کنسیزوماب

Alhemo برای پیشگیری معمول برای پیشگیری یا کاهش دفعات خونریزی در بیماران بزرگسال و کودکان 12 سال و بالاتر با موارد زیر نشان داده شده است:

• هموفیلی A (کمبود مادرزادی فاکتور VIII) با یا بدون مهارکننده های FVIII
• هموفیلی B (کمبود مادرزادی فاکتور IX) با یا بدون مهارکننده های FIX Alhemo یک آنتاگونیست مهارکننده مسیر فاکتور بافتی (TFPI) است که برای پیشگیری معمول برای جلوگیری یا کاهش دفعات خونریزی در بیماران بزرگسال و کودکان 12 ساله و بالاتر با موارد زیر نشان داده شده است:
• هموفیلی A (کمبود مادرزادی فاکتور VIII) با یا بدون مهارکننده های FVIII
• هموفیلی B (کمبود مادرزادی فاکتور IX) با یا بدون مهارکننده های FIX (1)

تزریق آلهمو یک محلول شفاف تا کمی مادی و بی رنگ تا کمی زرد است که ممکن است حاوی ذرات شفاف تا سفید باشد که در ارائه های زیر موجود است:

• 60 میلی گرم / 1.5 میلی لیتر (40 میلی گرم / میلی لیتر) در یک قلم از پیش پر شده برای یک بیمار
• 150 میلی گرم / 1.5 میلی لیتر (100 میلی گرم در میلی لیتر) در یک قلم از پیش پر شده برای یک بیمار
• 300 میلی‌گرم در 3 میلی‌لیتر (100 میلی‌گرم در میلی‌لیتر) در قلم از پیش پر شده برای یک بیمار تزریق:
• 60 میلی‌گرم/1.5 میلی‌لیتر (40 میلی‌گرم بر میلی‌لیتر) در یک قلم از پیش پر شده برای یک بیمار (3)
• 150 میلی‌گرم/1.5 میلی‌لیتر (100 میلی‌گرم بر میلی‌لیتر) در یک قلم از پیش پر شده برای یک بیمار (3)
• 300 میلی‌گرم/3 میلی‌لیتر (100 میلی‌گرم بر میلی‌لیتر) در یک قلم از پیش پر شده برای یک بیمار (3)

Alhemo در بیمارانی که سابقه حساسیت شدید شناخته شده به Alhemo یا اجزای آن یا اجزای غیرفعال آن را دارند، ممنوع است [به هشدارها و اقدامات احتیاطی (5.1) و توضیحات (11) مراجعه کنید]. آلهمو در بیمارانی که سابقه حساسیت شدید شناخته شده به آلهمو یا اجزای آن یا ترکیبات غیرفعال دارند منع مصرف دارد. (4)

5 هشدارها و اقدامات احتیاطی

• رویدادهای ترومبوآمبولی: بیماران را از نظر وقایع ترومبوآمبولیک تحت نظر بگیرید. به بیماران توصیه کنید که علائم و نشانه ها را گزارش کنند و در صورت بروز، پروفیلاکسی را قطع کنند. (5.1)
• واکنش‌های حساسیت مفرط: در صورت بروز واکنش‌های حساسیت شدید، Alhemo را قطع کنید. (5.2)
• افزایش ارزش آزمایشگاهی دیمر فیبرین D و قطعه پروترومبین 1.2: Alhemo مقادیر فیبرین D دایمر و قطعه پروترومبین 1.2 را افزایش می دهد. (5.3)

5.1 رویدادهای ترومبوآمبولی Alhemo ممکن است باعث بروز حوادث ترومبوآمبولیک شود. حوادث ترومبوآمبولی وریدی و شریانی در 1.9 درصد از بیماران (6/320) در کارآزمایی‌های بالینی Alhemo گزارش شده است. این موارد در بیماران با عوامل خطر متعدد برای ترومبوآمبولی، از جمله استفاده از دوزهای بالا یا درمان طولانی مدت با محصول فاکتور یا عامل بای پس (2 نفر از 6 بیمار) رخ داده است. عوامل خطر برای ترومبوآمبولی ممکن است شامل استفاده از دوزهای بالا و/یا مکرر درمان‌های خون‌ریزی اولیه (محصولات فاکتور یا عوامل بای‌پس) یا شرایطی باشد که در آن فاکتور بافتی بیش از حد بیان می‌شود (مانند بیماری آترواسکلروتیک، آسیب خرد شدن، سرطان، انعقاد داخل عروقی منتشر، میکروآنژیوپاتی ترومبوتیک، یا میکروآنژیوپاتی ترومبوتیک). بیماران تحت درمان Alhemo را از علائم و نشانه های رویدادهای ترومبوآمبولی مطلع کنید. بیماران را از نظر وقایع ترومبوآمبولیک مانیتور کنید. در صورت مشکوک شدن به رویدادهای ترومبوآمبولی، Alhemo را قطع کرده و تحقیقات بیشتر و استراتژی های مدیریتی را آغاز کنید.

5.2 واکنش های حساسیت بیش از حد Alhemo می تواند باعث واکنش حساسیت مفرط، از جمله موارد جدی شود. آلهمو در بیمارانی که سابقه حساسیت شدید شناخته شده به آلهمو یا اجزای آن یا ترکیبات غیرفعال دارند منع مصرف دارد. واکنش‌های حساسیت بیش از حد شامل اریتم، بثورات، خارش و درد شکم در بیماران تحت درمان با Alhemo رخ داده است. یک بیمار (کمتر از 1٪ از بیماران تحت درمان در مطالعات بالینی) آنافیلاکسی را تجربه کردند که پس از درمان با آنتی هیستامین ها و کورتیکواستروئیدها برطرف شد. علائم واکنش های حساسیت حاد را به بیماران آموزش دهید. به بیماران آموزش دهید که برای واکنش های خفیف با ارائه دهنده مراقبت های بهداشتی خود تماس بگیرند و برای واکنش های متوسط ​​تا شدید به دنبال مراقبت های فوری پزشکی باشند. در صورت بروز علائم حساسیت شدید Alhemo را قطع کنید و درمان پزشکی را شروع کنید.

5.3 افزایش ارزش آزمایشگاهی فیبرین دی-دایمر و قطعه پروترومبین 1.2 Alhemo می تواند باعث افزایش سطح فیبرین D-دایمر و قطعه پروترومبین 1.2 شود. افزایش سطح فیبرین D-دایمر و افزایش سطح قطعه پروترومبین 1.2 به ترتیب در 29 (9.1%) و 26 (8.1%) از بیماران مشاهده شد. غلظت پلاسمایی concizumab-mtci با فیبرین D-dimer و قطعات پروترومبین 1.2 همبستگی مثبت دارد که نشان دهنده اثر هموستاتیک concizumab-mtci است. برای بیمارانی که Alhemo مصرف می کنند، این بیومارکرهای انعقادی ممکن است نشانگرهای پیش بینی کننده قابل اعتمادی برای تصمیم گیری بالینی با مشکوک به ترومبوز مانند ترومبوز ورید عمقی (DVT) و آمبولی ریوی (PE) نباشند.

درمان خونریزی ناگهانی: در حالی که درمان با همه عوامل بای پس (مانند rFVIIa یا aPCC) می تواند برای خونریزی های اولیه استفاده شود، دوزهای زیاد و/یا مکرر FVIII، FIX، یا دور زدن عوامل با Alhemo خطر ترومبوآمبولی را افزایش می دهد. (7.1)

7.1 درمان خونریزی ناگهانی در بیماران هموفیلی که پروفیلاکسی Alhemo و FVIII یا FIX یا یک عامل بای پس کننده دریافت می کنند، اقدامات احتیاطی مناسب را هنگام درمان وقایع خونریزی ناگهانی انجام دهید [دوز و نحوه تجویز (2.1) را ببینید]. برای خونریزی های خفیف و متوسط ​​که نیاز به درمان اضافی با FVIII یا FIX یا عوامل بای پس (مانند rFVIIa یا aPCC) دارند، کمترین دوز تایید شده در برچسب محصول تایید شده توصیه می شود. برای aPCC، حداکثر دوز 100 واحد بر کیلوگرم وزن بدن در 24 ساعت توصیه می شود. برای خونریزی های شدید، دستورالعمل های دوز ارائه شده در برچسب تایید شده برای محصول خاص را بر اساس قضاوت بالینی دنبال کنید. افزایش افزاینده و گاهی هم افزایی در پیک ترومبین همانطور که در سنجش تولید ترومبین مشخص شده است، در پلاسما بیماران هموفیلی که تحت درمان پیشگیرانه با concizumab-mtci با حضور همزمان rFVIII، rFIX یا عوامل بای پس از جمله rFVIIa و aPCC بودند، مشاهده شده است.

عوارض جانبی قابل توجه بالینی زیر با جزئیات بیشتری در سایر بخش های برچسب مورد بحث قرار گرفته است:

• رویدادهای ترومبوآمبولیک [به هشدارها و اقدامات احتیاطی (5.1) مراجعه کنید]
• واکنش های حساسیت مفرط [به هشدارها و اقدامات احتیاطی (5.2) مراجعه کنید]
• افزایش مقادیر آزمایشگاهی فیبرین دی-دایمر و قطعه پروترومبین 1.2 [به هشدارها و اقدامات احتیاطی (5.3) مراجعه کنید] شایع ترین واکنش های جانبی گزارش شده (بروز ≥5%) واکنش های محل تزریق، سردرد و کهیر بود. (6.1) برای گزارش واکنش‌های نامطلوب مشکوک، با Novo Nordisk Inc. به شماره 1-800-727-6500 یا FDA به شماره 1-800-FDA-1088 یا www.fda.gov/medwatch تماس بگیرید.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice. The data in the WARNINGS AND PRECAUTIONS reflect exposure to Alhemo based on pooled data from clinical trials explorer3 (phase 1b), explorer4 (phase 2), explorer5 (phase 2), explorer7 (phase 3) and explorer8 (phase 3), in which a total of 320 male patients with hemophilia A with and without inhibitors and hemophilia B with and without inhibitors received at least one dose of Alhemo as routine prophylaxis. The patients were exposed for a total of 475 exposure years. Patients with HAwI (hemophilia A with inhibitors) and HBwI (hemophilia B with inhibitors) The data described below reflect exposure of 52 patients with HAwI and HBwI who were previously treated on-demand therapy and who were randomized in explorer7 to arm 1 to receive on- demand treatment with bypassing agents (n = 19) or arm 2 to receive Alhemo prophylaxis (n = 33) at the recommended dosing regimen [see Clinical Studies ( 14.1 )] . The median duration of treatment was 31.1 weeks (range 3.9, 72.9 weeks) in arm 1 (on-demand arm) and 40.1 weeks (range 3.1, 56.3 weeks) in arm 2 (Alhemo prophylaxis). Serious adverse reactions were reported in 6.1% of patients who received Alhemo. These serious adverse reactions were renal infarct and hypersensitivity reaction. Permanent discontinuation of Alhemo due to an adverse reaction occurred in 1 patient due to a renal infarct. Dosage interruptions of Alhemo due to an adverse reaction occurred in 1 patient (3%) and was a hypersensitivity reaction. The most common adverse reactions (≥5%) were injection site reactions and urticaria (see Table 1 ). Table 1. Adverse Reactions Reported in ≥5% HAwI and HBwI Patients Randomized to Alhemo in Explorer7 Adverse Reaction Alhemo Prophylaxis N=33 (%) On-demand Treatment N=19 (%) Injection site reactions 18% 0% Urticaria 6% 0% Injection site reactions included: Injection site bruising, Injection site erythema, Injection site hematoma, Injection site hemorrhage, Injection site reaction and Injection site urticaria. Urticaria included: Urticaria and Injection site urticaria. Patients with HA (hemophilia A without inhibitors) and HB (hemophilia B without inhibitors) The data described below reflect exposure of 63 patients with HA and HB who were previously treated on-demand therapy and who were randomized in explorer8 to arm 1 to receive on- demand treatment with factor product (n = 21) or arm 2 to receive Alhemo prophylaxis (n = 42) at the recommended dosing regimen [see Clinical Studies ( 14.2 )] . The median duration of treatment was 24.1 weeks (range 23.6, 56.1 weeks) in arm 1 (on- demand arm) and 32.1 weeks (range 3.9, 33.6 weeks) in arm 2 (Alhemo prophylaxis). The most common adverse reactions (≥5%) were injection site reactions and headache (see Table 2 ). Table 2. Adverse Reactions Reported in ≥5% HA and HB Patients Randomized to Alhemo in Explorer8 Adverse Reaction Alhemo Prophylaxis N=42 (%) On-demand Treatment N=21 (%) Injection site reactions 7% 0% Headache 7% 0% Injection site reactions included: injection site reaction, injection site rash, and injection site nodule

8.1 Pregnancy Risk Summary Based on its mechanism of action, Alhemo may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . There are no available data on Alhemo use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with Alhemo. Although there are no data on concizumab-mtci, monoclonal antibodies can be actively transported across the placenta, and concizumab-mtci may cause fetal harm. It is unknown whether Alhemo can affect reproductive capacity. Alhemo should only be used during pregnancy if the potential benefit for the mother outweighs the potential risk to the fetus. The estimated background risk of birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

8.2 Lactation Risk Summary There is no information regarding the presence of Alhemo in either human or animal milk, the effect on the breastfed child, or the effects on milk production. Clinical Considerations Human IgGs are known to be excreted in breast milk during the first few days after birth, decreasing to low concentrations soon afterwards; consequently, a risk to the breast-fed infant cannot be excluded during this short period. Afterwards, Alhemo could be used during breast-feeding if clinically needed.

8.3 Females and Males of Reproductive Potential Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential. Contraception Women of childbearing potential should use a highly effective form of contraception during treatment with Alhemo and for 7 weeks after ending treatment. The benefits and thromboembolic risks of the type of contraceptives used should be evaluated by the treating physician.

8.4 Pediatric Use The safety and effectiveness of Alhemo for hemophilia A and B with and without inhibitors have been established in pediatric patients aged 12 years and older. Use of Alhemo for this indication is supported by evidence from adequate and well-controlled studies in adult and pediatric patients aged 12 years and older [see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14 )] . The safety and effectiveness of Alhemo for hemophilia A and B with and without inhibitors have not been established in pediatric patients younger than 12 years of age.

8.5 Geriatric Use Clinical studies of Alhemo did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

8.6 Body Weight The exposure of concizumab-mtci increased with increasing body weight [see Clinical Pharmacology ( 12.3 )] . However, patients should receive the approved recommended Alhemo dosage titration and concizumab-mtci plasma concentration monitoring regardless of body weight [see Dosage and Administration ( 2.1 )] .

Risk Summary Based on its mechanism of action, Alhemo may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . There are no available data on Alhemo use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with Alhemo. Although there are no data on concizumab-mtci, monoclonal antibodies can be actively transported across the placenta, and concizumab-mtci may cause fetal harm. It is unknown whether Alhemo can affect reproductive capacity. Alhemo should only be used during pregnancy if the potential benefit for the mother outweighs the potential risk to the fetus. The estimated background risk of birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

The safety and effectiveness of Alhemo for hemophilia A and B with and without inhibitors have been established in pediatric patients aged 12 years and older. Use of Alhemo for this indication is supported by evidence from adequate and well-controlled studies in adult and pediatric patients aged 12 years and older [see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14 )] . The safety and effectiveness of Alhemo for hemophilia A and B with and without inhibitors have not been established in pediatric patients younger than 12 years of age.

Clinical studies of Alhemo did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

Concizumab-mtci, is a humanized IgG4 monoclonal antibody produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cells with an approximate molecular weight of 149 kDa. Alhemo (concizumab-mtci) injection is a clear to slightly opalescent, and colorless to slightly yellow solution that may contain translucent to white particles. Alhemo is supplied as a single-patient-use prefilled pen for subcutaneous injection. Each 1 mL of Alhemo single-patient-use prefilled pen (60 mg/1.5 mL) contains 40 mg active ingredient concizumab-mtci. Each 1 mL of Alhemo single-patient-use prefilled pen (150 mg/1.5 mL) contains 100 mg active ingredient concizumab-mtci. Each 1 mL of Alhemo single-patient-use prefilled pen (300 mg/3 mL) contains 100 mg active ingredient concizumab-mtci. Each 1 mL of Alhemo single-patient-use prefilled pen contains the following excipients: arginine hydrochloride (5.27 mg), histidine (5.12 mg), phenol (3.5 mg), polysorbate 80 (0.25 mg), sodium chloride (1.46 mg), sucrose (51.3 mg), and water for injection. Hydrochloric acid and sodium hydroxide may be added to adjust the pH to 6.0.

Concizumab-mtci is a monoclonal antibody antagonist of endogenous Tissue Factor Pathway Inhibitor (TFPI). Through the inhibition of TFPI, concizumab-mtci acts to enhance FXa production during the initiation phase of coagulation which leads to improved thrombin generation and clot formation with the goal of achieving hemostasis in patients with Hemophilia A or B regardless of their inhibitor status. The effect of concizumab-mtci is not influenced by the presence of inhibitory antibodies to FVIII or FIX. There is no structural relationship or sequence homology between concizumab-mtci and FVIII or FIX and, as such, treatment with concizumab-mtci does not induce or enhance the development of direct inhibitors to FVIII or FIX.

Increasing concizumab-mtci dose levels resulted in decreased levels of free TFPI (plasma TFPI not bound to concizumab-mtci) and increased duration of free TFPI suppression. In hemophilia patients with inhibitors, free TFPI plasma levels predose decreased from a geometric mean (CV%) of 88.3 (20%) ng/mL at baseline to 10.7 (105%) ng/mL at week 24 in patients on Alhemo prophylaxis, while the geometric mean (CV%) was 76 (18%) ng/mL at week 24 for patients treated on-demand. In hemophilia patients without inhibitors, free TFPI plasma levels predose decreased from a geometric mean (CV%) of 84.2 (19%) ng/mL at baseline to 11.1 (102%) ng/mL at week 24 in patients on Alhemo prophylaxis, while the geometric mean (CV%) was 80.6 (18%) ng/mL at week 24 for patients treated on-demand. Mean thrombin peak within the range of normal plasma reflected that concizumab‑mtci re‐established thrombin generation capacity. Drug Interaction In vitro studies Additive and sometimes synergistic increase in thrombin peak as quantified in the thrombin generation assay has been observed in plasma from hemophilia patients who were on prophylactic treatment with concizumab-mtci with concomitant presence of rFVIII, rFIX or bypassing agents including rFVIIa and aPCC. Depending on concentrations of concizumab-mtci and hemostatic agents, the impact on thrombin peak ranged from being additive with all hemostatic agents to an extra 40% effect with rFVIIa, an extra 33% effect with aPCC, an extra 22% with rFVIII and less than 13% with rFIX.

Peak and trough geometric mean plasma concizumab-mtci concentrations at steady state are shown in Table 3 . Following a single Alhemo loading dose of 1 mg/kg, the steady state concentrations were reached around Day 4 and remained within a stable exposure range with daily maintenance doses. Concizumab-mtci AUC and C max increased with increasing dose in a greater than dose-proportional manner following subcutaneous administration. Table 3. Steady State Concizumab-mtci Concentrations During 24-hour Dosing Interval at Week 24 Parameters Hemophilia A and B without inhibitors All maintenance doses N=127 a HAwI and HBwI All maintenance doses N=99 a C max,ss (ng/mL), geometric mean (CV%) N 893.4 (144.5%) N=103 1167.1 (128%) N=69 C trough,ss (ng/mL), geometric mean (CV%) N 647.3 (178.8%) N=116 665.4 (221%) N=94 C max / C trough ratio, mean (SD) N 1.5 (0.5) N=103 2.2 (5.2) N=69 Abbreviations: C max,ss, maximum plasma concentration at steady state; C trough,ss, trough plasma concentration at steady state; HAwI, hemophilia A with inhibitors; HBwI, hemophilia B with inhibitors. a On concizumab-mtci dosing regimen. Absorption Concizumab-mtci time to maximum plasma concentration ranged from 8 hours to 99 hours (4.1 days) following a single Alhemo subcutaneous dose of 0.05 to 3 mg/kg in healthy and hemophilia subjects. Distribution Concizumab-mtci volume of distribution for a typical 70 kg patient is about 3 L. Elimination Concizumab-mtci is cleared via linear and nonlinear mechanisms. Concizumab-mtci exhibited nonlinear pharmacokinetics due to target-mediated drug disposition (TMDD) which occurs when it forms concizumab-mtci/TFPI complex. Once the target becomes saturated, linear pathway (i.e., catabolism) dominates. Based on population pharmacokinetic analysis, 90% of concizumab-mtci is expected to be eliminated by the end of approximately 4 days after the last dose (time for 50% of drug to be eliminated is approximately 1 day). Metabolism Concizumab-mtci is expected to be metabolized into small peptides by catabolic pathways. Specific Populations No clinically significant differences in the pharmacokinetics of concizumab-mtci were observed based on age (12 years to 79 years), race (White 64.3%, Asian 25.9%, Black 4.9%), hemophilia type (A and B with or without inhibitors). No dedicated studies have been conducted to evaluate the impact of renal or hepatic impairment. As concizumab-mtci is a monoclonal antibody, there is no expectation for concizumab-mtci exposures to be different in patients with renal or hepatic impairment. Body weight The exposure of concizumab-mtci increased with increasing body weight (27 kg to 130.7 kg) [see Use in Specific Populations ( 8.6 )] .

, Mutagenesis, Impairment of Fertility No long-term animal studies have been conducted to evaluate the carcinogenic potential of concizumab-mtci nor have studies been performed to determine the effects of concizumab-mtci on genotoxicity. In a 26-week toxicity study in sexually mature male and female cynomolgus monkeys with subcutaneous doses up to 9 mg/kg/day (corresponding to 3400-fold the human exposure, based on AUC 0 to 24h ), concizumab-mtci did not affect fertility (testicular size, sperm functionality or menstrual cycle duration) and did not cause any changes in the male or female reproductive organs.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

• Thromboembolic events: Inform patients of the signs and symptoms of thromboembolic events, including swelling, warmth, pain, or redness of the skin (and that these could be symptoms of a blood clot in the legs or arms); shortness of breath or severe chest pain (and that these could be symptoms of blood clots in the chest [heart and lungs]).; headache, confusion, difficulty with speech or movement, numbness of the face, eye pain or swelling, or vision problems (and that these could be symptoms of a blood clot in the brain or eyes); or sudden pain in the stomach or lumbar area (and that these could be symptoms of blood clots in the gut or kidneys). Advise patients to contact their healthcare provider for mild reactions and to seek urgent medical attention for moderate to severe reactions [see Warnings and Precautions ( 5.1 )] . o In conditions in which tissue factor is overexpressed (e.g., advanced atherosclerotic disease, crush injury, cancer, or septicemia), there may be a risk of thromboembolic events or disseminated intravascular coagulation (DIC) with Alhemo treatment.
• Hypersensitivity: Inform patients of the early signs of hypersensitivity reactions, including rash, redness, hives, and itching, facial swelling, tightness of the chest, and wheezing as well the signs of an anaphylactic reaction such as itching on large areas of skin; redness and/or swelling of lips, tongue, face, or hands; difficulty swallowing; shortness of breath; wheezing; tightness of the chest; pale and cold skin; fast heartbeat; or dizziness/low blood pressure. Advise patients to discontinue use of Alhemo immediately and contact their healthcare provider if any signs or symptoms occur [see Warnings and Precautions ( 5.2 )] . Advise patients on the importance of adherence to daily dosing and to speak with their healthcare provider before discontinuing treatment with Alhemo as patients who are not adhering to daily dosing or stop treatment with Alhemo may no longer be protected against bleeding. Advise patients to follow the recommendations regarding proper sharps disposal provided in the FDA-approved Instructions for Use. Patent Information : http://novonordisk-us.com/products/product-patents.html Alhemo ® is a registered trademark of Novo Nordisk Health Care AG. NovoFine ® , NovoFine ® Plus, and Novo Nordisk ® are registered trademarks of Novo Nordisk A/S. For information about Alhemo contact: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, NJ 08536 1-844-668-6732 Manufactured by: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, NJ 08536 U.S. License No. 1261 At: Novo Nordisk A/S Novo Allé 1 2880 Bagsvaerd Denmark © 2025 Novo Nordisk