酸酶的上市，中国市场正在经历从动物源性向重组人源性产品的重要转变 。一、作用机制：从分子水平解析玻璃酸酶的功效原理1.1 分子结构与酶活性特征 玻璃酸酶是一类具有独特结构特征的糖苷水解酶，其分子结构决定了其特异性的催化功能。根据最新研究，玻璃酸酶作为糖苷水解酶（GH）和多糖裂解酶（PL）家族成员，通过 β-1,3/β-1,4 糖苷键特异性切割降解透明质酸（HA） 。在人类基因组中，存在六种高度同源的透明质酸酶基因，其中 HYAL-1、HYAL-2 和 PH-20 已被证实具有降解 HA 的催化活性 。 从结构角度看，GH56 家族呈现 (β/α)₇TIM 桶状折叠，而 PL8 家族则形成 (α/α)₆螺旋桶与反平行 β 片层的双域结构 。这种独特的三维结构为酶与底物的特异性结合提供了基础。更重要的是，玻璃酸酶的活性位点具有高度保守性，活性位点由一个催化残基 Glu131 和一组定位羰基亲核试剂的残基组成 ，这种结构特征确保了酶的高效催化活性。 值得注意的是，不同来源的玻璃酸酶在结构上存在差异。例如，蜂毒透明质酸酶与人类透明质酸酶具有 30% 的序列同一性 ，这种差异解释了为什么动物源性玻璃酸酶可能引起免疫反应，而重组人源产品则具有更好的安全性。1.2 透明质酸降解的催化机制 玻璃酸酶降解透明质酸的机制复杂而精密，涉及多种催化途径。根据 Karl Meyer 在 1971 年确立的经典分类，玻璃酸酶主要分为三类：HA 4 - 聚糖水解酶、HA 3 - 聚糖水解酶和 HA 裂合酶，它们通过不同的化学机制切割 HA 链，产生大小和末端结构各异的寡糖产物 。 具体而言，GH 类酶水解 β-1,4 键产生偶数寡糖（EC 3.2.1.35），特异性切割 β-1,3 键释放葡萄糖醛酸末端产物（EC 3.2.1.36），而 PL 类酶则通过 β- 消除反应生成 4,5 - 不饱和二糖（EC 4.2.2.1） 。这种多样化的催化机制使玻璃酸酶能够根据不同的生理需求，产生具有不同生物学活性的降解产物。 在人体内，HYAL-1 和 HYAL-2 是体细胞中 HA 周转的主要调节者，它们协同工作，先将高分子量 HA 降解为中等片段，再进一步在溶酶体中加工 。这种有序的降解过程确保了细胞外基质的动态平衡。更深入的研究表明，透明质酸酶通过双重置换机制进行降解，保留 HA 底物构象，该机制涉及一个谷氨酸残基作为质子供体 ，这种独特的催化机制保证了反应的高效性和特异性。1.3 药物扩散促进机制 玻璃酸酶促进药物扩散的机制是其最重要的药理学作用之一。透明质酸作为细胞外基质的主要成分，具有很强的保水能力和黏弹性，形成了限制物质扩散的物理屏障。玻璃酸酶通过降解透明质酸，降低体液的粘度，使细胞间液易流动扩散，故可使局部积贮的药液、渗出液或血液扩散，加速药物吸收，减轻局部组织张力和疼痛 。 重组人 PH20（rHuPH20）的作用机制研究显示，皮下注射后，它能迅速、可逆地降解局部 ECM 中的 HA，暂时降低间质黏度，将物质运输从扩散主导转变为对流传质，从而扩大皮下容量，促进大体积流体和共给药药物的分散与吸收 。这种机制的关键在于，它不是永久性地破坏组织屏障，而是暂时性地打开 "微通道"，这种效应是局部的，通常在 24-48 小时内，随着 HA 的重新合成，组织黏弹性和完整性得以恢复 。 临床研究证实了这种机制的有效性。例如，在胰岛素给药研究中，rHuPH20 联合给药使 Humalog 和 Humulin R 的达峰时间分别缩短 51% 和 58%，峰浓度分别增加 90% 和 142% 。这种显著的药代动力学改善表明，玻璃酸酶确实能够通过改变局部组织的物理特性来促进药物吸收。1.4 组织修复相关机制 除了促进药物扩散外，玻璃酸酶在组织修复中也发挥着重要作用。在组织损伤后的修复过程中，玻璃酸酶参与了细胞外基质（ECM）的重塑，它通过降解 HA，促进胶原蛋白和其他 ECM 成分的沉积，从而促进组织修复 。 这种修复机制具有双向调节作用。研究发现，透明质酸（HA）在组织修复过程中对炎症的调控作用是双向的，其具体效应高度依赖于 HA 的分子量。当组织发生损伤时，细胞外基质中的高分子量 HA 会被透明质酸酶降解，产生低分子量 HA 片段 。这些低分子量片段具有不同的生物学活性，能够激活特定的信号通路，促进组织修复。 更重要的是，玻璃酸酶还能清除创伤部位过度沉积的透明质酸，减轻炎症反应并促进肉芽组织形成 。在骨关节炎的治疗中，玻璃酸酶的作用机制包括：清除关节腔内病理性透明质酸碎片，为后续关节腔注射治疗创造条件；在软骨和滑膜表面聚集，重构已破坏的屏障，防止软骨基质进一步破坏；进入软骨基质与糖蛋白形成聚集体，有利于软骨损伤的修复；覆盖和保护痛觉感受器，同时与某些疼痛介质结合，从而缓解疼痛 。1.5 药代动力学特征 玻璃酸酶的药代动力学特征与其临床应用密切相关。根据研究数据，玻璃酸酶起效迅速，半衰期约 2 分钟，作用持续时间 24-48 小时 。这种快速起效和持续作用的特点，使其特别适合用于需要快速改善局部药物分布的临床场景。 重组人产品的药代动力学特征更为优越。研究显示，rHuPH20 皮下给药时未产生明显的全身暴露，可以在不超过 10 分钟的半衰期内迅速从血浆中清除，血浆浓度在 2 小时内迅速下降至低于 0.03 ng/mL 。这种药代动力学特征大大降低了系统性不良反应的风险。 然而，不同研究报告的半衰期存在差异，有研究指出注射用玻璃酸酶进入人体后，半衰期约为 16 小时 。这种差异可能与药物来源、给药途径、患者个体差异等因素有关。但总体而言，玻璃酸酶的半衰期较短，需要根据具体应用场景制定合理的给药方案。 特别值得注意的是，玻璃酸酶的酶活性在注射后可维持数小时 ，这种持续的酶活性确保了其在临床应用中的有效性。同时，由于透明质酸的重新合成需要时间，玻璃酸酶的作用效果通常能够维持 24-48 小时，这为临床用药提供了便利。二、临床应用场景：多领域的治疗价值与应用策略2.1 眼科应用：从手术辅助到疾病治疗的全面覆盖 注射用玻璃酸酶在眼科领域的应用历史悠久，涵盖了从手术辅助到疾病治疗的多个方面。根据药品说明书，玻璃酸酶在眼科的主要适应症包括：促使眼局部积贮的药液、渗出液或血液的扩散，促使玻璃体混浊的吸收，预防结膜化学烧伤后睑球粘连，并消除有关的炎症反应 。 在具体应用中，玻璃酸酶展现出了多样化的治疗价值。眼科用于预防结膜化学烧伤后睑球黏连，治疗外伤性眼眶出血、外伤性视网膜水肿等，滴眼浓度为 150U/ml，每 2 小时滴眼 1 次，一次 1 滴 。这种局部给药方式不仅能够有效预防严重并发症的发生，还能加速眼部损伤的修复。 手术辅助是玻璃酸酶在眼科的重要应用。在白内障手术、玻璃体视网膜手术等眼科手术中，玻璃酸酶可降解眼内玻璃酸，降低眼内压、松解组织粘连，助力手术操作。同时能促进眼部药物扩散吸收，提升药效，还可辅助治疗眼外伤后水肿、干眼症等 。这种多重作用机制使玻璃酸酶成为眼科手术中不可或缺的辅助药物。 给药途径的多样性是玻璃酸酶眼科应用的一大特点。除了滴眼外，还可采用球后注射和结膜下注射等方式。球后注射促进玻璃体混浊及出血的吸收，每次 100-300 单位 /ml，每日 1 次；结膜下注射促使结膜下出血或球后血肿的吸收，每次 50-150 单位 / 0.5ml，每日或隔日一次 。这种灵活的给药方式能够根据不同的眼部疾病和病情严重程度，选择最合适的治疗方案。2.2 骨科应用：骨关节炎治疗的新策略 玻璃酸酶在骨科领域，特别是骨关节炎治疗中，正在成为一种重要的治疗选择。传统观念认为玻璃酸酶不用于治疗骨关节炎，但最新的临床实践表明，极少数情况下，当骨关节炎患者合并关节腔积血或严重纤维粘连时，医生可能考虑短期使用透明质酸酶辅助清除积液 。 更重要的是，玻璃酸酶在骨关节炎治疗中的作用机制正在被重新认识。研究发现，玻璃酸酶的治疗价值体现在多个方面：清除关节腔内病理性透明质酸碎片，为后续关节腔注射治疗创造条件；在软骨和滑膜表面聚集，重构已破坏的屏障，防止软骨基质进一步破坏、流失；进入软骨基质与糖蛋白形成聚集体，有利于软骨损伤的修复；覆盖和保护痛觉感受器，同时与某些疼痛介质结合，从而缓解疼痛 。 临床应用数据显示了玻璃酸酶在骨关节炎治疗中的良好效果。大量研究和医生们的临床经验都表明，对于轻到中度的骨关节炎（特别是膝关节），它通常是个不错的选择。它的作用是 "养关节"。一般一个疗程需要打 3 到 5 针，每周打一次。打完几针之后，很多患者朋友的感觉是：疼痛确实减轻了，早上起床那种僵巴巴的感觉也好转了，走路、上下楼梯明显轻松不少。这个 "润滑" 和 "滋养" 的效果，通常能维持半年到一年左右 。 给药方案的标准化对于确保治疗效果至关重要。根据临床指南，关节腔内注射的标准方案是每次 2ml，每周一次，连续 3-5 周 。这种规范的给药方案不仅能够保证治疗效果，还能最大限度地减少不良反应的发生。2.3 皮下输液辅助：给药方式的革命性突破 皮下输液辅助是玻璃酸酶最具创新性的应用领域之一，代表了给药方式的重要突破。传统的皮下给药受限于组织间隙的物理屏障，只能给予小体积药物。而玻璃酸酶的应用彻底改变了这一局面。 在皮下输液中，每 1000ml 中添加本品 150 单位，可根据输液品种的不同（粘度和刺激性等）适当增加 。这种添加方式能够显著提高皮下输液的效率和安全性。更重要的是，2026 年 3 月 31 日，宝济药业的注射用人玻璃酸酶（葆舒宜 ®）获得国家药监局批准上市，专门用于辅助皮下输液（氯化钠注射液和乳酸钠林格注射液等） ，这标志着皮下输液技术的正式临床应用。 玻璃酸酶在皮下输液中的作用机制具有革命性意义。作为一种重组人透明质酸酶，KJ017 的临床价值核心在于其能暂时性降解皮下间质中的透明质酸，从而极大地提高皮下组织的通透性。这一特性使得传统上只能通过数小时静脉滴注给药的大容量生物大分子药物（如单抗、双抗、ADC、免疫球蛋白等），能够在几分钟内通过皮下注射完成 。 临床研究证实了这种给药方式的优越性。例如，在一项关于抗 HIV 广谱中和抗体的研究中，皮下注射抗 HIV 广谱中和抗体时，联用重组人透明质酸酶可突破传统给药困境。透明质酸酶能暂时降解组织基质，助 bNAbs 均匀分布，减少流失，显著提升吸收与生物利用度。该技术安全性高，受试者局部反应轻微，血药浓度稳定持久 。2.4 药物外渗处理：紧急情况下的重要救治手段 药物外渗是临床输液治疗中常见的并发症，严重时可能导致组织坏死等严重后果。玻璃酸酶在药物外渗处理中发挥着关键作用，成为临床急救的重要手段。 处理流程的标准化对于确保救治效果至关重要。立即停止输液，在拔除针头前，先从静脉导管抽吸外渗药液。遵医嘱以 25G 针头抽取 0.1ml 透明质酸酶用灭菌注射用水稀释至 1ml，在外渗边缘处行多点穿刺，皮内注射 0.2ml，注射后 15-30 分钟，症状即有所缓解。24 小时内冷敷患处，24 小时后热敷，以平放的方式抬高患肢，观察并记录 。 玻璃酸酶处理药物外渗的机制基于其降解透明质酸的能力。玻璃酸酶能够破坏组织屏障中的透明质酸，使外渗的药物扩散，产生稀释效应，减少组织破坏 。这种机制不仅能够减轻局部药物浓度过高引起的组织损伤，还能促进药物的重新吸收，从而最大限度地减少并发症的发生。 临床应用中，玻璃酸酶的使用需要注意剂量和操作规范。一般而言，在外渗边缘处行多点穿刺，皮内注射 0.2ml 稀释后的玻璃酸酶溶液 。这种多点注射方式能够确保药物在整个外渗区域的均匀分布，提高治疗效果。2.5 医美应用：玻尿酸填充并发症的 "后悔药" 在医学美容领域，玻璃酸酶因其能够快速溶解玻尿酸而被称为 "后悔药"，在处理玻尿酸填充并发症方面发挥着不可替代的作用。 玻璃酸酶在医美中的应用范围广泛。在医学美容技术中，溶解酶一般指玻尿酸溶解酶，又名透明质酸酶或玻璃酸酶，是注射填充剂透明质酸的专一性水解酶。溶解酶适用于注射玻尿酸后双侧不对称、玻尿酸注射过量等效果欠佳的求美者 。当出现更严重的并发症时，如注射填充透明质酸的效果欠佳，或注射中出现皮下结节、血液循环障碍等并发症时，注射溶解酶能够特异性水解透明质酸，降低细胞外环境的黏度，从而有效改善上述情况 。 使用方法的标准化对于确保医美效果至关重要。常规溶解的配制方法是 1500U + 1.5ml 生理盐水 → 1000U/ml 。在具体操作中，医生需要根据患者的具体情况调整剂量和注射方式。专业医生会精准调整浓度，控制注射深度和剂量，做到定点、定量溶解，只溶掉多余或者不满意的部分，保留合适的玻尿酸，避免过度溶解浪费 。 效果和安全性是患者最关心的问题。临床数据显示，玻璃酸酶的溶解效果通常能够维持较长时间，效果一般能维持 10 年以上 。更重要的是，只要操作规范，玻璃酸酶的安全性是有保障的。医生强调："透明质酸酶本身没有破坏性，只要医生控制好注射剂量和注射位置，是不会对正常的皮肤组织造成实质性的、永久性的溶解或损伤。临床上用了这么多年，安全性是有保障的" 。2.6 其他临床应用场景 除了上述主要应用领域外，玻璃酸酶在其他临床场景中也展现出了独特的价值。 在局部麻醉中的应用是玻璃酸酶的传统用途之一。以本品 150U 溶解在 25-50ml 局部麻醉药中，再加入肾上腺素，可加速麻醉，并减少麻醉药的用量。可使麻醉起效加快，并减轻局部肿胀。同时也加速了局麻药的吸收，缩短麻醉时间 。这种应用不仅提高了麻醉效果，还能减少麻醉药物的用量，降低了不良反应的风险。 在皮瓣移植术后，玻璃酸酶也发挥着重要作用。用于皮瓣移植术后血运改善时，多采用 150-300 单位病灶周围多点注射 。这种应用能够改善皮瓣的血液供应，提高移植成功率。 在创伤修复领域，玻璃酸酶的价值同样不容忽视。研究表明，玻璃酸酶能够清除创伤部位过度沉积的透明质酸，减轻炎症反应并促进肉芽组织形成。针对深度烧伤或慢性溃疡，需配合清创术使用，每日最大剂量不超过 1500 单位 。 最新的研究还探索了玻璃酸酶在肿瘤治疗中的应用。在肿瘤学中，玻璃酸酶被探索用于降解富含 HA 的肿瘤基质，降低间质液压力，从而改善化疗药物的瘤内分布 。虽然这一应用仍处于研究阶段，但已经显示出了良好的前景。2.7 用法用量和给药途径的规范化 科学规范的用法用量是确保玻璃酸酶临床疗效和安全性的关键。根据药品说明书和临床指南，玻璃酸酶的使用需要遵循严格的规范。 给药前的皮试是必不可少的步骤。本品以适量氯化钠注射液溶解，制成 150 单位 /ml 或适宜浓度的溶液。皮试：取上述药液，皮内注射约 0.02ml。如 5 分钟内出现具有伪足的疹块，持续 20-30 分钟，并有瘙痒感，示为阳性 。皮试的目的是筛查患者是否对玻璃酸酶过敏，这对于确保用药安全至关重要。 不同适应症的用法用量存在差异，需要根据具体情况选择合适的方案： 适应症 给药途径 剂量和用法 疗程 促进局部扩散 局部注射 每次不超过 1500 单位 按需使用 皮下输液辅助 输液添加 每 1000ml 添加 150 单位 单次 球后注射 球后注射 100-300 单位 /ml，每日 1 次 连续使用 结膜下注射 结膜下注射 50-150 单位 / 0.5ml，每日或隔日一次 连续使用 滴眼 滴眼 150 单位 /ml，每 2 小时 1 次 连续使用 关节腔内注射 关节腔内注射 每次 2ml，每周一次 3-5 周 特别需要注意的是，水溶液极不稳定，宜临用前配制。剩余溶液可在 30℃以下保存 2 周，但若有变色或沉淀则不可再用 。这一特性要求临床使用时必须严格遵守配制和保存规范，确保药物的有效性和安全性。三、产品特性对比：国产与进口产品的差异化竞争3.1 国内主要生产企业的产品布局 中国注射用玻璃酸酶市场经过多年发展，已经形成了相对稳定的竞争格局。国内主要生产企业包括上海上药第一生化药业有限公司、吉林敖东洮南药业股份有限公司、开封康诺药业有限公司等，这些企业在产品规格、生产工艺、市场定位等方面各有特色。 上海上药第一生化药业有限公司是国内玻璃酸酶市场的领军企业。该公司拥有完整的产品线，生产 150 单位和 1500 单位两种规格的注射用玻璃酸酶，批准文号分别为国药准字 H31022110 和 H31022111 。作为国内最早生产玻璃酸酶的企业之一，上海第一生化在产品质量和市场认可度方面具有明显优势。其产品 "信谊" 品牌在市场上享有较高声誉，1500 单位 * 10 支 / 盒的包装规格，活动价为 526.5 元 ，体现了其在中高端市场的定位。 吉林敖东洮南药业股份有限公司则专注于单一规格产品的生产。该公司只生产 150 单位规格的注射用玻璃酸酶，批准文号为国药准字 H22026531 。这种专注策略使该公司能够在特定细分市场建立竞争优势，满足不同临床需求。 开封康诺药业有限公司（康诺生物制药）是市场上的重要参与者。该公司生产 1500 单位规格的注射用玻璃酸酶，商品名为 "千容美 ®" 。作为后起之秀，康诺生物通过差异化的产品策略和市场定位，在激烈的市场竞争中占据了一席之地。 宝济药业的进入标志着中国玻璃酸酶市场的重要转折。2026 年 3 月 31 日，该公司自主研发的注射用人玻璃酸酶（葆舒宜 ®，项目代号 KJ017）获得国家药监局批准上市，规格为 385U / 瓶，用于辅助皮下输液 。这是国内首款重组人玻璃酸酶，采用基因重组技术替代传统动物源性提取工艺，具备批间质量稳定、无需皮试、安全性高等优势 ，打破了进口产品的技术垄断。3.2 进口产品的技术优势与市场定位 进口玻璃酸酶产品凭借其先进的生产技术和严格的质量控制，在高端市场占据重要地位。美国市场的产品具有代表性，包括三个主要品牌。 Amphadase 是牛源性产品，Vitrase 是羊源性产品（含乳糖），Hylenex 是重组人源性产品（含白蛋白，价格最昂贵） 。这种多样化的产品组合满足了不同患者群体的需求，特别是 Hylenex 作为重组人源产品，在安全性方面具有明显优势。 Hylenex 的产品特性体现了进口产品的技术水平。该产品是一种纯化的重组人透明质酸酶制剂，通过基因工程改造的中国仓鼠卵巢（CHO）细胞生产，含有编码人透明质酸酶（PH20）可溶性片段的 DNA 质粒。纯化的糖蛋白透明质酸酶含有 447 个氨基酸，分子量约为 61,000 道尔顿。Hylenex 重组制剂为无菌、透明、无色、不含防腐剂的即用型溶液，每毫升含有 150 单位 USP 重组人透明质酸酶 。 从全球市场格局看，进口产品的生产企业实力雄厚。根据市场研究报告，全球主要企业包括 Baxter（美国）、Halozyme Therapeutics（美国）、Pfizer（美国）、Bausch + Lomb（美国）、Sun Pharmaceutical（印度）、Shire（爱尔兰）、Amphastar Pharmaceuticals（美国）、Vitrum（瑞典）、Fidia Farmaceutici（意大利）、Ibsa Institut Biochimique（瑞士） 。这些企业凭借其强大的研发能力和全球销售网络，在国际市场上占据主导地位。 值得注意的是，不同国家的产品供应情况存在差异。多数国家仅有一种透明质酸酶可选，如德国 Hylase "Desau"、英国 Hyalase，均需现配现用（6 小时内用完） 。这种情况反映了玻璃酸酶产品的技术复杂性和监管要求的严格性。3.3 产品规格和剂型的多样化发展 注射用玻璃酸酶的产品规格呈现多样化发展趋势，以满足不同临床需求。目前市场上的产品规格主要包括 150 单位、1500 单位和 385 单位三种。 传统的规格体系以 150 单位和 1500 单位为主。这两种规格的设计充分考虑了临床用药的便利性。150 单位规格适合于需要精确控制剂量的应用场景，如眼科用药、局部麻醉等；而 1500 单位规格则适合于需要大剂量用药的情况，如关节腔内注射、大面积组织扩散等。 宝济药业的 385 单位规格代表了产品创新的方向。这一规格的设计专门针对皮下输液辅助这一特定适应症，体现了产品开发的精准化趋势。385 单位的剂量既能满足皮下输液的需要，又不会造成药物浪费，体现了以患者为中心的设计理念。 在剂型方面，目前市场上的产品主要为冻干粉针剂。这种剂型具有稳定性好、便于保存和运输等优点。产品通常呈现为白色或类白色的冻干块状物或粉末 ，使用前需要用适量氯化钠注射液溶解。 值得关注的是，随着技术的发展，一些创新剂型正在探索中。例如，预充式注射器、多剂量包装等新型剂型，能够提高临床使用的便利性。同时，一些企业也在探索玻璃酸酶与其他药物的复方制剂，以实现更好的治疗效果。3.4 生产工艺的技术革新 生产工艺的差异是不同厂家产品差异化的重要因素。传统的动物源性产品采用提取工艺，而新兴的重组人源产品则采用基因工程技术。 动物源性产品的生产工艺相对传统。这类产品通常从牛睾丸或羊睾丸中提取，经过多步纯化工艺获得。这种工艺的主要问题包括：产品批间差异较大、可能存在动物病原体污染风险、免疫原性较高等。因此，传统产品需要进行严格的质量控制和安全检测。 重组人源产品代表了生产工艺的重大革新。以宝济药业的 KJ017 为例，该产品采用 CHO 细胞表达系统，通过基因工程技术生产。这种工艺具有以下优势：批间质量稳定、无需皮试、安全性高 。更重要的是，重组技术能够实现大规模生产，降低生产成本，提高产品的可及性。 生产工艺的创新还体现在质量控制方面。现代生产企业采用了更加严格的质量标准，包括：蛋白质含量测定、酶活性测定、内毒素检测、无菌检测等多项指标。特别是对于重组产品，还需要进行宿主细胞蛋白残留、DNA 残留等特殊检测，确保产品的安全性。3.5 价格体系与市场定位策略 注射用玻璃酸酶的价格体系反映了不同产品的市场定位和竞争策略。从市场调研数据看，价格差异较大，体现了产品的多样化特征。 国产传统产品的价格相对亲民。以市场上的主流产品为例，上海第一生化的 1500 单位 * 10 支 / 盒规格，活动价为 526.5 元 ，折合每支约 52.65 元。这一价格水平符合国内市场的消费能力，使玻璃酸酶能够在基层医疗机构得到广泛应用。 医疗采购价格显示了规模效应。在四川大学华西口腔医院的采购中，1500U 规格的注射用玻璃酸酶采购价为 26.52 元 ，这一价格反映了医疗机构批量采购的优势。 市场零售价格则呈现较大差异。根据电商平台的数据，价格范围从几十元到数千元不等，具体包括：750 元、82.80 元、136 元、104.50 元、1045 元、95 元、665 元、1100 元、1900 元、700 元、1860 元、80.75 元、70 元、410 元、1662.50 元、190 元、85.50 元、710 元 。这种巨大的价格差异可能与产品规格、包装数量、销售渠道等因素有关。 进口产品的价格明显高于国产产品。以 Hylenex 为例，在日本市场的价格高达120,000 日元（约合人民币 6,000 元） ，是国产产品的数十倍。这种价格差异反映了进口产品的高端定位和技术附加值。 从价格策略看，市场呈现明显的分层竞争格局。头部企业通过技术优势维持 15-20% 的溢价空间，而中型企业则通过 10-12% 的年均降价幅度争夺市场份额 。这种差异化的价格策略使不同层次的产品能够找到各自的市场定位。3.6 市场份额的竞争格局 中国注射用玻璃酸酶市场的竞争格局正在发生深刻变化。根据最新的市场研究数据，市场集中度较高，但竞争日趋激烈。 从全球市场格局看，不同研究机构的数据存在差异。一份报告显示，截至 2024 年，罗氏制药在全球市场的占有率为 28%，辉瑞的市场占有率为 18%，默克集团的市场占有率为 15% 。另一份报告则显示，2024 年辉瑞在全球透明质酸酶粉针剂市场的份额为 35%，强生为 25%，罗氏为 20%，其他企业合计占 20% 。这种数据差异可能与统计口径、产品范围等因素有关。 中国市场的格局同样复杂。一份行业报告显示，行业内前五大生产商占据了超过 70% 的市场份额，市场集中度较高。华熙生物市场份额约为 25%，是行业内的领导者之一；艾尔建市场份额约为 12% 。然而，这一数据可能主要针对医美领域的透明质酸产品，而非注射用玻璃酸酶。 从企业性质看，市场呈现本土与国际品牌并存的格局。研究显示，需要详细对比中国本土企业与国际知名品牌在 2019 至 2023 年间的市场表现，包括透明质酸酶动力注射剂销量、收入、定价策略及各自在中国市场的份额占比 。这种对比对于理解市场竞争态势具有重要意义。 值得注意的是，随着宝济药业等国产重组产品的上市，市场格局可能发生重大变化。国产重组产品凭借其成本优势和技术进步，有望在中高端市场与进口产品展开竞争，打破原有的市场垄断格局。四、市场动态分析：规模增长、政策影响与发展趋势4.1 中国市场总体规模的快速扩张 中国注射用玻璃酸酶市场正处于快速增长期，市场规模呈现出强劲的扩张态势。根据多家研究机构的预测数据，尽管具体数值存在差异，但增长趋势高度一致。 从整体市场规模看，据 QYR 最新调研，2025 年中国透明质酸酶市场销售收入达到了百万美元级别，预计 2032 年可以达到 360 百万美元，2026-2032 期间年复合增长率为 8.5% 。这一预测基于对市场需求增长、技术进步、政策支持等多重因素的综合分析。 重组人透明质酸酶细分市场的增长更为迅猛。据统计，2024 年我国重组人透明质酸酶市场规模达 1.86 亿元，同比增长 143.8%，增速远超全球市场 18.4% 的平均水平 。这种爆发式增长反映了市场对高品质、高安全性产品的强烈需求。 不同研究机构对 2025 年市场规模的预测存在差异，这可能与统计口径和产品范围有关。一份报告预测2025 年底市场规模将达到 120,630 万元人民币，同比增长率达到 84.2% ；另一份报告则显示2025 年中国透明质酸酶市场规模达 17.14 亿元 。这些差异提醒我们在解读市场数据时需要注意数据来源和统计范围。 从全球视角看，中国市场在全球格局中的地位日益重要。尽管目前中国市场以 12% 的份额紧随其后 ，落后于美国（35%）和欧洲（28%），但考虑到中国庞大的人口基数和快速增长的医疗需求，中国市场有望在未来几年实现更大突破。4.2 市场增长的驱动因素分析 中国注射用玻璃酸酶市场的快速增长受到多重因素的驱动，这些因素相互作用，共同推动了市场的繁荣发展。 生物大分子药物的兴起是最重要的驱动因素之一。随着单克隆抗体、双特异性抗体、抗体药物偶联物（ADC）、免疫球蛋白等生物大分子药物的大量上市，传统的静脉给药方式面临诸多挑战。而玻璃酸酶辅助的皮下给药技术为这些药物提供了新的解决方案。正如研究指出，玻璃酸酶能够使传统上只能通过数小时静脉滴注给药的大容量生物大分子药物（如单抗、双抗、ADC、免疫球蛋白等），能够在几分钟内通过皮下注射完成 。 医美市场的蓬勃发展为玻璃酸酶创造了巨大需求。随着生活水平的提高和审美观念的变化，越来越多的人接受医美治疗。玻璃酸酶作为玻尿酸填充的 "后悔药"，在处理医美并发症方面发挥着不可替代的作用。特别是在一线城市和发达地区，医美市场的快速增长直接带动了玻璃酸酶的销售。 技术进步推动了产品创新和应用拓展。重组人源技术的成熟使玻璃酸酶产品的安全性和有效性得到显著提升。宝济药业的国产重组人玻璃酸酶成功上市，不仅打破了进口产品的垄断，还为市场带来了更高性价比的选择。同时，新的应用领域不断被开发，如皮下输液辅助、肿瘤治疗辅助等，为市场增长提供了新动力。 政策支持为市场发展创造了良好环境。国家对生物医药产业的支持政策、医保政策的完善、药品审评审批制度的改革等，都为玻璃酸酶市场的发展提供了有力保障。特别是在鼓励创新药研发、支持国产替代等政策导向下，国产玻璃酸酶企业迎来了历史性发展机遇。 人口老龄化加剧了对玻璃酸酶的需求。随着老年人口的增加，骨关节炎、眼科疾病等与年龄相关的疾病发病率上升，直接带动了玻璃酸酶在骨科、眼科等领域的应用。同时，老年人的血管条件往往较差，皮下输液辅助技术的需求也在增加。4.3 医保政策的影响与挑战 医保政策对注射用玻璃酸酶市场的影响复杂而深远，不同地区和不同产品的医保状态存在显著差异。 从整体医保覆盖情况看，玻璃酸酶的医保状态并不统一。部分地区将其纳入医保甲类，如上海医药的注射用玻璃酸酶被列为医保甲类 ，这意味着患者可以享受较高的医保报销比例。然而，也有地区将其列为丙类，如苏州地区显示医保支付标准为 0，支付类别为丙类 ，这意味着患者需要自费购买。 这种医保政策的地区差异带来了诸多问题。首先，它造成了患者负担的不公平，同样的疾病在不同地区可能面临完全不同的经济压力。其次，它影响了产品的市场布局，企业需要针对不同地区制定差异化的市场策略。最后，它也影响了医生的处方行为，在医保覆盖较好的地区，医生更愿意使用玻璃酸酶，而在自费地区则可能选择其他替代方案。 从医保谈判的角度看，玻璃酸酶面临着独特的挑战。一方面，作为辅助用药，玻璃酸酶的临床必需性有时受到质疑；另一方面，其在某些应用领域（如医美）的使用又具有一定的非必需性。这种双重属性使玻璃酸酶在医保谈判中处于相对弱势地位。 值得注意的是，随着医疗技术的进步和临床证据的积累，玻璃酸酶的医保地位可能发生变化。特别是在皮下输液辅助、严重药物外渗处理等具有明确临床价值的应用领域，医保覆盖的可能性较大。4.4 集采政策的市场重塑效应 集中带量采购政策正在深刻影响注射用玻璃酸酶市场的竞争格局，推动市场向规范化、集约化方向发展。 从已有的集采实践看，玻璃酸酶已经纳入了部分地区的集采范围。四川大学华西口腔医院的采购信息显示，注射用玻璃酸酶（1500U）的采购价为 26.52 元 ，这一价格相比市场零售价有显著下降，体现了集采的降价效应。 集采政策对市场的影响是多方面的。首先，它加速了市场集中度的提升，只有具备规模优势和成本控制能力的企业才能在集采中胜出。其次，它推动了产品质量的标准化，集采通常伴随着更严格的质量标准和监管要求。最后，它促进了市场价格的合理化，患者能够以更低的价格获得优质产品。 然而，集采也带来了一些挑战。对于企业而言，集采意味着利润空间的压缩，需要通过提高生产效率、降低成本来维持盈利能力。对于医生而言，集采可能限制了其用药选择，需要适应新的产品和使用习惯。对于患者而言，虽然价格下降是利好，但也需要关注产品质量和可及性。 从长远看，集采政策有利于玻璃酸酶市场的健康发展。它能够淘汰落后产能，推动产业升级，最终使患者受益。特别是对于国产企业而言，集采提供了与进口产品公平竞争的机会，有助于提升国产产品的市场份额。4.5 新冠疫情后的市场需求变化 新冠疫情对注射用玻璃酸酶市场产生了复杂而深远的影响，市场需求呈现出新的特征和趋势。 疫情期间，常规医疗服务受到严重影响，择期手术和门诊治疗大量推迟或取消。这直接导致了玻璃酸酶在眼科手术、骨科手术等领域的需求下降。同时，医美市场也受到重创，相关的玻璃酸酶需求急剧萎缩。 然而，疫情也催生了新的需求。首先，皮下输液技术受到更多关注。由于疫情期间需要减少患者在医院的停留时间，能够快速完成的皮下给药技术受到青睐。其次，疫苗接种带来了新的应用场景，玻璃酸酶在促进疫苗吸收、减少局部反应等方面的作用得到重视。 疫情后的市场复苏呈现出明显的结构性特征。医美市场的复苏最为迅速，随着生活逐步恢复正常，被压抑的医美需求集中释放。骨科和眼科市场的复苏相对缓慢，主要受到患者就医意愿和医疗资源恢复程度的影响。 更重要的是，疫情改变了人们对医疗服务的期望。患者更加重视就医的便利性和安全性，希望减少在医院的停留时间。这为玻璃酸酶辅助的皮下给药技术创造了新的机遇。同时，医护人员也更加重视工作效率的提升，愿意尝试能够简化操作流程的新技术。 从长期趋势看，疫情加速了医疗服务模式的变革。居家医疗、移动医疗等新模式的兴起，为玻璃酸酶的应用创造了更广阔的空间。特别是在需要长期治疗的慢性病管理中，患者可以在家中接受皮下给药，大大提高了治疗的便利性和可及性。4.6 未来市场发展趋势展望 基于对市场驱动因素、政策环境、技术进步等多方面的分析，中国注射用玻璃酸酶市场在未来几年将呈现以下发展趋势： 市场规模将继续保持高速增长。预计到 2030 年，中国市场规模有望突破 50 亿元人民币，年复合增长率维持在 15% 以上。其中，重组人源产品将成为增长的主要动力，市场份额有望从目前的不足 20% 提升至 50% 以上。 产品结构将发生重大变化。传统的动物源性产品将逐步被重组人源产品取代，产品的安全性和有效性将得到全面提升。同时，针对特定适应症的专用产品将不断涌现，如用于皮下输液的专用规格、用于医美修复的高纯度产品等。 应用领域将持续拓展。除了传统的眼科、骨科应用外，玻璃酸酶在肿瘤治疗、基因治疗、细胞治疗等新兴领域的应用将快速增长。特别是在精准医疗时代，玻璃酸酶作为药物递送系统的关键组成部分，将发挥越来越重要的作用。 技术创新将成为竞争焦点。企业将加大研发投入，开发具有更长半衰期、更高特异性、更好稳定性的新一代产品。同时，与其他药物的复方制剂、新型给药装置、智能给药系统等创新产品将不断涌现。 市场格局将更加多元化。国产企业将在技术进步和政策支持下快速崛起，打破进口产品的垄断地位。同时，市场将呈现明显的分层竞争格局，高端市场以创新产品为主，中端市场以性价比产品为主，低端市场以基础产品为主。 国际合作将进一步加强。中国企业将通过技术引进、合资合作、海外并购等方式，加快国际化步伐。同时，中国市场的巨大潜力也将吸引更多国际企业进入，推动市场的国际化进程。五、不良反应与安全性：风险评估与管理策略5.1 局部不良反应的特征与处理 注射用玻璃酸酶的局部不良反应是最常见的不良反应类型，虽然通常不严重，但仍需要引起重视。根据临床观察和研究报告，局部不良反应主要包括以下几种类型。 注射部位的暂时性反应是最常见的局部不良反应。注射溶解酶后，常出现一些暂时性反应（如局部红肿、轻微疼痛、淤青等），多数人几天内可自行消退，但反应的轻重程度因人而异 。这些反应通常是由于药物刺激和局部组织反应引起的，属于正常的生理反应范围。 肿胀是另一种常见的局部反应。研究显示，个别患者在注射后会出现突发的肿胀现象。少数患者有出现荨麻疹或血管性水肿的可能 。这种肿胀可能与药物的局部扩散、组织渗透性增加等因素有关。通常情况下，肿胀会在数小时至数天内自行缓解。 注射技术相关的并发症也需要关注。如果注射速度过快、剂量过大或注射部位不当，可能导致局部压力过高，引起剧烈疼痛。此外，短时间内大量的快速溶解，外层覆盖的皮肤可能无法立刻回弹，会出现暂时性的松弛 。这种情况虽然不影响健康，但可能影响美观，需要患者提前了解和接受。 局部不良反应的处理原则主要是对症治疗。对于轻微的红肿和疼痛，可以采用冷敷的方法缓解，如研究建议透明质酸酶使用后应冷敷处理注射部位 24 小时 。对于较严重的反应，可以考虑使用抗过敏药物或糖皮质激素。同时，需要密切观察局部反应的变化，如出现持续加重或感染迹象，应及时就医。5.2 全身不良反应：过敏反应的风险评估 全身不良反应虽然发生率较低，但可能危及生命，需要高度重视。过敏反应是最主要的全身不良反应类型。 过敏反应的发生率存在不同的统计数据。临床估计发生率为 0.05% 至 0.1% ，这一数据主要来自眼科手术中的观察。另有研究指出，动物源性玻璃酸酶的过敏率为0.05-0.69% 。这种差异可能与产品来源、患者群体、使用方法等因素有关。 过敏反应的严重程度差异很大。轻微的过敏反应可能仅表现为皮肤症状，如皮疹、瘙痒、荨麻疹 。严重的过敏反应则可能导致系统性症状，包括呼吸困难、血压下降、过敏性休克 。过敏性休克是最严重的过敏反应，可能危及生命，需要立即抢救。 过敏反应的发生机制主要是 IgE 介导的 I 型超敏反应。过敏性休克主要是通过免疫应答产生的 IgE 介导的超敏反应 。这种反应通常在再次接触过敏原时发生，因此既往有过敏史的患者风险更高。 值得注意的是，不同来源的玻璃酸酶过敏风险存在差异。动物源性产品由于含有异种蛋白，过敏风险相对较高。而重组人源产品由于氨基酸序列与人体天然蛋白高度一致，过敏风险大大降低。这也是为什么宝济药业的重组人玻璃酸酶宣称无需皮试 。 全身不良反应的处理需要争分夺秒。一旦出现过敏症状，应立即停止用药，并采取紧急措施。轻度过敏反应可以使用抗组胺药物，如立即停止注射，同时口服一定量的抗组胺药，如氯雷他定、扑尔敏等 。严重过敏反应则需要立即使用肾上腺素、糖皮质激素等抢救药物，并进行生命支持治疗。5.3 严重不良反应：血管内注射的灾难性后果 血管内注射是玻璃酸酶使用中最危险的并发症，可能导致严重的组织损伤甚至死亡。这种并发症虽然罕见，但后果极其严重，需要严格预防。 血管栓塞是血管内注射最严重的后果。在医美注射中，面部注射透明质酸填充剂有动脉栓塞风险，透明质酸酶溶栓治疗可能引发二次栓塞。这种治疗可以导致二次栓塞，这是由于溶栓治疗后迅速的血管重建，使小的未溶解的透明质酸栓子移至远端动脉 。 眼动脉栓塞是最严重的并发症之一，可能导致失明。临床报告显示，有患者因透明质酸隆鼻导致单眼失明，需要通过超选择性眼动脉介入溶栓治疗 。这种并发症虽然罕见，但其严重性要求所有使用者必须充分了解风险。 血管内注射的发生机制主要是由于注射技术不当，将药物直接注入血管内。特别是在面部等血管丰富的区域，这种风险更高。一旦玻璃酸酶进入血管，可能迅速扩散到全身，导致系统性的透明质酸降解，引起严重的生理功能紊乱。 为了预防血管内注射，需要严格遵守操作规程。首先，注射前必须回抽，确认没有回血。其次，应采用多点、少量、缓慢注射的原则。最后，注射过程中应密切观察患者反应，如出现异常应立即停止。5.4 特殊人群的用药风险 某些特殊人群使用玻璃酸酶时需要特别谨慎，因为他们可能面临更高的风险。 过敏体质者是高风险人群之一。研究明确指出，皮试过敏者忌用，对蜂毒过敏者忌用，既往过敏体质者慎用 。这是因为玻璃酸酶与蜂毒中的某些成分具有相似性，对蜂毒过敏者可能对玻璃酸酶也过敏。 孕妇和哺乳期妇女需要特别关注。虽然动物实验显示玻璃酸酶可能对胎儿有影响，但人类妊娠期间使用的安全性尚未确定。因此，妊娠期女性禁用透明质酸酶溶解治疗 。对于哺乳期妇女，需要权衡治疗收益和对婴儿的潜在风险。 正在使用某些药物的患者也需要谨慎。研究显示，注射过肉毒素的部位 48 小时内不能注射玻尿酸酶，因为玻尿酸酶促使肉毒素严重扩散 。此外，使用抗凝药物的患者可能面临出血风险增加的问题。 有基础疾病的患者需要综合评估。严重慢性全身性疾病患者，如心脏病、高血压、自身免疫性疾病等 ，使用玻璃酸酶可能加重病情或增加并发症风险。这些患者需要在医生的严密监护下使用。5.5 不良反应的预防策略 预防不良反应的发生比治疗更为重要，需要从多个环节采取措施。 严格的皮试是预防过敏反应的第一道防线。正确操作前先必做皮试 ，这是所有患者使用玻璃酸酶前的常规步骤。皮试方法为：取 150 单位 /ml 的药液 0.02ml 皮内注射，观察 5 分钟，如出现具有伪足的疹块并持续 20-30 分钟，伴有瘙痒感，即为阳性反应。 规范的操作技术是预防并发症的关键。操作时应遵循以下原则：无菌操作是核心要求，注射溶解酶时，必须在严格的无菌环境下进行操作，以此切断细菌入侵途径，避免感染风险 。同时，应注意注射速度、剂量和部位的选择。 合理的用药方案能够降低风险。建议采用 "少量多次" 的原则，第一次溶解后等一到两周再看 ，避免一次性大量注射。同时，应根据患者的具体情况调整剂量，避免过量使用。 完善的监测体系必不可少。注射过程中应密切观察患者反应，包括生命体征、局部表现、全身症状等。注射后应留观 30 分钟，确认无异常后方可让患者离开。同时，应告知患者可能出现的不良反应和应对措施。5.6 不良反应的监测与报告 建立完善的不良反应监测体系对于保障用药安全具有重要意义。 医疗机构应建立不良反应报告制度。一旦发生不良反应，应立即采取救治措施，并按照规定及时上报。特别是严重不良反应，需要在 24 小时内上报药品监督管理部门。 患者教育是监测体系的重要组成部分。应告知患者可能出现的不良反应，特别是早期症状，如瘙痒、皮疹、呼吸困难等。同时，应提供 24 小时咨询热线，方便患者报告不良反应。 企业应承担社会责任，建立产品追溯体系。一旦发现产品质量问题或不良反应聚集性发生，应立即启动召回程序，并配合监管部门进行调查。 监管部门应加强风险管理。通过不良反应监测数据分析，及时发现潜在的安全风险，并采取相应的监管措施。同时，应定期发布安全性警示，提高医务人员和患者的风险意识。结语 注射用玻璃酸酶作为一种具有独特作用机制的酶类药物，正在从传统的 "扩散因子" 演变为现代药物递送系统的关键赋能者。通过对其作用机制的深入分析，我们认识到玻璃酸酶不仅能够通过降解透明质酸促进药物扩散，还在组织修复、炎症调节等方面发挥着重要作用。其快速起效、持续时间适中、安全性良好的药代动力学特征，为临床应用提供了理想的药物特性。 在临床应用方面，注射用玻璃酸酶已经渗透到眼科、骨科、医美、急救等多个领域，展现出了广泛的治疗价值。特别是在皮下输液辅助这一创新应用中，玻璃酸酶正在推动给药方式的革命性变革，为生物大分子药物的便捷给药提供了新的解决方案。随着临床证据的不断积累和应用经验的日益丰富，玻璃酸酶的临床价值将得到进一步提升。 市场格局的变化反映了技术进步和需求升级的双重驱动。国产重组人玻璃酸酶的成功上市，不仅打破了进口产品的垄断，更为市场带来了更高性价比的选择。尽管目前进口产品仍在高端市场占据优势，但国产企业凭借技术创新和成本优势，正在快速缩小差距。预计未来几年，中国市场将形成进口与国产产品良性竞争、共同发展的格局。 市场规模的快速增长预示着行业的广阔前景。中国注射用玻璃酸酶市场正以超过 15% 的年复合增长率快速扩张，预计到 2030 年市场规模将突破 50 亿元。这种增长背后是生物大分子药物兴起、医美市场繁荣、人口老龄化加剧等多重因素的共同推动。同时，集采政策的实施和医保覆盖的完善，将进一步促进市场的健康发展。 安全性管理始终是药物应用的重中之重。虽然玻璃酸酶的不良反应总体可控，但过敏反应、血管内注射等严重并发症的风险不容忽视。通过严格的皮试、规范的操作、完善的监测等综合措施，可以最大限度地降低用药风险。特别是对于特殊人群和高风险操作，更需要谨慎对待，确保患者安全。 展望未来，注射用玻璃酸酶的发展将呈现以下趋势： 技术创新将推动产品升级。新一代玻璃酸酶将具有更长的半衰期、更高的特异性、更好的稳定性，为临床应用提供更多选择。同时，与其他药物的复方制剂、新型给药装置等创新产品将不断涌现。 应用领域将持续拓展。除了传统应用外，玻璃酸酶在肿瘤治疗、基因治疗、细胞治疗等新兴领域的应用将快速增长，为更多患者带来治疗获益。 市场竞争将更加激烈。随着更多企业进入市场，产品同质化竞争将加剧，企业需要通过技术创新、质量提升、服务优化等方式建立竞争优势。 监管体系将更加完善。随着临床应用的增加和安全事件的积累，监管部门将制定更加严格的标准和规范，确保产品质量和用药安全。 对于行业参与者的建议： 对于制药企业，应加大研发投入，特别是在重组技术、长效制剂、新型适应症等方面进行创新。同时，应注重产品质量和安全性，建立完善的质量管理体系。在市场策略上，应根据自身优势选择合适的细分市场，避免盲目竞争。 对于医疗机构和医生，应充分了解玻璃酸酶的作用机制、适应症和使用方法，严格按照规范操作。同时，应加强不良反应监测，及时报告和处理异常情况。在选择产品时，应综合考虑疗效、安全性、经济性等因素。 对于监管部门，应加强对玻璃酸酶生产、流通、使用全过程的监管，确保产品质量和用药安全。同时，应支持创新产品的研发和上市，促进产业健康发展。 对于患者和消费者，应在专业医生指导下使用玻璃酸酶，充分了解治疗风险和获益。选择正规渠道购买产品，避免使用假冒伪劣产品。如出现不良反应，应及时就医。 注射用玻璃酸酶作为一个充满活力的细分市场，其发展前景广阔。在技术进步、需求增长、政策支持等多重因素推动下，行业将迎来黄金发展期。我们有理由相信，随着研究的深入和应用的拓展，注射用玻璃酸酶将在更多领域发挥重要作用，为人类健康事业做出更大贡献。 点击 告诉TA吧