SAPHNELO

5 WARNINGS AND PRECAUTIONS • Serious Infections: Serious and sometimes fatal infections have occurred in patients receiving SAPHNELO. SAPHNELO increases the risk of respiratory infections and herpes zoster. Avoid initiating treatment during an active infection. Consider the individual benefit-risk if using in patients with severe or chronic infections. Consider interrupting therapy with SAPHNELO if patients develop a new infection during treatment. ( 5.1 ) • Hypersensitivity Reactions Including Anaphylaxis: Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported. ( 5.2 ) • Malignancy: Consider the individual benefit-risk in patients with known risk factors for malignancy prior to prescribing SAPHNELO. ( 5.3 ) • Immunizations: Avoid use of live or live-attenuated vaccines in patients receiving SAPHNELO. ( 5.4 ) • Not Recommended for Use with Other Biologic Therapies. ( 5.5 ) 5.1 Serious Infections Serious and sometimes fatal infections (including COVID‑19) have occurred in patients receiving immunosuppressive agents, including SAPHNELO. In controlled trials, fatal infections occurred more frequently in patients receiving SAPHNELO [see Adverse Reactions (6.1) ] . In controlled trials, SAPHNELO increased the risk of respiratory infections and herpes zoster (disseminated herpes zoster events have been reported) [see Adverse Reactions (6.1) ] . Avoid initiating treatment with SAPHNELO in patients with any clinically significant active infection until the infection is resolved or adequately treated. Consider the benefit and risk of administering SAPHNELO in patients with a chronic infection, a history of recurrent infections, or known risk factors for infection. Instruct patients to seek medical advice if signs or symptoms of a clinically significant infection occur. If a patient develops an infection or is not responding to standard anti-infective therapy while on SAPHNELO, monitor the patient closely and consider interrupting SAPHNELO until the infection resolves. 5.2 Hypersensitivity Reactions Including Anaphylaxis Serious hypersensitivity reactions (including anaphylaxis) have been reported following SAPHNELO administration [see Contraindication (4) ] . Events of angioedema have also been reported [see Adverse Reactions (6.1) ] . Other hypersensitivity reactions and infusion-related reactions have occurred following administration of SAPHNELO [see Adverse Reactions (6.1) ] . Consider pre-medication before infusion of SAPHNELO for patients with a history of these reactions. SAPHNELO should be administered by healthcare providers prepared to manage hypersensitivity reactions, including anaphylaxis, and infusion-related reactions. If a serious infusion-related or hypersensitivity reaction (e.g., anaphylaxis) occurs, immediately interrupt the administration of SAPHNELO and initiate appropriate therapy. 5.3 Malignancy There is an increased risk of malignancies with the use of immunosuppressants. The impact of SAPHNELO treatment on the potential development of malignancies is not known. Consider the individual benefit-risk in patients with known risk factors for the development or reoccurrence of malignancy prior to prescribing SAPHNELO. In patients who develop malignancies, consider the benefit-risk of continued treatment with SAPHNELO. 5.4 Immunizations Update immunizations, according to current immunization guidelines, prior to initiating SAPHNELO therapy. Avoid concurrent use of live or live-attenuated vaccines in patients treated with SAPHNELO. 5.5 Not Recommended for Concomitant Use with Other Biologic Therapies SAPHNELO has not been studied in combination with other biologic therapies, including B-cell-targeted therapies. Therefore, use of SAPHNELO is not recommended for use in combination with biologic therapies.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are also discussed elsewhere in the labeling: • Serious Infections [see Warnings and Precautions (5.1) ] • Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions (5.2) ] • Malignancy [see Warnings and Precautions (5.3) ] Most common adverse drug reactions (incidence ≥5%) are nasopharyngitis, upper respiratory tract infections, bronchitis, infusion related reactions, herpes zoster and cough. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions with Intravenous Administration The safety of SAPHNELO was assessed in adult patients with moderate to severe SLE who received SAPHNELO 300 mg by intravenous infusion every 4 weeks (N=459) for 52 weeks, compared to placebo (N=466) in controlled clinical trials (Trials 1, 2 and 3) [see Clinical Studies (14.1) ]. The population studied had a mean age of 41 years (range: 18 to 69), of which 93% were female, 60% White, 13% Black/African American, and 10% Asian. In the controlled-clinical trials, adverse reactions, irrespective of causality, were reported in 87% of patients receiving SAPHNELO and 79% of patients receiving placebo. Adverse reactions that occurred at greater than or equal to 2% incidence are shown in Table 1. Table 1 Adverse Reactions Occurring in ≥2% of Adults with Moderate to Severe SLE Treated with Intravenous SAPHNELO for 52 weeks in Trials 1, 2 and 3 Adverse Reaction SAPHNELO (N=459) % Placebo (N=466) % Upper respiratory tract infection Upper respiratory tract infections (including Upper respiratory tract infections, Nasopharyngitis, Pharyngitis) 34 23 Bronchitis Bronchitis (including Bronchitis, Bronchitis viral, Tracheobronchitis) 11 5.2 Infusion‑related reactions 9.4 7.1 Herpes Zoster 6.1 1.3 Cough 5.0 3.2 Respiratory tract infection Respiratory tract infection (including Respiratory tract infection, Respiratory tract infection viral, Respiratory tract infection bacterial) 3.3 1.5 Hypersensitivity 2.8 0.6 All patients received standard therapy. Long-term Safety Patients who completed Trials 2 and 3 (Phase III feeder trials) were eligible to continue on treatment in a randomized, double-blind, placebo-controlled long-term extension (LTE) trial, for an additional 3 years. The long-term safety of SAPHNELO was assessed in 257 patients who received SAPHNELO 300 mg every 4 weeks and 112 patients who received placebo in both a feeder trial and the LTE. Of these, 177 patients who received SAPHNELO (68.9%) and 52 patients who received placebo (46.4%) completed a total of 4 years on treatment. The overall long-term safety profile of SAPHNELO was consistent with Trials 1, 2 and 3. Specific Adverse Reactions Infections: In the 52‑week controlled-clinical trials, infections were reported in a greater proportion of patients while on treatment with SAPHNELO compared to placebo (69.7% versus 55.4%, respectively). Herpes Zoster: In the 52‑week controlled-clinical trials, the incidence of herpes zoster in patients while on treatment with SAPHNELO was 6.1% and 1.3% in patients on placebo. Cases with multidermatomal involvement and disseminated presentation have been reported. Of the 28 SAPHNELO-treated patients with herpes zoster, 2 experienced disseminated disease requiring hospitalization compared to none among placebo-treated patients. Hypersensitivity Reactions Including Anaphylaxis: During the SLE intravenous development program, there was one report of an anaphylactic reaction in a patient who received SAPHNELO 150 mg, and 4 reports of angioedema after 300 mg. In general, the hypersensitivity reactions were predominantly mild or moderate in intensity and did not lead to discontinuation of SAPHNELO. In the 52‑week controlled‑clinical trials, hypersensitivity reactions occurred in 2.8% of patients while on treatment with SAPHNELO and 0.6% of patients on placebo. Serious hypersensitivity reactions were reported in 0.6% of patients receiving SAPHNELO, including angioedema (n=2). Infusion‑related Reactions: Infusion‑related reactions were mild to moderate in intensity; the most common symptoms were headache, nausea, vomiting, fatigue, and dizziness. In the 52‑week controlled‑clinical trials, the incidence of infusion‑related reactions while on treatment was 9.4% in patients while on treatment with SAPHNELO and 7.1% in patients on placebo. Malignancies: In 52‑week controlled-clinical trials, malignancies (excluding non‑melanoma skin cancers) were observed in 0.7% and 0.6% of SAPHNELO-treated and placebo-treated patients. Malignant neoplasm (including non‑melanoma skin cancers) was reported in 1.3% of SAPHNELO-treated patients, compared to 0.6% placebo-treated patients. The malignancies that were reported in more than one patient treated with SAPHNELO included breast cancer and squamous cell carcinoma. Adverse Reactions with Subcutaneous Administration The safety profile of SAPHNELO administered subcutaneously in adult patients with moderate to severe SLE is derived from Trial 5 [see Clinical Studies (14.2) ] . The data reflect SAPHNELO exposure in 185 patients who received SAPHNELO 120 mg by subcutaneous injection once every week, with a median duration of 52 weeks, as compared with comparable exposure to placebo in 182 patients. All patients received standard therapy. The population studied had a mean age of 43 years (range: 18 to 70), of which 92% were female, 74% White, 9% Asian, 8% American Indian or Alaska Native, and 5% Black/African American. The safety profile observed for SAPHNELO administered subcutaneously was consistent with the known safety profile of SAPHNELO administered intravenously . Serious Infections in the Pool of Intravenous and Subcutaneous Trials In the pool of four placebo-controlled clinical trials in adults with moderate to severe SLE where SAPHNELO was administered either intravenously or subcutaneously (Trials 1, 2, 3, and 5), the incidence of serious infections while on treatment was 5.4% in patients treated with SAPHNELO compared to 4.9% in patients receiving placebo. Fatal infections occurred while on treatment in 0.5% of SAPHNELO-treated patients and 0% in placebo-treated patients. The most frequent serious infection reported in patients treated with SAPHNELO was pneumonia. During the LTE of Trials 2 and 3, the most common serious infections were COVID‑19 and pneumonia. 6.2 Postmarketing Experience The following adverse reaction has been identified during post-approval use of SAPHNELO. Because the reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Arthralgia

<table width="100%"><caption>Table 1 Adverse Reactions Occurring in &#x2265;2% of Adults with Moderate to Severe SLE Treated with Intravenous SAPHNELO for 52 weeks in Trials 1, 2 and 3</caption><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">SAPHNELO</content></paragraph><paragraph><content styleCode="bold">(N=459)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(N=466)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph> Upper respiratory tract infection<footnote ID="_Ref43384025">Upper respiratory tract infections (including Upper respiratory tract infections, Nasopharyngitis, Pharyngitis)</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>34</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>23</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Bronchitis<footnote ID="_Ref43384040">Bronchitis (including Bronchitis, Bronchitis viral, Tracheobronchitis)</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5.2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Infusion&#x2011;related reactions</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>9.4</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>7.1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Herpes Zoster</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>6.1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Cough</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>5.0</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Respiratory tract infection<footnote ID="_Ref43384063">Respiratory tract infection (including Respiratory tract infection, Respiratory tract infection viral, Respiratory tract infection bacterial)</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>3.3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.5</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypersensitivity</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>2.8</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>0.6</paragraph></td></tr><tr><td colspan="3" valign="top"><paragraph>All patients received standard therapy.</paragraph></td></tr></tbody></table>